Hypotonia

MedlinePlus

... can be seen in Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, and Tay-Sachs ... can be seen in Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, and Tay-Sachs ...

Laparoscopic cholecystectomy in a patient with Steinert myotonic dystrophy. Case report.

PubMed

Agrusa, A; Mularo, S; Alessi, R; Di Paola, P; Mularo, A; Amato, G; Romano, G

2011-01-01

Myotonic dystrophy (MD) is a serious multi-systemic autosomal dominant disease. The estimated incidence is 1 in every 8000 births, with an estimated prevalence of between 2.1 and 14.3 cases per 100,000 inhabitants. Signs and symptoms vary from a severe form of congenital myopathy, present from birth and often fatal, to a classic form and a delayed form, which generally presents after the age of 50 and in which the only sign is a cataract and life expectancy is completely normal. We describe the clinical case of a 40-year-old woman with Steinert myotonic dystrophy who underwent laparoscopic cholecystectomy (under general anesthesia) for symptomatic gallbladder stones. The conduct of anesthesia in such patients must be carefully considered, as hypothermia, shivering, electrical and mechanical stimulation, and the drugs used can all trigger myotonia.

Ventricular fibrillation induced by coagulating mode bipolar electrocautery during pacemaker implantation in Myotonic Dystrophy type 1 patient.

PubMed

Russo, Vincenzo; Rago, Anna; DI Meo, Federica; Cioppa, Nadia Della; Papa, Andrea Antonio; Russo, Maria Giovanna; Nigro, Gerardo

2014-12-01

The occurrence of ventricular fibrillation, induced by bipolar electrocautery during elective dual chamber pacemaker implantation, is reported in a patient affected by Myotonic Distrophy type 1 with normal left ventricular ejection fraction.

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.

PubMed

Okkersen, Kees; Jimenez-Moreno, Cecilia; Wenninger, Stephan; Daidj, Ferroudja; Glennon, Jeffrey; Cumming, Sarah; Littleford, Roberta; Monckton, Darren G; Lochmüller, Hanns; Catt, Michael; Faber, Catharina G; Hapca, Adrian; Donnan, Peter T; Gorman, Gráinne; Bassez, Guillaume; Schoser, Benedikt; Knoop, Hans; Treweek, Shaun; van Engelen, Baziel G M

2018-06-18

Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep-wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10-14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0-100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI -0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (-2·02, -4·02 to -0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. The European Union Seventh Framework Programme. Copyright © 2018 Elsevier Ltd. All rights reserved.

French translation and cross-cultural adaptation of The Myotonic Dystrophy Health Index.

PubMed

Gagnon, Cynthia; Tremblay, Marjolaine; CôTé, Isabelle; Heatwole, Chad

2018-04-01

Validation studies of disease-specific instruments for myotonic dystrophy type-1 (DM1) are required prior to their global use in clinical trials involving different cultures and countries. Here we translate and culturally adapt the Myotonic Dystrophy Health Index (MDHI), a disease-specific patient-reported outcome (PRO) measure, for a French DM1 population. Using the International Society for Pharmacoeconomics and Outcomes Research Task Force method for translation and adaptation of PRO questionnaires, we created a French translation of the MDHI. We subsequently tested this instrument in a cohort of French-speaking patients with DM1. The MDHI was forward and back translated and modified by consensus to create the most compatible translation. Cognitive interviews were conducted with 5 patients with DM1 to ensure the usability and understanding of the translation. The French version of the MDHI is an optimal translation of the original instrument that is acceptable to native patients and ready for clinical trial use. Muscle Nerve 57: 686-689, 2018. © 2017 Wiley Periodicals, Inc.

Anterior capsule phimosis and capsular block syndrome in a patient with Steinert myotonic dystrophy: a case report

PubMed Central

2009-01-01

A 55-year-old man with myotonic dystrophy underwent phacoemulsification with IOL implantation in the right eye. 3 months after surgery, the patient showed a decreased visual acuity and an intraocular pressure (IOP) of 30 mmHg. Slit lamp examination showed a dense fibrosis of the anterior capsule with capsulorexis' shrinkage. Gonioscopy showed a closed angle. After a YAG laser iridotomy no decrease in the IOP was detected; following surgical peeling of the anterior capsule, the slit lamp showed a distended capsular bag. A YAG laser posterior capsulotomy was performed, without decrease in the IOP. Myotonic patients need to be closely followed up after cataract surgery, because in case of CBS development a prompt posterior capsulotomy could avoid more severe complications. PMID:20062622

Eosinophilic myositis as first manifestation in a patient with type 2 myotonic dystrophy CCTG expansion mutation and rheumatoid arthritis.

PubMed

Meyer, Alain; Lannes, Béatrice; Carapito, Raphaël; Bahram, Seiamak; Echaniz-Laguna, Andoni; Geny, Bernard; Sibilia, Jean; Gottenberg, Jacques Eric

2015-02-01

Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8 kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2. Copyright © 2014 Elsevier B.V. All rights reserved.

[Educational and Professional Qualifications of Adults With Myotonic Dystrophies - A Misleading Perception by the Myopathic Face?].

PubMed

Stahl, K; Wenninger, S; Schüller, A; Montagnese, F; Schoser, B

2016-04-01

Myotonic dystrophies types 1 and 2 (DM1 / DM2) are the most frequent inherited progressive, segmental progeroid, multisystemic neuromuscular diseases in adulthood. The executive impairment is one of the key disease features. The myopathic face triggers the general perception of DM1 patients being associated with a low educational level. We used a standardized questionnaire to evaluate educational levels in adults with genetically confirmed DM1 and DM2 in comparison to data of the general population. Investigated topics included the level of education, e. g. the highest university degree aquired. Out of a total cohort of 546 DM patients, 125 DM1 and 156 DM2 patients (51 %) participated in this study. There was no statistically significant difference between the two collectives as far as high school levels are concerned. 50.4 % of DM1 and 48.3 % of DM2 patients obtained the higher education entrance qualification compared to 29.6 % of the normal German population. However, there were significant differences between the two collectives in "spelling problems" (DM1 cohort: p = 0.039), "difficulty in mental arithmetic" (p = 0.043), and classification of patients "with learning difficulties" (p = 0.012). Misled by a myopathic face, many physicians associate myotonic dystrophy with cognitive deficiency. Based on our study, the minimal deviation between DM1 and DM2 and the normal German population indicates that the multisystemic disease does not significantly influence the maximum attainable level of education in adults with DM1. In summary, physicians should be aware that the general educational levels are rather normal in patients with myotonic dystrophy type 1 and rethink their perception of DM1 patients. © Georg Thieme Verlag KG Stuttgart · New York.

Surgical Orthodontic Treatment of a Patient Affected by Type 1 Myotonic Dystrophy (Steinert Syndrome)

PubMed Central

Cacucci, Laura; Ricci, Beatrice; Moretti, Maria; Gasparini, Giulio; Pelo, Sandro

2017-01-01

Myotonic dystrophy, or Steinert's disease, is the most common form of muscular dystrophy that occurs in adults. This multisystemic form involves the skeletal muscles but affects also the eye, the endocrine system, the central nervous system, and the cardiac system. The weakness of the facial muscles causes a characteristic facial appearance frequently associated with malocclusions. Young people with myotonic dystrophy, who also have severe malocclusions, have bad oral functions such as chewing, breathing, and phonation. We present a case report of a 15-year-old boy with anterior open bite, upper and lower dental crowding, bilateral crossbite, and constriction of the upper jaw with a high and narrow palate. The patient's need was to improve his quality of life. Because of the severity of skeletal malocclusion, it was necessary to schedule a combined orthodontic and surgical therapy in order to achieve the highest aesthetic and functional result. Although therapy caused an improvement in patient's quality of life, the clinical management of the case was hard. The article shows a balance between costs and benefits of a therapy that challenges the nature of the main problem of the patient, and it is useful to identify the most appropriate course of treatment for similar cases. PMID:28642828

Surgical Orthodontic Treatment of a Patient Affected by Type 1 Myotonic Dystrophy (Steinert Syndrome).

PubMed

Cacucci, Laura; Ricci, Beatrice; Moretti, Maria; Gasparini, Giulio; Pelo, Sandro; Grippaudo, Cristina

2017-01-01

Myotonic dystrophy, or Steinert's disease, is the most common form of muscular dystrophy that occurs in adults. This multisystemic form involves the skeletal muscles but affects also the eye, the endocrine system, the central nervous system, and the cardiac system. The weakness of the facial muscles causes a characteristic facial appearance frequently associated with malocclusions. Young people with myotonic dystrophy, who also have severe malocclusions, have bad oral functions such as chewing, breathing, and phonation. We present a case report of a 15-year-old boy with anterior open bite, upper and lower dental crowding, bilateral crossbite, and constriction of the upper jaw with a high and narrow palate. The patient's need was to improve his quality of life. Because of the severity of skeletal malocclusion, it was necessary to schedule a combined orthodontic and surgical therapy in order to achieve the highest aesthetic and functional result. Although therapy caused an improvement in patient's quality of life, the clinical management of the case was hard. The article shows a balance between costs and benefits of a therapy that challenges the nature of the main problem of the patient, and it is useful to identify the most appropriate course of treatment for similar cases.

Temperament and character in patients with classical myotonic dystrophy type 1 (DM-1).

PubMed

Winblad, S; Lindberg, C; Hansen, S

2005-04-01

This study was designed to investigate personality in classical Myotonic Dystrophy (DM-1). Forty-six patients with DM-1 (25 women and 21 men), 31 healthy controls and 37 subjects in a contrast group, consisting of patients with other muscle disorders (spinal muscular atrophy, facioscapulohumeral dystrophy and limb girdle muscular dystrophy), completed the Temperament and Character Inventory (TCI) (Cloninger, 1994). We aimed to establish whether CTG triplet repeat size correlated with ratings of personality dimensions in the TCI. The DM-1 patients scored significantly higher on the TCI dimension Harm avoidance and lower on Persistence, Self-directedness and Cooperativeness. Signs of a personality disorder were found in 20% of the DM-1 patients. No correlation was found between the number of CTG repeats and scores in the TCI. This study indicates deviant personality in classical DM-1 regarding temperament and character, both in comparison to healthy controls and to patients with other muscle disorders with no known brain disorder.

Can long-term thiamine treatment improve the clinical outcomes of myotonic dystrophy type 1?

PubMed

Costantini, Antonio; Trevi, Erika; Pala, Maria Immacolata; Fancellu, Roberto

2016-09-01

Myotonic dystrophy type 1, also known as Steinert's disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine (vitamin B1) is a cofactor of fundamental enzymes involved in the energetic cell metabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We described two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council (MRC), the Muscular Impairment Rating Scale (MIRS), and the Modified Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients' activities of daily living using the Modified Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2-4 in the distal muscles (the MRC score before the treatment was 3-4 and 1-3, respectively). The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modified Barthel Index improved by 44%, and in patient #2 by 29%. These findings suggest that clinical outcomes are improved by long-term thiamine treatment.

[Dystrophia myotonica (Steinert disease)--a frequently misdiagnosed disease].

PubMed

Kuhn, E; Lehmann-Horn, F; Rüdel, R

1990-06-01

Dystrophia myotonica (Steinert's disease) is the most common hereditary disease of the neuromuscular system in adults. Its mode of inheritance is autosomal dominant. The gene responsible for its is located on chromosome 19 in the linkage domain of the loci for the apolipoproteins C2, C1 und E and of the creatine kinase of skeletal muscle (CKMM). Myotonic dystrophy is categorized in an adult and in a congenital form. In the adult form, the characteristic findings are muscular atrophy in certain regions of the body (face, neck and distally in the extremities) and myotonia. Cataract, intraocular hypotension, gonadal atrophy, conduction abnormalities in the heart and hearing deficiencies appear quite often in the course of the disease. In the congenital form, general muscle weekness (particularly pronounced in the face) is the leading finding, combined with retarded loco motor and mental development. A decisive criterion for the diagnosis of this form is the occurrence of myotonic dystrophy in the patient's mother. Electromyographic investigation is indicated when a suspicion of myotonic dystrophy cannot be ascertained on the basis of clinical and genetic findings. Myotonic runs in the EMG will then corroborate the suspicion. Recent electrophysiological investigations have indicated that at least three different types of channels for the passage of ions through the membrane of the skeletal muscle cells show abnormal behaviour, i.e. the channel for Cl-, Na+ and K+. These findings corroborate the hypothesis that the abnormality responsible for myotonic dystrophy is situated in the membrane systems. A pharmacological treatment of the muscular dystrophy has not yet been developed.(ABSTRACT TRUNCATED AT 250 WORDS)

Myotonic Dystrophies: State of the Art of New Therapeutic Developments for the CNS

PubMed Central

Gourdon, Genevieve; Meola, Giovanni

2017-01-01

Myotonic dystrophies are multisystemic diseases characterized not only by muscle and heart dysfunction but also by CNS alteration. They are now recognized as brain diseases affecting newborns and children for myotonic dystrophy type 1 and adults for both myotonic dystrophy type 1 and type 2. In the past two decades, much progress has been made in understanding the mechanisms underlying the DM symptoms allowing development of new molecular therapeutic tools with the ultimate aim of curing the disease. This review describes the state of the art for the characterization of CNS related symptoms, the development of molecular strategies to target the CNS as well as the available tools for screening and testing new possible treatments. PMID:28473756

Equine muscular dystrophy with myotonia.

PubMed

Montagna, P; Liguori, R; Monari, L; Strong, P N; Riva, R; Di Stasi, V; Gandini, G; Cipone, M

2001-02-01

To describe a case of equine muscular dystrophy with myotonia. A 5-year-old horse presented with hypertrophy and delayed relaxation of the muscles of the hindlimbs from age 2 months. Testicular atrophy developed from 2 years of age. Action and percussion myotonia was associated with weakness in these muscles, and EMG showed diffuse myotonic discharges and myopathic features. Biopsy of the gluteal muscle showed adipose and connective tissue infiltration, marked variation in muscle fibre size, and moth-eaten, ring and whorled fibres. Injection of apamin, a peptide blocker of calcium-activated potassium channels, which inhibits myotonia in human myotonic dystrophy, was ineffective in blocking myotonic discharges. Discharges promptly abated with 2% lidocaine injection. Myotonia in this horse is associated with dystrophic changes similar to human myotonic dystrophy, though there are some pharmacological differences.

Development of a Genomic DNA Reference Material Panel for Myotonic Dystrophy Type 1 (DM1) Genetic Testing

PubMed Central

Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E.; Luebbe, Elizabeth A.; Moxley, Richard T.; Toji, Lorraine

2014-01-01

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3′ untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. PMID:23680132

Core Clinical Phenotypes in Myotonic Dystrophies

PubMed Central

Wenninger, Stephan; Montagnese, Federica; Schoser, Benedikt

2018-01-01

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent multisystemic muscular dystrophies in adulthood. They are progressive, autosomal dominant diseases caused by an abnormal expansion of an unstable nucleotide repeat located in the non-coding region of their respective genes DMPK for DM1 and CNBP in DM2. Clinically, these multisystemic disorders are characterized by a high variability of muscular and extramuscular symptoms, often causing a delay in diagnosis. For both subtypes, many symptoms overlap, but some differences allow their clinical distinction. This article highlights the clinical core features of myotonic dystrophies, thus facilitating their early recognition and diagnosis. Particular attention will be given to signs and symptoms of muscular involvement, to issues related to respiratory impairment, and to the multiorgan involvement. This article is part of a Special Issue entitled “Beyond Borders: Myotonic Dystrophies—A European Perception.”

[Sleep and respiratory disorders in myotonic dystrophy of Steinert].

PubMed

López-Esteban, P; Peraita-Adrados, R

2000-03-01

It has been hypothesized that hypersomnia and sleep related respiratory impairment are both central in origin in myotonic dystrophy. To describe by means of video-polysomnographic recordings the central origin of the sleep respiratory disorders. We studied 11 patients, 6 men and 5 women (mean age 42.7 years) with myotonic dystrophy. A moderate to severe ventilatory impairment of a primarily restrictive type was seen in all patients, three of them after the first episode of respiratory insufficiency. The patients were evaluated in order to determine their body mass index and presence of sleep-related complaints. Video-polysomnographic recordings (EEG, EOG, EKG, submental and tibialis anterior EMGs, respiration and Sa02) and pulmonary function tests were performed in each patient. Identical recordings were repeated in six cases, which were to undergo non-invasive bi-level ventilation (BiPAP) in order to adjust the inspiratory and expiratory pressures and the machine mode. We found slight hypopnea and apnea, predominantly of a central type, in stage 1 and REM sleep and alveolar hypoventilation in all patients. Sleep was disrupted and the efficiency index was very low. In three patients HLA typing showed a positive DQ6 haplotype. Six patients were treated with n-BiPAP. Nasal-BIPAP should be considered as an alternative in ventilatory support during sleep in these patients and video-polysomnography as a valid method of evaluating the ideal time to start treatment.

Myotonic dystrophytype 1 - report of non-24-h sleep-wake disorder with excessive daytime sleepiness.

PubMed

Filho, Lucio Huebra Pimentel; Gomes, Ana Carolina Dias; Gonçalves, Bruno; Tufik, Sergio; Coelho, Fernando Morgadinho

2018-05-15

Myotonic dystrophy (MD) is a neuromuscular disease with myotonia, progressive weakness, and involvement of CNS, heart, and gastrointestinal system. Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 (MD1) is related to sleep breathing diseases, restless leg syndrome, periodic limb movements during sleep and narcoleptic-like phenotype. However, authors highlight a central dysfunction of sleep regulation. We describe a 26-year-old, female, MD1 patient with EDS. Sleep diary/actigraphy evidenced two different circadian periods with values of 1442 and 1522 min. Agomelatine, 50 mg at night, was prescribed with improvement of the circadian rhythm and complaints of sleepiness. The identification of unanticipated causes of EDS, such as circadian rhythm disorders permits an appropriated treatment. As we know, it is the first relate of non-24-h sleep-wake disorder in patient with MD1. Sleep diary and actigraphy could be good options to investigate sleep-wake cycle disorder in patients with MD and EDS.

[Rapid sequence induction in a patient with Steinert myotonic dystrophy: Interest of the association of high doses of rocuronium and sugammadex].

PubMed

Pellegrini, L; Mercier, M-F; Cornese, A; Blasco, V; Albanèse, J

2012-02-01

We report in this clinical case the successful use of a combination of rocuronium and sugammadex in a patient with Steinert myotonic dystrophy to perform a rapid sequence induction of anaesthesia. The patient had both contraindication to succinylcholine and a risk of prolonged neuromuscular blockade with non-depolarizing neuromuscular blocking agents. The use of high dose rocuronium (1mg/kg) allowed a quick and easy orotracheal intubation but induced a prolonged neuromuscular block, reversed with success by sugammadex (8 mg/kg). Copyright © 2011 Société française d'anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

Development of a genomic DNA reference material panel for myotonic dystrophy type 1 (DM1) genetic testing.

PubMed

Kalman, Lisa; Tarleton, Jack; Hitch, Monica; Hegde, Madhuri; Hjelm, Nick; Berry-Kravis, Elizabeth; Zhou, Lili; Hilbert, James E; Luebbe, Elizabeth A; Moxley, Richard T; Toji, Lorraine

2013-07-01

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG triplet repeat in the 3' untranslated region of the DMPK gene that encodes a serine-threonine kinase. Patients with larger repeats tend to have a more severe phenotype. Clinical laboratories require reference and quality control materials for DM1 diagnostic and carrier genetic testing. Well-characterized reference materials are not available. To address this need, the Centers for Disease Control and Prevention-based Genetic Testing Reference Material Coordination Program, in collaboration with members of the genetic testing community, the National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members, and the Coriell Cell Repositories, has established and characterized cell lines from patients with DM1 to create a reference material panel. The CTG repeats in genomic DNA samples from 10 DM1 cell lines were characterized in three clinical genetic testing laboratories using PCR and Southern blot analysis. DMPK alleles in the samples cover four of five DM1 clinical categories: normal (5 to 34 repeats), mild (50 to 100 repeats), classical (101 to 1000 repeats), and congenital (>1000 repeats). We did not identify or establish Coriell cell lines in the premutation range (35 to 49 repeats). These samples are publicly available for quality control, proficiency testing, test development, and research and should help improve the accuracy of DM1 testing. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Peripheral neuropathy in patients with myotonic dystrophy type 2.

PubMed

Leonardis, L

2017-05-01

Myotonic dystrophy type 2 (dystrophia myotonica type 2-DM2) is an autosomal dominant multi-organ disorder. The involvement of the peripheral nervous system was found in 25%-45% of patients with myotonic dystrophy type 1, although limited data are available concerning polyneuropathy in patients with DM2, which was the aim of this study with a thorough presentation of the cases with peripheral neuropathy. Patients with genetically confirmed DM2 underwent motor nerve conduction studies of the median, ulnar, tibial and fibular nerves and sensory nerve conduction studies of the median (second finger), ulnar (fifth finger), radial (forearm) and sural nerves. Seventeen adult patients with DM2 participated in the study. Fifty-three percent (9/17) of our patients had abnormality of one or more attributes (latency, amplitude or conduction velocity) in two or more separate nerves. Four types of neuropathies were found: (i) predominantly axonal motor and sensory polyneuropathy, (ii) motor polyneuropathy, (iii) predominantly demyelinating motor and sensory polyneuropathy and (iv) mutilating polyneuropathy with ulcers. The most common forms are axonal motor and sensory polyneuropathy (29%) and motor neuropathy (18% of all examined patients). No correlations were found between the presence of neuropathy and age, CCTG repeats, blood glucose or HbA1C. Peripheral neuropathy is common in patients with DM2 and presents one of the multisystemic manifestations of DM2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Perceived functioning and disability in adults with myotonic dystrophy type 1: a survey according to the International Classification Of Functioning, Disability and Health.

PubMed

Kierkegaard, Marie; Harms-Ringdahl, Karin; Widén Holmqvist, Lotta; Tollbäck, Anna

2009-06-01

The purpose of this study was to describe and analyse self-rated perceived functioning, disability and environmental facilitators/barriers with regard to disease severity, using the International Classification of Functioning, Disability and Health (ICF) checklist, in adults with myotonic dystrophy type 1. Cross-sectional design. Forty-one women and 29 men with myotonic dystrophy type 1. A modified ICF checklist was used for self-rating of perceived problems in 29 body-function categories, difficulties in 52 activity and participation categories, and facilitators/barriers in 23 environmental-factor categories according to the verbal anchors of the ICF qualifiers. Disease severity classification was based on the muscular impairment rating scale. Of the persons with myotonic dystrophy type 1, 80% perceived problems of excessive daytime sleepiness, 76% of muscle power, and 66% of energy and drive functions, while over 59% perceived difficulties in physically demanding mobility activities. Disabilities in mobility, self-care and domestic life were more frequently reported by persons with severe disease. Support from the immediate family, medicines and social security services were perceived as facilitators for 50-60% of the participants. Disabilities and important environmental facilitators in adults with myotonic dystrophy type 1 were identified, and this clinically-relevant information can be used for developing health services for people with this condition.

Myotonic Dystrophy Type 1 Management and Therapeutics.

PubMed

Smith, Cheryl A; Gutmann, Laurie

2016-12-01

Myotonic dystrophy (DM1) is the most common form of adult muscular dystrophy. It is a multisystem disorder with a complex pathophysiology. Although inheritance is autosomal dominant, disease variability is attributed to anticipation, a maternal expansion bias, variable penetrance, somatic mosaicism, and a multitude of aberrant pre-mRNA splicing events. Patient presentations range from asymptomatic or mild late onset adult to severe congenital forms. Multiple organ systems may be affected. Patients may experience early cataracts, myotonia, muscle weakness/atrophy, fatigue, excessive daytime sleepiness, central/obstructive apnea, respiratory failure, cardiac arrhythmia, insulin resistance, dysphagia, GI dysmotility, cognitive impairment, Cluster C personality traits, and/or mood disorders. At present, there is no curative or disease-modifying treatment, although clinical treatment trials have become more promising. Management focuses on genetic counseling, preserving function and independence, preventing cardiopulmonary complications, and symptomatic treatment (e.g., pain, myotonia, hypersomnolence, etc.). Currently, there is an increasing international consensus on monitoring and treatment options for these patients which necessitates a multidisciplinary team to provide comprehensive, coordinated clinical care.

A Population-based survey of risk for cancer in individuals diagnosed with myotonic dystrophy

PubMed Central

Abbott, Diana; Johnson, Nicholas E; Cannon-Albright, Lisa A.

2018-01-01

Introduction The risk of cancer in patients diagnosed with myotonic dystrophy (DM) is reported for the homogeneous Utah population. Methods Clinical data accessed from the largest Utah healthcare providers have been record-linked to the Utah Population Database (UPDB), a population-based resource also linked to the Utah Cancer Registry. Relative risks were estimated for 36 cancers of different types in 281 DM patients. Results Testicular cancer (RR=10.74; 95% CI: 1.91, 38.79), endometrial cancer (6.98; 1.24, 25.22), and Non-Hodgkins lymphoma (4.25; 1.16, 12.43) were all observed at significant excess in DM patients. Discussion This study confirms an overall increased risk of cancer in DM. Individuals diagnosed with DM might benefit from risk counseling. PMID:27064430

PubMed Central

NIGRO, GERARDO; PAPA, ANDREA ANTONIO; POLITANO, LUISA

2012-01-01

Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment. PMID:23097601

Types of CMT

MedlinePlus

... Marie-Tooth Disease (CMT) Congenital Muscular Dystrophy (CMD) Duchenne Muscular Dystrophy (DMD) Emery-Dreifuss Muscular Dystrophy Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Dystrophy (DM) Spinal-Bulbar ...

Pigmentation Phenotype, Photosensitivity, and Skin Neoplasms in Patients with Myotonic Dystrophy

PubMed Central

Gadalla, Shahinaz M.; Hilbert, James E.; Martens, William B.; Givens, Shannon; Moxley, Richard T.; Greene, Mark H.

2017-01-01

Background Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined. Method We collected information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure from 266 DM patients who were enrolled in the US NIH National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members. Results Seventy-seven subjects reported having skin tumors that were either benign (n=31), malignant (n=32), or both (n=14). Female gender (OR=2.27, 95%CI=1.02–5.05, p=0.04), older age (OR=1.10, 95%CI=1.05–1.16, p<0.001), and DM1 subtype (OR=3.42, 95%CI=1.27–9.26, p=0.02) were associated with a malignant skin tumor. The association between malignant skin tumors and known risk factors [light eye color (OR=1.62, 95%CI=0.78–3.39, p=0.20); light skin complexion (OR=1.31, 95% CI=0.63–2.73, p=0.48), moderate/extensive face freckles (OR=1.47, 95% CI=0.50–4.34, p=0.49)] were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR=4.28, 95%CI=0.91–19.95, p=0.06, and 2.19, 95%CI=0.67–7.09, p=0.19 for sunburns with and without blistering, respectively). Conclusions Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. We recommend that DM patients adhere to sun exposure protective behavior. PMID:28317292

Effects of Functional Electrical Stimulation Lower Extremity Training in Myotonic Dystrophy Type I: A Pilot Controlled Study.

PubMed

Cudia, Paola; Weis, Luca; Baba, Alfonc; Kiper, Pawel; Marcante, Andrea; Rossi, Simonetta; Angelini, Corrado; Piccione, Francesco

2016-11-01

Functional electrical stimulation (FES) is a new rehabilitative approach that combines electrical stimulation with a functional task. This pilot study evaluated the safety and effectiveness of FES lower extremity training in myotonic dystrophy type 1. This is a controlled pilot study that enrolled 20 patients with myotonic dystrophy type 1 over 2 years. Eight patients (age, 39-67 years) fulfilled the inclusion criteria. Four participants performed FES cycling training for 15 days (one daily session of 30 minutes for 5 days a week). A control group, matched for clinical and genetic variables, who had contraindications to electrical stimulation, performed 6 weeks of conventional resistance and aerobic training. The modified Medical Research Council Scale and functional assessments were performed before and after treatment. Cohen d effect size was used for statistical analysis. Functional electrical stimulation induced lower extremity training was well tolerated and resulted in a greater improvement of tibialis anterior muscle strength (d = 1,583), overall muscle strength (d = 1,723), and endurance (d = 0,626) than conventional training. Functional electrical stimulation might be considered a safe and valid tool to improve muscle function, also in muscles severely compromised in which no other restorative options are available. Confirmation of FES efficacy through further clinical trials is strongly advised.

[Perioperative treatment of a patient with myotonic muscular dystrophy (Curschmann-Steinert disease)].

PubMed

Thölke, M H; Tolksdorf, W; Mitrenga, I

1991-04-01

The perioperative period is hazardous for patients with neuromuscular disorder. In case of dystrophia myotonica the anaesthesist must avoid all stimuli that may cause a myotonic crisis. If neuromuscular blockade is required, the moderately long-acting vecuronium bromide seems to be the drug of first choice. Blockade and recovery should be monitored. Postoperative pulmonary complications can be minimised by using regional anaesthetic techniques including epidural anaesthesia with local anaesthetics and/or opioids.

Benign and malignant tumors in the UK myotonic dystrophy patient registry.

PubMed

Alsaggaf, Rotana; Wang, Youjin; Marini-Bettolo, Chiara; Wood, Libby; Nikolenko, Nikoletta; Lochmüller, Hanns; Greene, Mark H; Gadalla, Shahinaz M

2018-02-01

In light of recent evidence indicating that cancer is part of the myotonic dystrophy (DM) phenotype, we assessed the prevalence of benign and malignant tumors among 220 patients enrolled in the UK Myotonic Dystrophy Patient Registry and evaluated factors associated with their development. A survey was distributed to collect tumor history and lifestyle information. We used multinomial logistic regression for the analysis. Thirty-nine benign (30 patients), and 16 malignant (15 patients) tumors were reported. Increasing age (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.05-1.21, P = 0.001) and earlier age at DM diagnosis (OR = 1.06, 95% CI = 1.00-1.13, P = 0.04) were associated with benign and malignant tumors (OR = 1.20, 95% CI = 1.10-1.30, P < 0.001 and OR = 1.08, 95% CI = 1.01-1.15, P = 0.02, respectively). Female gender was associated with benign tumors only (OR = 6.43, 95% CI = 1.79-23.04, P = 0.004). No associations were observed between tumors and smoking (P = 0.24), alcohol consumption (P = 0.50), or body mass index (P = 0.21). Our results confirm previous findings suggesting a limited role for common lifestyle factors and a potential genetic contribution in DM tumor predisposition. Muscle Nerve 57: 316-320, 2018. © 2017 Wiley Periodicals, Inc.

Longitudinal in vivo muscle function analysis of the DMSXL mouse model of myotonic dystrophy type 1.

PubMed

Decostre, Valérie; Vignaud, Alban; Matot, Béatrice; Huguet, Aline; Ledoux, Isabelle; Bertil, Emilie; Gjata, Bernard; Carlier, Pierre G; Gourdon, Geneviève; Hogrel, Jean-Yves

2013-12-01

Myotonic dystrophy is the most common adult muscle dystrophy. In view of emerging therapies, which use animal models as a proof of principle, the development of reliable outcome measures for in vivo longitudinal study of mouse skeletal muscle function is becoming crucial. To satisfy this need, we have developed a device to measure ankle dorsi- and plantarflexion torque in rodents. We present an in vivo 8-month longitudinal study of the contractile properties of the skeletal muscles of the DMSXL mouse model of myotonic dystrophy type 1. Between 4 and 12 months of age, we observed a reduction in muscle strength in the ankle dorsi- and plantarflexors of DMSXL compared to control mice although the strength per muscle cross-section was normal. Mild steady myotonia but no abnormal muscle fatigue was also observed in the DMSXL mice. Magnetic resonance imaging and histological analysis performed at the end of the study showed respectively reduced muscle cross-section area and smaller muscle fibre diameter in DMSXL mice. In conclusion, our study demonstrates the feasibility of carrying out longitudinal in vivo studies of muscle function over several months in a mouse model of myotonic dystrophy confirming the feasibility of this method to test preclinical therapeutics. Copyright © 2013 Elsevier B.V. All rights reserved.

The heart and cardiac pacing in Steinert disease.

PubMed

Nigro, Gerardo; Papa, Andrea Antonio; Politano, Luisa

2012-10-01

Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.

Psychiatric and Cognitive Phenotype of Childhood Myotonic Dystrophy Type 1

ERIC Educational Resources Information Center

Douniol, Marie; Jacquette, Aurelia; Cohen, David; Bodeau, Nicolas; Rachidi, Linda; Angeard, Nathalie; Cuisset, Jean-Marie; Vallee, Louis; Eymard, Bruno; Plaza, Monique; Heron, Delphine; Guile, Jean-Marc

2012-01-01

Aim: To investigate the psychiatric and cognitive phenotype in young individuals with the childhood form of myotonic dystrophy type 1 (DM1). Method: Twenty-eight individuals (15 females, 13 males) with childhood DM1 (mean age 17y, SD 4.6, range 7-24y) were assessed using standardized instruments and cognitive testing of general intelligence,…

European Home Mechanical Ventilation Registry

ClinicalTrials.gov

2016-10-25

Pulmonary Disease, Chronic Obstructive; Amyotrophic Lateral Sclerosis; Spinal Cord Injury; Muscular Dystrophies; Obesity Hypoventilation Syndrome; Kyphoscoliosis; Congenital Central Hypoventilation Syndrome; Duchenne Muscular Dystrophy; Myopathies; Myotonic Dystrophy

Learning about Myotonic Dystrophy

MedlinePlus

... Links for Patient Care Education All About the Human Genome Project Fact Sheets Genetic Education Resources for Teachers ... Education Kit Online Genetics Education Resources Smithsonian NHGRI Genome ... Subjects Research Informed Consent for Genomics Research Intellectual ...

Hypothesis: neoplasms in myotonic dystrophy

PubMed Central

Hilbert, James E.; Martens, William; Thornton, Charles A.; Moxley, Richard T.; Greene, Mark H.

2011-01-01

Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities. PMID:19642006

Tissue- and age-specific DNA replication patterns at the CTG/CAG-expanded human myotonic dystrophy type 1 locus.

PubMed

Cleary, John D; Tomé, Stéphanie; López Castel, Arturo; Panigrahi, Gagan B; Foiry, Laurent; Hagerman, Katharine A; Sroka, Hana; Chitayat, David; Gourdon, Geneviève; Pearson, Christopher E

2010-09-01

Myotonic dystrophy, caused by DM1 CTG/CAG repeat expansions, shows varying instability levels between tissues and across ages within patients. We determined DNA replication profiles at the DM1 locus in patient fibroblasts and tissues from DM1 transgenic mice of various ages showing different instability. In patient cells, the repeat is flanked by two replication origins demarcated by CTCF sites, with replication diminished at the expansion. In mice, the expansion replicated from only the downstream origin (CAG as lagging template). In testes from mice of three different ages, replication toward the repeat paused at the earliest age and was relieved at later ages-coinciding with increased instability. Brain, pancreas and thymus replication varied with CpG methylation at DM1 CTCF sites. CTCF sites between progressing forks and repeats reduced replication depending on chromatin. Thus, varying replication progression may affect tissue- and age-specific repeat instability.

Mechanisms of diarrhoea in myotonic dystrophy.

PubMed

Rönnblom, A; Andersson, S; Danielsson, A

1998-07-01

Gastrointestinal (GI) symptoms are common in myotonic dystrophy (MD). Diarrhoea is one of the more disabling of these GI complaints. The mechanisms behind diarrhoea in MD have not previously been investigated systematically. To elucidate the mechanisms behind diarrhoea in MD. Twenty patients with MD and suffering from diarrhoea were investigated in order to detect malabsorption (blood tests and faecal fat excretion) and bile acid malabsorption ([75Se]selenahomocholic acid-taurine (SeHCAT) retention) and to study intestinal morphology (duodenal and rectal biopsies). Two patients had deficiency of folic acid and four showed reduced levels of pancreatic isoamylase, but none of them had steatorrhoea. Two out of eight patients had abnormal bile acid breath tests with normal SeHCAT, indicating small bowel bacterial overgrowth and 12 displayed reduced SeHCAT retention. Duodenal biopsies were normal in eight patients and five out of nine rectal biopsies displayed slight inflammation. A possible mechanism of diarrhoea in MD could be identified in most of the patients. Bile acid malabsorption seems to be a frequent cause and can be treated successfully.

Myotonic dystrophies type 1 and 2: anesthetic care.

PubMed

Veyckemans, Francis; Scholtes, Jean-Louis

2013-09-01

Myotonic dystrophy is classified as one of the myotonic syndromes although myotonia is only a minor characteristic of it. It is, in fact, also a multisystem disease with cardiac, digestive, ocular, and endocrine abnormalities. Two subgroups are currently identified with many similarities: DM1 refers to classic dystrophia myotonica (Steinert disease), while DM2, formerly called proximal myotonic myopathy has a later onset. The congenital form is present only in DM1. The genetic causes of DM1 and 2 are different but end up in a similar way of altering RNAm processing and splicing of other genes. The anesthetic risk is increased in case of DM1 type. This review summarizes current knowledge concerning the pathophysiology and anesthetic management of this disease in children and adults. © 2013 John Wiley & Sons Ltd.

Oropharyngeal dysphagia in myotonic dystrophy type 1: a systematic review.

PubMed

Pilz, Walmari; Baijens, Laura W J; Kremer, Bernd

2014-06-01

A systematic review was conducted to investigate the pathophysiology of and diagnostic procedures for oropharyngeal dysphagia in myotonic dystrophy (MD). The electronic databases Embase, PubMed, and The Cochrane Library were used. The search was limited to English, Dutch, French, German, Spanish, and Portuguese publications. Sixteen studies met the inclusion criteria. Two independent reviewers assessed the methodological quality of the included articles. Swallowing assessment tools, the corresponding protocols, the studies' outcome measurements, and main findings are summarized and presented. The body of literature on pathophysiology of swallowing in dysphagic patients with MD type 1 remains scant. The included studies are heterogeneous with respect to design and outcome measures and hence are not directly comparable. More importantly, most studies had methodological problems. These are discussed in detail and recommendations for further research on diagnostic examinations for swallowing disorders in patients with MD type 1 are provided.

PubMed Central

MEOLA, GIOVANNI

2013-01-01

Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment. PMID:24803843

Brain pathology in myotonic dystrophy: when tauopathy meets spliceopathy and RNAopathy

PubMed Central

Caillet-Boudin, Marie-Laure; Fernandez-Gomez, Francisco-Jose; Tran, Hélène; Dhaenens, Claire-Marie; Buee, Luc; Sergeant, Nicolas

2013-01-01

Myotonic dystrophy (DM) of type 1 and 2 (DM1 and DM2) are inherited autosomal dominant diseases caused by dynamic and unstable expanded microsatellite sequences (CTG and CCTG, respectively) in the non-coding regions of the genes DMPK and ZNF9, respectively. These mutations result in the intranuclear accumulation of mutated transcripts and the mis-splicing of numerous transcripts. This so-called RNA gain of toxic function is the main feature of an emerging group of pathologies known as RNAopathies. Interestingly, in addition to these RNA inclusions, called foci, the presence of neurofibrillary tangles (NFT) in patient brains also distinguishes DM as a tauopathy. Tauopathies are a group of nearly 30 neurodegenerative diseases that are characterized by intraneuronal protein aggregates of the microtubule-associated protein Tau (MAPT) in patient brains. Furthermore, a number of neurodegenerative diseases involve the dysregulation of splicing regulating factors and have been characterized as spliceopathies. Thus, myotonic dystrophies are pathologies resulting from the interplay among RNAopathy, spliceopathy, and tauopathy. This review will describe how these processes contribute to neurodegeneration. We will first focus on the tauopathy associated with DM1, including clinical symptoms, brain histology, and molecular mechanisms. We will also discuss the features of DM1 that are shared by other tauopathies and, consequently, might participate in the development of a tauopathy. Moreover, we will discuss the determinants common to both RNAopathies and spliceopathies that could interfere with tau-related neurodegeneration. PMID:24409116

[A prompt diagnosis of Steinert's dystrophy in emergency unit].

PubMed

Suppa, M; Migliozzi, E; Magnanelli, E; Negri, S; Cavicchi, F; Colzi, M; Coppola, A

2012-11-01

Atrial fibrillation is frequently observed in Fist Aid. A rare cause is myotonic dystrophy There are two forms: Steinert's dystrophy caused by a defect of a gene myotoninaprotein kinase and Promm secondary to a defect of a Zinc Finger Protein Gene Clinical manifestations are localized in skeletal and face muscles, vitreous body, sexual glands, endocrine system, smooth muscle, central nervous system and myocardium. Sometimes, in mild and unrecognized forms of this rare disease there are arrhythmias as atrial fibrillation. We report the clinical case of a 52 year-old man, with a suspect diagnosis of Steinert's dystrophy, admitted to the emergency room for a persistent atrial fibrillation. The patient begins oral anticoagulation therapy. The patient perform a transesophageal echocardiogram before the electrical cardioversion with reset to sinus rhythm. In conclusion, with improving the screening methods of patients with primary and secondary myopathies, it has been seen an increase of cases in which a cardiac involvement occurred before or after the onset of the neuromuscular disorders. One of the most frequent alterations is represented by atrial fibrillation, responsible for an increased risk of cerebral embolism, with absolute indication for oral anticoagulation therapy. The myopathy more frequently associated with atrial fibrillation, is myotonic dystrophy, although the risk of cerebral embolism in these patients does not appear to be higher than the general population. The present case report is a spur to perform the diagnosis of Steinert disease in cases admitted to an Emergency Room because of arrhytmias, because of the possibility to perform fast and reliable specific genetic tests. A similar praxis confers to these Units an even more diagnostic clinical role.

Myotonic Dystrophy Type 2 Found in Two of Sixty-Three Persons Diagnosed as Having Fibromyalgia

PubMed Central

Auvinen, Satu; Suominen, Tiina; Hannonen, Pekka; Bachinski, Linda L.; Krahe, Ralf; Udd, Bjarne

2008-01-01

Because of its high prevalence, fibromyalgia (FM) is a major general health issue. Myotonic dystrophy type 2 (DM2) is a recently described autosomal-dominant multisystem disorder. Besides variable proximal muscle weakness, myotonia, and precocious cataracts, muscle pain and stiffness are prominent presenting features of DM2. After noting that several of our mutation-positive DM2 patients had a previous diagnosis of FM, suggesting that DM2 may be misdiagnosed as FM, we invited 90 randomly selected patients diagnosed as having FM to undergo genetic testing for DM2. Of the 63 patients who agreed to participate, 2 (3.2%) tested positive for the DM2 mutation. Their cases are described herein. DM2 was not found in any of 200 asymptomatic controls. We therefore suggest that the presence of DM2 should be investigated in a large sample of subjects diagnosed as having FM, and clinicians should be aware of overlap in the clinical presentation of these 2 distinct disorders. PMID:18975316

Primary Hyperparathyroidism and Hyperthyroidism in a Patient with Myotonic Dystrophy: A Case Report and Review of the Literature

PubMed Central

Alaya, Wafa; Berriche, Olfa; Younes, Samia; Sfar, Mohamed Habib

2015-01-01

Various endocrine manifestations are commonly described in myotonic dystrophy (MD), including primary hypogonadism, diabetes mellitus, and thyroid and parathyroid dysfunction. We describe a 46-year-old woman with a family history of MD with her son. She was diagnosed with cardiac arrhythmia and required the implantation of a pacemaker. She was noted to have a bilateral cataract. She complained of muscle weakness, diffuse myalgia, and palpitation. The electromyography (EMG) showed myotonic discharges. Laboratory tests showed high serum calcium 2.83 mmol/L, serum phosphate 1.2 mmol/L, parathormone 362.5 pg/mL, thyroid stimulating hormone TSH 0.02 mIU/L (normal range: 0.34–5.6 mIU/L), FT4 21.17 ng/mL, and negative anti-thyroperoxidase antibodies. Cervical ultrasound revealed a multinodular goiter. The 99mTc-MIBI scintigraphy localized a lower right parathyroid adenoma. The clinical data, the family history of MD, EMG data, and endocrine disturbances were strongly suggestive of MD associated with hyperthyroidism and primary hyperparathyroidism. PMID:26175917

Feasibility and effects of a physical exercise programme in adults with myotonic dystrophy type 1: a randomized controlled pilot study.

PubMed

Kierkegaard, Marie; Harms-Ringdahl, Karin; Edström, Lars; Widén Holmqvist, Lotta; Tollbäck, Anna

2011-07-01

To investigate the feasibility and effects of a physical exercise programme on functioning and health-related quality of life in adults with myotonic dystrophy type 1. A randomized controlled trial. Thirty-five adults with myotonic dystrophy type 1. After stratification for level of functioning, study participants were assigned by lot to either a training group or a control group. Training-group participants attended a 60-minute comprehensive group-training programme, Friskis&Svettis® Open Doors, twice a week for 14 weeks. The six-minute walk test was the primary outcome measure and the timed-stands test, the timed up-and-go test, the Epworth sleepiness scale and the Short Form-36 health survey were secondary outcome measures. Intention-to-treat analyses revealed no significant differences in any outcome measures, except for an increased between-group difference after intervention in the Short Form-36 mental health subscale and a decrease in the vitality subscale for the control group. The programme was well tolerated and many training-group participants perceived subjective changes for the better. No negative effects were reported. The Friskis&Svettis® Open Doors programme was feasible for adults with myotonic dystrophy type 1 who had been screened for cardiac involvement, had distal or mild-to-moderate proximal muscle impairment, and no severe cognitive impairments. No beneficial or detrimental effects were evident.

Analysis of MTMR1 expression and correlation with muscle pathological features in juvenile/adult onset myotonic dystrophy type 1 (DM1) and in myotonic dystrophy type 2 (DM2).

PubMed

Santoro, Massimo; Modoni, Anna; Masciullo, Marcella; Gidaro, Teresa; Broccolini, Aldobrando; Ricci, Enzo; Tonali, Pietro Attilio; Silvestri, Gabriella

2010-10-01

Among genes abnormally expressed in myotonic dystrophy type1 (DM1), the myotubularin-related 1 gene (MTMR1) was related to impaired muscle differentiation. Therefore, we analyzed MTMR1 expression in correlation with CUG-binding protein1 (CUG-BP1) and muscleblind-like1 protein (MBNL1) steady-state levels and with morphological features in muscle tissues from DM1 and myotonic dystrophy type 2 (DM2) patients. Semi-quantitative RT-PCR for MTMR1 was done on muscle biopsies and primary muscle cultures. The presence of impaired muscle fiber maturation was evaluated using immunochemistry for neural cell adhesion molecule (NCAM), Vimentin and neonatal myosin heavy chain. CUG-BP1 and MBNL1 steady-state levels were estimated by Western blot. RNA-fluorescence in situ hybridization combined with immunochemistry for CUG-BP1, MBNL1 and NCAM were performed on serial muscle sections. An aberrant splicing of MTMR1 and a significant amount of NCAM-positive myofibers were detected in DM1 and DM2 muscle biopsies; these alterations correlated with DNA repeat expansion size only in DM1. CUG-BP1 levels were increased only in DM1 muscles, while MBNL1 levels were similar among DM1, DM2 and controls. Normal and NCAM-positive myofibers displayed no differences either in the amount of ribonuclear foci and the intracellular distribution of MBNL1 and CUG-BP1. In conclusion, an aberrant MTMR1 expression and signs of altered myofiber maturation were documented in both DM1 and in DM2 muscle tissues. The more severe dysregulation of MTMR1 expression in DM1 versus DM2, along with increased CUG-BP1 levels only in DM1 tissues, suggests that the mutual antagonism between MBNL1 and CUG-BP1 on alternative splicing is more unbalanced in DM1. Copyright © 2010 Elsevier Inc. All rights reserved.

Opioid-free general anesthesia in patient with Steinert syndrome (myotonic dystrophy)

PubMed Central

Gaszynski, Tomasz

2016-01-01

Abstract Introduction: We report on the anesthetic management using opioid-free method of a patient with Steinert syndrome (myotonic dystrophy, MD), autosomal dominant dystrophy which is characterized by consistent contracture of muscle following stimulation. A myotonic crisis can be induced by numerous factors including hypothermia, shivering, and mechanical or electrical stimulation. In patients with MD, hypersensitivity to anesthetic drugs, especially muscle relaxants and opioids, may complicate postoperative management. If opioids are employed (systemic or neuraxial), then ICU care and continuous pulse oximetry must be considered given the high risk for respiratory depression and aspiration. Patients with MD present high sensitivity to the usual anesthetics such as volatile and muscle relaxants (both depolarizing and nondepolarizing). Opioids may induce muscle rigidity in this type of MD. Therefore, omitting opioids is recommended. Due to hypersensitivity to opioids and increased susceptibility to intra- and postoperative complications, it is recommended to introduce opioid-free anesthesia (OFA), for example, with use of dexmedetomidine (DEX). This is a new method of conducting general anesthesia without opioids and is based on concept of multimodal approach to pain management. Methods: A 31-year-old male patient (183 cm, 69 kg) was scheduled for laparoscopic operation of cholecystectomy. The patient received intravenously (IV): propofol in a dose of 250 mg followed by continuous infusion, rocuronium in a dose of 20 mg, and DEX in a loading dose of 0.6 μg/kg over 10 minutes followed by continuous infusion of dose of 0.2 μg/kg/hour. Results: The course of anesthesia and postoperative period were uneventful. The patient exited the operating theatre in a good medical state, with vitals within normal limits and fully regained consciousness. Conclusion: DEX is effective and safe for moderately painful procedures in patients with the elevated risk of respiratory and cardiovascular failure. This substance provides adequate analgesia level during surgeries of patients suffering from MD. PMID:27631259

Opioid-free general anesthesia in patient with Steinert syndrome (myotonic dystrophy): Case report.

PubMed

Gaszynski, Tomasz

2016-09-01

We report on the anesthetic management using opioid-free method of a patient with Steinert syndrome (myotonic dystrophy, MD), autosomal dominant dystrophy which is characterized by consistent contracture of muscle following stimulation. A myotonic crisis can be induced by numerous factors including hypothermia, shivering, and mechanical or electrical stimulation. In patients with MD, hypersensitivity to anesthetic drugs, especially muscle relaxants and opioids, may complicate postoperative management. If opioids are employed (systemic or neuraxial), then ICU care and continuous pulse oximetry must be considered given the high risk for respiratory depression and aspiration. Patients with MD present high sensitivity to the usual anesthetics such as volatile and muscle relaxants (both depolarizing and nondepolarizing). Opioids may induce muscle rigidity in this type of MD. Therefore, omitting opioids is recommended. Due to hypersensitivity to opioids and increased susceptibility to intra- and postoperative complications, it is recommended to introduce opioid-free anesthesia (OFA), for example, with use of dexmedetomidine (DEX). This is a new method of conducting general anesthesia without opioids and is based on concept of multimodal approach to pain management. A 31-year-old male patient (183 cm, 69 kg) was scheduled for laparoscopic operation of cholecystectomy. The patient received intravenously (IV): propofol in a dose of 250 mg followed by continuous infusion, rocuronium in a dose of 20 mg, and DEX in a loading dose of 0.6 μg/kg over 10 minutes followed by continuous infusion of dose of 0.2 μg/kg/hour. The course of anesthesia and postoperative period were uneventful. The patient exited the operating theatre in a good medical state, with vitals within normal limits and fully regained consciousness. DEX is effective and safe for moderately painful procedures in patients with the elevated risk of respiratory and cardiovascular failure. This substance provides adequate analgesia level during surgeries of patients suffering from MD.

Myotonic dystrophy type 1: clinical manifestations in children and adolescents.

PubMed

Ho, Genevieve; Carey, Kate A; Cardamone, Michael; Farrar, Michelle A

2018-06-05

Myotonic dystrophy type 1 (DM1) is an autosomal-dominant neuromuscular disease with variable severity affecting all ages; however, current care guidelines are adult-focused. The objective of the present study was to profile DM1 in childhood and propose a framework to guide paediatric-focused management. 40 children with DM1 (mean age 12.8 years; range 2-19) were studied retrospectively for a total of 513 follow-up years at Sydney Children's Hospital. 143 clinical parameters were recorded. The clinical spectrum of disease in childhood differs from adults, with congenital myotonic dystrophy (CDM1) having more severe health issues than childhood-onset/juvenile patients (JDM1). Substantial difficulties with intellectual (CDM1 25/26 96.2%; JDM1 9/10, 90.0%), fine motor (CDM1 23/30, 76.6%; JDM1 6/10, 60.0%), gastrointestinal (CDM1 17/30, 70.0%; JDM1 3/10, 30.0%) and neuromuscular function (CDM1 30/30, 100.0%; JDM1 25/30, 83.3%) were evident. The health consequences of DM1 in childhood are diverse, highlighting the need for paediatric multidisciplinary management approaches that encompass key areas of cognition, musculoskeletal, gastrointestinal, respiratory, cardiac and sleep issues. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Isolation of Genes Involved in Rac Induced Invasion and Metastasis of Breast Carcinoma Cells

DTIC Science & Technology

2001-08-01

dystrophy kinase-related Cdc42-binding kinase acts 64 oetGPernCaL.adMcr,1..(20) Myotonic4dystrophyrkinaseoretatedCdc42-bindingekrnasezatson. The cell...kinase homologous to myotonic dystrophy kinase. EMBO J. J. Biol. Chem. 273, 5542-5548. 15, 1885-1893. 97. Fukata, Y., Oshiro, N., Kinoshita, N., Kawano... Becker , D., Williams, D.S., Thorpe, J., Fleming, J., Brown, S.D. and Steel, K.P.: A missense mutation in myosin VIIA prevents aminoglycoside accumulation

Reliability and feasibility of the six minute walk test in subjects with myotonic dystrophy.

PubMed

Kierkegaard, Marie; Tollbäck, Anna

2007-12-01

The objective was to describe test-retest reliability and feasibility of the six minute walk test in adult subjects with myotonic dystrophy type 1. Twelve subjects (28-68 years, mean 44) performed three six minute walk tests on two occasions, one week apart. Relative reliability was high (ICC(2.1)=0.99) and absolute reliability values were low (standard error of measurement 12 m, repeatability 33 m). Feasibility was investigated in a sample of 64 subjects (19-70 years, mean 43). Fifty-two subjects were able to perform two tests on the same day. Subjects with severe proximal weakness had difficulties performing repeated tests. A practice trial followed by a second test on the same day can be recommended for most subjects, and the best test should be used for evaluations. In conclusion, even though the study sample was small, the present study indicates that the six minute walk test is reliable and feasible in subjects with myotonic dystrophy type 1.

Echocardiographic diagnosis, management and monitoring of pulmonary embolism with right heart thrombus in a patient with myotonic dystrophy: a case report

PubMed Central

2010-01-01

Acute pulmonary embolism (PE) is a common disease which frequently results in life-threatening right ventricular (RV) failure. High-risk PE, presenting with hypotension, shock, RV dysfunction or right heart thrombus is associated with a high mortality, particularly during the first few hours. Accordingly, it is important to commence effective therapy as soon as possible. In the case described in this report, a 49-year-old woman with myotonic dystrophy type 1 presented with acute respiratory failure and hypotension. Transthoracic echocardiography showed signs of right heart failure and a mobile right heart mass highly suspicious of a thrombus. Based on echocardiographic findings, acute thrombolysis was performed resulting in hemodynamic stabilization of the patient and complete resolution of the right heart thrombus. This case underscores the important role of transthoracic echocardiography for the diagnosis, management and monitoring of PE and underlines the efficacy and safety of thrombolysis in the treatment of PE associated with right heart thrombus. PMID:20470437

PubMed Central

Paunic, Teodora; Parojcic, Aleksandra; Savic-Pavicevic, Dusanka; Vujnic, Milorad; Pesovic, Jovan; Basta, Ivana; Lavrnic, Dragana; Rakocevic-Stojanovic, Vidosava

2017-01-01

Myotonic dystrophy type 2 (DM2) is a multisystem disorder that affects many organs and systems, including the brain. The objective is to analyze personality patterns in myotonic dystrophy type 2 (DM2) compared to DM1 control group. The study comprised 27 consecutive genetically confirmed DM2 patients and control group of 44 DM1 patients. Personality traits were assessed with the Millon Multiaxial Clinical Inventory III (MMCI III). In DM2 group there were no scale with pathological scores, although compulsive and paranoid traits were the most prominent. DM2 patients had lower scores compared to DM1 patients in almost all scales. Pathological scores on clinical symptom scales were not observed, although anxiety scale almost approached this value. Patients with higher compulsive score had higher level of education (rho = +0.53, p < 0.01). On the other hand, higher paranoid score correlated with younger age at onset (rho = -0.34, p < 0.01) and lower educational level (rho = -0.26, p < 0.05). Our results did not show significant personality impairments in patients with DM2. However, following personality traits were predominant: compulsive (in patients with higher education) and paranoid (in patients with lower education and earlier age at onset). The most common clinical symptoms were anxiety and somatization. PMID:28690389

ZNF9 Activation of IRES-Mediated Translation of the Human ODC mRNA Is Decreased in Myotonic Dystrophy Type 2

PubMed Central

Sammons, Morgan A.; Antons, Amanda K.; Bendjennat, Mourad; Udd, Bjarne; Krahe, Ralf; Link, Andrew J.

2010-01-01

Myotonic dystrophy types 1 and 2 (DM1 and DM2) are forms of muscular dystrophy that share similar clinical and molecular manifestations, such as myotonia, muscle weakness, cardiac anomalies, cataracts, and the presence of defined RNA-containing foci in muscle nuclei. DM2 is caused by an expansion of the tetranucleotide CCTG repeat within the first intron of ZNF9, although the mechanism by which the expanded nucleotide repeat causes the debilitating symptoms of DM2 is unclear. Conflicting studies have led to two models for the mechanisms leading to the problems associated with DM2. First, a gain-of-function disease model hypothesizes that the repeat expansions in the transcribed RNA do not directly affect ZNF9 function. Instead repeat-containing RNAs are thought to sequester proteins in the nucleus, causing misregulation of normal cellular processes. In the alternative model, the repeat expansions impair ZNF9 function and lead to a decrease in the level of translation. Here we examine the normal in vivo function of ZNF9. We report that ZNF9 associates with actively translating ribosomes and functions as an activator of cap-independent translation of the human ODC mRNA. This activity is mediated by direct binding of ZNF9 to the internal ribosome entry site sequence (IRES) within the 5′UTR of ODC mRNA. ZNF9 can activate IRES-mediated translation of ODC within primary human myoblasts, and this activity is reduced in myoblasts derived from a DM2 patient. These data identify ZNF9 as a regulator of cap-independent translation and indicate that ZNF9 activity may contribute mechanistically to the myotonic dystrophy type 2 phenotype. PMID:20174632

Swallowing assessment in myotonic dystrophy type 1 using fiberoptic endoscopic evaluation of swallowing (FEES).

PubMed

Pilz, Walmari; Baijens, Laura W J; Passos, Valéria Lima; Verdonschot, Rob; Wesseling, Frederik; Roodenburg, Nel; Faber, Catharina G; Kremer, Bernd

2014-12-01

This study describes the swallowing function of patients with myotonic dystrophy type 1 (DM1) and the effect of bolus consistency on swallowing in this group. The aim of the study is twofold: (a) to identify which (and to what extent) swallowing variables change for DM1 patients relative to healthy control subjects and (b) to examine whether the degree of oropharyngeal dysphagia is associated with disease severity. Forty-five consecutive DM1 patients and ten healthy subjects underwent a swallowing assessment, at Maastricht University medical Center in the Netherlands. The assessment included a standardized fiberoptic endoscopic evaluation of swallowing (FEES) protocol using different bolus consistencies. Clinical severity of the disease was assessed using the muscular impairment rating scale (MIRS). Significant differences were found between patients and controls for all FEES variables. The magnitude of these differences depended on the bolus consistency. The odds of a more pathological swallowing outcome increased significantly with higher MIRS levels. In conclusion, swallowing function is found to be significantly altered in DM1 patients. The results emphasize the importance of conducting a detailed swallowing assessment in all patients, even those with mild muscle weakness. Copyright © 2014 Elsevier B.V. All rights reserved.

[Obstetrical care in myotonic dystrophy type 1 (Steinert disease)].

PubMed

Jah, H; Schalinksi, E; Fischer, J; Maier, J T; Schunck, K U; Hellmeyer, L

2015-08-01

In 1909 the neurologist Dr. Hans Steinert was the first to describe the most common of all neural-muscular diseases: Mytotonic Dystrophy Curschmann Steinert. Up to today this disease is seldom published particularly in obstetrics. This is a case report of a 23-year-old patient. Following extensive interdisciplinary diagnostic a successful caesarian delivery of a healthy boy was performed in the 39(th) week of pregnancy without any complications. © Georg Thieme Verlag KG Stuttgart · New York.

Management of Cardiac Involvement in NeuroMuscular Diseases: Review

PubMed Central

Bouhouch, Rachida; Elhouari, Tarik; Oukerraj, Latifa; Fellat, Ibtissam; Zarzur, Jamila; Bennani, Rajaa; Arharbi, Mhamed

2008-01-01

Neuromuscular Diseases are a heterogeneous molecular, clinical and prognosis group. Progress has been achieved in the understanding and classification of these diseases. Cardiac involvement in neuromuscular diseases namely conduction disorders, ventricular dilatation and dilated cardiomyopathy with its impact on prognosis, is often dissociated from the peripheral myopathy. Therefore, close surveillance is mandatory in the affected patients. In this context, preventive therapy (beta-blockers and angiotensin converting enzyme inhibitors) has been recently recommended in the most common Neuromuscular Diseases, Duchenne Muscular Dystrophy and Myotonic Dystrophy. PMID:19337361

Preferential Nucleosome Assembly at DNA Triplet Repeats from the Myotonic Dystrophy Gene

NASA Astrophysics Data System (ADS)

Wang, Yuh-Hwa; Amirhaeri, Sorour; Kang, Seongman; Wells, Robert D.; Griffith, Jack D.

1994-07-01

The expansion of CTG repeats in DNA occurs in or near genes involved in several human diseases, including myotonic dystrophy and Huntington's disease. Nucleosomes, the basic structural element of chromosomes, consist of 146 base pairs of DNA coiled about an octamer of histone proteins and mediate general transcriptional repression. Electron microscopy was used to examine in vitro the nucleosome assembly of DNA containing repeating CTG triplets. The efficiency of nucleosome formation increased with expanded triplet blocks, suggesting that such blocks may repress transcription through the creation of stable nucleosomes.

Using digital technologies to engage with medical research: views of myotonic dystrophy patients in Japan.

PubMed

Coathup, Victoria; Teare, Harriet J A; Minari, Jusaku; Yoshizawa, Go; Kaye, Jane; Takahashi, Masanori P; Kato, Kazuto

2016-08-24

As in other countries, the traditional doctor-patient relationship in the Japanese healthcare system has often been characterised as being of a paternalistic nature. However, in recent years there has been a gradual shift towards a more participatory-patient model in Japan. With advances in technology, the possibility to use digital technologies to improve patient interactions is growing and is in line with changing attitudes in the medical profession and society within Japan and elsewhere. The implementation of an online patient engagement platform is being considered by the Myotonic Dystrophy Registry of Japan. The aim of this exploratory study was to understand patients' views and attitudes to using digital tools in patient registries and engagement with medical research in Japan, prior to implementation of the digital platform. We conducted an exploratory, cross-sectional, self-completed questionnaire with a sample of myotonic dystrophy (MD) patients attending an Open Day at Osaka University, Japan. Patients were eligible for inclusion if they were 18 years or older, and were diagnosed with MD. A total of 68 patients and family members attended the Open Day and were invited to participate in the survey. Of those, 59 % submitted a completed questionnaire (n = 40). The survey showed that the majority of patients felt that they were not receiving the information they wanted from their clinicians, which included recent medical research findings and opportunities to participate in clinical trials, and 88 % of patients indicated they would be willing to engage with digital technologies to receive relevant medical information. Patients also expressed an interest in having control over when and how they received this information, as well as being informed of how their data is used and shared with other researchers. Overall, the findings from this study suggest that there is scope to develop a digital platform to engage with patients so that they can receive information about medical care and research opportunities. While this study group is a small, self-selecting population, who suffer from a particular condition, the results suggest that there are interested populations within Japan that would appreciate enhanced communication and interaction with healthcare teams.

[Pneumatosis cystoides intestinalis associated with Steinert disease].

PubMed

Boland, C; De Ronde, T; Lacrosse, M; Trigaux, J P; Delaunois, L; Melange, M

1995-03-01

We report the case of a 63-year-old patient suffering from myotonic dystrophy, complicated with respiratory insufficiency, who presented a pneumoperitoneum without sign of peritonitis. Diagnosis of pneumatosis cystoides coli was based on CT scan evidence. Given oxygenotherapy and antibiotherapy, the patient rapidly improved. The association between the two affections has, to our knowledge, not been previously described.

Somatic expansion behaviour of the (CTG)n repeat in myotonic dystrophy knock-in mice is differentially affected by Msh3 and Msh6 mismatch-repair proteins.

PubMed

van den Broek, Walther J A A; Nelen, Marcel R; Wansink, Derick G; Coerwinkel, Marga M; te Riele, Hein; Groenen, Patricia J T A; Wieringa, Bé

2002-01-15

The mechanism of expansion of the (CTG)n repeat in myotonic dystrophy (DM1) patients and the cause of its pathobiological effects are still largely unknown. Most likely, long repeats exert toxicity at the level of nuclear RNA transport or splicing. Here, we analyse cis- and trans-acting parameters that determine repeat behaviour in novel mouse models for DM1. Our mice carry 'humanized' myotonic dystrophy protein kinase (Dmpk) allele(s) with either a (CTG)84 or a (CTG)11 repeat, inserted at the correct position into the endogenous DM locus. Unlike in the human situation, the (CTG)84 repeat in the syntenic mouse environment was relatively stable during intergenerational segregation. However, somatic tissues showed substantial repeat expansions which were progressive upon aging and prominent in kidney, and in stomach and small intestine, where it was cell-type restricted. Other tissues examined showed only marginal size changes. The (CTG)11 allele was completely stable, as anticipated. Introducing the (CTG)84 allele into an Msh3-deficient background completely blocked the somatic repeat instability. In contrast, Msh6 deficiency resulted in a significant increase in the frequency of somatic expansions. Competition of Msh3 and Msh6 for binding to Msh2 in functional complexes with different DNA mismatch-recognition specificity may explain why the somatic (CTG)n expansion rate is differentially affected by ablation of Msh3 and Msh6.

PubMed Central

Palladino, Alberto; D'Ambrosio, Paola; Papa, Andrea Antonio; Petillo, Roberta; Orsini, Chiara; Scutifero, Marianna; Nigro, Gerardo

2016-01-01

Muscular dystrophies are a group of genetic disorders characterized by muscle degeneration and consequent substitution by fat and fibrous tissue. Cardiac involvement is an almost constant feature in a great part of these diseases, as both primary myocardial involvement and secondary involvement due to respiratory insufficiency, pulmonary hypertension or reduced mobility. Primary myocardial involvement usually begins more precociously compared to the secondary involvement. In fact the first signs of cardiomyopathy can be observed in the first decade of life in muscular dystrophies with childhood onset and later in adult form of muscular dystrophies as myotonic dystrophy type 1. At least an annual cardiac follow-up is recommended in these patients including clinical and instrumental examination (ECG, 24h Holter monitoring, ECHO), to detect cardiac involvement. A more frequent monitoring may be required according to the type of cardiomyopathy and the patient's needs. In this short review practical guide-lines are shown for physicians routinely involved in the management of these patients. PMID:28484313

Emerging strategies for cell and gene therapy of the muscular dystrophies

PubMed Central

Muir, Lindsey A.; Chamberlain, Jeffrey S.

2016-01-01

The muscular dystrophies are a heterogeneous group of over 40 disorders that are characterised by muscle weakness and wasting. The most common are Duchenne muscular dystrophy and Becker muscular dystrophy, which result from mutations within the gene encoding dystrophin; myotonic dystrophy type 1, which results from an expanded trinucleotide repeat in the myotonic dystrophy protein kinase gene; and facioscapulohumeral dystrophy, which is associated with contractions in the subtelomeric region of human chromosome 1. Currently the only treatments involve clinical management of symptoms, although several promising experimental strategies are emerging. These include gene therapy using adeno-associated viral, lentiviral and adenoviral vectors and nonviral vectors, such as plasmid DNA. Exon-skipping and cell-based therapies have also shown promise in the effective treatment and regeneration of dystrophic muscle. The availability of numerous animal models for Duchenne muscular dystrophy has enabled extensive testing of a wide range of therapeutic approaches for this type of disorder. Consequently, we focus here on the therapeutic developments for Duchenne muscular dystrophy as a model of the types of approaches being considered for various types of dystrophy. We discuss the advantages and limitations of each therapeutic strategy, as well as prospects and recent successes in the context of future clinical applications. PMID:19555515

Management of cardiac involvement in muscular dystrophies: paediatric versus adult forms.

PubMed

Palladino, Alberto; D'Ambrosio, Paola; Papa, Andrea Antonio; Petillo, Roberta; Orsini, Chiara; Scutifero, Marianna; Nigro, Gerardo; Politano, Luisa

2016-12-01

Muscular dystrophies are a group of genetic disorders characterized by muscle degeneration and consequent substitution by fat and fibrous tissue. Cardiac involvement is an almost constant feature in a great part of these diseases, as both primary myocardial involvement and secondary involvement due to respiratory insufficiency, pulmonary hypertension or reduced mobility. Primary myocardial involvement usually begins more precociously compared to the secondary involvement. In fact the first signs of cardiomyopathy can be observed in the first decade of life in muscular dystrophies with childhood onset and later in adult form of muscular dystrophies as myotonic dystrophy type 1. At least an annual cardiac follow-up is recommended in these patients including clinical and instrumental examination (ECG, 24h Holter monitoring, ECHO), to detect cardiac involvement. A more frequent monitoring may be required according to the type of cardiomyopathy and the patient's needs. In this short review practical guide-lines are shown for physicians routinely involved in the management of these patients.

DHEA

MedlinePlus

... an immune condition characterized by dry mouth and dry eyes (Sjögren's syndrome), weak bones (osteoporosis), a form of muscular dystrophy called myotonic dystrophy, fibromyalgia, multiple sclerosis (MS), low levels of ... no DHEA at all, while others contained more than the labeled amount.

Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules.

PubMed

Childs-Disney, Jessica L; Stepniak-Konieczna, Ewa; Tran, Tuan; Yildirim, Ilyas; Park, HaJeung; Chen, Catherine Z; Hoskins, Jason; Southall, Noel; Marugan, Juan J; Patnaik, Samarjit; Zheng, Wei; Austin, Chris P; Schatz, George C; Sobczak, Krzysztof; Thornton, Charles A; Disney, Matthew D

2013-01-01

The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)(exp)). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. A thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)(exp) and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)(exp). This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)(exp) and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of myotonic dystrophy type 1.

Modifications to toxic CUG RNAs induce structural stability, rescue mis-splicing in a myotonic dystrophy cell model and reduce toxicity in a myotonic dystrophy zebrafish model

DOE PAGES

deLorimier, Elaine; Coonrod, Leslie A.; Copperman, Jeremy; ...

2014-10-10

In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase ( DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecularmore » dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.« less

Fuchs' Endothelial Corneal Dystrophy in Patients With Myotonic Dystrophy, Type 1

PubMed Central

Winkler, Nelson S.; Milone, Margherita; Martinez-Thompson, Jennifer M.; Raja, Harish; Aleff, Ross A.; Patel, Sanjay V.; Fautsch, Michael P.; Wieben, Eric D.

2018-01-01

Purpose RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. Methods FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. Results FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (<40 repeats). Considering a 75% prevalence of TCF4 TNR expansion in FECD, the probability of four FECD probands lacking TNR expansion was 0.4%. Neither severity of DM1 nor DMPK TNR length predicted the presence of FECD in DM1 patients. Conclusions FECD was common in DM1 families, and the diseases cosegregated. TCF4 TNR expansion was lacking in DM1 families. These findings support a hypothesis that DMPK TNR expansion contributes to clinical FECD.

Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice.

PubMed

Jauvin, Dominic; Chrétien, Jessina; Pandey, Sanjay K; Martineau, Laurie; Revillod, Lucille; Bassez, Guillaume; Lachon, Aline; MacLeod, A Robert; Gourdon, Geneviève; Wheeler, Thurman M; Thornton, Charles A; Bennett, C Frank; Puymirat, Jack

2017-06-16

Myotonic dystrophy type 1 (DM1), a dominant hereditary muscular dystrophy, is caused by an abnormal expansion of a (CTG) n trinucleotide repeat in the 3' UTR of the human dystrophia myotonica protein kinase (DMPK) gene. As a consequence, mutant transcripts containing expanded CUG repeats are retained in nuclear foci and alter the function of splicing regulatory factors members of the MBNL and CELF families, resulting in alternative splicing misregulation of specific transcripts in affected DM1 tissues. In the present study, we treated DMSXL mice systemically with a 2'-4'-constrained, ethyl-modified (ISIS 486178) antisense oligonucleotide (ASO) targeted to the 3' UTR of the DMPK gene, which led to a 70% reduction in CUG exp RNA abundance and foci in different skeletal muscles and a 30% reduction in the heart. Furthermore, treatment with ISIS 486178 ASO improved body weight, muscle strength, and muscle histology, whereas no overt toxicity was detected. This is evidence that the reduction of CUG exp RNA improves muscle strength in DM1, suggesting that muscle weakness in DM1 patients may be improved following elimination of toxic RNAs. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Specific Genetic Disorders

MedlinePlus

... Gaucher Disease Hemochromatosis Hemophilia Holoprosencephaly Huntington's disease Klinefelter syndrome Marfan syndrome Myotonic Dystrophy Neurofibromatosis Noonan Syndrome Osteogenesis Imperfecta ...

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

PubMed

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F; Furling, Denis

2017-04-01

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. © 2017. Published by The Company of Biologists Ltd.

Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

PubMed Central

Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F.

2017-01-01

ABSTRACT Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. PMID:28188264

Detection of linkage disequilibrium between the myotonic dystrophy locus and a new polymorphic DNA marker.

PubMed Central

Harley, H G; Brook, J D; Floyd, J; Rundle, S A; Crow, S; Walsh, K V; Thibault, M C; Harper, P S; Shaw, D J

1991-01-01

We have examined the linkage of two new polymorphic DNA markers (D19S62 and D19S63) and a previously unreported polymorphism with an existing DNA marker (ERCC1) to the myotonic dystrophy (DM) locus. In addition, we have used pulsed-field gel electrophoresis to obtain a fine-structure map of this region. The detection of linkage disequilibrium between DM and one of these markers (D19S63) is the first demonstration of this phenomenon in a heterogeneous DM population. The results suggest that at least 58% of DM patients in the British population, as well as those in a French-Canadian subpopulation, are descended from the same ancestral DM mutation. We discuss the implications of this finding in terms of strategies for cloning the DM gene, for a possible role in modification of risk for prenatal and presymptomatic testing, and we speculate on the origin and number of existing mutations which may result in a DM phenotype. PMID:2063878

[30-year-old Patient with suspected Marfan Syndrome and Progressive Gait disturbance].

PubMed

Balke, Maryam; Lehmann, Helmar C; Fink, Gereon R; Wunderlich, Gilbert

2017-07-01

History  A 30-year-old man presented with a history of progressive muscle weakness, difficulty in concentrating, and a slender habitus since early childhood. Marfan syndrome was suspected since the age of 14. Examinations  13 years later he was examined by Marfan experts and by genetic testing and Marfan syndrome could not be confirmed. Further neurological examination revealed the suspected diagnosis of myotonic dystrophy type 1, which was confirmed by genetic testing. Treatment and course  Similar to Marfan syndrome, myotonic dystrophy is a multisystemic disorder with the risk of cardiac arrythmias. It is necessary to provide an interdisciplinary care by neurologists, internists, ophthalmologists, speech therapists, and physiotherapists. Conclusion  It is not enough to take the habitus as the principle sign to diagnose Marfan syndrome. Furthermore, it is essential to consider symptoms that are not typical for Marfan syndrome, such as cognitive deficiencies or progressive paresis. © Georg Thieme Verlag KG Stuttgart · New York.

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy.

PubMed

Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang-Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S; Le Rumeur, Elisabeth; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

2015-05-28

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1.

Abnormal splicing switch of DMD's penultimate exon compromises muscle fibre maintenance in myotonic dystrophy

PubMed Central

Rau, Frédérique; Lainé, Jeanne; Ramanoudjame, Laetitita; Ferry, Arnaud; Arandel, Ludovic; Delalande, Olivier; Jollet, Arnaud; Dingli, Florent; Lee, Kuang-Yung; Peccate, Cécile; Lorain, Stéphanie; Kabashi, Edor; Athanasopoulos, Takis; Koo, Taeyoung; Loew, Damarys; Swanson, Maurice S.; Le Rumeur, Elisabeth; Dickson, George; Allamand, Valérie; Marie, Joëlle; Furling, Denis

2015-01-01

Myotonic Dystrophy type 1 (DM1) is a dominant neuromuscular disease caused by nuclear-retained RNAs containing expanded CUG repeats. These toxic RNAs alter the activities of RNA splicing factors resulting in alternative splicing misregulation and muscular dysfunction. Here we show that the abnormal splicing of DMD exon 78 found in dystrophic muscles of DM1 patients is due to the functional loss of MBNL1 and leads to the re-expression of an embryonic dystrophin in place of the adult isoform. Forced expression of embryonic dystrophin in zebrafish using an exon-skipping approach severely impairs the mobility and muscle architecture. Moreover, reproducing Dmd exon 78 missplicing switch in mice induces muscle fibre remodelling and ultrastructural abnormalities including ringed fibres, sarcoplasmic masses or Z-band disorganization, which are characteristic features of dystrophic DM1 skeletal muscles. Thus, we propose that splicing misregulation of DMD exon 78 compromises muscle fibre maintenance and contributes to the progressive dystrophic process in DM1. PMID:26018658

The relative frequency of common neuromuscular diagnoses in a reference center.

PubMed

Cotta, Ana; Paim, Júlia Filardi; Carvalho, Elmano; da-Cunha-Júnior, Antonio Lopes; Navarro, Monica M; Valicek, Jaquelin; Menezes, Miriam Melo; Nunes, Simone Vilela; Xavier-Neto, Rafael; Baptista, Sidney; Lima, Luciano Romero; Takata, Reinaldo Issao; Vargas, Antonio Pedro

2017-11-01

The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests. To report the relative frequency of common neuromuscular diagnoses in a reference center. A 17-year chart review of patients with suspicion of myopathy. Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%). Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications.

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases

PubMed Central

Varela, Miguel A; Curtis, Helen J; Douglas, Andrew GL; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew JA

2016-01-01

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets. PMID:25990798

Transfer of genetic therapy across human populations: molecular targets for increasing patient coverage in repeat expansion diseases.

PubMed

Varela, Miguel A; Curtis, Helen J; Douglas, Andrew G L; Hammond, Suzan M; O'Loughlin, Aisling J; Sobrido, Maria J; Scholefield, Janine; Wood, Matthew J A

2016-02-01

Allele-specific gene therapy aims to silence expression of mutant alleles through targeting of disease-linked single-nucleotide polymorphisms (SNPs). However, SNP linkage to disease varies between populations, making such molecular therapies applicable only to a subset of patients. Moreover, not all SNPs have the molecular features necessary for potent gene silencing. Here we provide knowledge to allow the maximisation of patient coverage by building a comprehensive understanding of SNPs ranked according to their predicted suitability toward allele-specific silencing in 14 repeat expansion diseases: amyotrophic lateral sclerosis and frontotemporal dementia, dentatorubral-pallidoluysian atrophy, myotonic dystrophy 1, myotonic dystrophy 2, Huntington's disease and several spinocerebellar ataxias. Our systematic analysis of DNA sequence variation shows that most annotated SNPs are not suitable for potent allele-specific silencing across populations because of suboptimal sequence features and low variability (>97% in HD). We suggest maximising patient coverage by selecting SNPs with high heterozygosity across populations, and preferentially targeting SNPs that lead to purine:purine mismatches in wild-type alleles to obtain potent allele-specific silencing. We therefore provide fundamental knowledge on strategies for optimising patient coverage of therapeutics for microsatellite expansion disorders by linking analysis of population genetic variation to the selection of molecular targets.

Myotonic dystrophy type 1, daytime sleepiness and REM sleep dysregulation.

PubMed

Dauvilliers, Yves A; Laberge, Luc

2012-12-01

Myotonic dystrophy type 1 (DM1), or Steinert's disease, is the most common adult-onset form of muscular dystrophy. DM1 also constitutes the neuromuscular condition with the most significant sleep disorders including excessive daytime sleepiness (EDS), central and obstructive sleep apneas, restless legs syndrome (RLS), periodic leg movements in wake (PLMW) and periodic leg movements in sleep (PLMS) as well as nocturnal and diurnal rapid eye movement (REM) sleep dysregulation. EDS is the most frequent non-muscular complaint in DM1, being present in about 70-80% of patients. Different phenotypes of sleep-related problems may mimic several sleep disorders, including idiopathic hypersomnia, narcolepsy without cataplexy, sleep apnea syndrome, and periodic leg movement disorder. Subjective and objective daytime sleepiness may be associated with the degree of muscular impairment. However, available evidence suggests that DM1-related EDS is primarily caused by a central dysfunction of sleep regulation rather than by sleep fragmentation, sleep-related respiratory events or periodic leg movements. EDS also tends to persist despite successful treatment of sleep-disordered breathing in DM1 patients. As EDS clearly impacts on physical and social functioning of DM1 patients, studies are needed to identify the best appropriate tools to identify hypersomnia, and clarify the indications for polysomnography (PSG) and multiple sleep latency test (MSLT) in DM1. In addition, further structured trials of assisted nocturnal ventilation and randomized trials of central nervous system (CNS) stimulant drugs in large samples of DM1 patients are required to optimally treat patients affected by this progressive, incurable condition. Copyright © 2012 Elsevier Ltd. All rights reserved.

Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias

ClinicalTrials.gov

2017-08-10

Inherited Cardiac Arrythmias; Long QT Syndrome (LQTS); Brugada Syndrome (BrS); Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT); Early Repolarization Syndrome (ERS); Arrhythmogenic Cardiomyopathy (AC, ARVD/C); Hypertrophic Cardiomyopathy (HCM); Dilated Cardiomyopathy (DCM); Muscular Dystrophies (Duchenne, Becker, Myotonic Dystrophy); Normal Control Subjects

Prenatal molecular diagnosis of inherited neuromuscular diseases: Duchenne/Becker muscular dystrophy, myotonic dystrophy type 1 and spinal muscular atrophy.

PubMed

Esposito, Gabriella; Ruggiero, Raffaella; Savarese, Maria; Savarese, Giovanni; Tremolaterra, Maria Roberta; Salvatore, Francesco; Carsana, Antonella

2013-12-01

Neuromuscular disease is a broad term that encompasses many diseases that either directly, via an intrinsic muscle disorder, or indirectly, via a nerve disorder, impairs muscle function. Here we report the experience of our group in the counselling and molecular prenatal diagnosis of three inherited neuromuscular diseases, i.e., Duchenne/Becker muscular dystrophy (DMD/BMD), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA). We performed a total of 83 DMD/BMD, 15 DM1 and 54 SMA prenatal diagnoses using a combination of technologies for either direct or linkage diagnosis. We identified 16, 5 and 10 affected foetuses, respectively. The improvement of analytical procedures in recent years has increased the mutation detection rate and reduced the analytical time. Due to the complexity of the experimental procedures and the high, specific professional expertise required for both laboratory activities and the related counselling, these types of analyses should be preferentially performed in reference molecular diagnostic centres.

Brain MRI abnormalities in the adult form of myotonic dystrophy type 1: A longitudinal case series study.

PubMed

Conforti, Renata; de Cristofaro, Mario; Cristofano, Adriana; Brogna, Barbara; Sardaro, Angela; Tedeschi, Gioacchino; Cirillo, Sossio; Di Costanzo, Alfonso

2016-02-01

This study aimed to verify whether brain abnormalities, previously described in patients with myotonic dystrophy type 1 (DM1) by magnetic resonance imaging (MRI), progressed over time and, if so, to characterize their progression. Thirteen DM1 patients, who had at least two MRI examinations, were retrospectively evaluated and included in the study. The mean duration (± standard deviation) of follow-up was 13.4 (±3.8) years, over a range of 7-20 years. White matter lesions (WMLs) were rated by semi-quantitative method, the signal intensity of white matter poster-superior to trigones (WMPST) by reference to standard images and brain atrophy by ventricular/brain ratio (VBR). At the end of MRI follow-up, the scores relative to lobar, temporal and periventricular WMLs, to WMPST signal intensity and to VBR were significantly increased compared to baseline, and MRI changes were more evident in some families than in others. No correlation was found between the MRI changes and age, onset, disease duration, muscular involvement, CTG repetition and follow-up duration. These results demonstrated that white matter involvement and brain atrophy were progressive in DM1 and suggested that progression rate varied from patient to patient, regardless of age, disease duration and genetic defect. © The Author(s) 2016.

NMR Spectroscopy and Molecular Dynamics Simulation of r(CCGCUGCGG)2 Reveal a Dynamic UU Internal Loop Found in Myotonic Dystrophy Type 1†

PubMed Central

Parkesh, Raman; Fountain, Matthew; Disney, Matthew D.

2011-01-01

The NMR structure of an RNA with a copy of the 5′CUG/3′GUC motif found in the triplet repeating disorder myotonic dystrophy type 1 (DM1) is disclosed. The lowest energy conformation of the UU pair is a single hydrogen bonded structure; however, the UU protons undergo exchange indicating structural dynamics. Molecular dynamics simulations show that the single hydrogen bonded structure is the most populated one but the UU pair interconverts between 0, 1, and 2 hydrogen bonded pairs. These studies have implications for the recognition of the DM1 RNA by small molecules and proteins. PMID:21204525

Brain gray matter structural network in myotonic dystrophy type 1.

PubMed

Sugiyama, Atsuhiko; Sone, Daichi; Sato, Noriko; Kimura, Yukio; Ota, Miho; Maikusa, Norihide; Maekawa, Tomoko; Enokizono, Mikako; Mori-Yoshimura, Madoka; Ohya, Yasushi; Kuwabara, Satoshi; Matsuda, Hiroshi

2017-01-01

This study aimed to investigate abnormalities in structural covariance network constructed from gray matter volume in myotonic dystrophy type 1 (DM1) patients by using graph theoretical analysis for further clarification of the underlying mechanisms of central nervous system involvement. Twenty-eight DM1 patients (4 childhood onset, 10 juvenile onset, 14 adult onset), excluding three cases from 31 consecutive patients who underwent magnetic resonance imaging in a certain period, and 28 age- and sex- matched healthy control subjects were included in this study. The normalized gray matter images of both groups were subjected to voxel based morphometry (VBM) and Graph Analysis Toolbox for graph theoretical analysis. VBM revealed extensive gray matter atrophy in DM1 patients, including cortical and subcortical structures. On graph theoretical analysis, there were no significant differences between DM1 and control groups in terms of the global measures of connectivity. Betweenness centrality was increased in several regions including the left fusiform gyrus, whereas it was decreased in the right striatum. The absence of significant differences between the groups in global network measurements on graph theoretical analysis is consistent with the fact that the general cognitive function is preserved in DM1 patients. In DM1 patients, increased connectivity in the left fusiform gyrus and decreased connectivity in the right striatum might be associated with impairment in face perception and theory of mind, and schizotypal-paranoid personality traits, respectively.

Responsiveness of performance-based outcome measures for mobility, balance, muscle strength and manual dexterity in adults with myotonic dystrophy type 1.

PubMed

Kierkegaard, Marie; Petitclerc, Émilie; Hébert, Luc J; Mathieu, Jean; Gagnon, Cynthia

2018-02-28

To assess changes and responsiveness in outcome measures of mobility, balance, muscle strength and manual dexterity in adults with myotonic dystrophy type 1. A 9-year longitudinal study conducted with 113 patients. The responsiveness of the Timed Up and Go test, Berg Balance Scale, quantitative muscle testing, grip and pinch-grip strength, and Purdue Pegboard Test was assessed using criterion and construct approaches. Patient-reported perceived changes (worse/stable) in balance, walking, lower-limb weakness, stair-climbing and hand weakness were used as criteria. Predefined hypotheses about expected area under the receiver operating characteristic curves (criterion approach) and correlations between relative changes (construct approach) were explored. The direction and magnitude of median changes in outcome measures corresponded with patient-reported changes. Median changes in the Timed Up and Go test, grip strength, pinch-grip strength and Purdue Pegboard Test did not, in general, exceed known measurement errors. Most criterion (72%) and construct (70%) approach hypotheses were supported. Promising responsiveness was found for outcome measures of mobility, balance and muscle strength. Grip strength and manual dexterity measures showed poorer responsiveness. The performance-based outcome measures captured changes over the 9-year period and responsiveness was promising. Knowledge of measurement errors is needed to interpret the meaning of these longitudinal changes.

Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1.

PubMed

Esposito, Fabio; Cè, Emiliano; Rampichini, Susanna; Limonta, Eloisa; Venturelli, Massimo; Monti, Elena; Bet, Luciano; Fossati, Barbara; Meola, Giovanni

2016-01-01

The electromechanical delay during muscle contraction and relaxation can be partitioned into mainly electrochemical and mainly mechanical components by an EMG, mechanomyographic, and force combined approach. Component duration and measurement reliability were investigated during contraction and relaxation in a group of patients with myotonic dystrophy type 1 (DM1, n = 13) and in healthy controls (n = 13). EMG, mechanomyogram, and force were recorded in DM1 and in age- and body-matched controls from tibialis anterior (distal muscle) and vastus lateralis (proximal muscle) muscles during maximum voluntary and electrically-evoked isometric contractions. The electrochemical and mechanical components of the electromechanical delay during muscle contraction and relaxation were calculated off-line. Maximum strength was significantly lower in DM1 than in controls under both experimental conditions. All electrochemical and mechanical components were significantly longer in DM1 in both muscles. Measurement reliability was very high in both DM1 and controls. The high reliability of the measurements and the differences between DM1 patients and controls suggest that the EMG, mechanomyographic, and force combined approach could be utilized as a valid tool to assess the level of neuromuscular dysfunction in this pathology, and to follow the efficacy of pharmacological or non-pharmacological interventions. Copyright © 2015 Elsevier B.V. All rights reserved.

Neuromuscular diseases: Diagnosis and management.

PubMed

Mary, P; Servais, L; Vialle, R

2018-02-01

Neuromuscular diseases (NMDs) affect the peripheral nervous system, which includes the motor neurons and sensory neurons; the muscle itself; or the neuromuscular junction. Thus, the term NMDs encompasses a vast array of different syndromes. Some of these syndromes are of direct relevance to paediatric orthopaedic surgeons, either because the presenting manifestation is a functional sign (e.g., toe-walking) or deformity (e.g., pes cavus or scoliosis) suggesting a need for orthopaedic attention or because orthopaedic abnormalities requiring treatment develop during the course of a known NMD. The main NMDs relevant to the orthopaedic surgeon are infantile spinal muscular atrophy (a motor neuron disease), peripheral neuropathies (chiefly, Charcot-Marie-Tooth disease), congenital muscular dystrophies, progressive muscular dystrophies, and Steinert myotonic dystrophy (or myotonic dystrophy type 1). Muscle weakness is a symptom shared by all these conditions. The paediatric orthopaedic surgeon must be familiar, not only with the musculoskeletal system, but also with many other domains (particularly respiratory and cardiac function and nutrition) that may interfere with the treatment and require preoperative management. Good knowledge of the natural history of each NMD is essential to ensure optimal timing of the therapeutic interventions, which must be performed under the best possible conditions in these usually frail patients. Timing is particularly crucial for the treatment of spinal deformities due to paraspinal muscle hypotonia during growth: depending on the disease and natural history, the treatment may involve non-operative methods or growing rods, followed by spinal fusion. A multidisciplinary approach is always required. Finally, the survival gains achieved in recent years increasingly require attention to preparing for adult life, to orthopaedic problems requiring treatment before the patient leaves the paediatric environment, and to the transition towards the adult healthcare system. Copyright © 2017. Published by Elsevier Masson SAS.

Influence of the sex of the transmitting grandparent in congenital myotonic dystrophy.

PubMed

López de Munain, A; Cobo, A M; Poza, J J; Navarrete, D; Martorell, L; Palau, F; Emparanza, J I; Baiget, M

1995-09-01

To analyse the influence of the sex of the transmitting grandparents on the occurrence of the congenital form of myotonic dystrophy (CDM), we have studied complete three generation pedigrees of 49 CDM cases, analysing: (1) the sex distribution in the grandparents' generation, and (2) the intergenerational amplification of the CTG repeat, measured in its absolute and relative values, between grandparents and the mothers of CDM patients and between the latter and their CDM children. The mean relative intergenerational increase in the 32 grandparent-mother pairs was significantly greater than in the 56 mother-CDM pairs (Mann-Whitney U test, p < 0.001). The mean expansion of the grandfathers (103 CTG repeats) was also significantly different from that seen in the grandmothers' group (154 CTG repeats) (Mann-Whitney U test, p < 0.01). This excess of non-manifesting males between the CDM grandparents' generation with a smaller CTG length than the grandmothers could suggest that the premutation has to be transmitted by a male to reach the degree of instability responsible for subsequent intergenerational CTG expansions without size constraints characteristic of the CDM range.

Simple Repeat-Primed PCR Analysis of the Myotonic Dystrophy Type 1 Gene in a Clinical Diagnostics Environment

PubMed Central

Dryland, Philippa A.; Doherty, Elaine; Love, Jennifer M.; Love, Donald R.

2013-01-01

Myotonic dystrophy type 1 is an autosomal dominant neuromuscular disorder that is caused by the expansion of a CTG trinucleotide repeat in the DMPK gene. The confirmation of a clinical diagnosis of DM-1 usually involves PCR amplification of the CTG repeat-containing region and subsequent sizing of the amplification products in order to deduce the number of CTG repeats. In the case of repeat hyperexpansions, Southern blotting is also used; however, the latter has largely been superseded by triplet repeat-primed PCR (TP-PCR), which does not yield a CTG repeat number but nevertheless provides a means of stratifying patients regarding their disease severity. We report here a combination of forward and reverse TP-PCR primers that allows for the simple and effective scoring of both the size of smaller alleles and the presence or absence of expanded repeat sequences. In addition, the CTG repeat-containing TP-PCR forward primer can target both the DM-1 and Huntington disease genes, thereby streamlining the work flow for confirmation of clinical diagnoses in a diagnostic laboratory. PMID:26317000

Neuromuscular Highlights-AAN 2005.

PubMed

Cheema, Zahid; Saperstein, David; Jackson, Carolyn; Newman, Daniel

2006-06-01

Summary of Neuromuscular Presentations at the 57 Annual AAN 2005 meeting in Miami Florida on topics of Facioscapulohumeral muscular dystrophy (FSHD), Duchenne muscular dystrophy (DMD), Diabetic Neuropathy, Charco Marie Tooth disease (CMT), Comparison of injected steroids versus Surgery for carpal tunnel syndrome, Rituximab in Anti-MAG associated polyneuropathy, Cannabis based medicine (CBM) in the treatment of neuropathic pain, utility of skin biopsy with intraepidermal nerve fiber density (IENFD) in sensory complaints, comparing sympathetic skin responses (SSRs) and skin biopsy in diagnosing small fiber sensory neuropathy, Chronic inflammatory demyelinating polyneuropathy (CIDP) clinical and electrophysiologic predictors, affect of limb warming in mild ulnar nerve conduction study (NCS) abnormalities, Tamoxifen affect in ALS, open label study of 3,4 DAP, Pyridostigmine and Ephedrine in fast channel syndrome, Mexilitine as an antimyotonia treatment in myotonic dystrophy (DM1), frontal lobe impairment evaluation in DM1 and DM2 patients and phenotype-genotype correlation in patients with dysferlinopathy.

Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations

PubMed Central

Cruz Guzmán, Oriana del Rocío; Chávez García, Ana Laura; Rodríguez-Cruz, Maricela

2012-01-01

Common metabolic and endocrine alterations exist across a wide range of muscular dystrophies. Skeletal muscle plays an important role in glucose metabolism and is a major participant in different signaling pathways. Therefore, its damage may lead to different metabolic disruptions. Two of the most important metabolic alterations in muscular dystrophies may be insulin resistance and obesity. However, only insulin resistance has been demonstrated in myotonic dystrophy. In addition, endocrine disturbances such as hypogonadism, low levels of testosterone, and growth hormone have been reported. This eventually will result in consequences such as growth failure and delayed puberty in the case of childhood dystrophies. Other consequences may be reduced male fertility, reduced spermatogenesis, and oligospermia, both in childhood as well as in adult muscular dystrophies. These facts all suggest that there is a need for better comprehension of metabolic and endocrine implications for muscular dystrophies with the purpose of developing improved clinical treatments and/or improvements in the quality of life of patients with dystrophy. Therefore, the aim of this paper is to describe the current knowledge about of metabolic and endocrine alterations in diverse types of dystrophinopathies, which will be divided into two groups: childhood and adult dystrophies which have different age of onset. PMID:22701119

[Vecuronium in dystrophia myotonica (Curschmann-Steinert)].

PubMed

Wruck, G; Tryba, M

1989-05-01

An emergency laparotomy was performed in a 31-year-old female (body wt 48 kg) with known myotonic dystrophy. Premedication with dantrolene (1 mg/kg i.v.) was used to prevent a myotonic response. Muscle relaxation was monitored electromyographically. Following induction with fentanyl (0.3 mg) and thiopental (200 mg), muscle relaxation was achieved with 2 mg vecuronium titrated for about 3 min until the T1-response was reduced to 10%. The recovery time was normal. A repetitive dose of 0.5 mg vecuronium was necessary after 20 min, when the T1 reached 60%. Extubation and the early postoperative period were uneventful. Because of the unknown predisposition of our patient for the development of malignant hyperthermia, anesthesia was performed with trigger-free anesthetics.

Participation restriction in childhood phenotype of myotonic dystrophy type 1: a systematic retrospective chart review.

PubMed

Gagnon, Cynthia; Kierkegaard, Marie; Blackburn, Catherine; Chrestian, Nicolas; Lavoie, Mélissa; Bouchard, Marie-Frédéric; Mathieu, Jean

2017-03-01

Myotonic dystrophy type 1 (DM1), a neuromuscular disorder, is divided into four clinical phenotypes: congenital; childhood; adult-onset, and late-onset. Publications about the childhood phenotype, especially the long-term outcome, are scarce. The aims of this study were to assess and describe participation outcomes in adults with the childhood phenotype. A retrospective chart methodology. Data were extracted from health records for 63 adults with childhood DM1 (32 males, 31 females; mean age 34y, standard deviation [SD] 11y 6mo; range 18-54y) who had attended the Saguenay Neuromuscular Clinic, Canada. Thirty-four adults (54%) lived with their parents or in foster homes, and most patients needed services or help to live independently. A significant proportion (22%) were isolated in regard to friendship. Very few adults had children, although 33% lived with a spouse. The majority of patients (86%) relied on social security and only one person was currently working. Financial responsibilities were often an issue and 13 (21%) were under legal guardianship. This study showed that patients with the childhood phenotype present a guarded prognosis regarding long-term social participation. These participation restrictions could be related to behavioural, cognitive, and social stigma problems in childhood. This study illustrates the absolute necessity to pursue an interdisciplinary follow-up of these patients when they are reaching adulthood. © 2016 Mac Keith Press.

Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1.

PubMed

Serra, Laura; Silvestri, Gabriella; Petrucci, Antonio; Basile, Barbara; Masciullo, Marcella; Makovac, Elena; Torso, Mario; Spanò, Barbara; Mastropasqua, Chiara; Harrison, Neil A; Bianchi, Maria L E; Giacanelli, Manlio; Caltagirone, Carlo; Cercignani, Mara; Bozzali, Marco

2014-05-01

Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. Resting-state functional magnetic resonance imaging. Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.

Characterization of sarcoplasmic reticulum Ca(2+) ATPase pumps in muscle of patients with myotonic dystrophy and with hypothyroid myopathy.

PubMed

Guglielmi, V; Oosterhof, A; Voermans, N C; Cardani, R; Molenaar, J P; van Kuppevelt, T H; Meola, G; van Engelen, B G; Tomelleri, G; Vattemi, G

2016-06-01

Sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) pumps play the major role in lowering cytoplasmic calcium concentration in skeletal muscle by catalyzing the ATP-dependent transport of Ca(2+) from the cytosol to the lumen of the sarcoplasmic reticulum (SR). Although SERCA abnormalities have been hypothesized to contribute to the dysregulation of intracellular Ca(2+) homeostasis and signaling in muscle of patients with myotonic dystrophy (DM) and hypothyroid myopathy, the characterization of SERCA pumps remains elusive and their impairment is still unclear. We assessed the activity of SR Ca(2+)-ATPase, expression levels and fiber distribution of SERCA1 and SERCA2, and oligomerization of SERCA1 protein in muscle of patients with DM type 1 and 2, and with hypothyroid myopathy. Our data provide evidence that SR Ca(2+) ATPase activity, protein levels and muscle fiber distribution of total SERCA1 and SERCA2, and SERCA1 oligomerization pattern are similar in patients with both DM1 and DM2, hypothyroid myopathy and in control subjects. We prove that SERCA1b, the neonatal isoform of SERCA1, is expressed at protein level in muscle of patients with DM2 and, in lower amount, of patients with DM1. Our present study demonstrates that SERCA function is not altered in muscle of patients with DM and with hypothyroid myopathy. Copyright © 2016 Elsevier B.V. All rights reserved.

Analysis of meiotic segregation, using single-sperm typing: Meiotic drive at the myotonic dystrophy locus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leeflang, E.P.; Arnheim, N.; McPeek, M.S.

Meiotic drive at the myotonic dystrophy (DM) locus has recently been suggested as being responsible for maintaining the frequency, in the human population, of DM chromosomes capable of expansion to the disease state. In order to test this hypothesis, we have studied samples of single sperm from three individuals heterozygous at the DM locus, each with one allele larger and one allele smaller than 19 CTG repeats. To guard against the possible problem of differential PCR amplification rates based on the lengths of the alleles, the sperm were also typed at another closely linked marker whose allele size was unrelatedmore » to the allele size at the DM locus. Using statistical models specifically designed to study single-sperm segregation data, we find no evidence of meiotic segregation distortion. The upper limit of the two-sided 95% confidence interval for the estimate of the common segregation probability for the three donors is at or below .515 for all models considered, and no statistically significant difference from .5 is detected in any of the models. This suggests that any greater amount of segregation distortion at the myotonic dystrophy locus must result from events following sperm ejaculation. The mathematical models developed make it possible to study segregation distortion with high resolution by using sperm-typing data from any locus. 26 refs., 1 fig., 8 tabs.« less

Myotonic Dystrophy and Huntington's Disease Care: "We Like to Think We're Making a Difference".

PubMed

LaDonna, Kori A; Watling, Christopher J; Ray, Susan L; Piechowicz, Christine; Venance, Shannon L

2016-09-01

Patient-centered care for individuals with myotonic dystrophy (DM1) and Huntington's disease (HD)-chronic, progressive, and life-limiting neurological conditions-may be challenged by patients' cognitive and behavioral impairments. However, no research has explored health care providers' (HCPs') perspectives about patient-centered care provision for these patients along their disease trajectory. Constructivist grounded theory informed the iterative data collection and analysis process. Eleven DM1 or HD HCPs participated in semistructured interviews, and three stages of coding were used to analyze their interview transcripts. Codes were collapsed into themes and categories. Three categories including an evolving care approach, fluid roles, and making a difference were identified. Participants described that their clinical care approach evolved depending on the patient's disease stage and caregivers' degree of involvement. HCPs described that their main goal was to provide hope to patients and caregivers through medical management, crisis prevention, support, and advocacy. Despite the lack of curative treatments, HCPs perceived that patients benefited from ongoing clinical care provided by proactive clinicians. Providing care for individuals with DM1 and HD is a balancing act. HCPs must strike a balance between (1) the frustrations and rewards of patient-centered care provision, (2) addressing symptoms and preventing and managing crises while focusing on patients' and caregivers' quality of life concerns, and (3) advocating for patients while addressing caregivers' needs. This raises important questions: Is patient-centered care possible for patients with cognitive decline? Does chronic neurological care need to evolve to better address patients' and caregivers' complex needs?

Global muscular dystrophy research: A 25-year bibliometric perspective.

PubMed

Ram, Shri

2017-01-01

Muscular dystrophy is a genetic disorder leading to progressive weakness of muscles caused due to dysfunction in or lack of protein in muscle cells. The prevalence of muscular dystrophy has been observed globally and is becoming a critical area of study for better health services. The purpose of the study is to analyze the research strength of muscular dystrophy using bibliographic literature. A quantitative literature analysis was carried out on muscular dystrophy from 1991 to 2015 for assessing the global research trends. This literature-based study was conducted using the documents retrieved from the Science Citation Index using the keywords: Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Congenital Muscular Dystrophy (CMD), Myotonic Dystrophy, Emery-Dreifuss Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, and Limb-Girdle Muscular Dystrophy. Analysis was done for annual productivity of publication, authorship, collaboration, country performance, citation frequency, characteristics of most cited document, journal productivity, etc.

Non-dystrophic myotonia: prospective study of objective and patient reported outcomes.

PubMed

Trivedi, Jaya R; Bundy, Brian; Statland, Jeffrey; Salajegheh, Mohammad; Rayan, Dipa Raja; Venance, Shannon L; Wang, Yunxia; Fialho, Doreen; Matthews, Emma; Cleland, James; Gorham, Nina; Herbelin, Laura; Cannon, Stephen; Amato, Anthony; Griggs, Robert C; Hanna, Michael G; Barohn, Richard J

2013-07-01

Non-dystrophic myotonias are rare diseases caused by mutations in skeletal muscle chloride and sodium ion channels with considerable phenotypic overlap between diseases. Few prospective studies have evaluated the sensitivity of symptoms and signs of myotonia in a large cohort of patients. We performed a prospective observational study of 95 participants with definite or clinically suspected non-dystrophic myotonia recruited from six sites in the USA, UK and Canada between March 2006 and March 2009. We used the common infrastructure and data elements provided by the NIH-funded Rare Disease Clinical Research Network. Outcomes included a standardized symptom interview and physical exam; the Short Form-36 and the Individualized Neuromuscular Quality of Life instruments; electrophysiological short and prolonged exercise tests; manual muscle testing; and a modified get-up-and-go test. Thirty-two participants had chloride channel mutations, 34 had sodium channel mutations, nine had myotonic dystrophy type 2, one had myotonic dystrophy type 1, and 17 had no identified mutation. Phenotype comparisons were restricted to those with sodium channel mutations, chloride channel mutations, and myotonic dystrophy type 2. Muscle stiffness was the most prominent symptom overall, seen in 66.7% to 100% of participants. In comparison with chloride channel mutations, participants with sodium mutations had an earlier age of onset of stiffness (5 years versus 10 years), frequent eye closure myotonia (73.5% versus 25%), more impairment on the Individualized Neuromuscular Quality of Life summary score (20.0 versus 9.44), and paradoxical eye closure myotonia (50% versus 0%). Handgrip myotonia was seen in three-quarters of participants, with warm up of myotonia in 75% chloride channel mutations, but also 35.3% of sodium channel mutations. The short exercise test showed ≥10% decrement in the compound muscle action potential amplitude in 59.3% of chloride channel participants compared with 27.6% of sodium channel participants, which increased post-cooling to 57.6% in sodium channel mutations. In evaluation of patients with clinical and electrical myotonia, despite considerable phenotypic overlap, the presence of eye closure myotonia, paradoxical myotonia, and an increase in short exercise test sensitivity post-cooling suggest sodium channel mutations. Outcomes designed to measure stiffness or the electrophysiological correlates of stiffness may prove useful for future clinical trials, regardless of underlying mutation, and include patient-reported stiffness, bedside manoeuvres to evaluate myotonia, muscle specific quality of life instruments and short exercise testing.

Myotonic Muscular Dystrophy

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Genetics Home Reference: myotonic dystrophy

MedlinePlus

... mutated gene produces an expanded version of messenger RNA , which is a molecular blueprint of the gene ... the production of proteins. The abnormally long messenger RNA forms clumps inside the cell that interfere with ...

[Development, problems and results of specialty-specific genetic counseling at the Neurology Clinic of the Karl Marx University].

PubMed

Bachmann, H

1987-11-01

Genetic counselling for inherited neurological diseases has been established at the Clinic for Neurology of Karl Marx University. Comprehensive experiences have been got with the specific and sometimes markedly different problems and aims of counselling in Wilsons disease, X-linked recessive muscular dystrophies, myotonic dystrophy and other neuromuscular disorders, Huntingtons chorea and hereditary ataxias.

Genome Editing of Monogenic Neuromuscular Diseases: A Systematic Review.

PubMed

Long, Chengzu; Amoasii, Leonela; Bassel-Duby, Rhonda; Olson, Eric N

2016-11-01

Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing. PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9-mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed. Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing-meditated correction of monogenic neuromuscular diseases in cultured cells and animal models. Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies.

Knowledge, views, and experience of 25 women with myotonic dystrophy.

PubMed

Faulkner, C L; Kingston, H M

1998-12-01

Twenty-five affected women of reproductive age known to the North West Regional Genetics Family Register (NWRGFR) were interviewed. A semistructured questionnaire, completed by the interviewer, was used to assess understanding and experience of the clinical and genetic aspects of myotonic dystrophy (MD) and attitudes to prenatal diagnosis (PND). Characteristic features of MD (muscle weakness and wasting and myotonia) were well known. Knowledge of other features and complications reflected experience. All subjects were aware that MD is inherited, but only 56% (14/25) knew the risk to their own children and subjects tended to overestimate this risk. Anticipation and maternal transmission of congenital myotonic dystrophy (CMD) were often misunderstood. Almost half of the subjects (12/25) perceived themselves to be moderately or severely affected and 40% (10/25) felt that their symptoms restricted daily life. Feelings of devastation, depression, worry about the future, and guilt at the risk of transmission to their children were described. Many subjects (10/25) said that the worst aspect of MD is the risk of transmission to their children. Over half (14/25) said that the risk of transmitting MD had influenced or would influence their own reproduction. Three-quarters of subjects who felt that MD had influenced their reproductive decisions (9/12) chose to limit their family or have no children; only 25% (3/12) requested PND. Subjects felt that the lack of information concerning clinical severity made PND for MD difficult to consider.

Quality of life in patients with myotonic dystrophy type 2.

PubMed

Rakocevic Stojanovic, Vidosava; Peric, Stojan; Paunic, Teodora; Pesovic, Jovan; Vujnic, Milorad; Peric, Marina; Nikolic, Ana; Lavrnic, Dragana; Savic Pavicevic, Dusanka

2016-06-15

To analyze quality of life (QoL) in a large cohort of myotonic dystrophy type 2 (DM2) patients in comparison to DM1 control group using both generic and disease specific questionnaires. In addition, we intended to identify different factors that might affect QoL of DM2 subjects. 49 DM2 patients were compared with 42 adult-onset DM1 patients. Patients completed SF-36 questionnaire and individualized neuromuscular quality of life questionnaire (INQoL). Following measures were also included: Medical Research Council 0-5 point scale for muscle strength, Addenbrooke's cognitive examination revised for cognitive status, Hamilton rating scale for depression, Krupp's fatigue severity scale and daytime sleepiness scale (DSS) RESULTS: SF-36 total score and physical composite score did not differ between DM1 and DM2 patients (p>0.05). However, role emotional and mental composite score were better in DM2 (p<0.05). INQoL total score was similar in both groups (p>0.05), although DM2 patients showed less impairment in independence (p<0.05) and body image domains (p<0.01). Regarding symptoms assessed by INQoL, DM2 patients showed less severe complaint of myotonia (p<0.01). Multiple linear regression analysis showed that significant predictors of worse QoL in DM2 patients were older age, worse muscle strength and higher level of fatigue. QoL reports of DM2 patients with the most severe form of the disease are comparable to those of DM1 patients. Special attention of clinicians should be paid to DM2 patients with older age, more severe muscle weakness and higher level of fatigue since they may be at higher risk to have worse QoL. Copyright © 2016 Elsevier B.V. All rights reserved.

Gait pattern in myotonic dystrophy (Steinert disease): a kinematic, kinetic and EMG evaluation using 3D gait analysis.

PubMed

Galli, Manuela; Cimolin, Veronica; Crugnola, Veronica; Priano, Lorenzo; Menegoni, Francesco; Trotti, Claudio; Milano, Eva; Mauro, Alessandro

2012-03-15

We investigated the gait pattern of 10 patients with myotonic dystrophy (Steinert disease; 4 females, 6 males; age: 41.5+7.6 years), compared to 20 healthy controls, through manual muscle test and gait analysis, in terms of kinematic, kinetic and EMG data. In most of patients (80%) distal muscle groups were weaker than proximal ones. Weakness at lower limbs was in general moderate to severe and MRC values evidenced a significant correlation between tibialis anterior and gastrocnemius medialis (R=0.91). An overall observation of gait pattern in patients when compared to controls showed that most spatio-temporal parameters (velocity, step length and cadence) were significantly different. As concerns kinematics, patients' pelvic tilt was globally in a higher position than control group, with reduced hip extension ability in stance phase and limited range of motion; 60% of the limbs revealed knee hyperextension during midstance and ankle joints showed a quite physiological position at initial contact and higher dorsiflexion during stance phase if compared to healthy individuals. Kinetic plots evidenced higher hip power during loading response and lower ankle power generation in terminal stance. The main EMG abnormalities were seen in tibialis anterior and gastrocnemius medialis muscles. In this study gait analysis gives objective and quantitative information about the gait pattern and the deviations due to the muscular situation of these patients; these results are important from a clinical point of view and suggest that rehabilitation programs for them should take these findings into account. Copyright © 2011 Elsevier B.V. All rights reserved.

[Genetic Variability and Structure of SNP Haplotypes in the DMPK Gene in Yakuts and Other Ethnic Groups of Northern Eurasia in Relation to Myotonic Dystrophy].

PubMed

Swarovskaya, M G; Stepanova, S K; Marussin, A V; Sukhomyasova, A L; Maximova, N R; Stepanov, V A

2015-06-01

The genetic variability of the DMPK locus has been studied in relation to six SNP markers (rs2070736, rs572634, rs1799894, rs527221, rs915915, and rs10415988) in Yakuts with myotonic dystrophy (MD) in the Yakut population and in populations of northern Eurasia. Significant differences were observed in the allele frequencies between patients and a population sample of Yakuts for three SNP loci (rs915915, rs1799894, and rs10415988) associated with a high chance of disease manifestation. The odds ratios (OR) of MD development in representatives of the Yakut population for these three loci were 2.59 (95% CI, p = 0,004), 4.99 (95% CI, p = 0.000), and 3.15 (95% CI, p = 0.01), respectively. Haplotype TTTCTC, which is associated with MD, and haplotype GTCCTT, which was observed only in Yakut MD patients (never in MD patients of non-Yakut origin), were revealed. A low level of variability in the locus of DMRK gene in Yakuts (H(e) = 0.283) compared with other examined populations was noted. An analysis of pairwise genetic relationships between populations revealed their significant differentiation for all the examined loci. In addition, a low level of differentiation in territorial groups of Yakut populations (F(ST) = 0.79%), which was related to the high subdivision of the northern Eurasian population (F(ST) = 11.83%), was observed.

Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2.

PubMed

Perfetti, Alessandra; Greco, Simona; Fasanaro, Pasquale; Bugiardini, Enrico; Cardani, Rosanna; Garcia-Manteiga, Jose M; Manteiga, Jose M Garcia; Riba, Michela; Cittaro, Davide; Stupka, Elia; Meola, Giovanni; Martelli, Fabio

2014-01-01

Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis.

Genome Wide Identification of Aberrant Alternative Splicing Events in Myotonic Dystrophy Type 2

PubMed Central

Fasanaro, Pasquale; Bugiardini, Enrico; Cardani, Rosanna; Manteiga, Jose M. Garcia.; Riba, Michela; Cittaro, Davide; Stupka, Elia; Meola, Giovanni; Martelli, Fabio

2014-01-01

Myotonic dystrophy type 2 (DM2) is a genetic, autosomal dominant disease due to expansion of tetraplet (CCTG) repetitions in the first intron of the ZNF9/CNBP gene. DM2 is a multisystemic disorder affecting the skeletal muscle, the heart, the eye and the endocrine system. According to the proposed pathological mechanism, the expanded tetraplets have an RNA toxic effect, disrupting the splicing of many mRNAs. Thus, the identification of aberrantly spliced transcripts is instrumental for our understanding of the molecular mechanisms underpinning the disease. The aim of this study was the identification of new aberrant alternative splicing events in DM2 patients. By genome wide analysis of 10 DM2 patients and 10 controls (CTR), we identified 273 alternative spliced exons in 218 genes. While many aberrant splicing events were already identified in the past, most were new. A subset of these events was validated by qPCR assays in 19 DM2 and 15 CTR subjects. To gain insight into the molecular pathways involving the identified aberrantly spliced genes, we performed a bioinformatics analysis with Ingenuity system. This analysis indicated a deregulation of development, cell survival, metabolism, calcium signaling and contractility. In conclusion, our genome wide analysis provided a database of aberrant splicing events in the skeletal muscle of DM2 patients. The affected genes are involved in numerous pathways and networks important for muscle physio-pathology, suggesting that the identified variants may contribute to DM2 pathogenesis. PMID:24722564

Cognition and event-related potentials in adult-onset non-demented myotonic dystrophy type 1.

PubMed

Tanaka, H; Arai, M; Harada, M; Hozumi, A; Hirata, K

2012-02-01

To clarify the cognitive and event-related potentials (ERPs) profiles of adult-onset genetically-proven non-demented myotonic dystrophy type 1 (DM1). Fourteen DM1 patients and matched 14 normal controls were enrolled. DM1 patients were compared with normal controls, using a variety of neuropsychological tests; an auditory "oddball" counting paradigm for the ERPs, and low-resolution brain electromagnetic tomography (LORETA). For patients, ERPs and neuropsychological parameters were correlated with CTG repeat size, duration of illness, grip strength, and arterial blood gas analysis. Frontal lobe dysfunction, prolonged N1 latency, and attenuated N2/P3 amplitudes were observed in DM1. Longer CTG repeat size was associated with fewer categories achieved on Wisconsin Card Sorting Test. Greater grip strength was associated with better scores on color-word "interference" of Stroop test. P3 latency was negatively correlated with PaO(2). LORETA revealed significant hypoactivities at the orbitofrontal and medial temporal lobe, cingulate, and insula. There was no correlation between ERPs and CTG expansion. Adult-onset non-demented DM1 presented frontal lobe dysfunction. Absence of correlations between CTG repeat size and objective ERP parameters suggested CTG expansion in lymphocytes does not directly contribute to cognitive dysfunction. CTG expansion in lymphocytes does not directly contribute to cognitive dysfunction of adult-onset non-demented DM1. Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Balance outcomes following a tap dance program for a child with congenital myotonic muscular dystrophy.

PubMed

Biricocchi, Charlanne; Drake, JaimeLynn; Svien, Lana

2014-01-01

This case report describes the effects of a 6-week progressive tap dance program on static and dynamic balance for a child with type 1 congenital myotonic muscular dystrophy (congenital MMD1). A 6-year-old girl with congenital MMD1 participated in a 1-hour progressive tap dance program. Classes were held once a week for 6 consecutive weeks and included 3 children with adaptive needs and 1 peer with typical development. The Bruininks-Oseretsky Test of Motor Proficiency, second edition (BOT-2) balance subsection and the Pediatric Balance Scale were completed at the beginning of the first class and the sixth class. The participant's BOT-2 score improved from 3 to 14. Her Pediatric Balance Scale score did not change. Participation in a progressive tap dance class by a child with congenital MMD1 may facilitate improvements in static and dynamic balance.

The effect of myotonic dystrophy transcript levels and location on muscle differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mastroyiannopoulos, Nikolaos P.; Chrysanthou, Elina; Kyriakides, Tassos C.

2008-12-12

In myotonic dystrophy type I (DM1), nuclear retention of mutant DMPK transcripts compromises muscle cell differentiation. Although several reports have identified molecular defects in myogenesis, it remains still unclear how exactly the retention of the mutant transcripts induces this defect. We have recently created a novel cellular model in which the mutant DMPK 3' UTR transcripts were released to the cytoplasm of myoblasts by using the WPRE genetic element. As a result, muscle cell differentiation was repaired. In this paper, this cellular model was further exploited to investigate the effect of the levels and location of the mutant transcripts onmore » muscle differentiation. Results show that the levels of these transcripts were proportional to the inhibition of both the initial fusion of myoblasts and the maturity of myotubes. Moreover, the cytoplasmic export of the mutant RNAs to the cytoplasm caused less inhibition only in the initial fusion of myoblasts.« less

Lower limb muscle impairment in myotonic dystrophy type 1: the need for better guidelines.

PubMed

Petitclerc, Émilie; Hébert, Luc J; Desrosiers, Johanne; Gagnon, Cynthia

2015-04-01

In myotonic dystrophy type 1 (DM1), leg muscle weakness is a major impairment. There are challenges to obtaining a clear portrait of muscle strength impairment. A systematic literature review was conducted on lower limb strength impairment in late-onset and adult phenotypes to document variables which affect strength measurement. Thirty-two articles were reviewed using the COSMIN guidelines. Only a third of the studies described a reproducible protocol. Only 2 muscle groups have documented reliability for quantitative muscle testing and only 1 total score for manual muscle testing. Variables affecting muscle strength impairment are not described in most studies. This review illustrates the variability in muscle strength assessment in relation to DM1 characteristics and the questionable validity of the results with regard to undocumented methodological properties. There is therefore a clear need to adopt a consensus on the use of a standardized muscle strength assessment protocol. © 2015 Wiley Periodicals, Inc.

Epigenetics of the myotonic dystrophy-associated DMPK gene neighborhood

PubMed Central

Buckley, Lauren; Lacey, Michelle; Ehrlich, Melanie

2016-01-01

Aim: Identify epigenetic marks in the vicinity of DMPK (linked to myotonic dystrophy, DM1) that help explain tissue-specific differences in its expression. Materials & methods: At DMPK and its flanking genes (DMWD, SIX5, BHMG1 and RSPH6A), we analyzed many epigenetic and transcription profiles from myoblasts, myotubes, skeletal muscle, heart and 30 nonmuscle samples. Results: In the DMPK gene neighborhood, muscle-associated DNA hypermethylation and hypomethylation, enhancer chromatin, and CTCF binding were seen. Myogenic DMPK hypermethylation correlated with high expression and decreased alternative promoter usage. Testis/sperm hypomethylation of BHMG1 and RSPH6A was associated with testis-specific expression. G-quadruplex (G4) motifs and sperm-specific hypomethylation were found near the DM1-linked CTG repeats within DMPK. Conclusion: Tissue-specific epigenetic features in DMPK and neighboring genes help regulate its expression. G4 motifs in DMPK DNA and RNA might contribute to DM1 pathology. PMID:26756355

[Perioperative management of a patient with myotonic dystrophy developing the cardiac symptoms initially prior to the neuromuscular symptoms].

PubMed

Wake, M; Matsushita, M; Aono, H; Matsumoto, M; Kohri, Y

1994-08-01

The authors anesthetized a 48-year-old woman with endometrial cancer and a large ovarian cyst. She developed cardiac failure initially followed by the sick sinus syndrome and A-V block from hypertrophic cardiomyopathy, prior to neuromuscular symptoms. Epidural anesthesia assisted by general anesthesia was carried out safely without intravenous administration of any muscle relaxants. From this experience, it is considered that epidural anesthesia assisted with some other proper methods is suitable for surgery of lower abdomen.

The Role of the Atrial Electromechanical Delay in Predicting Atrial Fibrillation in Myotonic Dystrophy Type 1 Patients.

PubMed

Russo, Vincenzo; Rago, Anna; Ciardiello, Carmine; Russo, Maria Giovanna; Calabrò, Paolo; Politano, Luisa; Nigro, Gerardo

2016-01-01

Paroxysmal atrial tachyarrhythmias frequently occur in myotonic dystrophy type 1 (DM1) patients. The aim of the current study was to evaluate the atrial electromechanical-delay (AEMD) in a DM1-population with normal cardiac function and its relationship to atrial fibrillation (AF) onset. Fifty DM1 patients (28 male; mean age 34.2 ± 11.4 years) and 50 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of atrial fibrillation during a 4-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 6 months. Intra-AEMD and inter-AEMD of both atrium were measured through tissue-Doppler echocardiography. Compared to the healthy control group, the DM1 group showed a statistically significant increase in inter-AEMD and intraleft-AEMD. Dividing the DM1-group into 2 subgroups (patients with or without AF), the inter-AEMD and intraleft-AEMD were significantly higher in the subgroup with AF compared to the subgroup without AF. A cut off value of 39.2 milliseconds for intraleft-AEMD had a sensitivity of 90% and a specificity of 90% in identifying DM1 patients with AF risk. A cut off value of 57.7 milliseconds for inter-AEMD had a sensitivity of 84.2% and a specificity of 93.5% in identifying this category of patients. Our results showed that the echocardiographic atrial electromechanical delay indices (intraleft and inter-AEMD) were significantly increased in DM1 subjects with normal cardiac function. Intraleft and inter-AEMD represent noninvasive, inexpensive, useful and simple parameters to assess the AF risk in DM1 patients. © 2015 Wiley Periodicals, Inc.

Antisense Therapy in Neurology

PubMed Central

Lee, Joshua J.A.; Yokota, Toshifumi

2013-01-01

Antisense therapy is an approach to fighting diseases using short DNA-like molecules called antisense oligonucleotides. Recently, antisense therapy has emerged as an exciting and promising strategy for the treatment of various neurodegenerative and neuromuscular disorders. Previous and ongoing pre-clinical and clinical trials have provided encouraging early results. Spinal muscular atrophy (SMA), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), Fukuyama congenital muscular dystrophy (FCMD), dysferlinopathy (including limb-girdle muscular dystrophy 2B; LGMD2B, Miyoshi myopathy; MM, and distal myopathy with anterior tibial onset; DMAT), and myotonic dystrophy (DM) are all reported to be promising targets for antisense therapy. This paper focuses on the current progress of antisense therapies in neurology. PMID:25562650

[Ocular disturbances in neuromuscular disorders].

PubMed

Pénisson-Besnier, I; Lamirel, C

2008-11-01

Compared with other skeletal muscles, extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain neuromuscular disorders. When the oculomotor signs are predominant, their temporal progression allows the clinician to make the distinction between a muscular disease (mitochondrial disorder, oculopharyngeal muscular dystrophy...) and a disorder of the neuromuscular junction (myasthenia gravis, botulism...). In other instances, such as myotonic dystrophy or facioscapulohumeral dystrophy, the ocular signs are not in the forefront but must be recognized by the ophthalmologist as hallmarks of a muscular disorder. In all cases, the collaboration between the neurologist and the ophthalmologist is fruitful.

Feasibility of Lung Volume Recruitment in Early Neuromuscular Weakness: A Comparison Between Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, and Postpolio Syndrome.

PubMed

Kaminska, Marta; Browman, Franceen; Trojan, Daria A; Genge, Angela; Benedetti, Andrea; Petrof, Basil J

2015-07-01

Lung volume recruitment (LVR) is a cough assistance technique used in persons with neuromuscular disorders (NMDs), most typically in those requiring noninvasive ventilation (NIV). Whether it may be useful in persons with NMDs who have milder respiratory impairment is unknown. To assess the feasibility, impact on quality of life (QOL), and preliminary physiological effects of daily LVR in different categories of persons with NMDs who have an early stage of respiratory impairment. Feasibility study. Academic tertiary care center. Outpatients diagnosed with amyotrophic lateral sclerosis (n = 8), postpolio syndrome (n = 10), and myotonic dystrophy (n = 6) who had restrictive respiratory defects but were not yet using NIV. Participants were asked to perform LVR up to 4 times daily and log their LVR use in a diary. Physiological measurements and questionnaires were completed at baseline and after 3 months. Compliance with LVR use was assessed, along with QOL and willingness to continue the treatment. Physiological measurements included forced vital capacity (FVC), lung insufflation capacity (LIC), and the LIC minus FVC difference. Of the 24 recruited subjects, 7 with amyotrophic lateral sclerosis, 7 with postpolio syndrome, and 5 with myotonic dystrophy completed the study (n = 19). At baseline, mean values for FVC and spontaneous peak cough flow were 59.9% predicted and 373.1 L/min, respectively. For subjects completing the study, 74% were willing to continue long-term LVR use, and QOL scores were not adversely affected by LVR in any NMD subgroup. The LIC-FVC difference increased from baseline to follow-up by a mean of 0.243 L (P = .006) in all subjects (n = 19), suggesting a possible improvement in respiratory system mechanics. In patients with NMDs who have early restrictive respiratory defects but do not yet require NIV, regular use of LVR is feasible with no negative impact on QOL over a 3-month period and may have physiological benefits. Further work is needed to determine whether early institution of LVR can improve respiratory system mechanics and help delay ventilatory failure in persons with NMDs. Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.

Recapitulating muscle disease phenotypes with myotonic dystrophy 1 iPS cells: a tool for disease modeling and drug discovery.

PubMed

Mondragon-Gonzalez, Ricardo; Perlingeiro, Rita C R

2018-06-13

Myotonic Dystrophy 1 (DM1) is a multi-system disorder primarily affecting the central nervous system, heart and skeletal muscle. It is caused by an expansion of the CTG trinucleotide repeats in the 3' untranslated region of the DMPK gene. Although patient myoblasts have been used for studying the disease in vitro , the invasiveness as well as the low accessibility to muscle biopsies motivate the development of alternative reliable myogenic models. Here, we established two DM1 iPS cell lines from patient-derived fibroblasts, and using the PAX7 conditional expression system, differentiated these into myogenic progenitors, and subsequently, terminally differentiated myotubes. Both DM1 myogenic progenitors and myotubes were found to express the intranuclear RNA foci exhibiting sequestration of MBNL1. Moreover, we found the DM1-related mis-splicing, namely BIN1 exon 11 in DM1 myotubes. We use this model to test a specific therapy, antisense oligonucleotide treatment, and find that this efficiently abolished RNA foci and rescued BIN1 mis-splicing in DM1 iPS cell-derived myotubes. Together, our results demonstrate that myotubes derived from DM1 iPS cells recapitulate the critical molecular features of DM1 and are sensitive to ASO treatment, confirming that these cells can be used for in vitro disease modeling and candidate drug testing or screening. © 2018. Published by The Company of Biologists Ltd.

The cognitive profile of myotonic dystrophy type 1: A systematic review and meta-analysis.

PubMed

Okkersen, Kees; Buskes, Melanie; Groenewoud, Johannes; Kessels, Roy P C; Knoop, Hans; van Engelen, Baziel; Raaphorst, Joost

2017-10-01

To examine the cognitive profile of patients with myotonic dystrophy type 1 (DM1) on the basis of a systematic review and meta-analysis of the literature. Embase, Medline and PsycInfo were searched for studies reporting ≥1 neuropsychological test in both DM1 patients and healthy controls. Search, data extraction and risk of bias analysis were independently performed by two authors to minimize error. Neuropsychological tests were categorized into 12 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for tests administered in ≥5 studies. DM1 participants demonstrated a significantly worse performance compared to controls in all cognitive domains. Effect sizes ranged from -.33 (small) for verbal memory to -1.01 (large) for visuospatial perception. Except for the domains global cognition, intelligence and social cognition, wide confidence intervals (CIs) were associated with moderate to marked statistical heterogeneity that necessitates careful interpretation of results. Out of the individual tests, the Rey-Osterrieth complex figure-copy (both non-verbal memory and visuoconstruction) showed consistent impairment with acceptable heterogeneity. In DM1 patients, cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory and visuospatial functioning. Although DM1 is a heterogeneous disorder, our study shows that meta-analysis is feasible, contributes to the understanding of brain involvement and may direct bedside testing. The protocol for this study has been registered in PROSPERO (International prospective register of systematic reviews) under ID: 42016037415. Copyright © 2017 Elsevier Ltd. All rights reserved.

Three novel serum biomarkers, miR-1, miR-133a, and miR-206 for Limb-girdle muscular dystrophy, Facioscapulohumeral muscular dystrophy, and Becker muscular dystrophy.

PubMed

Matsuzaka, Yasunari; Kishi, Soichiro; Aoki, Yoshitsugu; Komaki, Hirofumi; Oya, Yasushi; Takeda, Shin-Ichi; Hashido, Kazuo

2014-11-01

Muscular dystrophies are a clinically and genetically heterogeneous group of inherited myogenic disorders. In clinical tests for these diseases, creatine kinase (CK) is generally used as diagnostic blood-based biomarker. However, because CK levels can be altered by various other factors, such as vigorous exercise, etc., false positive is observed. Therefore, three microRNAs (miRNAs), miR-1, miR-133a, and miR-206, were previously reported as alternative biomarkers for duchenne muscular dystrophy (DMD). However, no alternative biomarkers have been established for the other muscular dystrophies. We, therefore, evaluated whether these miR-1, miR-133a, and miR-206 can be used as powerful biomarkers using the serum from muscular dystrophy patients including DMD, myotonic dystrophy 1 (DM1), limb-girdle muscular dystrophy (LGMD), facioscapulohumeral muscular dystrophy (FSHD), becker muscular dystrophy (BMD), and distal myopathy with rimmed vacuoles (DMRV) by qualitative polymerase chain reaction (PCR) amplification assay. Statistical analysis indicated that all these miRNA levels in serum represented no significant differences between all muscle disorders examined in this study and controls by Bonferroni correction. However, some of these indicated significant differences without correction for testing multiple diseases (P < 0.05). The median values of miR-1 levels in the serum of patients with LGMD, FSHD, and BMD were approximately 5.5, 3.3 and 1.7 compared to that in controls, 0.68, respectively. Similarly, those of miR-133a and miR-206 levels in the serum of BMD patients were about 2.5 and 2.1 compared to those in controls, 1.03 and 1.32, respectively. Taken together, our data demonstrate that levels of miR-1, miR-133a, and miR-206 in serum of BMD and miR-1 in sera of LGMD and FSHD patients showed no significant differences compared with those of controls by Bonferroni correction. However, the results might need increase in sample sizes to evaluate these three miRNAs as variable biomarkers.

[Myotonic dystrophies: clinical presentation, pathogenesis, diagnostics and therapy].

PubMed

Finsterer, Josef; Rudnik-Schöneborn, S

2015-01-01

The autosomal-dominant myotonic dystrophies dystrophia myotonica type-1 (DM1, Curschmann-Steinert disease) and dystrophia myotonica type-2 (DM2, proximal myotonic myopathy (PROMM)), are, contrary to the non-dystrophic myotonias, progressive multisystem disorders. DM1 and DM2 are the most frequent of the muscular dystrophies. In both diseases the skeletal muscle is the most severely affected organ (weakness, wasting, myotonia, myalgia). Additionally, they manifest in the eye, heart, brain, endocrine glands, gastrointestinal tract, skin, skeleton, and peripheral nerves. Phenotypes of DM1 may be classified as congenital, juvenile, classical, or late onset. DM2 is a disorder of the middle or older age and usually has a milder course compared to DM1. DM1 is due to a CTG-repeat expansion > 50 repeats in the non-coding 3' UTR of the DMPK-gene. DM2 is caused by a CCTG-repeat expansion to 75 - 11 000 repeats in intron-1 of the CNBP/ZNF9 gene. Mutant pre-mRNAs of both genes aggregate within the nucleus (nuclear foci), which sequester RNA-binding proteins and result in an abnormal protein expression via alternative splicing in downstream effector genes (toxic RNA diseases). Other mechanisms seem to play an additional pathogenetic role. Clinical severity of DM1 increases from generation to generation (anticipation). The higher the repeat expansion the more severe the DM1 phenotype. In DM2 severity of symptoms and age at onset do not correlate with the expansion size. Contrary to DM2, there is a congenital form and anticipation in DM1. © Georg Thieme Verlag KG Stuttgart · New York.

Clinical trial network for the promotion of clinical research for rare diseases in Japan: muscular dystrophy clinical trial network.

PubMed

Shimizu, Reiko; Ogata, Katsuhisa; Tamaura, Akemi; Kimura, En; Ohata, Maki; Takeshita, Eri; Nakamura, Harumasa; Takeda, Shin'ichi; Komaki, Hirofumi

2016-07-11

Duchenne muscular dystrophy (DMD) is the most commonly inherited neuromuscular disease. Therapeutic agents for the treatment of rare disease, namely "orphan drugs", have recently drawn the attention of researchers and pharmaceutical companies. To ensure the successful conduction of clinical trials to evaluate novel treatments for patients with rare diseases, an appropriate infrastructure is needed. One of the effective solutions for the lack of infrastructure is to establish a network of rare diseases. To accomplish the conduction of clinical trials in Japan, the Muscular dystrophy clinical trial network (MDCTN) was established by the clinical research group for muscular dystrophy, including the National Center of Neurology and Psychiatry, as well as national and university hospitals, all which have a long-standing history of research cooperation. Thirty-one medical institutions (17 national hospital organizations, 10 university hospitals, 1 national center, 2 public hospitals, and 1 private hospital) belong to this network and collaborate to facilitate clinical trials. The Care and Treatment Site Registry (CTSR) calculates and reports the proportion of patients with neuromuscular diseases in the cooperating sites. In total, there are 5,589 patients with neuromuscular diseases in Japan and the proportion of patients with each disease is as follows: DMD, 29 %; myotonic dystrophy type 1, 23 %; limb girdle muscular dystrophy, 11 %; Becker muscular dystrophy, 10 %. We work jointly to share updated health care information and standardized evaluations of clinical outcomes as well. The collaboration with the patient registry (CTSR), allows the MDCTN to recruit DMD participants with specific mutations and conditions, in a remarkably short period of time. Counting with a network that operates at a national level is important to address the corresponding national issues. Thus, our network will be able to contribute with international research activity, which can lead to an improvement of neuromuscular disease treatment in Japan.

Staufen1s role as a splicing factor and a disease modifier in Myotonic Dystrophy Type I

PubMed Central

Bondy-Chorney, Emma; Crawford Parks, Tara E.; Ravel-Chapuis, Aymeric; Jasmin, Bernard J.; Côté, Jocelyn

2016-01-01

ABSTRACT In a recent issue of PLOS Genetics, we reported that the double-stranded RNA-binding protein, Staufen1, functions as a disease modifier in the neuromuscular disorder Myotonic Dystrophy Type I (DM1). In this work, we demonstrated that Staufen1 regulates the alternative splicing of exon 11 of the human Insulin Receptor, a highly studied missplicing event in DM1, through Alu elements located in an intronic region. Furthermore, we found that Staufen1 overexpression regulates numerous alternative splicing events, potentially resulting in both positive and negative effects in DM1. Here, we discuss our major findings and speculate on the details of the mechanisms by which Staufen1 could regulate alternative splicing, in both normal and DM1 conditions. Finally, we highlight the importance of disease modifiers, such as Staufen1, in the DM1 pathology in order to understand the complex disease phenotype and for future development of new therapeutic strategies. PMID:27695661

Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

PubMed Central

Yanovsky-Dagan, Shira; Avitzour, Michal; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Mitrani-Rosenbaum, Stella; Levy-Lahad, Ephrat; Birnbaum, Ramon Y.; Gepstein, Lior; Epsztejn-Litman, Silvina; Eiges, Rachel

2015-01-01

Summary CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation. PMID:26190529

Prevalence and correlates of apathy in myotonic dystrophy type 1.

PubMed

Gallais, Benjamin; Montreuil, Michèle; Gargiulo, Marcela; Eymard, Bruno; Gagnon, Cynthia; Laberge, Luc

2015-08-22

Apathy in DM1 has long been acknowledged in clinical practice. However, a major drawback is that the concept has been only sparsely explored in previous specific studies. This study aimed to determine the prevalence of apathy in myotonic dystrophy (DM1), to compare it with facioscapulohumeral dystrophy (FSHD) patients and normal healthy controls, and explore its relationship to psychopathological features and cognitive function. Levels of apathy in 38 DM1 patients with adult phenotypes were compared with 19 patients with FSHD and 20 matched controls. Patient participants were consecutively recruited, regarding their interdisciplinary annual evaluation at the neuromuscular pathology reference center (Institute of Myology, Paris, France), within an 18-month period. Additional measurements included motor disability, fatigue, depression, anxiety, and cognitive abilities. Inter-group comparisons were performed using non-parametric Kruskal-Wallis tests and Mann-Whitney U Tests. Intra-group comparisons were carried out with the Wilcoxon Signed rank and Friedman tests. Also, Spearman's correlations were used to assess the strength of linear relationships between pairs of variables. The significance level was set at 0.05. Global score of apathy was significantly higher in DM1 patients than in FSHD patients (p < 0.01) and in controls (p < 0.001). Sixteen of 38 DM1 patients (39.5 %) met the criterion for apathy, contrasting with only 4 of the 19 (21.1 %) FSHD patients. No control subject was apathetic. Moreover, apathy in DM1 patients was negatively correlated to MMSE (r = -.46, p < .05) and Stroop Word (r = -.55, p < .01) scores, but not with age, educational level, disease duration, CTG repeats, motor functional disability, fatigue, depression, and anxiety. Apathy is a frequent symptom in DM1 (almost 40 %). It is more prevalent than in a similarly disabled group of patients with FSHD and in controls. Results also show that apathy in DM1 is independent of the psychopathological domain, fatigue, age, and motor disability, but associated to general cognitive status. These results altogether could suggest a central cause for apathy in DM1 rather than an adjustment process to cope with the progressive and debilitating nature of the disease. Data emphasize the importance to evaluate this symptom in routine clinical management of DM1 patients.

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

PubMed Central

Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M.; Vilchez, Juan J.; Llamusi, Beatriz; Artero, Ruben

2015-01-01

ABSTRACT Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. PMID:26092529

Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model.

PubMed

Bargiela, Ariadna; Cerro-Herreros, Estefanía; Fernandez-Costa, Juan M; Vilchez, Juan J; Llamusi, Beatriz; Artero, Ruben

2015-07-01

Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1) disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor) or muscleblind, or by RNA interference (RNAi)-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis. © 2015. Published by The Company of Biologists Ltd.

Intelligence quotient profile in myotonic dystrophy, intergenerational deficit, and correlation with CTG amplification.

PubMed Central

Turnpenny, P; Clark, C; Kelly, K

1994-01-01

An abbreviated Wechsler Adult Intelligence Scale Revised (WAIS-R) was used to assess verbal and arithmetical cognitive performance in 55 subjects with myotonic dystrophy (DM), covering all grades of disease severity, and 31 controls at 50% risk of inheriting DM. Scaled scores from the assessment were converted into an intelligence quotient (IQ) estimation on each person. Significant IQ differences were found between: (1) all 55 DM subjects (mean 90.2, SD 16.1) and 31 controls (102.6, SD 9.4), with no sex differences in either group; (2) 15 affected parents (99.3, SD 12.2) and their affected children (88.1, SD 17.2), where significance was dependent on parental sex being female; and (3) 15 pairs of affected sibs (89.6, SD 13.2) and their normal sibs (100.2, SD 7.6). IQ steadily declined as (1) the age of onset of signs and symptoms decreased, and (2) the CTG expansion size increased. The correlation appeared to be more linear with age of onset. The correlation of IQ difference and CTG expansion difference in both the DM parent-child pairs and normal sib-affected sib pairs was poor, indicating that CTG expansion is not a reliable predictor of IQ either in individual persons or families. Further analysis of cognitive function in DM is required to clarify specific deficits characteristic of this patient group. PMID:8071955

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy.

PubMed

André, Laurène M; Ausems, C Rosanne M; Wansink, Derick G; Wieringa, Bé

2018-01-01

Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3' non-coding region of DMPK and in intron 1 of CNBP , respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient's lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM.

Dependent and paranoid personality patterns in myotonic dystrophy type 1.

PubMed

Peric, S; Sreckov, M; Basta, I; Lavrnic, D; Vujnic, M; Marjanovic, I; Rakocevic Stojanovic, V

2014-04-01

To analyze frequency and type of personality pattern in patients with myotonic dystrophy type 1 (DM1), to correlate these findings with clinical data, and to assess its possible influence on quality of life (QoL). This cross-sectional study comprised 62 patients with DM1. Following measures were used: Muscular Impairment Rating Scale, Raven's Standard Progressive Matrices (RSPM), Millon Multiaxial Clinical Inventory I (MMCI), SF-36, and Individualized Neuromuscular Quality of Life (INQoL) questionnaires. The presence of at least one pathological personality trait with score above 85 on MMCI was found in 47 (75.8%) patients. After clinical interview, 36 (58.1%) subjects had significant personality impairment. The most common personality trait in our cohort of patients was dependent found in 51.6% of patients, followed by paranoid (38.7%). Higher score on dependent personality scale correlated with lower education (rho = -0.251, P = 0.049). Dependent personality scores significantly differed between patients with physical and intellectual work (93.1 ± 8.9 vs 66.9 ± 31.7, P = 0.011). Paranoid score was higher in patients with lower education (rho = -0.293, P = 0.021), lower score on RSPM test (rho = -0.398, P = 0.004) and larger number of CTG repeats (rho = 0.254, P = 0.046). Presence of dependent personality was not in association with QoL scores (P > 0.05). On the other hand, patients with paranoid personality trait had worse QoL than those without it (P < 0.05). Almost 60% of our patients with DM1 had clinically significant personality impairment, with dependent and paranoid personality patterns being the most common. Paranoid personality may decrease QoL in these patients, which gives us new opportunities for symptomatic therapy in DM1. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Molecular Genetics and Genetic Testing in Myotonic Dystrophy Type 1

PubMed Central

Savić Pavićević, Dušanka; Miladinović, Jelena; Brkušanin, Miloš; Šviković, Saša; Djurica, Svetlana; Brajušković, Goran; Romac, Stanka

2013-01-01

Myotonic dystrophy type 1 (DM1) is the most common adult onset muscular dystrophy, presenting as a multisystemic disorder with extremely variable clinical manifestation, from asymptomatic adults to severely affected neonates. A striking anticipation and parental-gender effect upon transmission are distinguishing genetic features in DM1 pedigrees. It is an autosomal dominant hereditary disease associated with an unstable expansion of CTG repeats in the 3′-UTR of the DMPK gene, with the number of repeats ranging from 50 to several thousand. The number of CTG repeats broadly correlates with both the age-at-onset and overall severity of the disease. Expanded DM1 alleles are characterized by a remarkable expansion-biased and gender-specific germline instability, and tissue-specific, expansion-biased, age-dependent, and individual-specific somatic instability. Mutational dynamics in male and female germline account for observed anticipation and parental-gender effect in DM1 pedigrees, while mutational dynamics in somatic tissues contribute toward the tissue-specificity and progressive nature of the disease. Genetic test is routinely used in diagnostic procedure for DM1 for symptomatic, asymptomatic, and prenatal testing, accompanied with appropriate genetic counseling and, as recommended, without predictive information about the disease course. We review molecular genetics of DM1 with focus on those issues important for genetic testing and counseling. PMID:23586035

Stanford Chronic Disease Self-Management Program in myotonic dystrophy: New opportunities for occupational therapists: Stanford Chronic Disease Self-Management Program dans la dystrophie myotonique : De nouvelles opportunités pour les ergothérapeutes.

PubMed

Raymond, Kateri; Levasseur, Mélanie; Chouinard, Maud-Christine; Mathieu, Jean; Gagnon, Cynthia

2016-06-01

Chronic disease self-management is a priority in health care. Personal and environmental barriers for populations with neuromuscular disorders might diminish the efficacy of self-management programs, although they have been shown to be an effective intervention in many populations. Owing to their occupational expertise, occupational therapists might optimize self-management program interventions. This study aimed to adapt the Stanford Chronic Disease Self-Management Program (CDSMP) for people with myotonic dystrophy type 1 (DM1) and assess its acceptability and feasibility in this population. Using an adapted version of the Stanford CDSMP, a descriptive pilot study was conducted with 10 participants (five adults with DM1 and their caregivers). A semi-structured interview and questionnaires were used. The Stanford CDSMP is acceptable and feasible for individuals with DM1. However, improvements are required, such as the involvement of occupational therapists to help foster concrete utilization of self-management strategies into day-to-day tasks using their expertise in enabling occupation. Although adaptations are needed, the Stanford CDSMP remains a relevant intervention with populations requiring the application of self-management strategies. © CAOT 2016.

CRISPR/Cas9-Induced (CTG⋅CAG)n Repeat Instability in the Myotonic Dystrophy Type 1 Locus: Implications for Therapeutic Genome Editing.

PubMed

van Agtmaal, Ellen L; André, Laurène M; Willemse, Marieke; Cumming, Sarah A; van Kessel, Ingeborg D G; van den Broek, Walther J A A; Gourdon, Geneviève; Furling, Denis; Mouly, Vincent; Monckton, Darren G; Wansink, Derick G; Wieringa, Bé

2017-01-04

Myotonic dystrophy type 1 (DM1) is caused by (CTG⋅CAG) n -repeat expansion within the DMPK gene and thought to be mediated by a toxic RNA gain of function. Current attempts to develop therapy for this disease mainly aim at destroying or blocking abnormal properties of mutant DMPK (CUG)n RNA. Here, we explored a DNA-directed strategy and demonstrate that single clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-cleavage in either its 5' or 3' unique flank promotes uncontrollable deletion of large segments from the expanded trinucleotide repeat, rather than formation of short indels usually seen after double-strand break repair. Complete and precise excision of the repeat tract from normal and large expanded DMPK alleles in myoblasts from unaffected individuals, DM1 patients, and a DM1 mouse model could be achieved at high frequency by dual CRISPR/Cas9-cleavage at either side of the (CTG⋅CAG)n sequence. Importantly, removal of the repeat appeared to have no detrimental effects on the expression of genes in the DM1 locus. Moreover, myogenic capacity, nucleocytoplasmic distribution, and abnormal RNP-binding behavior of transcripts from the edited DMPK gene were normalized. Dual sgRNA-guided excision of the (CTG⋅CAG)n tract by CRISPR/Cas9 technology is applicable for developing isogenic cell lines for research and may provide new therapeutic opportunities for patients with DM1. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Altered Splicing of the BIN1 Muscle-Specific Exon in Humans and Dogs with Highly Progressive Centronuclear Myopathy

PubMed Central

Böhm, Johann; Vasli, Nasim; Maurer, Marie; Cowling, Belinda; Shelton, G. Diane; Kress, Wolfram; Toussaint, Anne; Prokic, Ivana; Schara, Ulrike; Anderson, Thomas James; Weis, Joachim; Tiret, Laurent; Laporte, Jocelyn

2013-01-01

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies. PMID:23754947

Induction and Reversal of Myotonic Dystrophy Type 1 Pre-mRNA Splicing Defects by Small Molecules

PubMed Central

Childs-Disney, Jessica L.; Stepniak-Konieczna, Ewa; Tran, Tuan; Yildirim, Ilyas; Park, HaJeung; Chen, Catherine Z.; Hoskins, Jason; Southall, Noel; Marugan, Juan J.; Patnaik, Samarjit; Zheng, Wei; Austin, Chris P.; Schatz, George C.; Sobczak, Krzysztof; Thornton, Charles A.; Disney, Matthew D.

2013-01-01

The ability to control pre-mRNA splicing with small molecules could facilitate the development of therapeutics or cell-based circuits that control gene function. Myotonic dystrophy type 1 (DM1) is caused by the dysregulation of alternative pre-mRNA splicing due to sequestration of muscleblind-like 1 protein (MBNL1) by expanded, non-coding r(CUG) repeats (r(CUG)exp). Here we report two small molecules that induce or ameliorate alternative splicing dysregulation. The thiophene-containing small molecule (1) inhibits the interaction of MBNL1 with its natural pre-mRNA substrates. Compound (2), a substituted naphthyridine, binds r(CUG)exp and displaces MBNL1. Structural models show that 1 binds MBNL1 in the Zn-finger domain and that 2 interacts with UU loops in r(CUG)exp. This study provides a structural framework for small molecules that target MBNL1 by mimicking r(CUG)exp and shows that targeting MBNL1 causes dysregulation of alternative splicing, suggesting that MBNL1 is thus not a suitable therapeutic target for the treatment of DM1. PMID:23806903

Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells.

PubMed

Yanovsky-Dagan, Shira; Avitzour, Michal; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Mitrani-Rosenbaum, Stella; Levy-Lahad, Ephrat; Birnbaum, Ramon Y; Gepstein, Lior; Epsztejn-Litman, Silvina; Eiges, Rachel

2015-08-11

CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Effects of hand-training in persons with myotonic dystrophy type 1--a randomised controlled cross-over pilot study.

PubMed

Aldehag, Anna; Jonsson, Hans; Lindblad, Jan; Kottorp, Anders; Ansved, Tor; Kierkegaard, Marie

2013-10-01

To investigate the effects of a hand-training programme on grip, pinch and wrist force, manual dexterity and activities of daily living, in adults with myotonic dystrophy type 1 (DM1). In this randomised controlled trial with a crossover design, 35 adults with DM1 were, after stratification for grip force, assigned by lot to two groups. Group A started with 12 weeks of hand training, while group B had no intervention. After a wash-out period of 12 weeks, where none received training, the order was reversed. The Grippit® was used as primary outcome measure and the hand-held Microfet2™ myometer, the Purdue Pegboard, the Canadian Occupational Performance Measure (COPM) and the Assessment of Motor and Process Skills (AMPS) were secondary outcome measures. Assessments were performed before and after training and control periods, i.e. four times altogether. Ten persons dropped out and 13 had acceptable adherence. Intention-to-treat analyses revealed significant intervention effects for isometric wrist flexor force (p = 0.048), and for COPM performance (p = 0.047) and satisfaction (p = 0.027). On an individual level, improvements were in general showed after a training period. The hand-training programme had positive effects on wrist flexor force and self-perception of occupational performance, and of satisfaction with performance. No evident detrimental effects were shown. Myotonic dystrophy type 1 (DM1) is a slowly progressive neuromuscular disease characterised by myotonia and muscle weakness and wasting. People with DM1 are often concerned about their ability to carry out ADL and to participate in, e.g. work, sports and hobbies when they gradually become weaker. This pilot study showed that a hand-training programme improved wrist flexor force and self-perception and satisfaction of occupational performance. Resistance training of hand muscles with a silicon-based putty can be a therapy option for people with DM1 in clinical practise.

Comparisons of intellectual capacities between mild and classic adult-onset phenotypes of myotonic dystrophy type 1 (DM1).

PubMed

Jean, Stéphane; Richer, Louis; Laberge, Luc; Mathieu, Jean

2014-11-26

Myotonic dystrophy type 1 (DM1) is an autosomal dominant genetic multisystem disorder and the commonest adult-onset form of muscular dystrophy. DM1 results from the expansion of an unstable trinucleotide cytosine-thymine-guanine (CTG) repeat mutation. CTG repeats in DM1 patients can range from 50 to several thousands, with a tendency toward increased repeats with successive generations (anticipation). Associated findings can include involvements in almost every systems, including the brain, and cognitive abnormalities occur in the large majority of patients. The objectives are to describe and compare the intellectual abilities of a large sample of DM1 patients with mild and classic adult-onset phenotypes, to estimate the validity of the Wechsler Adult Intelligence Scale-Revised (WAIS-R) in DM1 patients with muscular weakness, and to appraise the relationship of intelligence quotient (IQ) to CTG repeat length, age at onset of symptoms, and disease duration. A seven-subtest WAIS-R was administered to 37 mild and 151 classic adult-onset DM1 patients to measure their Full-Scale (FSIQ), Verbal (VIQ) and Performance IQ (PIQ). To control for potential bias due to muscular weakness, Standard Progressive Matrices (SPM), a motor-independent test of intelligence, were also completed. Total mean FSIQ was 82.6 corresponding to low average IQ, and 82% were below an average intelligence. Mild DM1 patients had a higher mean FSIQ (U=88.7 vs 81.1, p<0.001), VIQ (U=87.8 vs 82.3, p=0.001), and PIQ (U=94.8 vs 83.6, p<0.001) than classic adult-onset DM1 patients. In both mild and classic adult-onset patients, all subtests mean scaled scores were below the normative sample mean. FSIQ also strongly correlate with SPM (r s =0.67, p<0.001), indicating that low intelligence scores are not a consequence of motor impairment. FSIQ scores decreased with both the increase of (CTG)n (r s =-0.41, p<0.001) and disease duration (r s =-0.26, p=0.003). Results show that intellectual impairment is an extremely common and important feature in DM1, not only among the classic adult-onset patients but also among the least severe forms of DM1, with low IQ scores compared to general reference population. Health care providers involved in the follow-up of these patients should be aware of their intellectual capacities and should adapt their interventions accordingly.

Orthopaedic Disorders in Myotonic Dystrophy Type 1: descriptive clinical study of 21 patients

PubMed Central

2013-01-01

Background Myotonic Dystrophy Type 1 (DM1) is the most common form of hereditary myopathy presenting in adults. This autosomal-dominant systemic disorder is caused by a CTG repeat, demonstrating various symptoms. A mild, classic and congenital form can be distinguished. Often the quality of life is reduced by orthopaedic problems, such as muscle weakness, contractures, foot or spinal deformities, which limit patients’ mobility. The aim of our study was to gather information about the orthopaedic impairments in patients with DM1 in order to improve the medical care of patients, affected by this rare disease. Methods A retrospective clinical study was carried out including 21 patients (11 male and 10 female), all diagnosed with DM1 by genetic testing. All patients were seen during our special consultations for neuromuscular diseases, during which patients were interviewed and examined. We also reviewed surgery reports of our hospitalized patients. Results We observed several orthopaedic impairments: spinal deformities (scoliosis, hyperkyphosis, rigid spine), contractures (of the upper extremities and the lower extremities), foot deformities (equinus deformity, club foot, pes cavus, pes planovalgus, pes cavovarus, claw toes) and fractures. Five patients were affected by pulmonary diseases (obstructive airway diseases, restrictive lung dysfunctions). Twelve patients were affected by cardiac disorders (congenital heart defects, valvular heart defects, conduction disturbances, pulmonary hypertension, cardiomyopathy). Our patients received conservative therapy (physiotherapy, logopaedic therapy, ergotherapy) and we prescribed orthopaedic technical devices (orthopaedic custom-made shoes, insoles, lower and upper leg orthoses, wheelchair, Rehab Buggy). We performed surgery for spinal and foot deformities: the scoliosis of one patient was stabilized and seven patients underwent surgery for correction of foot deformities. Conclusions An orthopaedic involvement in DM1 patients should not be underestimated. The most common orthopaedic impairments are contractures, foot deformities and spinal deformities. Contractures are typically located distally in the lower extremities, but can also occur in the hip or shoulder joints. Foot deformities could be treated with orthopaedic custom-made shoes, orthoses or insoles. Surgery is indicated for severe foot deformities or contractures. PMID:24289806

Fatigue and neuromuscular diseases.

PubMed

Féasson, L; Camdessanché, J-P; El Mandhi, L; Calmels, P; Millet, G-Y

2006-07-01

To identify the role of fatigue, its evaluation and its causes in the pathophysiology context of acquired or hereditary neuromuscular diseases of the spinal anterior horn cell, peripheral nerve, neuromuscular junction and muscle. A literature review has been done on Medline with the following keywords: neuromuscular disease, peripheral neuropathy, myopathy, fatigue assessment, exercise intolerance, force assessment, fatigue scale and questionnaire, then with the terms: Fatigue Severity Scale, Chalder Fatigue Scale, Fatigue Questionnaire, Piper Fatigue Scale, electromyography and the combination of the word Fatigue with the following terms: Amyotrophic Lateral Sclerosis (ALS), Post-Polio Syndrome (PPS), Guillain-Barre Syndrome, Immune Neuropathy, Charcot-Marie-Tooth Disease, Myasthenia Gravis (MG), Metabolic Myopathy, Mitochondrial Myopathy, Muscular Dystrophy, Facioscapulohumeral Dystrophy, Myotonic Dystrophy. Fatigue is a symptom very frequently reported by patients. Fatigue is mainly evaluated by strength loss after an exercise, by change in electromyographic activity during a given exercise and by questionnaires that takes into account the subjective (psychological) part of fatigue. Due to the large diversity of motor disorders, there are multiple clinical expressions of fatigue that differ in their presentation, consequences and therapeutic approach. This review shows that fatigue has to be taken into account in patients with neuromuscular diseases. In this context, pathophysiology of fatigue often implies the motor component but the disease evolution and the physical obligates of daily life also induce an important psychological component.

Cardiac surgery in type-1-myotonic muscular dystrophy (Steinert syndrome) associated to Barlow disease.

PubMed

Gelsomino, Sandro; Lorusso, Roberto; Billè, Giuseppe; De Cicco, Giuseppe; Da Broi, Ugo; Rostagno, Carlo; Stefàno, Pierluigi; Gensini, Gian Franco

2008-04-01

No data exist in the English-language literature about patients with Barlow disease associated to Steinert syndrome and little is known about the employment of hypothermic cardiopulmonary bypass (CPB) and hyperkalemic cardioplegia in these patients. We present our experience with six patients affected by myxomatous degeneration associated to Steinert disease undergoing complex mitral valve repair. In all patients we employed mild hypothermic CPB (31 degrees C) and myocardial protection was achieved, in the entire cohort, by the use of blood hyperkalemic cold cardioplegia. The postoperative course was uneventful in all patients and neither shivering nor generalized muscle contraction were observed. Furthermore, all patients have remained well on an outpatient basis. Hypothermic CPB and hyperkalemic cardioplegia can be safely employed in patients with Steinert syndrome requiring complex cardiac surgery. Further large studies are necessary to confirm our findings.

improbable molecular results and the need to reevaluate a priori genetic risks: A report of 2 neuromuscular disorders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Giardine, R.M.; Rose, N.C.; Fischbeck, K.H.

Case 1: A 27-year-old woman whose brother and deceased father were diagnosed with myotonic dystrophy presented for preconceptional counseling. Three other first and second degree relatives were judged clinically affected on the basis of myotonia by positive electromyelograms (EMGs). The proband appeared to be clinically affected with mild percussion myotonia and a positive EMG. Initial studies by linkage analysis required postulation that the at-risk chromosome 19 inherited by the patient and her brother had undergone recombination in the brother between 2 very closely linked RFLP markers. Conclusion: Molecular testing did not support a unifying diagnosis for myotonia in this family.more » In addition to one classic example of myotonic dystrophy, it is possible a milder form of myotonia is also segregating in this pedigree. Case 2: The maternal aunt of a young man with Becker`s muscular dystrophy (BMD) presented for reproductive counseling. Serum CK values were elevated in her mother, who shared an X chromosome haplotype with the affected grandson and was judged an obligate carrier. The aunt was judged a likely carrier because of elevated serum CK values. Three maternal uncles, including ones with the same X chromosome haplotype as the affected nephew, were clinically normal. Finally, dosage analysis for dystrophin exons deleted in the grandson showed the grandmother and aunt to be non-carriers, but the mother of the affected boy to be a somatic carrier. The grandmother and aunt are not BMD carriers. Since the elevated CK levels do not segregate with the affected X chromosome, they may reflect autosomal inheritance or nongenetic influences; in either case their clinical significance is uncertain. These cases reinforce the importance of periodic reevaluation of initial genetic assignments, particularly when rare events must be invoked to explain molecular studies.« less

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy

PubMed Central

André, Laurène M.; Ausems, C. Rosanne M.; Wansink, Derick G.; Wieringa, Bé

2018-01-01

Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3′ non-coding region of DMPK and in intron 1 of CNBP, respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient’s lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM. PMID:29892259

Diagnosis and management of adult hereditary cardio-neuromuscular disorders: A model for the multidisciplinary care of complex genetic disorders.

PubMed

Sommerville, R Brian; Vincenti, Margherita Guzzi; Winborn, Kathleen; Casey, Anne; Stitziel, Nathan O; Connolly, Anne M; Mann, Douglas L

2017-01-01

Genetic disorders that disrupt the structure and function of the cardiovascular system and the peripheral nervous system are common enough to be encountered in routine cardiovascular practice. Although often these patients are diagnosed in childhood and come to the cardiologist fully characterized, some patients with hereditary neuromuscular disease may not manifest until adulthood and will present initially to the adult cardiologist for an evaluation of an abnormal ECG, unexplained syncope, LV hypertrophy, and or a dilated cardiomyopathy of unknown cause. Cardiologists are often ill-equipped to manage these patients due to lack of training and exposure as well as the complete absence of practice guidelines to aid in the diagnosis and management of these disorders. Here, we review three key neuromuscular diseases that affect the cardiovascular system in adults (myotonic dystrophy type 1, Friedreich ataxia, and Emery-Dreifuss muscular dystrophy), with an emphasis on their clinical presentation, genetic and molecular pathogenesis, and recent important research on medical and interventional treatments. We also advocate the development of interdisciplinary cardio-neuromuscular clinics to optimize the care for these patients. Copyright © 2016 Elsevier Inc. All rights reserved.

[Auricular arrhythmia in Steinert's myotonia. Apropos of a case with a familial study].

PubMed

Chagnon, A; Vidal, M E

1983-02-24

A case of bradycardia-tachycardia syndrome leading to the late discovery of Steinert syndrome is reported. There is a discrepancy between the frequency of the main features of the bradycardia-tachycardia syndrome (sinoatrial block and atrial flutter in our observation) usually reported in Steinert disease and the fact that no case similar to ours seems to have yet been reported; this suggests definite underrating. Insertion of a pacemaker should avoid sudden death from a conduction disturbance. The heart should be carefully monitored in patients with myotonic dystrophy; conversely, this diagnosis should be considered in the etiologic diagnosis of myocardiopathies.

Home mechanical ventilation: A Canadian Thoracic Society clinical practice guideline

PubMed Central

McKim, Douglas A; Road, Jeremy; Avendano, Monica; Abdool, Steve; Côté, Fabien; Duguid, Nigel; Fraser, Janet; Maltais, François; Morrison, Debra L; O’Connell, Colleen; Petrof, Basil J; Rimmer, Karen; Skomro, Robert

2011-01-01

Increasing numbers of patients are surviving episodes of prolonged mechanical ventilation or benefitting from the recent availability of user-friendly noninvasive ventilators. Although many publications pertaining to specific aspects of home mechanical ventilation (HMV) exist, very few comprehensive guidelines that bring together all of the current literature on patients at risk for or using mechanical ventilatory support are available. The Canadian Thoracic Society HMV Guideline Committee has reviewed the available English literature on topics related to HMV in adults, and completed a detailed guideline that will help standardize and improve the assessment and management of individuals requiring noninvasive or invasive HMV. The guideline provides a disease-specific review of illnesses including amyotrophic lateral sclerosis, spinal cord injury, muscular dystrophies, myotonic dystrophy, kyphoscoliosis, post-polio syndrome, central hypoventilation syndrome, obesity hypoventilation syndrome, and chronic obstructive pulmonary disease as well as important common themes such as airway clearance and the process of transition to home. The guidelines have been extensively reviewed by international experts, allied health professionals and target audiences. They will be updated on a regular basis to incorporate any new information. PMID:22059178

Application of FTA sample collection and DNA purification system on the determination of CTG trinucleotide repeat size by PCR-based Southern blotting.

PubMed

Hsiao, K M; Lin, H M; Pan, H; Li, T C; Chen, S S; Jou, S B; Chiu, Y L; Wu, M F; Lin, C C; Li, S Y

1999-01-01

Myotonic dystrophy (DM) is caused by a CTG trinucleotide expansion mutation at exon 15 of the myotonic dystrophy protein kinase gene. The clinical severity of this disease correlates with the length of the CTG trinucleotide repeats. Determination of the CTG repeat length has been primarily relied on by Southern blot analysis of restriction enzyme-digested genomic DNA. The development of PCR-based Southern blotting methodology provides a much more sensitive and simpler protocol for DM diagnosis. However, the quality of the template and the high (G+C) ratio of the amplified region hamper the use of PCR on the diagnosis of DM. A modified PCR protocol to amplify different lengths of CTG repeat region using various concentrations of 7deaza-dGTP has been reported (1). Here we describe a procedure including sample collection, DNA purification, and PCR analysis of CTG repeat length without using 7-deaza-dGTP. This protocol is very sensitive and convenient because only a small number of nucleate cells are needed for detection of CTG expansion. Therefore, it could be very useful in clinical and prenatal diagnosis as well as in prevalence study of DM.

Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1.

PubMed

Angelbello, Alicia J; González, Àlex L; Rzuczek, Suzanne G; Disney, Matthew D

2016-12-01

RNA is an important drug target, but current approaches to identify bioactive small molecules have been engineered primarily for protein targets. Moreover, the identification of small molecules that bind a specific RNA target with sufficient potency remains a challenge. Computer-aided drug design (CADD) and, in particular, ligand-based drug design provide a myriad of tools to identify rapidly new chemical entities for modulating a target based on previous knowledge of active compounds without relying on a ligand complex. Herein we describe pharmacophore virtual screening based on previously reported active molecules that target the toxic RNA that causes myotonic dystrophy type 1 (DM1). DM1-associated defects are caused by sequestration of muscleblind-like 1 protein (MBNL1), an alternative splicing regulator, by expanded CUG repeats (r(CUG) exp ). Several small molecules have been found to disrupt the MBNL1-r(CUG) exp complex, ameliorating DM1 defects. Our pharmacophore model identified a number of potential lead compounds from which we selected 11 compounds to evaluate. Of the 11 compounds, several improved DM1 defects both in vitro and in cells. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genome Editing of Monogenic Neuromuscular Diseases

PubMed Central

Long, Chengzu; Amoasii, Leonela; Bassel-Duby, Rhonda; Olson, Eric N.

2017-01-01

IMPORTANCE Muscle weakness, the most common symptom of neuromuscular disease, may result from muscle dysfunction or may be caused indirectly by neuronal and neuromuscular junction abnormalities. To date, more than 780 monogenic neuromuscular diseases, linked to 417 different genes, have been identified in humans. Genome-editing methods, especially the CRISPR (clustered regularly interspaced short palindromic repeats)–Cas9 (CRISPR-associated protein 9) system, hold clinical potential for curing many monogenic disorders, including neuromuscular diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1. OBJECTIVES To provide an overview of genome-editing approaches; to summarize published reports on the feasibility, efficacy, and safety of current genome-editing methods as they relate to the potential correction of monogenic neuromuscular diseases; and to highlight scientific and clinical opportunities and obstacles toward permanent correction of disease-causing mutations responsible for monogenic neuromuscular diseases by genome editing. EVIDENCE REVIEW PubMed and Google Scholar were searched for articles published from June 30, 1989, through June 9, 2016, using the following keywords: genome editing, CRISPR-Cas9, neuromuscular disease, Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, andmyotonic dystrophy type 1. The following sources were reviewed: 341 articles describing different approaches to edit mammalian genomes; 330 articles describing CRISPR-Cas9–mediated genome editing in cell culture lines (in vitro) and animal models (in vivo); 16 websites used to generate single-guide RNA; 4 websites for off-target effects; and 382 articles describing viral and nonviral delivery systems. Articles describing neuromuscular diseases, including Duchenne muscular dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, and myotonic dystrophy type 1, were also reviewed. FINDINGS Multiple proof-of-concept studies reveal the feasibility and efficacy of genome-editing–meditated correction of monogenic neuromuscular diseases in cultured cells and animal models. CONCLUSIONS AND RELEVANCE Genome editing is a rapidly evolving technology with enormous translational potential once efficacy, delivery, and safety issues are addressed. The clinical impact of this technology is that genome editing can permanently correct disease-causing mutations and circumvent the hurdles of traditional gene- and cell-based therapies. PMID:27668807

Reliable and versatile immortal muscle cell models from healthy and myotonic dystrophy type 1 primary human myoblasts.

PubMed

Pantic, Boris; Borgia, Doriana; Giunco, Silvia; Malena, Adriana; Kiyono, Tohru; Salvatori, Sergio; De Rossi, Anita; Giardina, Emiliano; Sangiuolo, Federica; Pegoraro, Elena; Vergani, Lodovica; Botta, Annalisa

2016-03-01

Primary human skeletal muscle cells (hSkMCs) are invaluable tools for deciphering the basic molecular mechanisms of muscle-related biological processes and pathological alterations. Nevertheless, their use is quite restricted due to poor availability, short life span and variable purity of the cells during in vitro culture. Here, we evaluate a recently published method of hSkMCs immortalization, relying on ectopic expression of cyclin D1 (CCND1), cyclin-dependent kinase 4 (CDK4) and telomerase (TERT) in myoblasts from healthy donors (n=3) and myotonic dystrophy type 1 (DM1) patients (n=2). The efficacy to maintain the myogenic and non-transformed phenotype, as well as the main pathogenetic hallmarks of DM1, has been assessed. Combined expression of the three genes i) maintained the CD56(NCAM)-positive myoblast population and differentiation potential; ii) preserved the non-transformed phenotype and iii) maintained the CTG repeat length, amount of nuclear foci and aberrant alternative splicing in immortal muscle cells. Moreover, immortal hSkMCs displayed attractive additional features such as structural maturation of sarcomeres, persistence of Pax7-positive cells during differentiation and complete disappearance of nuclear foci following (CAG)7 antisense oligonucleotide (ASO) treatment. Overall, the CCND1, CDK4 and TERT immortalization yields versatile, reliable and extremely useful human muscle cell models to investigate the basic molecular features of human muscle cell biology, to elucidate the molecular pathogenetic mechanisms and to test new therapeutic approaches for DM1 in vitro. Copyright © 2016 Elsevier Inc. All rights reserved.

[Steinert myotonic dystrophy and blepharoptosis surgery: 9 case reports].

PubMed

Karim, A; Schapiro, D; Morax, S

2003-01-01

Steinert myopathic dystrophy is a generalized, hereditary disease with bone, muscular, heart and ocular involvement. This is a retrospective study of nine patients with significant blepharoptosis due to Steinert disease, who were treated at the Adolphe de Rothschild Ophthalmology Foundation over a period of 5 years. Ptosis was symmetric and major in all cases with poor levator excursion. Severity criteria were an absence of the Bell phenomenon and diminished orbicularis tone. A frontalis suspension was performed in eight cases with intentional undercorrection. The outcome was favorable in all cases, 2 with a slight overcorrection underwent a second operation conclusion: Surgical treatment of ptosis in Steinert disease is difficult because of a risk of lagophthalmic, keratopathy due to the severity of the disease, an absence of the Bell phenomenon and ophthalmoplegia. This surgery must be undertaken with caution, most often using a frontalis suspension. Undercorrection must be systematic, with the single goal of freeing the pupil in the primary position.

[Neuromuscular diseases were always difficult to diagnose].

PubMed

Claus, D

2013-06-01

The Deutsche Zeitschrift fuer Nervenheilkunde (German Journal for Neurology) was founded as a specifically neurological journal at the end of the nineteenth century and soon became a European platform for scientific discussion of neurological topics. Papers also came from the USA, Scandinavia and Russia. The difficulties of the diagnosis and definition of clinical entities are illustrated in cases of botulism, myotonic dystrophy and myasthenia gravis.

Swallowing disorders in muscular diseases: functional assessment and indications of cricopharyngeal myotomy.

PubMed

St Guily, J L; Périé, S; Willig, T N; Chaussade, S; Eymard, B; Angelard, B

1994-01-01

Thirty-four patients with an identified muscular disease were referred to our department for assessment and treatment of swallowing difficulties. Their ages ranged from 16 to 91 years (mean 59). The diagnoses were oculopharyngeal dystrophy in 17 patients, Steinert myotonic dystrophy in 6, mitochondrial myopathies in 4, polymyositis in 3, and other types in 4 patients. The main consequences of the dysphagia were weight loss (12 patients), pulmonary infections (15 patients), modified food consistency (18 patients) and non-oral feeding (3 patients). Several techniques were used to assess the different stages of deglutition: physical examination during swallowing, videofluoroscopy, pharyngoesophageal manometry, videofibroscopy of the pharynx during swallowing. Major pathological features found in the pharynx were decreased pharynx peristaltis and impaired UES relaxation. Cricopharyngeal myotomy was performed in 11 myopathic patients (median follow-up 24.9 months), while it was unnecessary, refused or contraindicated in the other patients. The procedure was successful in 8 patients whose dysphagia was dramatically improved, and failed in 3 patients. Pharyngeal perstaltis was severely impaired only in the 3 failures and was partly preserved in the improved cases. We conclude that pharyngeal function is the major prognostic factor. Cricopharyngeal myotomy is an effective treatment in those cases where cricopharyngeal dysfunction is a predominant problem or where pharyngeal peristaltis is partly impaired, since the procedure removes one obstacle. It is contraindicated when pharynx propulsion is severely impaired.

Analysis of CTG repeat length variation in the DMPK gene in the general population and the molecular diagnosis of myotonic dystrophy type 1 in Malaysia.

PubMed

Ambrose, Kathlin K; Ishak, Taufik; Lian, Lay-Hoong; Goh, Khean-Jin; Wong, Kum-Thong; Ahmad-Annuar, Azlina; Thong, Meow-Keong

2017-03-31

The lack of epidemiological data and molecular diagnostic services in Malaysia has hampered the setting-up of a comprehensive management plan for patients with myotonic dystrophy type 1 (DM1), leading to delayed diagnosis, treatment and support for patients and families. The aim of this study was to estimate the prevalence of DM1 in the 3 major ethnic groups in Malaysia and evaluate the feasibility of a single tube triplet-primed PCR (TP-PCR) method for diagnosis of DM1 in Malaysia. We used PCR to determine the size of CTG repeats in 377 individuals not known to be affected by DM and 11 DM1 suspected patients, recruited from a tertiary hospital in Kuala Lumpur. TP-PCR was performed on selected samples, followed by Southern blot hybridisation of PCR amplified fragments to confirm and estimate the size of CTG expansion. The number of individuals not known to be affected by DM with (CTG) >18 was determined according to ethnic group and as a whole population. The χ 2 test was performed to compare the distribution of (CTG) >18 with 12 other populations. Additionally, the accuracy of TP-PCR in detecting CTG expansion in 11 patients with DM1 was determined by comparing the results with that from Southern blot hybridisation. Of the 754 chromosomes studied, (CTG) >18 frequency of 3.60%, 1.57% and 4.00% in the Malay, Chinese and Indian subpopulations, respectively, was detected, showing similarities to data from Thai, Taiwanese and Kuwaiti populations. We also successfully detected CTG expansions in 9 patients using the TP-PCR method followed by the estimation of CTG expansion size via Southern blot hybridisation. The results show a low DM1 prevalence in Malaysia with the possibility of underdiagnosis and demonstrates the feasibility of using a clinical and TP-PCR-based approach for rapid and cost-effective DM1 diagnosis in developing countries. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Analysis of CTG repeat length variation in the DMPK gene in the general population and the molecular diagnosis of myotonic dystrophy type 1 in Malaysia

PubMed Central

Ambrose, Kathlin K; Ishak, Taufik; Lian, Lay-Hoong; Goh, Khean-Jin; Wong, Kum-Thong; Ahmad-Annuar, Azlina; Thong, Meow-Keong

2017-01-01

Objective The lack of epidemiological data and molecular diagnostic services in Malaysia has hampered the setting-up of a comprehensive management plan for patients with myotonic dystrophy type 1 (DM1), leading to delayed diagnosis, treatment and support for patients and families. The aim of this study was to estimate the prevalence of DM1 in the 3 major ethnic groups in Malaysia and evaluate the feasibility of a single tube triplet-primed PCR (TP-PCR) method for diagnosis of DM1 in Malaysia. Design, setting and participants We used PCR to determine the size of CTG repeats in 377 individuals not known to be affected by DM and 11 DM1 suspected patients, recruited from a tertiary hospital in Kuala Lumpur. TP-PCR was performed on selected samples, followed by Southern blot hybridisation of PCR amplified fragments to confirm and estimate the size of CTG expansion. Outcome measures The number of individuals not known to be affected by DM with (CTG)>18 was determined according to ethnic group and as a whole population. The χ2 test was performed to compare the distribution of (CTG)>18 with 12 other populations. Additionally, the accuracy of TP-PCR in detecting CTG expansion in 11 patients with DM1 was determined by comparing the results with that from Southern blot hybridisation. Results Of the 754 chromosomes studied, (CTG)>18 frequency of 3.60%, 1.57% and 4.00% in the Malay, Chinese and Indian subpopulations, respectively, was detected, showing similarities to data from Thai, Taiwanese and Kuwaiti populations. We also successfully detected CTG expansions in 9 patients using the TP-PCR method followed by the estimation of CTG expansion size via Southern blot hybridisation. Conclusions The results show a low DM1 prevalence in Malaysia with the possibility of underdiagnosis and demonstrates the feasibility of using a clinical and TP-PCR-based approach for rapid and cost-effective DM1 diagnosis in developing countries. PMID:28363916

Ventricular dysfunction in type 1 myotonic dystrophy: electrical, mechanical, or both?

PubMed

Lindqvist, P; Mörner, S; Olofsson, B O; Backman, C; Lundblad, D; Forsberg, H; Henein, M Y

2010-09-03

Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR≥200 ms, 11 had QRS duration>120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

MKBP, a Novel Member of the Small Heat Shock Protein Family, Binds and Activates the Myotonic Dystrophy Protein Kinase

PubMed Central

Suzuki, Atsushi; Sugiyama, Yuki; Hayashi, Yukiko; Nyu-i, Nobuo; Yoshida, Michihiko; Nonaka, Ikuya; Ishiura, Sho-ichi; Arahata, Kiichi; Ohno, Shigeo

1998-01-01

Muscle cells are frequently subjected to severe conditions caused by heat, oxidative, and mechanical stresses. The small heat shock proteins (sHSPs) such as αB-crystallin and HSP27, which are highly expressed in muscle cells, have been suggested to play roles in maintaining myofibrillar integrity against such stresses. Here, we identified a novel member of the sHSP family that associates specifically with myotonic dystrophy protein kinase (DMPK). This DMPK-binding protein, MKBP, shows a unique nature compared with other known sHSPs: (a) In muscle cytosol, MKBP exists as an oligomeric complex separate from the complex formed by αB-crystallin and HSP27. (b) The expression of MKBP is not induced by heat shock, although it shows the characteristic early response of redistribution to the insoluble fraction like other sHSPs. Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-membrane as well as the neuromuscular junction, where DMPK has been suggested to be concentrated. In vitro, MKBP enhances the kinase activity of DMPK and protects it from heat-induced inactivation. These results suggest that MKBP constitutes a novel stress-responsive system independent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP. Importantly, since the amount of MKBP protein, but not that of other sHSP family member proteins, is selectively upregulated in skeletal muscle from DM patients, an interaction between DMPK and MKBP may be involved in the pathogenesis of DM. PMID:9490724

Gender as a Modifying Factor Influencing Myotonic Dystrophy Type 1 Phenotype Severity and Mortality: A Nationwide Multiple Databases Cross-Sectional Observational Study.

PubMed

Dogan, Celine; De Antonio, Marie; Hamroun, Dalil; Varet, Hugo; Fabbro, Marianne; Rougier, Felix; Amarof, Khadija; Arne Bes, Marie-Christine; Bedat-Millet, Anne-Laure; Behin, Anthony; Bellance, Remi; Bouhour, Françoise; Boutte, Celia; Boyer, François; Campana-Salort, Emmanuelle; Chapon, Françoise; Cintas, Pascal; Desnuelle, Claude; Deschamps, Romain; Drouin-Garraud, Valerie; Ferrer, Xavier; Gervais-Bernard, Helene; Ghorab, Karima; Laforet, Pascal; Magot, Armelle; Magy, Laurent; Menard, Dominique; Minot, Marie-Christine; Nadaj-Pakleza, Aleksandra; Pellieux, Sybille; Pereon, Yann; Preudhomme, Marguerite; Pouget, Jean; Sacconi, Sabrina; Sole, Guilhem; Stojkovich, Tanya; Tiffreau, Vincent; Urtizberea, Andoni; Vial, Christophe; Zagnoli, Fabien; Caranhac, Gilbert; Bourlier, Claude; Riviere, Gerard; Geille, Alain; Gherardi, Romain K; Eymard, Bruno; Puymirat, Jack; Katsahian, Sandrine; Bassez, Guillaume

2016-01-01

Myotonic Dystrophy type 1 (DM1) is one of the most heterogeneous hereditary disease in terms of age of onset, clinical manifestations, and severity, challenging both medical management and clinical trials. The CTG expansion size is the main factor determining the age of onset although no factor can finely predict phenotype and prognosis. Differences between males and females have not been specifically reported. Our aim is to study gender impact on DM1 phenotype and severity. We first performed cross-sectional analysis of main multiorgan clinical parameters in 1409 adult DM1 patients (>18 y) from the DM-Scope nationwide registry and observed different patterns in males and females. Then, we assessed gender impact on social and economic domains using the AFM-Téléthon DM1 survey (n = 970), and morbidity and mortality using the French National Health Service Database (n = 3301). Men more frequently had (1) severe muscular disability with marked myotonia, muscle weakness, cardiac, and respiratory involvement; (2) developmental abnormalities with facial dysmorphism and cognitive impairment inferred from low educational levels and work in specialized environments; and (3) lonely life. Alternatively, women more frequently had cataracts, dysphagia, digestive tract dysfunction, incontinence, thyroid disorder and obesity. Most differences were out of proportion to those observed in the general population. Compared to women, males were more affected in their social and economic life. In addition, they were more frequently hospitalized for cardiac problems, and had a higher mortality rate. Gender is a previously unrecognized factor influencing DM1 clinical profile and severity of the disease, with worse socio-economic consequences of the disease and higher morbidity and mortality in males. Gender should be considered in the design of both stratified medical management and clinical trials.

The myotonic dystrophy kinase 3{prime}-untranslated region and its effect on gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ang, C.W.Y.; Sabourin, L.A.; Narang, M.A.

1994-09-01

Myotonic dystrophy (DM) is an autosomal dominant neuromuscular disease involving the expansion of an unstable CTG repeat in the 3{prime}-untranslated (3{prime}-UTR) region of the DM kinase (DMK) gene. Increased levels of mRNA in congenital compared to normal tissue have been shown, suggesting elevated DMK levels may be responsible for the disease phenotype. To study the effect of the DMK 3{prime}UTR on gene expression, a reporter gene system was constructed using the constitutive CMV promoter with the chloramphenicol acetyl transferase (CAT) open reading frame and the DMK 3{prime}UTR containing from 5 repeats up to 90 repeats. Transient transfection into a rhabdomyosarcomamore » cell line shows a three-fold increase in CAT activity from constructs containing a wildtype 3{prime}UTR (5 and 20 repeats) compared to a control construct containing only a poly(A) signal. Reporter constructs with repeats in the protomutation (50 repeats) and mutation (90 repeats) range show a greater than 10-fold increase over control CAT activity. These results suggest the presence of elements in the DMK 3{prime}UTR capable of conferring increased gene expression. We are currently investigating cell-specific activity of the constructs and conducting deletion mapping to identify regulatory elements in the 3{prime}-UTR.« less

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I.

PubMed

Brockhoff, Marielle; Rion, Nathalie; Chojnowska, Kathrin; Wiktorowicz, Tatiana; Eickhorst, Christopher; Erne, Beat; Frank, Stephan; Angelini, Corrado; Furling, Denis; Rüegg, Markus A; Sinnreich, Michael; Castets, Perrine

2017-02-01

Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.

Functioning and disability in adults with myotonic dystrophy type 1.

PubMed

Kierkegaard, Marie; Harms-Ringdahl, Karin; Holmqvist, Lotta Widén; Tollbäck, Anna

2011-01-01

 To provide a comprehensive description of functioning and disability with regard to stages of disease progression in adults with myotonic dystrophy type 1 (DM1). Further to explore associations of measures of manual dexterity and of walking capacity with measures of activities of daily living (ADL) and participation in social and lifestyle activities. Seventy persons with DM1 underwent examinations, tests and answered questionnaires. Stages of disease progression were based on the muscular impairment rating scale.  Overweight, cardiac dysfunctions, respiratory restrictions, fatigue and/or low physical activity levels were found in approximately 40% of those with DM1. Over 75% had muscle impairments, and activity limitations in manual dexterity and walking. Dependence in personal and instrumental ADL was found in 16% and 39%, respectively, and participation restrictions in social and lifestyle activities in 52%. The presence of concurrent body-function impairments, activity limitations and participation restrictions was high. Significant differences were found in muscle impairment, manual dexterity, mobility, ADL and social and lifestyle activities with regard to disease progression. Cut-off values in measures of manual dexterity and walking capacity associated to functioning are proposed.  This information can be used for developing clinical practise and for health promotion for persons with DM1.

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

PubMed Central

Brockhoff, Marielle; Rion, Nathalie; Chojnowska, Kathrin; Wiktorowicz, Tatiana; Eickhorst, Christopher; Erne, Beat; Frank, Stephan; Angelini, Corrado; Rüegg, Markus A.; Sinnreich, Michael

2017-01-01

Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3′-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease. PMID:28067669

Quantitative Methods to Monitor RNA Biomarkers in Myotonic Dystrophy.

PubMed

Wojciechowska, Marzena; Sobczak, Krzysztof; Kozlowski, Piotr; Sedehizadeh, Saam; Wojtkowiak-Szlachcic, Agnieszka; Czubak, Karol; Markus, Robert; Lusakowska, Anna; Kaminska, Anna; Brook, J David

2018-04-12

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are human neuromuscular disorders associated with mutations of simple repetitive sequences in affected genes. The abnormal expansion of CTG repeats in the 3'-UTR of the DMPK gene elicits DM1, whereas elongated CCTG repeats in intron 1 of ZNF9/CNBP triggers DM2. Pathogenesis of both disorders is manifested by nuclear retention of expanded repeat-containing RNAs and aberrant alternative splicing. The precise determination of absolute numbers of mutant RNA molecules is important for a better understanding of disease complexity and for accurate evaluation of the efficacy of therapeutic drugs. We present two quantitative methods, Multiplex Ligation-Dependent Probe Amplification and droplet digital PCR, for studying the mutant DMPK transcript (DMPK exp RNA) and the aberrant alternative splicing in DM1 and DM2 human tissues and cells. We demonstrate that in DM1, the DMPK exp RNA is detected in higher copy number than its normal counterpart. Moreover, the absolute number of the mutant transcript indicates its low abundance with only a few copies per cell in DM1 fibroblasts. Most importantly, in conjunction with fluorescence in-situ hybridization experiments, our results suggest that in DM1 fibroblasts, the vast majority of nuclear RNA foci consist of a few molecules of DMPK exp RNA.

In vitro mapping of Myotonic Dystrophy (DM) gene promoter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Storbeck, C.J.; Sabourin, L.; Baird, S.

1994-09-01

The Myotonic Dystrophy Kinase (DMK) gene has been cloned and shared homology to serine/threonine protein kinases. Overexpression of this gene in stably transfected mouse myoblasts has been shown to inhibit fusion into myotubes while myoblasts stably transfected with an antisense construct show increased fusion potential. These experiments, along with data showing that the DM gene is highly expressed in muscle have highlighted the possibility of DMK being involved in myogenesis. The promoter region of the DM gene lacks a consensus TATA box and CAAT box, but harbours numerous transcription binding sites. Clones containing extended 5{prime} upstream sequences (UPS) of DMKmore » only weakly drive the reporter gene chloramphenicol acetyl transferase (CAT) when transfected into C2C12 mouse myoblasts. However, four E-boxes are present in the first intron of the DM gene and transient assays show increased expression of the CAT gene when the first intron is present downstream of these 5{prime} UPS in an orientation dependent manner. Comparison between mouse and human sequence reveals that the regions in the first intron where the E-boxes are located are highly conserved. The mapping of the promoter and the importance of the first intron in the control of DMK expression will be presented.« less

Chronic muscle stimulation improves muscle function and reverts the abnormal surface EMG pattern in Myotonic Dystrophy: a pilot study

PubMed Central

2013-01-01

Background To date, in Myotonic Dystrophy type 1 (DM1) the rehabilitative interventions have always been aimed at muscle strengthening, increasing of fatigue resistance and improving of aerobic metabolism efficiency whereas the electrical membrane fault has always been addressed pharmacologically. Neuromuscular electrical stimulation (NMES) is a useful therapeutic tool in sport medicine and in the rehabilitation of many clinical conditions characterized by motor impairment such as stroke, cerebral palsy and spinal cord injury. The aim of our pilot study was to evaluate the effects of chronic electrical stimulation both on functional and electrical properties of muscle in a small group of DM1 patients. Methods Five DM1 patients and one patient with Congenital Myotonia (CM) performed a home electrical stimulation of the tibialis anterior muscle lasting 15 days with a frequency of two daily sessions of 60 minutes each. Muscle strength was assessed according to the MRC scale (Medical Research Council) and functional tests (10 Meter Walking Test, 6 Minutes Walking Test and Timed Up and Go Test) were performed. We analyzed the average rectified value of sEMG signal amplitude (ARV) to characterize the sarcolemmal excitability. Results After the treatment an increase of muscle strength in those DM1 patients with a mild strength deficit was observed. In all subjects an improvement of 10MWT was recorded. Five patients improved their performance in the 6MWT. In TUG test 4 out of 6 patients showed a slight reduction in execution time. All patients reported a subjective improvement when walking. A complete recovery of the normal increasing ARV curve was observed in 4 out of 5 DM1 patients; the CM patient didn’t show modification of the ARV pattern. Conclusions NMES determined a clear-cut improvement of both the muscular weakness and the sarcolemmal excitability alteration in our small group of DM1 patients. Therefore this rehabilitative approach, if confirmed by further extensive studies, could be considered early in the management of muscular impairment in these patients. An attractive hypothesis to explain our encouraging result could be represented by a functional inhibition of SK3 channels expressed in muscle of DM1 subjects. PMID:23938156

Cancer Risk among Patients with Myotonic Muscular Dystrophy

PubMed Central

Gadalla, Shahinaz M; Lund, Marie; Pfeiffer, Ruth M; Gørtz, Sanne; Mueller, Christine M; Moxley, Richard T; Kristinsson, Sigurdur Y; Björkholm, Magnus; Shebl, Fatma M; Hilbert, James E; Landgren, Ola; Wohlfahrt, Jan; Melbye, Mads; Greene, Mark H

2012-01-01

Context Myotonic muscular dystrophy (MMD) is an autosomal dominant multisystem neuromuscular disorder characterized by unstable nucleotide repeat expansions. Case reports have suggested that MMD patients may be at increased risk of malignancy, putative risks which have never been quantified. Objective To quantitatively evaluate cancer risk in patients with MMD, overall, and by sex and age. Design, Setting, and Participants We identified 1,658 patients with an MMD discharge diagnosis in the Swedish Inpatient Hospital or Danish Patient Discharge Registries between 1977 and 2008. We linked these patients to their corresponding cancer registry. Patients were followed from date of first MMD-related inpatient or outpatient contact, to first cancer diagnosis, death, emigration, or completion of cancer registration. Main Outcome Measures Risks of all cancers combined, and by anatomic site, stratified by sex and age. Results 104 patients with an inpatient or outpatient discharge diagnosis of MMD developed cancer during post-discharge follow-up. This corresponds to an observed cancer rate of 73.4/10,000 person-years in MMD versus an expected rate of 36.9/10,000 in the general Swedish and Danish populations combined (SIR =2.0, 95% CI =1.6–2.4). Specifically, we observed significant excess risks of cancers of the endometrium (observed rate=16.1/10,000 person-years: SIR=7.6, 95%CI=4.0–13.2), brain (observed rate=4.9/10,000 person-years: SIR=5.3, 95%CI=2.3–10.4), ovary (observed rate=10.3/10,000 person-years: SIR=5.2, 95% CI=2.3–10.2), and colon (observed rate=7.1/10,000 person-years: SIR=2.9, 95%CI=1.5–5.1). Cancer risks were similar in females and males after excluding genital organ tumors (SIR=1.9, 95% CI=1.4–2.5 vs. 1.8, 95% CI=1.3–2.5, respectively, p-heterogeneity=0.81; observed rates=64.5 and 47.7/10,000 person-years in women and men, respectively), The same pattern of cancer excess was observed first in the Swedish, and then in the Danish cohorts, which were studied sequentially and initially analyzed independently. Conclusions MMD patients identified from the Swedish and Danish patient registries were at increased risk of cancer both overall and for selected anatomic sites. PMID:22166607

Scoliosis in Steinert syndrome: a case report.

PubMed

Themistocleous, George S; Sapkas, George S; Papagelopoulos, Panayiotis J; Stilianessi, Eugenia V; Papadopoulos, Elias Ch; Apostolou, Constantinos D

2005-01-01

Steinert syndrome is described as an autosomal dominant condition characterized by progressive muscular wasting, myotonia, musculoskeletal manifestations and rare spinal defects. Little is reported about spinal deformity associated with this syndrome. We present a patient with Steinert syndrome complicated by scoliosis. In the literature on muscular dystrophy, other than Duchenne, little mention is given to the problem of scoliosis in general and its treatment in particular. A case report of a patient with Steinert syndrome associated with thoracic scoliosis and hypokyphosis is presented. A 17-year-old boy presented with King type II right thoracic scoliosis (T5-T11, Cobb angle of 40 degrees) and hypokyphosis--10 degrees. He was treated with posterior stabilization and instrumentation at level T3-L2 with a postoperative correction of the scoliotic curve to 20 degrees. Histopathologic examination of the muscles confirmed the diagnosis of Steinert myotonic dystrophy. At 30-month follow-up, the patient was clinically pain free and well balanced. Plain radiographs showed solid spine fusion with no loss of deformity correction. Scoliosis in Steinert syndrome shares the characteristic of an arthrogrypotic neuromuscular curve and demands the extensive soft tissue release for optimal surgical correction. Intraoperative observations included profound tissue bleeding, abnormally tough soft tissues and a difficult recovery from anaesthesia.

[Combined spinal-epidural anesthesia for cesarean section in a parturient with myotonic dystrophy].

PubMed

Mori, Kosuke; Mizuno, Ju; Nagaoka, Takehiko; Harashima, Toshiya; Morita, Sigeho

2010-08-01

Myotonic dystrophy (MD) is a muscle disorder characterized by progressive muscle wasting and weakness, and is the most common form of muscular dystrophy that begins in adulthood, often after pregnancy. MD might be related to occurrence of malignant hyperthermia. Therefore, the cesarean section is often performed for the parturient with MD. We had an experience of combined spinal-epidural anesthesia for cesarean section in a parturient complicated with MD. A 40-year-old woman had rhabdomyolysis caused by ritodrine at 15-week gestation and was diagnosed as MD by electromyography. Her first baby died due to respiratory failure fourth day after birth. She had hatchet face, slight weakness of her lower extremities, and easy fatigability. Her manual muscle test was 5/5 at upper extremities and 4/5 at lower extremities. She underwent emergency cesarean section for premature rupture of the membrane, weak pain during labor, and obstructed labor at 33-week gestation. We placed an epidural catheter from T12/L1 and punctured arachnoid with 25 G spinal needle. We performed spinal anesthesia using 0.5% hyperbaric bupivacaine 1.5 ml and epidural anesthesia using 2% lidocaine 6 ml. Her anesthetic level reached bilaterally to T7 and operation started 18 minutes after combined spinal-epidural anesthesia. Her baby was born 23 minutes after the anesthesia. As her baby was 1/5 at Apgar score, the baby was tracheally intubated and artificially ventilated. The cesarean section was finished in 33 minutes uneventfully. She had no adverse events and was discharged on the 8th postoperative day. Later her baby was diagnosed as congenital MD by gene analysis. Combined spinal-epidural anesthesia with the amide-typed local anesthetic agents could be useful and safe for cesarean section in the parturient with MD.

Identification and Characterization of Modified Antisense Oligonucleotides Targeting DMPK in Mice and Nonhuman Primates for the Treatment of Myotonic Dystrophy Type 1

PubMed Central

Wheeler, Thurman M.; Justice, Samantha L.; Kim, Aneeza; Younis, Husam S.; Gattis, Danielle; Jauvin, Dominic; Puymirat, Jack; Swayze, Eric E.; Freier, Susan M.; Bennett, C. Frank; Thornton, Charles A.; MacLeod, A. Robert

2015-01-01

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by an expanded CTG repeat in the 3′-untranslated region of DMPK, the gene encoding dystrophia myotonica protein kinase (DMPK). Antisense oligonucleotides (ASOs) containing 2′,4′-constrained ethyl-modified (cEt) residues exhibit a significantly increased RNA binding affinity and in vivo potency relative to those modified with other 2′-chemistries, which we speculated could translate to enhanced activity in extrahepatic tissues, such as muscle. Here, we describe the design and characterization of a cEt gapmer DMPK ASO (ISIS 486178), with potent activity in vitro and in vivo against mouse, monkey, and human DMPK. Systemic delivery of unformulated ISIS 486718 to wild-type mice decreased DMPK mRNA levels by up to 90% in liver and skeletal muscle. Similarly, treatment of either human DMPK transgenic mice or cynomolgus monkeys with ISIS 486178 led to up to 70% inhibition of DMPK in multiple skeletal muscles and ∼50% in cardiac muscle in both species. Importantly, inhibition of DMPK was well tolerated and was not associated with any skeletal muscle or cardiac toxicity. Also interesting was the demonstration that the inhibition of DMPK mRNA levels in muscle was maintained for up to 16 and 13 weeks post-treatment in mice and monkeys, respectively. These results demonstrate that cEt-modified ASOs show potent activity in skeletal muscle, and that this attractive therapeutic approach warrants further clinical investigation to inhibit the gain-of-function toxic RNA underlying the pathogenesis of DM1. PMID:26330536

Identification and characterization of modified antisense oligonucleotides targeting DMPK in mice and nonhuman primates for the treatment of myotonic dystrophy type 1.

PubMed

Pandey, Sanjay K; Wheeler, Thurman M; Justice, Samantha L; Kim, Aneeza; Younis, Husam S; Gattis, Danielle; Jauvin, Dominic; Puymirat, Jack; Swayze, Eric E; Freier, Susan M; Bennett, C Frank; Thornton, Charles A; MacLeod, A Robert

2015-11-01

Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy in adults. DM1 is caused by an expanded CTG repeat in the 3'-untranslated region of DMPK, the gene encoding dystrophia myotonica protein kinase (DMPK). Antisense oligonucleotides (ASOs) containing 2',4'-constrained ethyl-modified (cEt) residues exhibit a significantly increased RNA binding affinity and in vivo potency relative to those modified with other 2'-chemistries, which we speculated could translate to enhanced activity in extrahepatic tissues, such as muscle. Here, we describe the design and characterization of a cEt gapmer DMPK ASO (ISIS 486178), with potent activity in vitro and in vivo against mouse, monkey, and human DMPK. Systemic delivery of unformulated ISIS 486718 to wild-type mice decreased DMPK mRNA levels by up to 90% in liver and skeletal muscle. Similarly, treatment of either human DMPK transgenic mice or cynomolgus monkeys with ISIS 486178 led to up to 70% inhibition of DMPK in multiple skeletal muscles and ∼50% in cardiac muscle in both species. Importantly, inhibition of DMPK was well tolerated and was not associated with any skeletal muscle or cardiac toxicity. Also interesting was the demonstration that the inhibition of DMPK mRNA levels in muscle was maintained for up to 16 and 13 weeks post-treatment in mice and monkeys, respectively. These results demonstrate that cEt-modified ASOs show potent activity in skeletal muscle, and that this attractive therapeutic approach warrants further clinical investigation to inhibit the gain-of-function toxic RNA underlying the pathogenesis of DM1. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

The CNDR: collaborating to translate new therapies for Canadians.

PubMed

Korngut, Lawrence; Campbell, Craig; Johnston, Megan; Benstead, Timothy; Genge, Angela; Mackenzie, Alex; McCormick, Anna; Biggar, Douglas; Bourque, Pierre; Briemberg, Hannah; O'Connell, Colleen; Dojeiji, Suzan; Dooley, Joseph; Grant, Ian; Hogan, Gillian; Johnston, Wendy; Kalra, Sanjay; Katzberg, Hans D; Mah, Jean K; McAdam, Laura; McMillan, Hugh J; Melanson, Michel; Selby, Kathryn; Shoesmith, Christen; Smith, Garth; Venance, Shannon L; Wee, Joy

2013-09-01

Patient registries represent an important method of organizing "real world" patient information for clinical and research purposes. Registries can facilitate clinical trial planning and recruitment and are particularly useful in this regard for uncommon and rare diseases. Neuromuscular diseases (NMDs) are individually rare but in aggregate have a significant prevalence. In Canada, information on NMDs is lacking. Barriers to performing Canadian multicentre NMD research exist which can be overcome by a comprehensive and collaborative NMD registry. We describe the objectives, design, feasibility and initial recruitment results for the Canadian Neuromuscular Disease Registry (CNDR). The CNDR is a clinic-based registry which launched nationally in June 2011, incorporates paediatric and adult neuromuscular clinics in British Columbia, Alberta, Ontario, Quebec, New Brunswick and Nova Scotia and, as of December 2012, has recruited 1161 patients from 12 provinces and territories. Complete medical datasets have been captured on 460 "index disease" patients. Another 618 "non-index" patients have been recruited with capture of physician-confirmed diagnosis and contact information. We have demonstrated the feasibility of blended clinic and central office-based recruitment. "Index disease" patients recruited at the time of writing include 253 with Duchenne and Becker muscular dystrophy, 161 with myotonic dystrophy, and 71 with ALS. The CNDR is a new nationwide registry of patients with NMDs that represents an important advance in Canadian neuromuscular disease research capacity. It provides an innovative platform for organizing patient information to facilitate clinical research and to expedite translation of recent laboratory findings into human studies.

Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity.

PubMed

Childs-Disney, Jessica L; Yildirim, Ilyas; Park, HaJeung; Lohman, Jeremy R; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C; Disney, Matthew D

2014-02-21

Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)(exp)) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5'CCUG/3'GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 Å. Structural analysis of the three 5'CCUG/3'GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na(+) and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5'CCUG/3'GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops.

Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules That Reduce Toxicity

PubMed Central

Park, HaJeung; Lohman, Jeremy R.; Guan, Lirui; Tran, Tuan; Sarkar, Partha; Schatz, George C.; Disney, Matthew D.

2014-01-01

Myotonic dystrophy type 2 (DM2) is an untreatable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)exp) that folds into an extended hairpin with periodically repeating 2×2 nucleotide internal loops (5’CCUG/3’GUCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA-small molecule interactions. We also report the first crystal structure of r(CCUG)exp refined to 2.35 Å. Structural analysis of the three 5’CCUG/3’GUCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na+ and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5’CCUG/3’GUCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops. PMID:24341895

Rational design of bioactive, modularly assembled aminoglycosides targeting the RNA that causes myotonic dystrophy type 1.

PubMed

Childs-Disney, Jessica L; Parkesh, Raman; Nakamori, Masayuki; Thornton, Charles A; Disney, Matthew D

2012-12-21

Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)(exp)) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6'-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)(exp). However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a d-Arg(9) molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)(exp); pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA.

Rational Design of Bioactive, Modularly Assembled Aminoglycosides Targeting the RNA that Causes Myotonic Dystrophy Type 1

PubMed Central

Childs-Disney, Jessica L.; Parkesh, Raman; Nakamori, Masayuki; Thornton, Charles A.; Disney, Matthew D.

2012-01-01

Myotonic dystrophy type 1 (DM1) is caused when an expanded r(CUG) repeat (r(CUG)exp) binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1) as well as other proteins. Previously, we reported that modularly assembled small molecules displaying a 6′-N-5-hexynoate kanamycin A RNA-binding module (K) on a peptoid backbone potently inhibit the binding of MBNL1 to r(CUG)exp. However, these parent compounds are not appreciably active in cell-based models of DM1. The lack of potency was traced to suboptimal cellular permeability and localization. To improve these properties, second-generation compounds that are conjugated to a D-Arg9 molecular transporter were synthesized. These modified compounds enter cells in higher concentrations than the parent compounds and are efficacious in cell-based DM1 model systems at low micromolar concentrations. In particular, they improve three defects that are the hallmarks of DM1: a translational defect due to nuclear retention of transcripts containing r(CUG)exp; pre-mRNA splicing defects due to inactivation of MBNL1; and the formation of nuclear foci. The best compound in cell-based studies was tested in a mouse model of DM1. Modest improvement of pre-mRNA splicing defects was observed. These studies suggest that a modular assembly approach can afford bioactive compounds that target RNA. PMID:23130637

Elevation of RNA-binding protein CUGBP1 is an early event in an inducible heart-specific mouse model of myotonic dystrophy

PubMed Central

Wang, Guey-Shin; Kearney, Debra L.; De Biasi, Mariella; Taffet, George; Cooper, Thomas A.

2007-01-01

Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide expansion in the 3′ untranslated region (3′ UTR) of DM protein kinase (DMPK). The key feature of DM1 pathogenesis is nuclear accumulation of RNA, which causes aberrant alternative splicing of specific pre-mRNAs by altering the functions of CUG-binding proteins (CUGBPs). Cardiac involvement occurs in more than 80% of individuals with DM1 and is responsible for up to 30% of disease-related deaths. We have generated an inducible and heart-specific DM1 mouse model expressing expanded CUG RNA in the context of DMPK 3′ UTR that recapitulated pathological and molecular features of DM1 including dilated cardiomyopathy, arrhythmias, systolic and diastolic dysfunction, and misregulated alternative splicing. Combined in situ hybridization and immunofluorescent staining for CUGBP1 and CUGBP2, the 2 CUGBP1 and ETR-3 like factor (CELF) proteins expressed in heart, demonstrated elevated protein levels specifically in nuclei containing foci of CUG repeat RNA. A time-course study demonstrated that colocalization of MBNL1 with RNA foci and increased CUGBP1 occurred within hours of induced expression of CUG repeat RNA and coincided with reversion to embryonic splicing patterns. These results indicate that CUGBP1 upregulation is an early and primary response to expression of CUG repeat RNA. PMID:17823658

Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for Development of Autologous Stem Cell Therapy.

PubMed

Gao, Yuanzheng; Guo, Xiuming; Santostefano, Katherine; Wang, Yanlin; Reid, Tammy; Zeng, Desmond; Terada, Naohiro; Ashizawa, Tetsuo; Xia, Guangbin

2016-08-01

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.

Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy

PubMed Central

Kanadia, Rahul N.; Shin, Jihae; Yuan, Yuan; Beattie, Stuart G.; Wheeler, Thurman M.; Thornton, Charles A.; Swanson, Maurice S.

2006-01-01

RNA-mediated pathogenesis is a recently developed disease model that proposes that certain types of mutant genes produce toxic transcripts that inhibit the activities of specific proteins. This pathogenesis model was proposed first for the neuromuscular disease myotonic dystrophy (DM), which is associated with the expansion of structurally related (CTG)n and (CCTG)n microsatellites in two unrelated genes. At the RNA level, these expansions form stable hairpins that alter the pre-mRNA splicing activities of two antagonistic factor families, the MBNL and CELF proteins. It is unclear which altered activity is primarily responsible for disease pathogenesis and whether other factors and biochemical pathways are involved. Here, we show that overexpression of Mbnl1 in vivo mediated by transduction of skeletal muscle with a recombinant adeno-associated viral vector rescues disease-associated muscle hyperexcitability, or myotonia, in the HSALR poly(CUG) mouse model for DM. Myotonia reversal occurs concurrently with restoration of the normal adult-splicing patterns of four pre-mRNAs that are misspliced during postnatal development in DM muscle. Our results support the hypothesis that the loss of MBNL1 activity is a primary pathogenic event in the development of RNA missplicing and myotonia in DM and provide a rationale for therapeutic strategies designed either to overexpress MBNL1 or inhibit MBNL1 interactions with CUG and CCUG repeat expansions. PMID:16864772

Hereditary myopathies with early respiratory insufficiency in adults.

PubMed

Naddaf, Elie; Milone, Margherita

2017-11-01

Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults. We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded. We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified. We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017. © 2017 Wiley Periodicals, Inc.

Is the epicardial left ventricular lead implantation an alternative approach to percutaneous attempt in patients with Steinert disease? A case report

PubMed Central

PAPA, ANDREA ANTONIO; RAGO, ANNA; PETILLO, ROBERTA; D’AMBROSIO, PAOLA; SCUTIFERO, MARIANNA; FEO, MARISA DE; MAIELLO, CIRO; PALLADINO, ALBERTO

2017-01-01

Steinert’s disease or Myotonic Dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder characterized by myotonia, muscle and facial weakness, cataracts, cognitive, endocrine and gastrointestinal involvement, and cardiac conduction abnormalities. Although mild myocardial dysfunction may be detected in this syndrome with age, overt myocardial dysfunction with heart failure is not frequent. Cardiac resynchronization therapy is an effective treatment to improve morbidity and reduce mortality in patients with DM1 showing intra-ventricular conduction delay and/or congestive heart failure. We report the case of a patient with Steinert disease showing an early onset ventricular dysfunction due to chronic right ventricular apical pacing, in which an epicardial left ventricular lead implantation was performed following the failure of the percutaneous attempt. As no relief in symptoms of heart failure, nor an improvement of left ventricular ejection fraction and reverse remodelling was observed six months later, the patient was addressed to the heart transplantation.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy

PubMed Central

Panaite, Petrica-Adrian; Kuntzer, Thierry; Gourdon, Geneviève; Lobrinus, Johannes Alexander; Barakat-Walter, Ibtissam

2013-01-01

SUMMARY Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1. PMID:23180777

Muscle wasting in myotonic dystrophies: a model of premature aging.

PubMed

Mateos-Aierdi, Alba Judith; Goicoechea, Maria; Aiastui, Ana; Fernández-Torrón, Roberto; Garcia-Puga, Mikel; Matheu, Ander; López de Munain, Adolfo

2015-01-01

Myotonic dystrophy type 1 (DM1 or Steinert's disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3' untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

Unravelling the myotonic dystrophy type 1 clinical spectrum: A systematic registry-based study with implications for disease classification.

PubMed

De Antonio, M; Dogan, C; Hamroun, D; Mati, M; Zerrouki, S; Eymard, B; Katsahian, S; Bassez, G

2016-10-01

The broad clinical spectrum of myotonic dystrophy type 1 (DM1) creates particular challenges for both medical care and design of clinical trials. Clinical onset spans a continuum from birth to late adulthood, with symptoms that are highly variable in both severity and nature of the affected organ systems. In the literature, this complex phenotype is divided into three grades (mild, classic, and severe) and four or five main clinical categories (congenital, infantile/juvenile, adult-onset and late-onset forms), according to symptom severity and age of onset, respectively. However, these classifications are still under discussion with no consensus thus far. While some specific clinical features have been primarily reported in some forms of the disease, there are no clear distinctions. As a consequence, no modifications in the management of healthcare or the design of clinical studies have been proposed based on the clinical form of DM1. The present study has used the DM-Scope registry to assess, in a large cohort of DM1 patients, the robustness of a classification divided into five clinical forms. Our main aim was to describe the disease spectrum and investigate features of each clinical form. The five subtypes were compared by distribution of CTG expansion size, and the occurrence and onset of the main symptoms of DM1. Analyses validated the relevance of a five-grade model for DM1 classification. Patients were classified as: congenital (n=93, 4.5%); infantile (n=303, 14.8%); juvenile (n=628, 30.7%); adult (n=694, 34.0%); and late-onset (n=326, 15.9%). Our data show that the assumption of a continuum from congenital to the late-onset form is valid, and also highlights disease features specific to individual clinical forms of DM1 in terms of symptom occurrence and chronology throughout the disease course. These results support the use of the five-grade model for disease classification, and the distinct clinical profiles suggest that age of onset and clinical form may be key criteria in the design of clinical trials when considering DM1 health management and research. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients.

PubMed

Morales, Fernando; Vásquez, Melissa; Santamaría, Carolina; Cuenca, Patricia; Corrales, Eyleen; Monckton, Darren G

2016-04-01

Somatic mosaicism of the expanded CTG repeat in myotonic dystrophy type 1 is age-dependent, tissue-specific and expansion-biased, contributing toward the tissue-specificity and progressive nature of the symptoms. Previously, using regression modelling of repeat instability we showed that variation in the rate of somatic expansion in blood DNA contributes toward variation in age of onset, directly implicating somatic expansion in the disease pathway. Here, we confirm these results using a larger more genetically homogenous Costa Rican DM1 cohort (p<0.001). Interestingly, we also provide evidence that supports subtle sex-dependent differences in repeat length-dependent age at onset and somatic mutational dynamics. Previously, we demonstrated that variation in the rate of somatic expansion was a heritable quantitative trait. Given the important role that DNA mismatch repair genes play in mediating expansions in mouse models, we tested for modifier gene effects with 13 DNA mismatch gene polymorphisms (one each in MSH2, PMS2, MSH6 and MLH1; and nine in MSH3). After correcting for allele length and age effects, we identified three polymorphisms in MSH3 that were associated with variation in somatic instability: Rs26279 (p=0.003); Rs1677658 (p=0.009); and Rs10168 (p=0.031). However, only the association with Rs26279 remained significant after multiple testing correction. Although we revealed a statistically significant association between Rs26279 and somatic instability, we did not detect an association with the age at onset. Individuals with the A/A genotype for Rs26279 tended to show a greater propensity to expand the CTG repeat than other genotypes. Interestingly, this SNP results in an amino acid change in the critical ATPase domain of MSH3 and is potentially functionally dimorphic. These data suggest that MSH3 is a key player in generating somatic variation in DM1 patients and further highlight MSH3 as a potential therapeutic target. Copyright © 2016 Elsevier B.V. All rights reserved.

Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1.

PubMed

Chen, Jonathan L; VanEtten, Damian M; Fountain, Matthew A; Yildirim, Ilyas; Disney, Matthew D

2017-07-11

RNA repeat expansions cause a host of incurable, genetically defined diseases. The most common class of RNA repeats consists of trinucleotide repeats. These long, repeating transcripts fold into hairpins containing 1 × 1 internal loops that can mediate disease via a variety of mechanism(s) in which RNA is the central player. Two of these disorders are Huntington's disease and myotonic dystrophy type 1, which are caused by r(CAG) and r(CUG) repeats, respectively. We report the structures of two RNA constructs containing three copies of a r(CAG) [r(3×CAG)] or r(CUG) [r(3×CUG)] motif that were modeled with nuclear magnetic resonance spectroscopy and simulated annealing with restrained molecular dynamics. The 1 × 1 internal loops of r(3×CAG) are stabilized by one-hydrogen bond (cis Watson-Crick/Watson-Crick) AA pairs, while those of r(3×CUG) prefer one- or two-hydrogen bond (cis Watson-Crick/Watson-Crick) UU pairs. Assigned chemical shifts for the residues depended on the identity of neighbors or next nearest neighbors. Additional insights into the dynamics of these RNA constructs were gained by molecular dynamics simulations and a discrete path sampling method. Results indicate that the global structures of the RNA are A-form and that the loop regions are dynamic. The results will be useful for understanding the dynamic trajectory of these RNA repeats but also may aid in the development of therapeutics.

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1.

PubMed

Algalarrondo, Vincent; Wahbi, Karim; Sebag, Frédéric; Gourdon, Geneviève; Beldjord, Chérif; Azibi, Kamel; Balse, Elise; Coulombe, Alain; Fischmeister, Rodolphe; Eymard, Bruno; Duboc, Denis; Hatem, Stéphane N

2015-04-01

Myotonic dystrophy type 1 (DM1) is the most common neuromuscular disorder and is associated with cardiac conduction defects. However, the mechanisms of cardiac arrhythmias in DM1 are unknown. We tested the hypothesis that abnormalities in the cardiac sodium current (INa) are involved, and used a transgenic mouse model reproducing the expression of triplet expansion observed in DM1 (DMSXL mouse). The injection of the class-I antiarrhythmic agent flecainide induced prominent conduction abnormalities and significantly lowered the radial tissular velocities and strain rate in DMSXL mice compared to WT. These abnormalities were more pronounced in 8-month-old mice than in 3-month-old mice. Ventricular action potentials recorded by standard glass microelectrode technique exhibited a lower maximum upstroke velocity [dV/dt](max) in DMSXL. This decreased [dV/dt](max) was associated with a 1.7 fold faster inactivation of INa in DMSXL myocytes measured by the whole-cell patch-clamp technique. Finally in the DMSXL mouse, no mutation in the Scn5a gene was detected and neither cardiac fibrosis nor abnormalities of expression of the sodium channel protein were observed. Therefore, alterations in the sodium current markedly contributed to electrical conduction block in DM1. This result should guide pharmaceutical and clinical research toward better therapy for the cardiac arrhythmias associated with DM1. Copyright © 2014 Elsevier B.V. All rights reserved.

Contractile dysfunction in muscle may underlie androgen-dependent motor dysfunction in spinal bulbar muscular atrophy

PubMed Central

Oki, Kentaro; Halievski, Katherine; Vicente, Laura; Xu, Youfen; Zeolla, Donald; Poort, Jessica; Katsuno, Masahisa; Adachi, Hiroaki; Sobue, Gen; Wiseman, Robert W.; Breedlove, S. Marc

2015-01-01

Spinal and bulbar muscular atrophy (SBMA) is characterized by progressive muscle weakness linked to a polyglutamine expansion in the androgen receptor (AR). Current evidence indicates that mutant AR causes SBMA by acting in muscle to perturb its function. However, information about how muscle function is impaired is scant. One fundamental question is whether the intrinsic strength of muscles, an attribute of muscle independent of its mass, is affected. In the current study, we assess the contractile properties of hindlimb muscles in vitro from chronically diseased males of three different SBMA mouse models: a transgenic (Tg) model that broadly expresses a full-length human AR with 97 CAGs (97Q), a knock-in (KI) model that expresses a humanized AR containing a CAG expansion in the first exon, and a Tg myogenic model that overexpresses wild-type AR only in skeletal muscle fibers. We found that hindlimb muscles in the two Tg models (97Q and myogenic) showed marked losses in their intrinsic strength and resistance to fatigue, but were minimally affected in KI males. However, diseased muscles of all three models showed symptoms consistent with myotonic dystrophy type 1, namely, reduced resting membrane potential and deficits in chloride channel mRNA. These data indicate that muscle dysfunction is a core feature of SBMA caused by at least some of the same pathogenic mechanisms as myotonic dystrophy. Thus mechanisms controlling muscle function per se independent of mass are prime targets for SBMA therapeutics. PMID:25663674

Von Hippel–Lindau and myotonic dystrophy of Steinert along with pancreatic neuroendocrine tumor and renal clear cell carcinomal neoplasm: Case report and review of the literature

PubMed Central

Addeo, A.; Bini, R.; Viora, T.; Bonaccorsi, L.; Leli, R.

2013-01-01

INTRODUCTION Myotonic dystrophy of Steinert, DM1, is the most common adult muscular dystrophy and generally is not associated to development on multiple site neoplasm. Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome that is associated to tumors such as hemangioblastoma of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. No data exist in literature describing the coexistence of both DM1 and VHL. PRESENTATION OF CASE Herein we report a case of renal and pancreatic neoplasm in a young adult female affected by DM1 and VHL simultaneously. DISCUSSION DM1 is due to an unstable trinucleotide (CTG) expansion in the 30 antranslated region of the dystrophia myotonica-protein kinase (DMPK) gene, located on chromosome 19q13.3. Several molecular mechanisms thought to be determining the classical DM phenotype have been shown. VHL disease is characterized by marked phenotypic variability and the most common tumors are hemangioblastomas of the retina or central nervous system, clear-cell renal carcinoma (RCC) and endocrine tumors, most commonly pheochromocytoma and non-secretory pancreatic islet cell cancers. The pancreatic manifestations seen in patients with VHL disease are divided into 2 categories: pancreatic neuroendocrine tumor (PNET) as solid tumors, and cystic lesions, including a simple cyst and serous cystadenoma. The surgical approach for these cistic lesions is to consider as golden standard. Blansfield has proposed 3 criteria to predict metastatic disease of PNET in patients with VHL disease: (1) tumor size greater than or equal to 3 cm; (2) presence of a mutation in exon 3; and (3) tumor doubling time less than 500 d. If the patient has none of these criteria the patient could be followed with physical examination and radiological surveillance on a 2/3 years base.4 If the patient has 1 criterion, the patient should be followed more closely every 6 months to 1 year. If the patient has 2 or 3 criteria, the patient should be considered for surgery given the high risk of future malignancy. Our patient owned only one criterion but in presence of a second malignant tumor. Our hypothesis for this rare findings is that both DM and VHL might be derived from genetic aberration and these might be linked to a major cancer susceptibility. As far as we know this is the first confirmed case of RCC and neuroendocrine pancreatic cancer occurring concurrently with VHL and, at the same time, DM1. According to this case report and the literature data a VHL should be ruled out in the presence of RCC presenting along with pancreatic cysts/tumor. CONCLUSION As far as we know this is the first confirmed case of RCC and neuroendocrine pancreatic cancer occurring concurrently with VHL and, at the same time, DM1. Our hypothesis for the unusual findings is that both DM and VHL derived from genetic aberration and these are linked to a major cancer susceptibility. PMID:23774333

Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye.

PubMed

Smits, Bart W; Fermont, Jiske; Delnooz, Cathérine C S; Kalkman, Joke S; Bleijenberg, Gijs; van Engelen, Baziel G M

2011-04-01

We determined the extent of disease impact in 28 patients with genetically confirmed chronic progressive external ophthalmoplegia (CPEO) and compared the outcomes to those of matched myotonic dystrophy type I patients. CPEO patients reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%) and dependency in daily life (46.4%). The frequency and extent of depression were significantly higher than in DM1 patients (32.1% vs. 7.1%, p=0.040; mean Beck's depression inventory for primary care score 3.8±3.5 vs. 1.3±1.4, p=0.001), as were fatigue severity, pain intensity and extent of functional impairments. CPEO patients with polymerase gamma-1 mutations reported more functional impairments than those with mitochondrial DNA mutations. Disease impact was however not influenced by most clinical features. The present results help physicians to identify and to treat the factors that influence quality of life in CPEO patients and to provide symptomatic treatment where needed. Copyright © 2010 Elsevier B.V. All rights reserved.

Is Going Beyond Rasch Analysis Necessary to Assess the Construct Validity of a Motor Function Scale?

PubMed

Guillot, Tiffanie; Roche, Sylvain; Rippert, Pascal; Hamroun, Dalil; Iwaz, Jean; Ecochard, René; Vuillerot, Carole

2018-04-03

To examine whether a Rasch analysis is sufficient to establish the construct validity of the Motor Function Measure (MFM) and discuss whether weighting the MFM item scores would improve the MFM construct validity. Observational cross-sectional multicenter study. Twenty-three physical medicine departments, neurology departments, or reference centers for neuromuscular diseases. Patients (N=911) aged 6 to 60 years with Charcot-Marie-Tooth disease (CMT), facioscapulohumeral dystrophy (FSHD), or myotonic dystrophy type 1 (DM1). None. Comparison of the goodness-of-fit of the confirmatory factor analysis (CFA) model vs that of a modified multidimensional Rasch model on MFM item scores in each considered disease. The CFA model showed good fit to the data and significantly better goodness of fit than the modified multidimensional Rasch model regardless of the disease (P<.001). Statistically significant differences in item standardized factor loadings were found between DM1, CMT, and FSHD in only 6 of 32 items (items 6, 27, 2, 7, 9 and 17). For multidimensional scales designed to measure patient abilities in various diseases, a Rasch analysis might not be the most convenient, whereas a CFA is able to establish the scale construct validity and provide weights to adapt the item scores to a specific disease. Copyright © 2018 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

Identification of Plant-derived Alkaloids with Therapeutic Potential for Myotonic Dystrophy Type I*

PubMed Central

Herrendorff, Ruben; Faleschini, Maria Teresa; Stiefvater, Adeline; Erne, Beat; Wiktorowicz, Tatiana; Kern, Frances; Hamburger, Matthias; Potterat, Olivier; Kinter, Jochen; Sinnreich, Michael

2016-01-01

Myotonic dystrophy type I (DM1) is a disabling neuromuscular disease with no causal treatment available. This disease is caused by expanded CTG trinucleotide repeats in the 3′ UTR of the dystrophia myotonica protein kinase gene. On the RNA level, expanded (CUG)n repeats form hairpin structures that sequester splicing factors such as muscleblind-like 1 (MBNL1). Lack of available MBNL1 leads to misregulated alternative splicing of many target pre-mRNAs, leading to the multisystemic symptoms in DM1. Many studies aiming to identify small molecules that target the (CUG)n-MBNL1 complex focused on synthetic molecules. In an effort to identify new small molecules that liberate sequestered MBNL1 from (CUG)n RNA, we focused specifically on small molecules of natural origin. Natural products remain an important source for drugs and play a significant role in providing novel leads and pharmacophores for medicinal chemistry. In a new DM1 mechanism-based biochemical assay, we screened a collection of isolated natural compounds and a library of over 2100 extracts from plants and fungal strains. HPLC-based activity profiling in combination with spectroscopic methods were used to identify the active principles in the extracts. The bioactivity of the identified compounds was investigated in a human cell model and in a mouse model of DM1. We identified several alkaloids, including the β-carboline harmine and the isoquinoline berberine, that ameliorated certain aspects of the DM1 pathology in these models. Alkaloids as a compound class may have potential for drug discovery in other RNA-mediated diseases. PMID:27298317

Studying a Drug-like, RNA-Focused Small Molecule Library Identifies Compounds That Inhibit RNA Toxicity in Myotonic Dystrophy.

PubMed

Rzuczek, Suzanne G; Southern, Mark R; Disney, Matthew D

2015-12-18

There are many RNA targets in the transcriptome to which small molecule chemical probes and lead therapeutics are desired. However, identifying compounds that bind and modulate RNA function in cellulo is difficult. Although rational design approaches have been developed, they are still in their infancies and leave many RNAs "undruggable". In an effort to develop a small molecule library that is biased for binding RNA, we computationally identified "drug-like" compounds from screening collections that have favorable properties for binding RNA and for suitability as lead drugs. As proof-of-concept, this collection was screened for binding to and modulating the cellular dysfunction of the expanded repeating RNA (r(CUG)(exp)) that causes myotonic dystrophy type 1. Hit compounds bind the target in cellulo, as determined by the target identification approach Competitive Chemical Cross-Linking and Isolation by Pull-down (C-ChemCLIP), and selectively improve several disease-associated defects. The best compounds identified from our 320-member library are more potent in cellulo than compounds identified by high-throughput screening (HTS) campaigns against this RNA. Furthermore, the compound collection has a higher hit rate (9% compared to 0.01-3%), and the bioactive compounds identified are not charged; thus, RNA can be "drugged" with compounds that have favorable pharmacological properties. Finally, this RNA-focused small molecule library may serve as a useful starting point to identify lead "drug-like" chemical probes that affect the biological (dys)function of other RNA targets by direct target engagement.

Rationally designed small molecules targeting the RNA that causes myotonic dystrophy type 1 are potently bioactive.

PubMed

Childs-Disney, Jessica L; Hoskins, Jason; Rzuczek, Suzanne G; Thornton, Charles A; Disney, Matthew D

2012-05-18

RNA is an important drug target, but it is difficult to design or discover small molecules that modulate RNA function. In the present study, we report that rationally designed, modularly assembled small molecules that bind the RNA that causes myotonic dystrophy type 1 (DM1) are potently bioactive in cell culture models. DM1 is caused when an expansion of r(CUG) repeats, or r(CUG)(exp), is present in the 3' untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) mRNA. r(CUG)(exp) folds into a hairpin with regularly repeating 5'CUG/3'GUC motifs and sequesters muscleblind-like 1 protein (MBNL1). A variety of defects are associated with DM1, including (i) formation of nuclear foci, (ii) decreased translation of DMPK mRNA due to its nuclear retention, and (iii) pre-mRNA splicing defects due to inactivation of MBNL1, which controls the alternative splicing of various pre-mRNAs. Previously, modularly assembled ligands targeting r(CUG)(exp) were designed using information in an RNA motif-ligand database. These studies showed that a bis-benzimidazole (H) binds the 5'CUG/3'GUC motif in r(CUG)(exp.) Therefore, we designed multivalent ligands to bind simultaneously multiple copies of this motif in r(CUG)(exp). Herein, we report that the designed compounds improve DM1-associated defects including improvement of translational and pre-mRNA splicing defects and the disruption of nuclear foci. These studies may establish a foundation to exploit other RNA targets in genomic sequence.

The reproductive outcome of female patients with myotonic dystrophy type 1 (DM1) undergoing PGD is not affected by the size of the expanded CTG repeat tract

PubMed Central

Seneca, Sara; De Rademaeker, Marjan; Sermon, Karen; De Rycke, Martine; De Vos, Michel; Haentjens, Patrick; Devroey, Paul; Liebaers, Ingeborg

2010-01-01

Purpose This study aims to analyze the relationship between trinucleotide repeat length and reproductive outcome in a large cohort of DM1 patients undergoing ICSI and PGD. Methods Prospective cohort study. The effect of trinucleotide repeat length on reproductive outcome per patient was analyzed using bivariate analysis (T-test) and multivariate analysis using Kaplan-Meier and Cox regression analysis. Results Between 1995 and 2005, 205 cycles of ICSI and PGD were carried out for DM1 in 78 couples. The number of trinucleotide repeats does not have an influence on reproductive outcome when adjusted for age, BMI, basal FSH values, parity, infertility status and male or female affected. Cox regression analysis indicates that cumulative live birth rate is not influenced by the number of trinucleotide repeats. The only factor with a significant effect is age (p < 0.05). Conclusion There is no evidence of an effect of trinucleotide repeat length on reproductive outcome in patients undergoing ICSI and PGD. PMID:20221684

[Steinert disease: abnormal onset or "casual" diagnosis?].

PubMed

Pempinello, R; Iannece, M D; Di Pierro, M

2001-01-01

The most frequent myopathy is "Steinert's disease" (also called myotonic dystrophy). We present a case of particular interest due to the way diagnosis was made. A 20-year-old male was transferred to our Department from another Hospital with a diagnosis of "acute liver disease". He presented with fever (39 degrees C), tetrahyposthenia, dehydration and spatial-temporal disorientation. The most apparent laboratory data was a significant increase in serum levels of creatine phosphokinase (196,260 IU/L; normal values < 50 IU/L). After therapy based on parenteral nutrition and steroids, our patient improved progressively, with normalization of laboratory values. Muscle biopsy and electromyography yielded a diagnosis of Steinert's disease, and the patient's mother was found to be the carrier of a myotonine-kinase gene mutation. In this case, the onset of what appeared to be an influenza-A virus infection (the only positive data observed in the serological analysis) permitted the diagnosis of a hereditary myopathy that had remained asymptomatic up to that time.

[The use of prokinetics for the correction of motor and tonic digestive disorders].

PubMed

Maev, I V; Samsonov, A A; Karmanova, E A; Ivanchenko, E A

2009-01-01

Abnormal tonic-motor activity is a key component in pathogenesis of many digestive disorders. Secondary disturbance of tonic-motor activity of digestive organs and the accompanying symptoms are known to develop in conjunction with diseases of other organs and systems, diabetes mellitus, Parkinson's disease, myotonic muscular dystrophy, amyloidosis, hyper- and hypothyroidism, hypoparathyroidism, etc. Disturbed motor activity in the gastro-duodenal region most frequently underlies functional dyspepsia, i.e. a group of symptoms unrelated to organic, systemic and metabolic diseases. Prokinetics are an important class of medicinal products for the treatment of all clinical forms of dyspepsia. One of the new ones is itopride hdrochloride having combined mechanism of action. Clinical studies of this drug revealed its high efficiency in patients with functional dyspepsia, chronic gastritis, and diabetic gastroparesis. It is well tolerated by the patients and produces no serious side effects. Inclusion of this drug in therapy improves the outcome of the treatment of disturbed motor activity of the gastrointestinal tract.

The potential of disease management for neuromuscular hereditary disorders.

PubMed

Chouinard, Maud-Christine; Gagnon, Cynthia; Laberge, Luc; Tremblay, Carmen; Côté, Charlotte; Leclerc, Nadine; Mathieu, Jean

2009-01-01

Neuromuscular hereditary disorders require long-term multidisciplinary rehabilitation management. Although the need for coordinated healthcare management has long been recognized, most neuromuscular disorders are still lacking clinical guidelines about their long-term management and structured evaluation plan with associated services. One of the most prevalent adult-onset neuromuscular disorders, myotonic dystrophy type 1, generally presents several comorbidities and a variable clinical picture, making management a constant challenge. This article presents a healthcare follow-up plan and proposes a nursing case management within a disease management program as an innovative and promising approach. This disease management program and model consists of eight components including population identification processes, evidence-based practice guidelines, collaborative practice, patient self-management education, and process outcomes evaluation (Disease Management Association of America, 2004). It is believed to have the potential to significantly improve healthcare management for neuromuscular hereditary disorders and will prove useful to nurses delivering and organizing services for this population.

Can Human Pluripotent Stem Cell-Derived Cardiomyocytes Advance Understanding of Muscular Dystrophies?

PubMed

Kalra, Spandan; Montanaro, Federica; Denning, Chris

2016-08-30

Muscular dystrophies (MDs) are clinically and molecularly a highly heterogeneous group of single-gene disorders that primarily affect striated muscles. Cardiac disease is present in several MDs where it is an important contributor to morbidity and mortality. Careful monitoring of cardiac issues is necessary but current management of cardiac involvement does not effectively protect from disease progression and cardiac failure. There is a critical need to gain new knowledge on the diverse molecular underpinnings of cardiac disease in MDs in order to guide cardiac treatment development and assist in reaching a clearer consensus on cardiac disease management in the clinic. Animal models are available for the majority of MDs and have been invaluable tools in probing disease mechanisms and in pre-clinical screens. However, there are recognized genetic, physiological, and structural differences between human and animal hearts that impact disease progression, manifestation, and response to pharmacological interventions. Therefore, there is a need to develop parallel human systems to model cardiac disease in MDs. This review discusses the current status of cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSC) to model cardiac disease, with a focus on Duchenne muscular dystrophy (DMD) and myotonic dystrophy (DM1). We seek to provide a balanced view of opportunities and limitations offered by this system in elucidating disease mechanisms pertinent to human cardiac physiology and as a platform for treatment development or refinement.

Rational and Modular Design of Potent Ligands Targeting the RNA that Causes Myotonic Dystrophy 2

PubMed Central

Lee, Melissa M.; Pushechnikov, Alexei; Disney, Matthew D.

2009-01-01

Most ligands targeting RNA are identified through screening a therapeutic target for binding members of a ligand library. A potential alternative way to construct RNA binders is through rational design using information about the RNA motifs ligands prefer to bind. Herein, we describe such an approach to design modularly assembled ligands targeting the RNA that causes myotonic dystrophy type 2 (DM2), a currently untreatable disease. A previous study identified that 6′-N-5-hexynoate kanamycin A (1) prefers to bind 2×2 nucleotide, pyrimidine-rich RNA internal loops. Multiple copies of such loops were found in the RNA hairpin that causes DM2. The 1 ligand was then modularly displayed on a peptoid scaffold with varied number and spacing to target several internal loops simultaneously. Modularly assembled ligands were tested for binding to a series of RNAs and for inhibiting the formation of the toxic DM2 RNA-muscleblind protein (MBNL-1) interaction. The most potent ligand displays three 1 modules, each separated by four spacing submonomers, and inhibits the formation of the RNA-protein complex with an IC50 of 25 nM. This ligand is higher affinity and more specific for binding DM2 RNA than MBNL-1. It binds the DM2 RNA at least 20-times more tightly than related RNAs and 15-fold more tightly than MBNL-1. A related control peptoid displaying 6′-N-5-hexynoate neamine (2) is >100-fold less potent at inhibiting the RNA-protein interaction and binds to DM2 RNA >125-fold more weakly. Uptake studies into a mouse myoblast cell line also show that the most potent ligand is cell permeable. PMID:19348464

Design of a bioactive small molecule that targets the myotonic dystrophy type 1 RNA via an RNA motif-ligand database and chemical similarity searching.

PubMed

Parkesh, Raman; Childs-Disney, Jessica L; Nakamori, Masayuki; Kumar, Amit; Wang, Eric; Wang, Thomas; Hoskins, Jason; Tran, Tuan; Housman, David; Thornton, Charles A; Disney, Matthew D

2012-03-14

Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3'-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5'CUG/3'GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, sarco(endo)plasmic reticulum Ca(2+) ATPase 1, and cardiac troponin T. Based on these observations, the development of small-molecule ligands that target specifically expanded DM1 repeats could be of use as therapeutics. In the present study, chemical similarity searching was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of in vitro inhibitors of the RNA-protein complex were identified with low micromolar IC(50)'s, which are >20-fold more potent than the query compounds. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif-ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA-ligand interactions with chemical similarity searching.

Myotonic Dystrophy Type 1 RNA Crystal Structures Reveal Heterogeneous 1×1 Nucleotide UU Internal Loop Conformations⊥

PubMed Central

Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W.; Disney, Matthew D.

2011-01-01

RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5′CUG/3′GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures are disclosed of a model DM1 triplet repeating construct, 5′r(UUGGGC(CUG)3GUCC)2, refined to 2.20 Å and 1.52 Å resolution. Here, differences in orientation of the 5′ dangling UU end between the two structures induce changes in the backbone groove width, which reveals that non-canonical 1×1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 Å structure, CUGa, the 5′UU forms one hydrogen-bonded pairs with a 5′UU of a neighboring helix in the unit cell to form a pseudo-infinite helix. The central 1×1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1×1 nucleotide UU internal loops each form a one hydrogen-bonded pair. In the 1.52 Å structure, CUGb, the 5′ UU dangling end is tucked into the major groove of the duplex. While the canonical paired bases show no change in base pairing, in CUGb the terminal 1×1 nucleotide UU internal loops form now two hydrogen-bonded pairs. Thus, the shift in major groove induced by the 5′UU dangling end alters non-canonical base patterns. Collectively, these structures indicate that 1×1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands. PMID:21988728

Myotonic dystrophy type 1 RNA crystal structures reveal heterogeneous 1 × 1 nucleotide UU internal loop conformations.

PubMed

Kumar, Amit; Park, HaJeung; Fang, Pengfei; Parkesh, Raman; Guo, Min; Nettles, Kendall W; Disney, Matthew D

2011-11-15

RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[UUGGGC(CUG)(3)GUCC](2), refined to 2.20 and 1.52 Å resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 × 1 nucleotide UU internal loops can display an ensemble of pairing conformations. In the 2.20 Å structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 × 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 × 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 Å structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 × 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 × 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.

Myotonic Dystrophy Type 1 RNA Crystal Structures Reveal Heterogeneous 1 × 1 Nucleotide UU Internal Loop Conformations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kumar, Amit; Park, HaJeung; Fang, Pengfei

2012-03-27

RNA internal loops often display a variety of conformations in solution. Herein, we visualize conformational heterogeneity in the context of the 5'CUG/3'GUC repeat motif present in the RNA that causes myotonic dystrophy type 1 (DM1). Specifically, two crystal structures of a model DM1 triplet repeating construct, 5'r[{und UU}GGGC(C{und U}G){sub 3}GUCC]{sub 2}, refined to 2.20 and 1.52 {angstrom} resolution are disclosed. Here, differences in the orientation of the 5' dangling UU end between the two structures induce changes in the backbone groove width, which reveals that noncanonical 1 x 1 nucleotide UU internal loops can display an ensemble of pairing conformations.more » In the 2.20 {angstrom} structure, CUGa, the 5' UU forms a one hydrogen-bonded pair with a 5' UU of a neighboring helix in the unit cell to form a pseudoinfinite helix. The central 1 x 1 nucleotide UU internal loop has no hydrogen bonds, while the terminal 1 x 1 nucleotide UU internal loops each form a one-hydrogen bond pair. In the 1.52 {angstrom} structure, CUGb, the 5' UU dangling end is tucked into the major groove of the duplex. While the canonically paired bases show no change in base pairing, in CUGb the terminal 1 x 1 nucleotide UU internal loops now form two hydrogen-bonded pairs. Thus, the shift in the major groove induced by the 5' UU dangling end alters noncanonical base patterns. Collectively, these structures indicate that 1 x 1 nucleotide UU internal loops in DM1 may sample multiple conformations in vivo. This observation has implications for the recognition of this RNA, and other repeating transcripts, by protein and small molecule ligands.« less

Design of a Bioactive Small Molecule that Targets the Myotonic Dystrophy Type 1 RNA Via an RNA Motif-Ligand Database & Chemical Similarity Searching

PubMed Central

Parkesh, Raman; Childs-Disney, Jessica L.; Nakamori, Masayuki; Kumar, Amit; Wang, Eric; Wang, Thomas; Hoskins, Jason; Tran, Tuan; Housman, David; Thornton, Charles A.; Disney, Matthew D.

2012-01-01

Myotonic dystrophy type 1 (DM1) is a triplet repeating disorder caused by expanded CTG repeats in the 3′ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The transcribed repeats fold into an RNA hairpin with multiple copies of a 5′CUG/3′GUC motif that binds the RNA splicing regulator muscleblind-like 1 protein (MBNL1). Sequestration of MBNL1 by expanded r(CUG) repeats causes splicing defects in a subset of pre-mRNAs including the insulin receptor, the muscle-specific chloride ion channel, Sarco(endo)plasmic reticulum Ca2+ ATPase 1 (Serca1/Atp2a1), and cardiac troponin T (cTNT). Based on these observations, the development of small molecule ligands that target specifically expanded DM1 repeats could serve as therapeutics. In the present study, computational screening was employed to improve the efficacy of pentamidine and Hoechst 33258 ligands that have been shown previously to target the DM1 triplet repeat. A series of inhibitors of the RNA-protein complex with low micromolar IC50’s, which are >20-fold more potent than the query compounds, were identified. Importantly, a bis-benzimidazole identified from the Hoechst query improves DM1-associated pre-mRNA splicing defects in cell and mouse models of DM1 (when dosed with 1 mM and 100 mg/kg, respectively). Since Hoechst 33258 was identified as a DM1 binder through analysis of an RNA motif-ligand database, these studies suggest that lead ligands targeting RNA with improved biological activity can be identified by using a synergistic approach that combines analysis of known RNA-ligand interactions with virtual screening. PMID:22300544

Genome Modification Leads to Phenotype Reversal in Human Myotonic Dystrophy type 1 iPS-cell Derived Neural Stem Cells

PubMed Central

Xia, Guangbin; Gao, Yuanzheng; Jin, Shouguang; Subramony, SH.; Terada, Naohiro; Ranum, Laura P.W.; Swanson, Maurice S.; Ashizawa, Tetsuo

2015-01-01

Objective Myotonic dystrophy type 1 (DM1) is caused by expanded CTG repeats in the 3'-untranslated region (3’ UTR) of the DMPK gene. Correcting the mutation in DM1 stem cells would be an important step towards autologous stem cell therapy. The objective of this study is to demonstrate in vitro genome editing to prevent production of toxic mutant transcripts and reverse phenotypes in DM1 stem cells. Methods Genome editing was performed in DM1 neural stem cells (NSCs) derived from human DM1 iPS cells. An editing cassette containing SV40/bGH polyA signals was integrated upstream of the CTG repeats by TALEN-mediated homologous recombination (HR). The expression of mutant CUG repeats transcript was monitored by nuclear RNA foci, the molecular hallmarks of DM1, using RNA fluorescence in situ hybridization (RNA-FISH). Alternative splicing of microtubule-associated protein tau (MAPT) and muscleblind-like (MBNL) proteins were analyzed to further monitor the phenotype reversal after genome modification. Results The cassette was successfully inserted into DMPK intron 9 and this genomic modification led to complete disappearance of nuclear RNA foci. MAPT and MBNL 1, 2 aberrant splicing in DM1 NSCs was reversed to normal pattern in genome-modified NSCs. Interpretation Genome modification by integration of exogenous polyA signals upstream of the DMPK CTG repeat expansion prevents the production of toxic RNA and leads to phenotype reversal in human DM1 iPS-cells derived stem cells. Our data provide proof-of-principle evidence that genome modification may be used to generate genetically modified progenitor cells as a first step toward autologous cell transfer therapy for DM1. PMID:25702800

Pentamidine rescues contractility and rhythmicity in a Drosophila model of myotonic dystrophy heart dysfunction

PubMed Central

Chakraborty, Mouli; Selma-Soriano, Estela; Magny, Emile; Couso, Juan Pablo; Pérez-Alonso, Manuel; Charlet-Berguerand, Nicolas; Artero, Ruben; Llamusi, Beatriz

2015-01-01

ABSTRACT Up to 80% of individuals with myotonic dystrophy type 1 (DM1) will develop cardiac abnormalities at some point during the progression of their disease, the most common of which is heart blockage of varying degrees. Such blockage is characterized by conduction defects and supraventricular and ventricular tachycardia, and carries a high risk of sudden cardiac death. Despite its importance, very few animal model studies have focused on the heart dysfunction in DM1. Here, we describe the characterization of the heart phenotype in a Drosophila model expressing pure expanded CUG repeats under the control of the cardiomyocyte-specific driver GMH5-Gal4. Morphologically, expression of 250 CUG repeats caused abnormalities in the parallel alignment of the spiral myofibrils in dissected fly hearts, as revealed by phalloidin staining. Moreover, combined immunofluorescence and in situ hybridization of Muscleblind and CUG repeats, respectively, confirmed detectable ribonuclear foci and Muscleblind sequestration, characteristic features of DM1, exclusively in flies expressing the expanded CTG repeats. Similarly to what has been reported in humans with DM1, heart-specific expression of toxic RNA resulted in reduced survival, increased arrhythmia, altered diastolic and systolic function, reduced heart tube diameters and reduced contractility in the model flies. As a proof of concept that the fly heart model can be used for in vivo testing of promising therapeutic compounds, we fed flies with pentamidine, a compound previously described to improve DM1 phenotypes. Pentamidine not only released Muscleblind from the CUG RNA repeats and reduced ribonuclear formation in the Drosophila heart, but also rescued heart arrhythmicity and contractility, and improved fly survival in animals expressing 250 CUG repeats. PMID:26515653

Bachmann bundle pacing reduces atrial electromechanical delay in type 1 myotonic dystrophy patients.

PubMed

Russo, Vincenzo; Rago, Anna; Papa, Andrea Antonio; Arena, Giulia; Politano, Luisa; Nigro, Gerardo

2018-04-01

Atrial electromechanical delay (AEMD) is an echocardiographic parameter correlated with the onset of supraventricular arrhythmias in several clinical conditions. Inter-atrial septal pacing in the region of Bachmann's bundle (BB) has been shown to be safe and feasible in myotonic dystrophy type 1 (DM1) patients, with a low rate of sensing and pacing defects. The aim of this study was to assess the impact of temporary BB pacing compared with right atrial appendage (RAA) pacing on AEMD in DM1 patients undergoing pacemaker (PM) implantation for cardiac rhythm abnormalities. The study enrolled 70 consecutive DM1 patients undergoing PM implantation for cardiac rhythm abnormalities in accordance with the current guidelines. Seventy age- and sex-matched non-DM1 patients undergoing dual-chamber PM implantation for cardiac rhythm abnormalities were used as controls. The atrial pacing lead was temporarily positioned in the RAA and on the right side of the inter-atrial septum in the region of Bachmann's bundle. For each site (BB and RAA), temporary atrial pacing in the AAI mode was established at 10 beats per minute above the sinus rate and a detailed trans-thoracic echocardiogram with tissue Doppler (TDI) analysis was recorded after at least 10 min of atrial pacing to evaluate AEMD. Temporary RAA pacing did not show statistically significant differences in inter-AEMD (48.2 ± 17.8 vs 50.5 ± 16.5 ms; P = 0.8), intra-left AEMD (43.3 ± 15.5 vs 44.6 ± 15.8 ms; P = 0.1), or intra-right-AEMD (14.1 ± 4.2 vs 15.4 ± 5.8 ms; P = 0.9), in comparison with sinus rhythm. Temporary BB pacing determined a significantly lower inter-AEMD (36.1 ± 17.1 vs 50.5 ± 16.5 ms; P = 0.001) and intra-left AEMD (32.5 ± 15.2 vs 44.6 ± 15.8 ms; P = 0.001) values in comparison with temporary RAA pacing. No statistically significant difference was found in intra-right AEMD (12.2 ± 4.6 vs 15.4 ± 5.8 ms; P = 0.2). In the control group, neither temporary RAA pacing nor temporary BB pacing showed statistically significant differences in inter-AEMD, intra-left AEMD, or intra-right AEMD values in comparison with sinus rhythm. In DM1 patients undergoing dual-chamber PM implantation, atrial pacing in the Bachmann bundle region is associated with significantly lower echocardiographic indices of atrial electromechanical delay (inter-AEMD and intra-left AEMD) in comparison with RAA pacing.

PubMed Central

RUSSO, VINCENZO; NIGRO, GERARDO; RAGO, ANNA; ANTONIO PAPA, ANDREA; PROIETTI, RICCARDO; DELLA CIOPPA, NADIA; CRISTIANO, ANNA; PALLADINO, ALBERTO; CALABRÒ, RAFFAELE; POLITANO, LUISA

2013-01-01

The role that atrial pacing therapy plays on the atrial fibrillation (AF) burden is still unclear. Aim of the study was to evaluate the effect of the atrial preference pacing algorithm on AF burden in patients affected by Myotonic Dystrophy type 1 (DM1) followed for a long follow up period. Sixty DM1 patients were -implanted with a dual chamber pacemaker (PM) for first degree or symptomatic type 1/type 2 second degree atrio-ventricular blocks- were followed for 2-years after implantation, by periodical examination. After 1 month of stabilization, they were randomized into two groups: 1) Patients implanted with conventional dual-chamber pacing mode (DDDR group) and 2) Patients implanted with DDDR plus Atrial Preference Pacing (APP) algorithm (APP ON group). The results showed that atrial tachycardia (AT)/AF burden was significantly reduced at 1 year follow up in the APP ON group (2122 ± 428 minutes vs 4127 ± 388 minutes, P = 0.03), with a further reduction at the end of the 2 year follow up period (4652 ± 348 minutes vs 7564 ± 638 minutes, P = 0.005). The data here reported show that the APP is an efficient algorithm to reduce AT/AF burden in DM1 patients implanted with dual chamber pacemaker. PMID:24803841

[Steinert disease].

PubMed

Bouhour, Françoise; Bost, Muriel; Vial, Christophe

2007-06-01

Steinert disease, also known as myotonic dystrophy type 1, is a muscle disease characterized by myotonia and by multiorgan damage that combines various degrees of muscle weakness, arrhythmia and/or cardiac conduction disorders, cataract, endocrine damage, sleep disorders and baldness. It is the most frequent of the adult-onset muscular dystrophies; its prevalence is estimated at 1/20,000 inhabitants. Diagnosis is confirmed by the demonstration of an abnormality at the 19q13-2 locus, with the use of molecular genetic techniques. Its transmission is autosomal dominant, and anticipation may occur, that is, disease may be more severe and occur earlier in offspring. Genetic counseling is often delicate for this condition because of the great variability of clinical expression, both within and between families. Prenatal diagnosis is proposed especially for maternal transmission because of the severity of the possible neonatal forms. Management ideally includes multidisciplinary annual follow-up. Disease course is usually slowly progressive but rapid deterioration may sometimes be observed. Life expectancy is reduced by the increased mortality associated with the pulmonary and cardiac complications.

Studies on congenital hereditary cataract and microphthalmia of the miniature schnauzer dog.

PubMed

Shastry, B S; Reddy, V N

1994-09-30

Hereditary cataract in dogs occurs as an autosomal recessive trait. The opacity is primarily in the lens nucleus and posterior cortex. The affected animals also have other ocular abnormalities such as microphthalmia. To understand the genetic basis of this disorder, we have analyzed leukocyte DNA from affected and normal dogs for possible mutations in the homeobox containing gene and myotonic dystrophy locus. The results show that there are no signs of microdeletion, insertion, point mutation and rearrangements in these loci. Although these observations cannot completely rule out the possibility of point mutations, they suggest that the above loci are unlikely to be associated with the disease.

Development and Validation of a New Scoring System to Predict Survival in Patients With Myotonic Dystrophy Type 1.

PubMed

Wahbi, Karim; Porcher, Raphaël; Laforêt, Pascal; Fayssoil, Abdallah; Bécane, Henri Marc; Lazarus, Arnaud; Sochala, Maximilien; Stojkovic, Tanya; Béhin, Anthony; Leonard-Louis, Sarah; Arnaud, Pauline; Furling, Denis; Probst, Vincent; Babuty, Dominique; Pellieux, Sybille; Clementy, Nicolas; Bassez, Guillaume; Péréon, Yann; Eymard, Bruno; Duboc, Denis

2018-05-01

Life expectancy is greatly shortened in patients presenting with myotonic dystrophy type 1 (DM1), the most common neuromuscular disease. A reliable prediction of survival in patients with DM1 is critically important to plan personalized health supervision. To develop and validate a prognostic score to predict 10-year survival in patients with DM1. In this longitudinal cohort study, between January 2000 and November 2014, we enrolled 1296 adults referred to 4 tertiary neuromuscular centers in France for management of genetically proven DM1, including 1066 patients in the derivation cohort and 230 in the validation cohort. Data were analyzed from December 2016 to March 2017. Factors associated with survival by multiple variable Cox modeling, including 95% confidence intervals, and development of a predictive score validated internally and externally. Mean values are reported with their standard deviations. Of the 1296 included patients, 670 (51.7%) were women, and the mean (SD) age was 39.8 (13.7) years. Among the 1066 patients (82.3%) in the derivation cohort, 241 (22.6%) died over a median (interquartile range) follow-up of 11.7 (7.7-14.3) years. Age, diabetes, need for support when walking, heart rate, systolic blood pressure, first-degree atrioventricular block, bundle-branch block, and lung vital capacity were associated with death. Simplified score points were attributed to each predictor, and adding these points yielded scores between 0 and 20, with 0 indicating the lowest and 20 the highest risk of death. The 10-year survival rate was 96.6% (95% CI, 94.4-98.9) in the group with 0 to 4 points, 92.2% (95% CI, 88.8-95.6) in the group with 5 to 7 points, 80.7% (95% CI, 75.4-86.1) in the group with 8 to 10 points, 57.9% (95% CI, 49.2-66.6) in the group with 11 to 13 points, and 19.4% (95% CI, 8.6-30.1) in the group with 14 points or more. In 230 patients (17.7%) included in the validation cohort, the 10-year survival rates for the groups with 0 to 4, 5 to 7, 8 to 10, 11 to 13, and 14 points or more were 99.3% (95% CI, 95.0-100), 80.6% (95% CI, 67.1-96.7), 79.3% (95% CI, 66.2-95.1), 43.2% (95% CI, 28.2-66.1), and 21.6% (95% CI, 10.0-46.8), respectively. The calibration curves did not deviate from the reference line. The C index was 0.753 (95% CI, 0.722-0.785) in the derivation cohort and 0.806 (95% CI, 0.758-0.855) in the validation cohort. The DM1 prognostic score is associated with long-term survival.

Do Psychosocial Interventions Improve Quality of Life and Wellbeing in Adults with Neuromuscular Disorders? A Systematic Review and Narrative Synthesis.

PubMed

Walklet, Elaine; Muse, Kate; Meyrick, Jane; Moss, Tim

2016-08-30

Quality of life and well-being are frequently restricted in adults with neuromuscular disorders. As such, identification of appropriate interventions is imperative. The objective of this paper was to systematically review and critically appraise quantitative studies (RCTs, controlled trials and cohort studies) of psychosocial interventions designed to improve quality of life and well-being in adults with neuromuscular disorders. A systematic review of the published and unpublished literature was conducted. Studies meeting inclusion criteria were appraised using a validated quality assessment tool and results presented in a narrative synthesis. Out of 3,136 studies identified, ten studies met criteria for inclusion within the review. Included studies comprised a range of interventions including: cognitive behavioural therapy, dignity therapy, hypnosis, expressive disclosure, gratitude lists, group psychoeducation and psychologically informed rehabilitation. Five of the interventions were for patients with Amyotrophic Lateral Sclerosis (ALS). The remainder were for patients with post-polio syndrome, muscular dystrophies and mixed disorders, such as Charcot-Marie-Tooth disease, myasthenia gravis and myotonic dystrophy. Across varied interventions and neuromuscular disorders, seven studies reported a short-term beneficial effect of intervention on quality of life and well-being. Whilst such findings are encouraging, widespread issues with the methodological quality of these studies significantly compromised the results. There is no strong evidence that psychosocial interventions improve quality of life and well-being in adults with neuromuscular disorders, due to a paucity of high quality research in this field. Multi-site, randomised controlled trials with active controls, standardised outcome measurement and longer term follow-ups are urgently required.

Do Psychosocial Interventions Improve Quality of Life and Wellbeing in Adults with Neuromuscular Disorders? A Systematic Review and Narrative Synthesis

PubMed Central

Walklet, Elaine; Muse, Kate; Meyrick, Jane; Moss, Tim

2016-01-01

Quality of life and well-being are frequently restricted in adults with neuromuscular disorders. As such, identification of appropriate interventions is imperative. The objective of this paper was to systematically review and critically appraise quantitative studies (RCTs, controlled trials and cohort studies) of psychosocial interventions designed to improve quality of life and well-being in adults with neuromuscular disorders. A systematic review of the published and unpublished literature was conducted. Studies meeting inclusion criteria were appraised using a validated quality assessment tool and results presented in a narrative synthesis. Out of 3,136 studies identified, ten studies met criteria for inclusion within the review. Included studies comprised a range of interventions including: cognitive behavioural therapy, dignity therapy, hypnosis, expressive disclosure, gratitude lists, group psychoeducation and psychologically informed rehabilitation. Five of the interventions were for patients with Amyotrophic Lateral Sclerosis (ALS). The remainder were for patients with post-polio syndrome, muscular dystrophies and mixed disorders, such as Charcot-Marie-Tooth disease, myasthenia gravis and myotonic dystrophy. Across varied interventions and neuromuscular disorders, seven studies reported a short-term beneficial effect of intervention on quality of life and well-being. Whilst such findings are encouraging, widespread issues with the methodological quality of these studies significantly compromised the results. There is no strong evidence that psychosocial interventions improve quality of life and well-being in adults with neuromuscular disorders, due to a paucity of high quality research in this field. Multi-site, randomised controlled trials with active controls, standardised outcome measurement and longer term follow-ups are urgently required. PMID:27854227

Molecular genetics in neurology.

PubMed

Martin, J B

1993-12-01

There has been remarkable progress in the identification of mutations in genes that cause inherited neurological disorders. Abnormalities in the genes for Huntington disease, neurofibromatosis types 1 and 2, one form of familial amyotrophic lateral sclerosis, fragile X syndrome, myotonic dystrophy, Kennedy syndrome, Menkes disease, and several forms of retinitis pigmentosa have been elucidated. Rare disorders of neuronal migration such as Kallmann syndrome, Miller-Dieker syndrome, and Norrie disease have been shown to be due to specific gene defects. Several muscle disorders characterized by abnormal membrane excitability have been defined as mutations of the muscle sodium or chloride channels. These advances provide opportunity for accurate molecular diagnosis of at-risk individuals and are the harbinger of new approaches to therapy of these diseases.

Children with central and peripheral neurologic disorders have distinguishable patterns of dysphagia on videofluoroscopic swallow study.

PubMed

van den Engel-Hoek, Lenie; Erasmus, Corrie E; van Hulst, Karen C M; Arvedson, Joan C; de Groot, Imelda J M; de Swart, Bert J M

2014-05-01

To determine whether findings on videofluoroscopic swallow studies reveal different patterns of dysphagia between children with central and peripheral neurologic disorders, a retrospective study of 118 videofluoroscopic swallow studies was completed. There were 3 groups: cerebral palsy with only spastic features (n = 53), cerebral palsy with dyskinetic features (n = 34), and neuromuscular disorders (myotonic dystrophy I, n = 5; spinal muscular atrophy I-II, n = 8; Duchenne muscular dystrophy, n = 8; other neuromuscular disorder, n = 10). Interpretation of the videofluoroscopic swallow studies was not blinded. The video fluoroscopic swallow study findings were compared dichotomously between the groups. Children with cerebral palsy demonstrated dysphagia in 1 or all phases of swallowing. In neuromuscular disorder, muscle weakness results in pharyngeal residue after swallow. The underlying swallowing problem in neuromuscular disorder is muscle weakness whereas that in cerebral palsy is more complex, having to do with abnormal control of swallowing. This study serves as a first exploration on specific characteristics of swallowing in different neurologic conditions and will help clinicians anticipate what they might expect.

Is one trial enough for repeated testing? Same-day assessments of walking, mobility and fine hand use in people with myotonic dystrophy type 1.

PubMed

Kierkegaard, Marie; Petitclerc, Emilie; Hébert, Luc J; Gagnon, Cynthia

2017-02-01

Performance-based assessments of physical function are essential in people with myotonic dystrophy type 1 (DM1) to monitor disease progression and evaluate interventions. Commonly used are the six-minute walk test, the 10 m-walk test, the timed up-and-go test, the timed-stands test, grip strength tests and the nine-hole peg test. The number of trials needed on a same-day test occasion and whether the first, best or average of trials should be reported as result is unknown. Thus, the aim was to describe and explore differences between trials in these measures of walking, mobility and fine hand use in 70 adults with DM1. Three trials were performed for each test except for the six-minute walk test where two trials were allowed. There were statistical significant differences over trials in all tests except for the 10 m-walk test and grip strength tests. Pair-wise comparisons showed that the second and third trials were in general better than the first, although effect sizes were small. At which trial the individuals performed their best differed between individuals and tests. People with severe muscular impairment had difficulties to perform repeated trials. Intraclass correlation coefficients were all high in analyses exploring how to report results. The conclusion and clinical implication is that, for a same-day test occasion, one trial is sufficient for the 10 m-walk test and grip strength tests, and that repeated trials should be allowed in the timed up-and-go test, timed-stands test and nine-hole peg tests. We recommend that two trials are performed for these latter tests as such a protocol could accommodate people with various levels of impairments and physical limitations. Copyright © 2016 Elsevier B.V. All rights reserved.

Living with myotonic dystrophy; what can be learned from couples? a qualitative study

PubMed Central

2011-01-01

Background Myotonic dystrophy type 1 (MD1) is one of the most prevalent neuromuscular diseases, yet very little is known about how MD1 affects the lives of couples and how they themselves manage individually and together. To better match health care to their problems, concerns and needs, it is important to understand their perspective of living with this hereditary, systemic disease. Methods A qualitative study was carried out with a purposive sample of five middle-aged couples, including three men and two women with MD1 and their partners. Fifteen in-depth interviews with persons with MD1, with their partners and with both of them as a couple took place in the homes of the couples in two cities and three villages in the Netherlands in 2009. Results People with MD1 associate this progressive, neuromuscular condition with decreasing abilities, describing physical, cognitive and psychosocial barriers to everyday activities and social participation. Partners highlighted the increasing care giving burden, giving directions and using reminders to compensate for the lack of initiative and avoidant behaviour due to MD1. Couples portrayed the dilemmas and frustrations of renegotiating roles and responsibilities; stressing the importance of achieving a balance between individual and shared activities. All participants experienced a lack of understanding from relatives, friends, and society, including health care, leading to withdrawal and isolation. Health care was perceived as fragmentary, with specialists focusing on specific aspects of the disease rather than seeking to understand the implications of the systemic disorder on daily life. Conclusions Learning from these couples has resulted in recommendations that challenge the tendency to treat MD1 as a condition with primarily physical impairments. It is vital to listen to couples, to elicit the impact of MD1, as a multisystem disorder that influences every aspect of their life together. Couple management, supporting the self-management skills of both partners is proposed as a way of reducing the mismatch between health services and health needs. PMID:21752270

Characteristics of pain in amyotrophic lateral sclerosis

PubMed Central

Hanisch, Frank; Skudlarek, Anika; Berndt, Janine; Kornhuber, Malte E

2015-01-01

Background Pain is an often underestimated and neglected symptom in amyotrophic lateral sclerosis (ALS). Methods In a cross-sectional survey, 46 patients with ALS, 46 age- and gender matched population-based controls, and 23 diseased controls with myotonic dystrophy type 2 (DM2) were screened for occurrence, type, distribution, and treatment of pain and cramps. Data were collected with the use of the short form brief pain inventory (BPI). Results Pain was reported in 78% of ALS patients,79% of DM2 patients, and 54% of controls (P < 0.05). More ALS patients than controls reported moderate to severe pain (42% vs. 20%). Pain in ALS patients interfered significantly more with daily activities than in controls (median pain interference score: 3.0 vs. 1.2, P < 0.05), especially enjoyment of life (5.0 vs. 1.0) and mood (3.0 vs. 1.0). There was no correlation between the duration of the disease and the severity of pain. Movement-induced cramps were reported in 63% of ALS patients, mostly in the distal extremities. There was no difference in the duration of ALS disease between patients reporting cramps and those who did not. Discussion Our study showed that pain was a relatively frequent symptom which had an important impact on the quality of life. Pain that requires treatment can occur at every stage of ALS. PMID:25642388

Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA.

PubMed

Costales, Matthew G; Rzuczek, Suzanne G; Disney, Matthew D

2016-06-01

Potential RNA targets for chemical probes and therapeutic modalities are pervasive in the transcriptome. Oligonucleotide-based therapeutics are commonly used to target RNA sequence. Small molecules are emerging as a modality to target RNA structures selectively, but their development is still in its infancy. In this work, we compare the activity of oligonucleotides and several classes of small molecules that target the non-coding r(CCUG) repeat expansion (r(CCUG)(exp)) that causes myotonic dystrophy type 2 (DM2), an incurable disease that is the second-most common cause of adult onset muscular dystrophy. Small molecule types investigated include monomers, dimers, and multivalent compounds synthesized on-site by using RNA-templated click chemistry. Oligonucleotides investigated include phosphorothioates that cleave their target and vivo-morpholinos that modulate target RNA activity via binding. We show that compounds assembled on-site that recognize structure have the highest potencies amongst small molecules and are similar in potency to a vivo-morpholino modified oligonucleotide that targets sequence. These studies are likely to impact the design of therapeutic modalities targeting other repeats expansions that cause fragile X syndrome and amyotrophic lateral sclerosis, for example. Copyright © 2016. Published by Elsevier Ltd.

Between-day reliability of MyotonPRO for the non-invasive measurement of muscle material properties in the lower extremities of patients with a chronic spinal cord injury.

PubMed

Ko, Chang-Yong; Choi, Hyuk-Jae; Ryu, Jeicheong; Kim, Gyoosuk

2018-05-17

Measuring the muscle properties of patients with spinal cord injuries (SCIs) is important to better understand their biomechanical features. In this study, we sought to evaluate the between-day reliability of MyotonPRO, a handheld device that can measure muscle mechanical properties, and assess whether it is reliable to measure muscle properties over time in patients with SCI. Thirteen men with complete SCIs (age 53.9 ± 6.3 years, height 171.0 ± 5.2 cm, weight 66.1 ± 5.8 kg), and injury levels ranging from L1 to T12, were enrolled. Oscillation frequency; logarithmic decrement; dynamic stiffness; mechanical stress relaxation time; and creep of the biceps femoris, medial and lateral gastrocnemius, rectus femoris, tibialis anterior, and Achilles tendon were measured on consecutive days using MyotonPRO. The intraclass coefficient for most muscles and the Achilles tendon ranged from 0.53 to 0.99 for all parameters. The percentage standard error of the measurement for many parameters in most muscles and the Achilles tendon was less than 10%. Bland-Altman analysis showed a high agreement for all mechanical properties. No significant differences were observed in any muscle or Achilles tendon properties between days (all p > 0.05). These results indicate that the MyotonPRO is reliable for between-day measurements of the mechanical properties of lower limb muscles and Achilles tendon in patients with SCI. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hypogonadism in DM1 and its relationship to erectile dysfunction.

PubMed

Antonini, Giovanni; Clemenzi, Alessandro; Bucci, Elisabetta; De Marco, Emanuela; Morino, Stefania; Di Pasquale, Antonella; Latino, Pamela; Ruga, Gilda; Lenzi, Andrea; Vanacore, Nicola; Radicioni, Antonio F

2011-07-01

Myotonic dystrophy type 1 (DM1) is characterized by both a premature appearance of age-related phenotypes and multiple organ involvement, which affects skeletal and smooth muscle as well as the eye, heart, central nervous system, and endocrine system. Although erectile dysfunction (ED) is a frequent complaint in patients with DM1, it has not been investigated in great depth. Hypogonadism, which is reported to be one of the physical causes of ED in the general population, frequently occurs in DM1. We planned this case-control study to evaluate the relationship between hypogonadism, as defined by the sexual hormone profile (FSH, LH, testosterone (T) and prolactin) and ED, as assessed by means of an internationally validated self-administered questionnaire (IIEF). DM1 patients had significantly increased mean levels of both gonadotropins (FSH and LH) (p < 0.0001) and a reduced mean level of T (p < 0.0001) when compared to controls. Twelve patients were eugonadic (normal LH, T, and FSH), while 18 displayed hormonal evidence of hypogonadism, characterized by tubular failure (increased FSH) in all the subjects and associated with interstitial failure in 14 subjects: seven with primary hypogonadism (increased LH and reduced T) and seven with compensated hypogonadism (increased LH and normal T). Patients with hormonal evidence of interstitial failure had a larger CTG expansion (p = 0.008), longer disease duration (p = 0.013), higher grade of disease (p = 0.004) and lower erectile function score (p = 0.02) than eugonadic patients. Impotence occurred in 13/14 hypogonadic patients with interstitial failure and in 5/12 eugonadic patients (p = 0.017, OR = 18.2).

Myotonic dystrophy protein kinase (DMPK) induces actin cytoskeletal reorganization and apoptotic-like blebbing in lens cells

NASA Technical Reports Server (NTRS)

Jin, S.; Shimizu, M.; Balasubramanyam, A.; Epstein, H. F.

2000-01-01

DMPK, the product of the DM locus, is a member of the same family of serine-threonine protein kinases as the Rho-associated enzymes. In DM, membrane inclusions accumulate in lens fiber cells producing cataracts. Overexpression of DMPK in cultured lens epithelial cells led to apoptotic-like blebbing of the plasma membrane and reorganization of the actin cytoskeleton. Enzymatically active DMPK was necessary for both effects; inactive mutant DMPK protein did not produce either effect. Active RhoA but not constitutive GDP-state mutant protein produced similar effects as DMPK. The similar actions of DMPK and RhoA suggest that they may function in the same regulatory network. The observed effects of DMPK may be relevant to the removal of membrane organelles during normal lens differentiation and the retention of intracellular membranes in DM lenses. Copyright 2000 Wiley-Liss, Inc.

Precise small molecule recognition of a toxic CUG RNA repeat expansion

PubMed Central

Rzuczek, Suzanne G; Colgan, Lesley A; Nakai, Yoshio; Cameron, Michael D; Furling, Denis; Yasuda, Ryohei; Disney, Matthew D

2017-01-01

Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context. PMID:27941760

Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

PubMed

Rzuczek, Suzanne G; Colgan, Lesley A; Nakai, Yoshio; Cameron, Michael D; Furling, Denis; Yasuda, Ryohei; Disney, Matthew D

2017-02-01

Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG) exp ) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG) exp . In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG) exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG) exp in its natural context.

Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts.

PubMed

Disney, Matthew D

2013-12-01

RNA is an important yet vastly underexploited target for small molecule chemical probes or lead therapeutics. Small molecules have been used successfully to modulate the function of the bacterial ribosome, viral RNAs and riboswitches. These RNAs are either highly expressed or can be targeted using substrate mimicry, a mainstay in the design of enzyme inhibitors. However, most cellular RNAs are neither highly expressed nor have a lead small molecule inhibitor, a significant challenge for drug discovery efforts. Herein, I describe the design of small molecules targeting expanded repeating transcripts that cause myotonic muscular dystrophy (DM). These test cases illustrate the challenges of designing small molecules that target RNA and the advantages of targeting repeating transcripts. Lastly, I discuss how small molecules might be more advantageous than oligonucleotides for targeting RNA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Small molecule alteration of RNA sequence in cells and animals.

PubMed

Guan, Lirui; Luo, Yiling; Ja, William W; Disney, Matthew D

2017-10-18

RNA regulation and maintenance are critical for proper cell function. Small molecules that specifically alter RNA sequence would be exceptionally useful as probes of RNA structure and function or as potential therapeutics. Here, we demonstrate a photochemical approach for altering the trinucleotide expanded repeat causative of myotonic muscular dystrophy type 1 (DM1), r(CUG) exp . The small molecule, 2H-4-Ru, binds to r(CUG) exp and converts guanosine residues to 8-oxo-7,8-dihydroguanosine upon photochemical irradiation. We demonstrate targeted modification upon irradiation in cell culture and in Drosophila larvae provided a diet containing 2H-4-Ru. Our results highlight a general chemical biology approach for altering RNA sequence in vivo by using small molecules and photochemistry. Furthermore, these studies show that addition of 8-oxo-G lesions into RNA 3' untranslated regions does not affect its steady state levels. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pilomatricoma in childhood: a retrospective study from three European paediatric centres.

PubMed

Cigliano, Bruno; Baltogiannis, Nikolaos; De Marco, Marianna; Faviou, Elsa; Settimi, Alesandro; Tilemis, Stefanos; Soutis, Michail; Papandreou, Evangellos; D'Agostino, Sergio; Fabbro, Maria Angelica

2005-11-01

Pilomatricoma is characterised as a common, slowly growing benign cutaneous tumour that appears generally within the first decades of life. The clinical diagnosis is frequently missed, especially by the paediatrician unfamiliar with these tumours. We present the experience gained in three European tertiary care paediatric centres with the treatment of pilomatricoma and also current data on the aetiology, clinical presentation and management. A retrospective study was carried out in 83 patients suspected for pilomatricoma during a 7-year period (1996-2002) at the departments of Paediatric Surgery of the Children's University Hospital "Federico II", Naples, Hospital "San Bortolo", Vicenza and "Aghia Sophia" Children's Hospital, Athens. The age range was from 10 months to 17 years, median age 8 years. All patients were treated by surgical excision and all specimens were examined by histopathological assessment. The follow-up varied from 5 months to 6 years. The correct diagnosis was made preoperatively in 68 patients (82%). The female/male ratio was 2:1. The sites of occurrence were the head (47.5%), especially in the periorbital region, the neck (9%), the upper limbs (35.5%), the inferior limbs (4%) and the thorax (4%). Each patient exhibited a single pilomatricoma except for two patients who had multiple lesions (2.4%). One of them had Steinert disease (myotonic dystrophy). No recurrences were observed during the follow-up period. Pilomatricoma is one of the most common cutaneous adnexal neoplasms in children. Surgical excision including clear margins and its overlying skin in most cases is the treatment of choice. The recurrence as well as malignant evolution is rare.

PubMed Central

Russo, Vincenzo; Papa, Andrea Antonio; Rago, Anna; D'Ambrosio, Paola; Cimmino, Giovanni; Palladino, Alberto; Nigro, Gerardo

2016-01-01

Sudden cardiac death in myotonic dystrophy type I (DM1) patients can be attributed to atrioventricular blocks as far as to the development of life-threatening arrhythmias which occur even in hearts with normal left ventricular systolic and diastolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D), JTc dispersion (JTc-D) and transmural dispersion of repolarization (TDR) could reflect the physiological variability of regional and transmural ventricular repolarization. Aim of the present study was to investigate the heterogeneity of ventricular repolarization in patients with DM1 and preserved diastolic and systolic cardiac function. The study enrolled 50 DM1 patients (mean age 44 ± 5 years; M:F: 29:21) with preserved systolic and diastolic function of left ventricle among 247 DM1 patients followed at Cardiomyology and Medical Genetics of Second University of Naples, and 50 sexand age-matched healthy controls. The electrocardiographic parameters investigated were the following: Heart Rate, QRS duration, maximum and minimum QT and JT intervals, QTc- D, JTc-D and TDR. Compared to the controls, the DM1 group presented increased values of QTc-D (86.7 ± 40.1 vs 52.3 ± 11.9 ms; p = 0.03), JTc-D (78.6 ± 31.3 vs 61.3 ± 10.2 ms; p = 0.001) and TDR (101.6 ± 18.06 vs 90.1 ± 14.3 ms; p = 0.004) suggesting a significant increase in regional and transmural heterogeneity of the ventricular repolarization in these patients, despite a preserved systolic and diastolic cardiac function. PMID:28344440

The proposal of a clinical protocol to assess central and peripheral fatigue in myotonic dystrophy type 1.

PubMed

Baldanzi, S; Ricci, G; Bottari, M; Chico, L; Simoncini, C; Siciliano, G

2017-07-01

DM1 is an autosomal-dominant disorder characterized by muscle weakness, myotonia, and multisystemic involvement. According to current literature fatigue and daytime sleepiness are among the main symptoms of DM1. Oxidative stress has been proposed to be one of the pathogenic factors of fatigue consequent to DM1. In this study, we investigated the dimensions of experienced fatigue and  physiological fatigue in a sample of 26 DM1 patients (17 males, 9 females, mean age 41.6 years, SD±12.7); experienced fatigue has been studied through Fatigue Severity Scale (FSS), and physiological fatigue was measured through an intermittent incremental exercise of the forearm muscles using a myometer; oxidative stress balance markers trend during aerobic exercise test have been collected. The occurrence of central fatigue in the sample means that central activation worsens during the motor contraction; interestingly FSS score was significantly correlated to MVC (before and after the effort, r-before=-0.583, p<0.01, r-after= -0.534, p<0.05), and to motor disability measured by MRC (r=-0.496, p<0.05); moreover we found a strong tendency towards significance in the association to lactate baseline (r=0.378, p=0.057).Results are discussed to define whether or not, based on clinical and laboratory grounds, such exercise training protocol may be suitable for proper management of DM1 patients; proper assessment of fatigue should be included in algorithms for data collection in DM1 patient registries.

[Neurological disease and facial recognition].

PubMed

Kawamura, Mitsuru; Sugimoto, Azusa; Kobayakawa, Mutsutaka; Tsuruya, Natsuko

2012-07-01

To discuss the neurological basis of facial recognition, we present our case reports of impaired recognition and a review of previous literature. First, we present a case of infarction and discuss prosopagnosia, which has had a large impact on face recognition research. From a study of patient symptoms, we assume that prosopagnosia may be caused by unilateral right occipitotemporal lesion and right cerebral dominance of facial recognition. Further, circumscribed lesion and degenerative disease may also cause progressive prosopagnosia. Apperceptive prosopagnosia is observed in patients with posterior cortical atrophy (PCA), pathologically considered as Alzheimer's disease, and associative prosopagnosia in frontotemporal lobar degeneration (FTLD). Second, we discuss face recognition as part of communication. Patients with Parkinson disease show social cognitive impairments, such as difficulty in facial expression recognition and deficits in theory of mind as detected by the reading the mind in the eyes test. Pathological and functional imaging studies indicate that social cognitive impairment in Parkinson disease is possibly related to damages in the amygdalae and surrounding limbic system. The social cognitive deficits can be observed in the early stages of Parkinson disease, and even in the prodromal stage, for example, patients with rapid eye movement (REM) sleep behavior disorder (RBD) show impairment in facial expression recognition. Further, patients with myotonic dystrophy type 1 (DM 1), which is a multisystem disease that mainly affects the muscles, show social cognitive impairment similar to that of Parkinson disease. Our previous study showed that facial expression recognition impairment of DM 1 patients is associated with lesion in the amygdalae and insulae. Our study results indicate that behaviors and personality traits in DM 1 patients, which are revealed by social cognitive impairment, are attributable to dysfunction of the limbic system.

Dmpk gene deletion or antisense knockdown does not compromise cardiac or skeletal muscle function in mice

PubMed Central

Carrell, Samuel T.; Carrell, Ellie M.; Auerbach, David; Pandey, Sanjay K.; Bennett, C. Frank; Dirksen, Robert T.; Thornton, Charles A.

2016-01-01

Myotonic dystrophy type 1 (DM1) is a genetic disorder in which dominant-active DM protein kinase (DMPK) transcripts accumulate in nuclear foci, leading to abnormal regulation of RNA processing. A leading approach to treat DM1 uses DMPK-targeting antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. However, basal levels of DMPK protein are reduced by half in DM1 patients. This raises concern that intolerance for further DMPK loss may limit ASO therapy, especially since mice with Dmpk gene deletion reportedly show cardiac defects and skeletal myopathy. We re-examined cardiac and muscle function in mice with Dmpk gene deletion, and studied post-maturity knockdown using Dmpk-targeting ASOs in mice with heterozygous deletion. Contrary to previous reports, we found no effect of Dmpk gene deletion on cardiac or muscle function, when studied on two genetic backgrounds. In heterozygous knockouts, the administration of ASOs reduced Dmpk expression in cardiac and skeletal muscle by > 90%, yet survival, electrocardiogram intervals, cardiac ejection fraction and muscle strength remained normal. The imposition of cardiac stress by pressure overload, or muscle stress by myotonia, did not unmask a requirement for DMPK. Our results support the feasibility and safety of using ASOs for post-transcriptional silencing of DMPK in muscle and heart. PMID:27522499

Early-Onset LMNA-Associated Muscular Dystrophy with Later Involvement of Contracture.

PubMed

Lee, Younggun; Lee, Jung Hwan; Park, Hyung Jun; Choi, Young Chul

2017-10-01

The early diagnosis of LMNA-associated muscular dystrophy is important for preventing sudden arrest related to cardiac conduction block. However, diagnosing early-onset Emery-Dreifuss muscular dystrophy (EDMD) with later involvement of contracture and limb-girdle muscular dystrophy type 1B is often delayed due to heterogeneous clinical presentations. We aimed to determine the clinical features that contribute to a delayed diagnosis. We reviewed four patients who were recently diagnosed with LMNA-associated muscular dystrophy by targeted exome sequencing and who were initially diagnosed with nonspecific or other types of muscular dystrophy. Certain clinical features such as delayed contracture involvement and calf hypertrophy were found to contribute to a delayed diagnosis. Muscle biopsies were not informative for the diagnosis in these patients. Genetic testing of single or multiple genes is useful for confirming a diagnosis of LMNA-associated muscular dystrophy. Even EDMD patients could experience the later involvement of contracture, so clinicians should consider early genetic testing for patients with undiagnosed muscular dystrophy or laminopathy. Copyright © 2017 Korean Neurological Association

Differences among four meat goat breeds for doe fitness indicator traits in the southeastern United States.

PubMed

Wang, L; Nguluma, A; Leite-Browning, M L; Browning, R

2017-04-01

Sustainable meat goat production begins with the identification and use of maternal breeds that demonstrate relatively enhanced levels of fitness under less-than-optimal conditions. The Myotonic goat is a heritage breed that is lacking in comparative assessment for female fitness. In this study, Boer ( = 73), Kiko ( = 115), Myotonic ( = 80), and Spanish ( = 114) meat goat does were compared for traits associated with health and reproduction. The herd was semi-intensively managed on humid subtropical pasture for 6 yr. The study included 838 doe-year matings and over 2,000 records for BW, fecal egg count (FEC), and packed cell volume (PCV). Body weights of Boer and Kiko does were heavier ( < 0.05) than for Spanish does, which, in turn, were heavier ( < 0.05) than for Myotonic does. In production does, FEC were lower ( < 0.05) for Myotonic does than for Boer does, whereas Kiko and Spanish does had intermediate FEC that differed ( < 0.05) from Myotonic and Boer does. Kiko, Myotonic, and Spanish does had greater ( < 0.05) PCV than Boer does. Doe age and physiological status also affected ( < 0.05) BW, FEC, and PCV. Annual kidding rates, weaning rates, doe retention rates, and kid crop weaned were greater ( < 0.05) for Kiko and Spanish does than for Boer does, whereas Myotonic does were intermediate and differed ( < 0.05) from the other 3 breeds. The results suggest that Kiko and Spanish does should be preferred over Boer and Myotonic does for sustainable meat goat doe performance under limited-input management conditions. Myotonic does maintained the lowest FEC among all doe breeds and warrant further evaluation as a genetic resource for controlling gastrointestinal parasitism.

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials.

PubMed

Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S; Verschuuren, Jan J; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E; Muntoni, Francesco

2011-12-01

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy.

Dystrophin quantification and clinical correlations in Becker muscular dystrophy: implications for clinical trials

PubMed Central

Anthony, Karen; Cirak, Sebahattin; Torelli, Silvia; Tasca, Giorgio; Feng, Lucy; Arechavala-Gomeza, Virginia; Armaroli, Annarita; Guglieri, Michela; Straathof, Chiara S.; Verschuuren, Jan J.; Aartsma-Rus, Annemieke; Helderman-van den Enden, Paula; Bushby, Katherine; Straub, Volker; Sewry, Caroline; Ferlini, Alessandra; Ricci, Enzo; Morgan, Jennifer E.

2011-01-01

Duchenne muscular dystrophy is caused by mutations in the DMD gene that disrupt the open reading frame and prevent the full translation of its protein product, dystrophin. Restoration of the open reading frame and dystrophin production can be achieved by exon skipping using antisense oligonucleotides targeted to splicing elements. This approach aims to transform the Duchenne muscular dystrophy phenotype to that of the milder disorder, Becker muscular dystrophy, typically caused by in-frame dystrophin deletions that allow the production of an internally deleted but partially functional dystrophin. There is ongoing debate regarding the functional properties of the different internally deleted dystrophins produced by exon skipping for different mutations; more insight would be valuable to improve and better predict the outcome of exon skipping clinical trials. To this end, we have characterized the clinical phenotype of 17 patients with Becker muscular dystrophy harbouring in-frame deletions relevant to on-going or planned exon skipping clinical trials for Duchenne muscular dystrophy and correlated it to the levels of dystrophin, and dystrophin-associated protein expression. The cohort of 17 patients, selected exclusively on the basis of their genotype, included 4 asymptomatic, 12 mild and 1 severe patient. All patients had dystrophin levels of >40% of control and significantly higher dystrophin (P = 0.013), β-dystroglycan (P = 0.025) and neuronal nitric oxide synthase (P = 0.034) expression was observed in asymptomatic individuals versus symptomatic patients with Becker muscular dystrophy. Furthermore, grouping the patients by deletion, patients with Becker muscular dystrophy with deletions with an end-point of exon 51 (the skipping of which could rescue the largest group of Duchenne muscular dystrophy deletions) showed significantly higher dystrophin levels (P = 0.034) than those with deletions ending with exon 53. This is the first quantitative study on both dystrophin and dystrophin-associated protein expression in patients with Becker muscular dystrophy with deletions relevant for on-going exon skipping trials in Duchenne muscular dystrophy. Taken together, our results indicate that all varieties of internally deleted dystrophin assessed in this study have the functional capability to provide a substantial clinical benefit to patients with Duchenne muscular dystrophy. PMID:22102647

PubMed Central

RUSSO, VINCENZO; RAGO, ANNA; DI MEO, FEDERICA; CIOPPA, NADIA DELLA; PAPA, ANDREA ANTONIO; RUSSO, MARIA GIOVANNA

2014-01-01

The occurrence of ventricular fibrillation, induced by bipolar electrocautery during elective dual chamber pacemaker implantation, is reported in a patient affected by Myotonic Distrophy type 1 with normal left ventricular ejection fraction PMID:25873784

PDK1-mediated activation of MRCKα regulates directional cell migration and lamellipodia retraction

PubMed Central

Gagliardi, Paolo Armando; di Blasio, Laura; Puliafito, Alberto; Seano, Giorgio; Sessa, Roberto; Chianale, Federica; Leung, Thomas; Bussolino, Federico

2014-01-01

Directional cell migration is of paramount importance in both physiological and pathological processes, such as development, wound healing, immune response, and cancer invasion. Here, we report that 3-phosphoinositide-dependent kinase 1 (PDK1) regulates epithelial directional migration and invasion by binding and activating myotonic dystrophy kinase–related CDC42-binding kinase α (MRCKα). We show that the effect of PDK1 on cell migration does not involve its kinase activity but instead relies on its ability to bind membrane phosphatidylinositol (3,4,5)-trisphosphate. Upon epidermal growth factor (EGF) stimulation, PDK1 and MRCKα colocalize at the cell membrane in lamellipodia. We demonstrate that PDK1 positively modulates MRCKα activity and drives its localization within lamellipodia. Likewise, the retraction phase of lamellipodia is controlled by PDK1 through an MRCKα-dependent mechanism. In summary, we discovered a functional pathway involving PDK1-mediated activation of MRCKα, which links EGF signaling to myosin contraction and directional migration. PMID:25092657

Drosophila melanogaster As a Model Organism to Study RNA Toxicity of Repeat Expansion-Associated Neurodegenerative and Neuromuscular Diseases

PubMed Central

Koon, Alex C.; Chan, Ho Yin Edwin

2017-01-01

For nearly a century, the fruit fly, Drosophila melanogaster, has proven to be a valuable tool in our understanding of fundamental biological processes, and has empowered our discoveries, particularly in the field of neuroscience. In recent years, Drosophila has emerged as a model organism for human neurodegenerative and neuromuscular disorders. In this review, we highlight a number of recent studies that utilized the Drosophila model to study repeat-expansion associated diseases (READs), such as polyglutamine diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), myotonic dystrophy type 1 (DM1) and type 2 (DM2), and C9ORF72-associated amyotrophic lateral sclerosis/frontotemporal dementia (C9-ALS/FTD). Discoveries regarding the possible mechanisms of RNA toxicity will be focused here. These studies demonstrate Drosophila as an excellent in vivo model system that can reveal novel mechanistic insights into human disorders, providing the foundation for translational research and therapeutic development. PMID:28377694

A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor.

PubMed

Rzuczek, Suzanne G; Park, HaJeung; Disney, Matthew D

2014-10-06

Potent modulators of RNA function can be assembled in cellulo by using the cell as a reaction vessel and a disease-causing RNA as a catalyst. When designing small molecule effectors of function, a balance between permeability and potency must be struck. Low molecular weight compounds are more permeable whereas higher molecular weight compounds are more potent. The advantages of both types of compounds could be synergized if low molecular weight molecules could be transformed into potent, multivalent ligands by a reaction that is catalyzed by binding to a target in cells expressing a genetic defect. It was shown that this approach is indeed viable in cellulo. Small molecule modules with precisely positioned alkyne and azide moieties bind adjacent internal loops in r(CCUG)(exp), the causative agent of myotonic dystrophy type 2 (DM2), and are transformed into oligomeric, potent inhibitors of DM2 RNA dysfunction by a Huisgen 1,3-dipolar cycloaddition reaction, a variant of click chemistry. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Msh2-Msh3 Interferes with Okazaki Fragment Processing to Promote Trinucleotide Repeat Expansions

PubMed Central

Kantartzis, Athena; Williams, Gregory M.; Balakrishnan, Lata; Roberts, Rick L.; Surtees, Jennifer A.; Bambara, Robert A.

2012-01-01

Summary Trinucleotide repeat (TNR) expansions are the underlying cause of more than forty neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington’s disease. Although genetic evidence has attributed the cause of these diseases to errors in DNA replication and/or repair, clear molecular mechanisms have not been described. We have focused on the role of the mismatch repair complex Msh2-Msh3 in promoting TNR expansions. We demonstrate that Msh2-Msh3 promotes CTG and CAG repeat expansions in vivo in Saccharomyces cerevisiae. We further provide biochemical evidence that Msh2-Msh3 directly interferes with normal Okazaki fragment processing by flap endonuclease1 (Rad27) and DNA Ligase I (Cdc9) in the presence of TNR sequences, thereby producing small, incremental expansion events. We believe that this is the first mechanistic evidence showing the interplay of replication and repair proteins in the expansion of sequences during lagging strand DNA replication. PMID:22938864

Msh2-Msh3 interferes with Okazaki fragment processing to promote trinucleotide repeat expansions.

PubMed

Kantartzis, Athena; Williams, Gregory M; Balakrishnan, Lata; Roberts, Rick L; Surtees, Jennifer A; Bambara, Robert A

2012-08-30

Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington's disease. Although genetic evidence points to errors in DNA replication and/or repair as the cause of these diseases, clear molecular mechanisms have not been described. Here, we focused on the role of the mismatch repair complex Msh2-Msh3 in promoting TNR expansions. We demonstrate that Msh2-Msh3 promotes CTG and CAG repeat expansions in vivo in Saccharomyces cerevisiae. Furthermore, we provide biochemical evidence that Msh2-Msh3 directly interferes with normal Okazaki fragment processing by flap endonuclease1 (Rad27) and DNA ligase I (Cdc9) in the presence of TNR sequences, thereby producing small, incremental expansion events. We believe that this is the first mechanistic evidence showing the interplay of replication and repair proteins in the expansion of sequences during lagging-strand DNA replication. Copyright © 2012 The Authors. Published by Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

deLorimier, Elaine; Coonrod, Leslie A.; Copperman, Jeremy

In this study, CUG repeat expansions in the 3' UTR of dystrophia myotonica protein kinase ( DMPK) cause myotonic dystrophy type 1 (DM1). As RNA, these repeats elicit toxicity by sequestering splicing proteins, such as MBNL1, into protein–RNA aggregates. Structural studies demonstrate that CUG repeats can form A-form helices, suggesting that repeat secondary structure could be important in pathogenicity. To evaluate this hypothesis, we utilized structure-stabilizing RNA modifications pseudouridine (Ψ) and 2'-O-methylation to determine if stabilization of CUG helical conformations affected toxicity. CUG repeats modified with Ψ or 2'-O-methyl groups exhibited enhanced structural stability and reduced affinity for MBNL1. Molecularmore » dynamics and X-ray crystallography suggest a potential water-bridging mechanism for Ψ-mediated CUG repeat stabilization. Ψ modification of CUG repeats rescued mis-splicing in a DM1 cell model and prevented CUG repeat toxicity in zebrafish embryos. This study indicates that the structure of toxic RNAs has a significant role in controlling the onset of neuromuscular diseases.« less

Rhabdomyolysis featuring muscular dystrophies.

PubMed

Lahoria, Rajat; Milone, Margherita

2016-02-15

Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice. To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature. We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation. Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600). Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

[Laparoscopic cholecystectomy in a patient with Steinert disease].

PubMed

Mercier, M F; Baghdadi, H; Frosini, C; Sielezneff, I; Sastre, B; Gouin, F

1996-01-01

Steinert's disease or myotonic myopathy is associated with chronic restrictive respiratory insufficiency. A case of a patient with Steinert's disease undergoing laparoscopic cholecystectomy, with a full recovery within three days is reported. It is concluded that laparoscopic surgery is a possible therapeutic tool in patients suffering from a myopathy.

Muscle-Derived Proteins as Serum Biomarkers for Monitoring Disease Progression in Three Forms of Muscular Dystrophy

PubMed Central

Burch, Peter M.; Pogoryelova, Oksana; Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmüller, Hanns; Morris, Carl

2015-01-01

Abstract Background: Identifying translatable, non-invasive biomarkers of muscular dystrophy that better reflect the disease pathology than those currently available would aid the development of new therapies, the monitoring of disease progression and the response to therapy. Objective: The goal of this study was to evaluate a panel of serum protein biomarkers with the potential to specifically detect skeletal muscle injury. Method: Serum concentrations of skeletal troponin I (sTnI), myosin light chain 3 (Myl3), fatty acid binding protein 3 (FABP3) and muscle-type creatine kinase (CKM) proteins were measured in 74 Duchenne muscular dystrophy (DMD), 38 Becker muscular dystrophy (BMD) and 49 Limb-girdle muscular dystrophy type 2B (LGMD2B) patients and 32 healthy controls. Results: All four proteins were significantly elevated in the serum of these three muscular dystrophy patient populations when compared to healthy controls, but, interestingly, displayed different profiles depending on the type of muscular dystrophy. Additionally, the effects of patient age, ambulatory status, cardiac function and treatment status on the serum concentrations of the proteins were investigated. Statistical analysis revealed correlations between the serum concentrations and certain clinical endpoints including forced vital capacity in DMD patients and the time to walk ten meters in LGMD2B patients. Serum concentrations of these proteins were also elevated in two preclinical models of muscular dystrophy, the mdx mouse and the golden-retriever muscular dystrophy dog. Conclusions: These proteins, therefore, are potential muscular dystrophy biomarkers for monitoring disease progression and therapeutic response in both preclinical and clinical studies. PMID:26870665

Genetic diagnosis of Duchenne and Becker muscular dystrophy using multiplex ligation-dependent probe amplification in Rwandan patients.

PubMed

Uwineza, Annette; Hitayezu, Janvier; Murorunkwere, Seraphine; Ndinkabandi, Janvier; Kalala Malu, Celestin Kaputu; Caberg, Jean Hubert; Dideberg, Vinciane; Bours, Vincent; Mutesa, Leon

2014-04-01

Duchenne and Becker muscular dystrophies are the most common clinical forms of muscular dystrophies. They are genetically X-linked diseases caused by a mutation in the dystrophin (DMD) gene. A genetic diagnosis was carried out in six Rwandan patients presenting a phenotype of Duchenne and Becker muscular dystrophies and six asymptomatic female carrier relatives using multiplex ligation-dependent probe amplification (MLPA). Our results revealed deletion of the exons 48-51 in one patient, an inherited deletion of the exons 8-21 in two brothers and a de novo deletion of the exons 46-50 in the fourth patient. No copy number variation was found in two patients. Only one female carrier presented exon deletion in the DMD gene. This is the first cohort of genetic analysis in Rwandan patients affected by Duchenne and Becker muscular dystrophies. This report confirmed that MLPA assay can be easily implemented in low-income countries.

Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

PubMed

Momma, Kazunari; Noguchi, Satoru; Malicdan, May Christine V; Hayashi, Yukiko K; Minami, Narihiro; Kamakura, Keiko; Nonaka, Ikuya; Nishino, Ichizo

2012-01-01

Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene.

Steinert syndrome and repercussions in dental medicine.

PubMed

Baptista, Helena; Lopes Cardoso, Inês

2017-03-01

Steinert syndrome, also called myotonic dystrophy type 1, is a genetic disorder with autosomal dominant transmission characterized by myotonia and a multisystemic clinical picture that affects several tissues of the human body. The most common systemic phenotypes are: muscular, cardiac, respiratory, CNS, ocular, gynecological, digestive, orthopedical, as well as cognitive and psychological symptoms (cognitive decline). Muscles involved in voluntary movement are highly affected by myotonia especially distal muscles of upper limbs. These patients also show changes in face, chewing and pharynx muscles that can lead to swallowing and speech problems, dysphagia and in most cases to food aspiration and suffocation. Poor oral hygiene resulting from reduced motor mobility and reduced saliva flux can lead to gingival inflammation and periodontal disease. Other oral manifestations include disturbances at the temporomandibular articulation, dental occlusion changes and reduction in teeth number as a result of caries. Main causes of death are pneumonia and cardiac arrhythmias. The etiopathogeny of this syndrome is still not clear, conditioning the existence of a specific treatment for this disease. Nowadays, treatments consist on the release of the existing symptoms, in an attempt to give a better life quality to patients. It is very important to implement actions that can prevent complications and consequently decrease death. Treatments should be applied in an early stage of the disease. Bronchoscopy and artificial respiration should be used to prevent pneumonia, and regular electrocardiographic monitoring should be done to evaluate defects in the conductive system. Several approaches have been applied to rehabilitate swallowing dysfunction and avoid aspiration like videofluoroscopy, postural techniques and adjustment of diet type. It is the aim of this paper to clarify the ethiology, diagnosis, systemic and oral characteristics of the syndrome, as well as to discuss treatments to be applied according to patients affected organs. Copyright © 2016 Elsevier Ltd. All rights reserved.

Repair of an inguinoscrotal hernia in a patient with Becker muscular dystrophy.

PubMed

Tatulli, F; Caraglia, A; Delcuratolo, A; Cassano, S; Chetta, G S

2017-01-01

Inguinal hernia repairs are routinely performed as outpatient procedures in most patients, whereas a few require admission due to clinical or social peculiarities. Muscular dystrophies are inherited disorders characterized by progressive muscle wasting and weakness. In case of surgery there is no definite recommendation for either general or regional anesthesia. This contribution regards a 48 y. o. male patient diagnosed with Becker Muscular Dystrophy by muscle biopsy 10 years earlier. He had a left-sided sizable inguinoscrotal hernia with repeat episodes of incarceration. An elective mesh repair with suction drainage was accomplished under selective spinal anesthesia. The post-operative course was uneventful. A few inguinal hernia repairs require admission due to peculiarities such as extensive scrotal hernias requiring suction drainage. Muscular dystrophies are inherited disorders with no cure and no two dystrophy patients are exactly alike, therefore the health issues will be different for each individual. In case of surgery there is no definite recommendation for either general or regional anesthesia. This contribution regards the successful elective mesh repair with suction drainage of a large left-sided inguino-scrotal hernia in a 48 y. o. male patient affected by Becker muscular dystrophy by selective spinal anesthesia obtained by 10 milligrams of hyperbaric bupivacaine. Effective mesh repair with suction drainage of large inguinal hernias under spinal anesthesia can be achieved in patients affected by muscular dystrophy.

Granular corneal dystrophy Groenouw type I (GrI) and Reis-Bücklers' corneal dystrophy (R-B). One entity?

PubMed

Møller, H U

1989-12-01

This paper maintains that Reis-Bücklers' corneal dystrophy and granular corneal dystrophy Groenouw type I are one and the same disease. Included are some of the technically best photographs of Reis-Bücklers' dystrophy found in the literature, and these are compared with photographs from patients with granular corneal dystrophy examined by the author. It is argued that most of the histological and ultrastructural findings on Reis Bücklers' dystrophy described in the literature are either congruent with what is found in granular corneal dystrophy or unspecific.

Perturbation of muscle metabolism in patients with muscular dystrophy in early or acute phase of disease: In vitro, high resolution NMR spectroscopy based analysis.

PubMed

Srivastava, Niraj Kumar; Yadav, Ramakant; Mukherjee, Somnath; Sinha, Neeraj

2018-03-01

Muscular dystrophy is an inherited muscle disease, characterized by progressive muscle wasting and weakness of variable distribution and severity. In vitro, high-resolution proton nuclear magnetic resonance (NMR) spectroscopy based analysis was performed on perchloric acid (PCA) extract of muscle specimens of patients suffering from various types of muscular dystrophies to identify alteration in hydrophilic low-molecular weight substances (aqueous metabolites) as compared to muscle of control subjects as well as in between the types of muscular dystrophy. Muscle tissue specimens were obtained from Duchenne muscular dystrophy (DMD) [n=11], Becker muscular dystrophy (BMD) [n=12], facioscapulohumeral dystrophy (FSHD) [n=9] and limb girdle muscular dystrophy (LGMD)-2B [n=22]. Control muscle specimens [n=40] were also taken. Concentration of branched chain amino acids (BCA), glutamine/glutamate (Gln/Glu), acetate (Ace) and fumarate (Fum) was decreased and His was increased in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control subjects. Alanine (Ala) was significantly reduced in BMD, FSHD and LGMD-2B patients as compared to control subjects. Tyrosine (Tyr) was present only in the muscle tissue of control subjects. Propionate (Prop) was present in muscle tissue of DMD, BMD, FSHD and LGMD-2B patients and was absent in muscle tissue of control subjects. Concentration of BCA and Prop is significantly reduced in patients with DMD as compared to BMD, but Glucose is significantly higher in patients with DMD as compared to BMD. Quantity of Glucose, His and Gln/glu are significantly higher in patients with DMD as compared to FSHD, but Prop is significantly reduced in patients with DMD as compared to FSHD. Concentration of Ala and His is significantly higher in patients with DMD as compared to LGMD-2B, but BCA, Glucose and Prop are significantly reduced in patients with DMD as compared to LGMD-2B. Concentration of His is significantly higher in patients with BMD as compared to FSHD. Concentration of His is significantly reduced and Glucose is higher in patients with LGMD-2B as compared to BMD. Glucose concentration is significantly reduced in patients with FSHD as compared to LGMD-2B. ROC curves supported the noticeable discrimination in between the patients with DMD and FSHD for the quantity of Gln/Glu, and patients with LGMD-2B and DMD for the quantity of Ala. Collectively, these findings showed the perturbation of muscle metabolism in muscular dystrophy. The data of presented study may be used as supporting information for existing methods of the diagnosis for patients with muscular dystrophy. Copyright © 2017 Elsevier B.V. All rights reserved.

Respiratory function in facioscapulohumeral muscular dystrophy 1.

PubMed

Wohlgemuth, M; Horlings, C G C; van der Kooi, E L; Gilhuis, H J; Hendriks, J C M; van der Maarel, S M; van Engelen, B G M; Heijdra, Y F; Padberg, G W

2017-06-01

To test the hypothesis that wheelchair dependency and (kypho-)scoliosis are risk factors for developing respiratory insufficiency in facioscapulohumeral muscular dystrophy, we examined 81 patients with facioscapulohumeral muscular dystrophy 1 of varying degrees of severity ranging from ambulatory patients to wheelchair-bound patients. We examined the patients neurologically and by conducting pulmonary function tests: Forced Vital Capacity, Forced Expiratory Volume in 1 second, and static maximal inspiratory and expiratory mouth pressures. We did not find pulmonary function test abnormalities in ambulant facioscapulohumeral muscular dystrophy patients. Even though none of the patients complained of respiratory dysfunction, mild to severe respiratory insufficiency was found in more than one third of the wheelchair-dependent patients. Maximal inspiratory pressures and maximal expiratory pressures were decreased in most patients, with a trend that maximal expiratory pressures were more affected than maximal inspiratory pressures. Wheelchair-dependent patients with (kypho-)scoliosis showed the most restricted lung function. Wheelchair-dependent patients with (kypho-)scoliosis are at risk for developing respiratory function impairment. We advise examining this group of facioscapulohumeral muscular dystrophy patients periodically, even in the absence of symptoms of respiratory insufficiency, given its frequency and impact on daily life and the therapeutic consequences. Copyright © 2017 Elsevier B.V. All rights reserved.

PubMed Central

RUSSO, VINCENZO; DI MEO, FEDERICA; PAPA, ANDREA ANTONIO; CIOPPA, NADIA DELLA; PROIETTI, RICCARDO; RUSSO, MARIA GIOVANNA; CALABRÒ, RAFFAELE; POLITANO, LUISA

2014-01-01

P-wave dispersion is a non invasive indicator of intra-atrial conduction heterogeneity producing substrate for reentry, which is a pathophysiological mechanism of atrial fibrillation. The relationship between P-wave dispersion (PD) and atrial fibrillation (AF) in Myotonic dystrophy type 1 (DM1) patients is still unclear. Atrial Preference Pacing (APP) is an efficient algorithm to prevent paroxysmal AF in patients implanted with dual-chamber pacemaker. Aim of our study was to evaluate the possible correlation between atrial preference pacing algorithm, P-wave dispersion and AF burden in DM1 patients with normal cardiac function underwent permanent dual-chamber pacemaker implantation. We enrolled 50 patients with DM1 (age 50.3 ± 7.3; 11 F) underwent dual-chamber pacemaker implantation for various degree of atrioventricula block. The study population was randomized following 1 months stabilization period to APP algorithm features programmed OFF or ON. Patients were assessed every 3 months for the first year, and every 6 months thereafter up to 3 years. At each follow-up visit, we counted: the number of premature atrial beats, the number and the mean duration of AF episodes, AF burden and the percentage of atrial and ventricular pacing. APP ON Group showed lower number of AF episodes (117 ± 25 vs. 143 ± 37; p = 0.03) and AF burden (3059 ± 275 vs. 9010 ± 630 min; p < 0.04) than APP OFF Group. Atrial premature beats count (44903 ± 30689 vs. 13720 ± 7717 beats; p = 0.005) and Pwave dispersion values (42,1 ± 11 ms vs. 29,1 ± 4,2 ms, p = 0,003) were decreased in APP ON Group. We found a significant positive correlation between PD and AF burden (R = 0,8, p = 0.007). Atrial preference pacing algorithm, decreasing the number of atrial premature beats and the P-wave dispersion, reduces the onset and perpetuator factors of AF episodes and decreases the AF burden in DM1 patients underwent dual chamber pacemaker implantation for various degree of atrioventricular blocks and documented atrial fibrillation. PMID:25873781

Cardiac manifestations of congenital LMNA-related muscular dystrophy in children: three case reports and recommendations for care.

PubMed

Heller, Felice; Dabaj, Ivana; Mah, Jean K; Bergounioux, Jean; Essid, Aben; Bönnemann, Carsten G; Rutkowski, Anne; Bonne, Gisèle; Quijano-Roy, Susana; Wahbi, Karim

2017-08-01

Skeletal and cardiac muscle laminopathies, caused by mutations in the lamin A/C gene, have a clinical spectrum from congenital LMNA-related muscular dystrophy to later-onset Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, and dilated cardiomyopathy. Although cardiac involvement is observed at all ages, it has only been well described in adults. We present the evolution of cardiac disease in three children with congenital muscular dystrophy presentation of LMNA-related muscular dystrophy. In this series, atrial arrhythmia was the presenting cardiac finding in all three patients. Heart failure developed up to 5 years later. Symptoms of right heart failure, including diarrhoea and peripheral oedema, preceded a rapid decline in left ventricular ejection fraction. Recommendations for cardiac surveillance and management in these patients are made.

Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts, unlinked to the LAMA2, FCMD, MEB and CMD1B loci, in three Tunisian patients.

PubMed

Triki, Chahnez; Louhichi, Nacim; Méziou, Mériam; Choyakh, Fakher; Kéchaou, Mohamed Salah; Jlidi, Rachid; Mhiri, Chokri; Fakhfakh, Faiza; Ayadi, Hamadi

2003-01-01

We report three Tunisian patients affected by congenital muscular dystrophy with mental retardation and cerebellar cysts on cranial magnetic resonance imaging. The clinical features were characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absence of speech, inability to walk in three patients, but calf hypertrophy was noted only in two patients. Brain magnetic resonance imaging showed several cerebellar cysts and vermis hypoplasia in all of the patients. Abnormality of the white matter was present in two patients. The pattern of gyration was normal in all cases. Serum creatine kinase was elevated in all three cases and their muscle biopsy showed dystrophic changes compatible with congenital muscular dystrophy. The immunohistochemical analysis of the skeletal muscle revealed partial merosin deficiency, more pronounced for the N-terminal antibody. Linkage analysis excluded congenital muscular dystrophy loci on chromosomes 6q22, 9q31, 1p32 and 1q42. These patients constituted a particular form of congenital muscular dystrophy with a combination of severe motor delay, mental retardation, partial merosin deficiency and cerebellar cysts. Two patients showed white matter abnormalities on magnetic resonance imaging and hypertrophy of the calves. These cases, in addition to those reported previously, confirmed the large phenotypic variability in the group of secondary merosin deficiency congenital muscular dystrophy.

[Application of targeted capture technology and next generation sequencing in molecular diagnosis of inherited myopathy].

PubMed

Fu, Xiaona; Liu, Aijie; Yang, Haipo; Wei, Cuijie; Ding, Juan; Wang, Shuang; Wang, Jingmin; Yuan, Yun; Jiang, Yuwu; Xiong, Hui

2015-10-01

To elucidate the usefulness of next generation sequencing for diagnosis of inherited myopathy, and to analyze the relevance between clinical phenotype and genotype in inherited myopathy. Related genes were selected for SureSelect target enrichment system kit (Panel Version 1 and Panel Version 2). A total of 134 patients who were diagnosed as inherited myopathy clinically underwent next generation sequencing in Department of Pediatrics, Peking University First Hospital from January 2013 to June 2014. Clinical information and gene detection result of the patients were collected and analyzed. Seventy-seven of 134 patients (89 males and 45 females, visiting ages from 6-month-old to 26-year-old, average visiting age was 6 years and 1 month) underwent next generation sequencing by Panel Version 1 in 2013, and 57 patients underwent next generation sequencing by Panel Version 2 in 2014. The gene detection revealed that 74 patients had pathogenic gene mutations, and the positive rate of genetic diagnosis was 55.22%. One patient was diagnosed as metabolic myopathy. Five patients were diagnosed as congenital myopathy; 68 were diagnosed as muscular dystrophy, including 22 with congenital muscular dystrophy 1A (MDC1A), 11 with Ullrich congenital muscular dystrophy (UCMD), 6 with Bethlem myopathy (BM), 12 with Duchenne muscular dystrophy (DMD) caused by point mutations in DMD gene, 5 with LMNA-related congenital muscular dystrophy (L-CMD), 1 with Emery-Dreifuss muscular dystrophy (EDMD), 7 with alpha-dystroglycanopathy (α-DG) patients, and 4 with limb-girdle muscular dystrophy (LGMD) patients. Next generation sequencing plays an important role in diagnosis of inherited myopathy. Clinical and biological information analysis was essential for screening pathogenic gene of inherited myopathy.

A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy

ClinicalTrials.gov

2018-06-16

Muscular Dystrophies; Muscular Dystrophy, Duchenne; Muscular Disorders, Atrophic; Muscular Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Phase 3 Study of Ataluren in Patients With Nonsense Mutation Duchenne Muscular Dystrophy

ClinicalTrials.gov

2017-12-11

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Selective alkylation of T–T mismatched DNA using vinyldiaminotriazine–acridine conjugate

PubMed Central

Onizuka, Kazumitsu; Usami, Akira; Yamaoki, Yudai; Kobayashi, Tomohito; Hazemi, Madoka E; Chikuni, Tomoko; Sato, Norihiro; Sasaki, Kaname; Katahira, Masato

2018-01-01

Abstract The alkylation of the specific higher-order nucleic acid structures is of great significance in order to control its function and gene expression. In this report, we have described the T–T mismatch selective alkylation with a vinyldiaminotriazine (VDAT)–acridine conjugate. The alkylation selectively proceeded at the N3 position of thymidine on the T–T mismatch. Interestingly, the alkylated thymidine induced base flipping of the complementary base in the duplex. In a model experiment for the alkylation of the CTG repeats DNA which causes myotonic dystrophy type 1 (DM1), the observed reaction rate for one alkylation increased in proportion to the number of T–T mismatches. In addition, we showed that primer extension reactions with DNA polymerase and transcription with RNA polymerase were stopped by the alkylation. The alkylation of the repeat DNA will efficiently work for the inhibition of replication and transcription reactions. These functions of the VDAT–acridine conjugate would be useful as a new biochemical tool for the study of CTG repeats and may provide a new strategy for the molecular therapy of DM1. PMID:29309639

The system with zwitterionic lactose-based surfactant for complexation and delivery of small interfering ribonucleic acid—A structural and spectroscopic study

NASA Astrophysics Data System (ADS)

Skupin, Michalina; Sobczak, Krzysztof; Zieliński, Ryszard; Kozak, Maciej

2016-05-01

Systems suitable for the effective preparation of complexes with siRNA (small interfering RNA) are at the center of interest in the area of research work on the delivery of the RNA-based drugs (RNA-therapeutics). This article presents results of a study on the structural effects associated with siRNA complexation by a surfactant comprising a lactose group (N-(3-propanesulfone)-N-dodecyl-amino-beta-D-lactose hydrochloride, LA12). The double stranded siRNA oligomer (21 base pairs) used in this study is responsible for silencing a gene that can be important in the therapy of myotonic dystrophy type 1. The obtained siRNA/LA12 lipoplexes were studied using the methods of small angle scattering of synchrotron radiation, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and electrophoretic mobility tests. Lipoplexes form in solution stable lamellar or cubic phases. The surfactant selected for the study shows much lower cytotoxicity and good complexation abilities of siRNA than dicationic or polycationic surfactants.

A case of neuromyotonia and axonal motor neuropathy: A report of a HINT1 mutation in the United States.

PubMed

Jerath, Nivedita U; Shy, Michael E; Grider, Tiffany; Gutmann, Ludwig

2015-12-01

HINT1 mutations cause an autosomal recessive distal hereditary motor axonal neuropathy with neuromyotonia. This is a case report of a HINT1 mutation in the United States. A 30-year-old man of Slovenian heritage and no significant family history presented with scoliosis as a child and later developed neuromyotonia and distal weakness. Electrodiagnostic testing revealed an axonal motor neuropathy and neuromyotonic discharges. Previous diagnostic work-up, including testing for Cx32, MPZ, PMP-22, NF-L, EGR2, CLCN1, DM1, DM2, SMN exon 7/8, emerin, LMNA, MPK, SCNA4, acid maltase gene, paraneoplastic disorder, and a sural nerve biopsy, was negative. Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at p.Arg37Pro. This entity should be distinguished clinically and genetically from myotonic dystrophy and channelopathies with the clinical features of neuromyotonia and an axonal neuropathy. This case illustrates the importance of identifying the correct phenotype to avoid unnecessary and costly evaluations. © 2015 Wiley Periodicals, Inc.

The system with zwitterionic lactose-based surfactant for complexation and delivery of small interfering ribonucleic acid—A structural and spectroscopic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Skupin, Michalina; Sobczak, Krzysztof; Zieliński, Ryszard

Systems suitable for the effective preparation of complexes with siRNA (small interfering RNA) are at the center of interest in the area of research work on the delivery of the RNA-based drugs (RNA-therapeutics). This article presents results of a study on the structural effects associated with siRNA complexation by a surfactant comprising a lactose group (N-(3-propanesulfone)-N-dodecyl-amino-beta-D-lactose hydrochloride, LA12). The double stranded siRNA oligomer (21 base pairs) used in this study is responsible for silencing a gene that can be important in the therapy of myotonic dystrophy type 1. The obtained siRNA/LA12 lipoplexes were studied using the methods of small anglemore » scattering of synchrotron radiation, circular dichroism spectroscopy, Fourier transform infrared spectroscopy, and electrophoretic mobility tests. Lipoplexes form in solution stable lamellar or cubic phases. The surfactant selected for the study shows much lower cytotoxicity and good complexation abilities of siRNA than dicationic or polycationic surfactants.« less

[Neurogenetics in Peru, example of translational research].

PubMed

Mazzetti, Pilar; Inca-Martínez, Miguel; Tirado-Hurtado, Indira; Milla-Neyra, Karina; Silva-Paredes, Gustavo; Vishnevetsky, Anastasia; Cornejo-Olivas, Mario

2015-10-01

Neurogenetics is an emerging discipline in Peru that links basic research with clinical practice. The Neurogenetics Research Center located in Lima, Peru is the only unit dedicated to the specialized care of neurogenetic diseases in the country. From the beginning, neurogenetics research has been closely linked to the study of Huntington’s Disease (HD), from the PCR genotyping of the HTT gene, to the current haplogroup studies in HD. Research in other monogenic diseases led to the implementation of alternative methodologies for the genotyping of Fragile X and Myotonic Dystrophy Type 1. Both, national and international collaborative efforts have facilitated the discovery of new genetic variants in complex multigenic diseases such as Parkinson’s disease and Alzheimer’s disease. Additionally, multidisciplinary education and mentoring have allowed for the training of new neurogenetics specialists, supporting the sustained growth of the discipline in the country. The promotion of research in Peru has spurred the growth of neurogenetics research, although limitations in infrastructure, technology, and education remain a challenge for the further growth of research in this field.

Optical Cross-Sectional Muscle Area Determination of Drosophila Melanogaster Adult Indirect Flight Muscles.

PubMed

Selma-Soriano, Estela; Artero, Rubén; Llamusi, Beatriz

2018-03-31

Muscle mass wasting, known as muscle atrophy, is a common phenotype in Drosophila models of neuromuscular diseases. We have used the indirect flight muscles (IFMs) of flies, specifically the dorso-longitudinal muscles (DLM), as the experimental subject to measure the atrophic phenotype brought about by different genetic causes. In this protocol, we describe how to embed fly thorax muscles for semi thin sectioning, how to obtain a good contrast between muscle and the surrounding tissue, and how to process optical microscope images for semiautomatic acquisition of quantifiable data and analysis. We describe three specific applications of the methodological pipeline. First, we show how the method can be applied to quantify muscle degeneration in a myotonic dystrophy fly model; second, measurement of muscle cross-sectional area can help to identify genes that either promote or prevent muscle atrophy and/or muscle degeneration; third, this protocol can be applied to determine whether a candidate compound is able to significantly modify a given atrophic phenotype induced by a disease-causing mutation or by an environmental trigger.

Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease.

PubMed

Srivastava, Niraj Kumar; Yadav, Ramakant; Mukherjee, Somnath; Pal, Lily; Sinha, Neeraj

2017-05-01

Qualitative (assignment of lipid components) and quantitative (quantification of lipid components) analysis of lipid components were performed in skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease as compared to control/normal subjects. Proton nuclear magnetic resonance (NMR) spectroscopy based experiment was performed on the lipid extract of skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease and normal individuals for the analysis of lipid components [triglycerides, phospholipids, total cholesterol and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Specimens of muscle tissue were obtained from patients with Duchenne muscular dystrophy (DMD) [n=11; Age, Mean±SD; 9.2±1.4years; all were males], Becker muscular dystrophy (BMD) [n=12; Age, Mean±SD; 21.4±5.0years; all were males], facioscapulohumeral muscular dystrophy (FSHD) [n=11; Age, Mean±SD; 23.7±7.5years; all were males] and limb girdle muscular dystrophy-2B (LGMD-2B) [n=18; Age, Mean±SD; 24.2±4.1years; all were males]. Muscle specimens were also obtained from [n=30; Mean age±SD 23.1±6.0years; all were males] normal/control subjects. Assigned lipid components in skeletal muscle tissue were triglycerides (TG), phospholipids (PL), total cholesterol (CHOL) and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Quantity of lipid components was observed in skeletal muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control/normal subjects. TG was significantly elevated in muscle tissue of DMD, BMD and LGMD-2B patients. Increase level of CHOL was found only in muscle of DMD patients. Level of PL was found insignificant for DMD, BMD and LGMD-2B patients. Quantity of TG, PL and CHOL was unaltered in the muscle of patients with FSHD as compared to control/normal subjects. Linoleic acids were significantly reduced in muscle tissue of DMD, BMD, FSHD and LGMD-2B as compared to normal/control individuals. Results clearly indicate alteration of lipid metabolism in patients with muscular dystrophy in early phase of the disease. Moreover, further evaluation is required to understand whether these changes are primary or secondary to muscular dystrophy. In future, these findings may prove an additional and improved approach for the diagnosis of different forms of muscular dystrophy. Copyright © 2017 Elsevier Inc. All rights reserved.

A comparison of swallowing dysfunction in Becker muscular dystrophy and Duchenne muscular dystrophy.

PubMed

Yamada, Yuka; Kawakami, Michiyuki; Wada, Ayako; Otsuka, Tomoyoshi; Muraoka, Kaori; Liu, Meigen

2018-06-01

Swallowing dysfunction has been reported in Duchenne muscular dystrophy (DMD), but has not been studied in Becker muscular dystrophy (BMD). The aims of this study were to report the characteristics of swallowing dysfunction in BMD compared with DMD. The study participants were 18 patients with BMD and 18 patients with DMD. All the patients were examined using videofluorography during swallowing of 5 mL of fluid. The penetration-aspiration scale (P-A scale) and the videofluorographic dysphagia scale (VDS) were used to evaluate dysphagia. Swinyard functional ability stage was not significantly different between the BMD and DMD groups. Rate of aspiration, P-A scale score, and total VDS score did not differ across groups, but the VDS item score for laryngeal elevation was lower in the BMD group than in the DMD group (median scores 4.5 and 9, respectively; p < 0.001). In the BMD group, total VDS score significantly correlated with Swinyard stage (r = 0.78, p < 0.001), but not with age or lung function. Patients with BMD have swallowing problems similar to those observed in patients with DMD when matched according to physical functional status. These patients should be evaluated and followed-up for the duration of their disease. Implications for rehabiliation Dysphagia is one of the most critical problems in patients with progressive neuromuscular disease but dysphagia in patients with Becker muscular dystrophy (BMD) was not well known. Eighteen patients with BMD and 18 patients with Duchenne muscular dystrophy were examined with videofluorography. Patients with BMD have swallowing problems similar to those observed in patients with DMD.

Decreased Insulin Receptors but Normal Glucose Metabolism in Duchenne Muscular Dystrophy

NASA Astrophysics Data System (ADS)

de Pirro, Roberto; Lauro, Renato; Testa, Ivano; Ferretti, Ginofabrizio; de Martinis, Carlo; Dellantonio, Renzo

1982-04-01

Compared to matched controls, 17 patients with Duchenne muscular dystrophy showed decreased insulin binding to monocytes due to decreased receptor concentration. These patients showed no signs of altered glucose metabolism and retrospective analysis of the clinical records of a further 56 such patients revealed no modification in carbohydrate metabolism. These data suggest that reduced insulin receptor number does not produce overt modifications of glucose metabolism in Duchenne muscular dystrophy.

Relative and Absolute Interrater Reliabilities of a Hand-Held Myotonometer to Quantify Mechanical Muscle Properties in Patients with Acute Stroke in an Inpatient Ward

PubMed Central

2017-01-01

Introduction The reliability of using MyotonPRO to quantify muscles mechanical properties in a ward setting for the acute stroke population remains unknown. Aims To investigate the within-session relative and absolute interrater reliability of MyotonPRO. Methods Mechanical properties of biceps brachii, brachioradialis, rectus femoris, and tibialis anterior were recorded at bedside. Participants were within 1 month of the first occurrence of stroke. Relative reliability was assessed by intraclass correlation coefficient (ICC). Absolute reliability was assessed by standard error of measurement (SEM), SEM%, smallest real difference (SRD), SRD%, and the Bland-Altman 95% limits of agreement. Results ICCs of all studied muscles ranged between 0.63 and 0.97. The SEM of all muscles ranged within 0.30–0.88 Hz for tone, 0.07–0.19 for decrement, 6.42–20.20 N/m for stiffness, and 0.04–0.07 for creep. The SRD of all muscles ranged within 0.70–2.05 Hz for tone, 0.16–0.45 for decrement, 14.98–47.15 N/m for stiffness, and 0.09–0.17 for creep. Conclusions MyotonPRO demonstrated acceptable relative and absolute reliability in a ward setting for patients with acute stroke. However, results must be interpreted with caution, due to the varying level of consistency between different muscles, as well as between different parameters within a muscle. PMID:29164148

Translational Research for Muscular Dystrophy

DTIC Science & Technology

2012-05-01

common in-frame deletions for which clinical information from human Becker muscular dystrophy patients (deletion of exons 44-45, 49-51, 48-53) is lacking... Dystrophy PRINCIPAL INVESTIGATOR: Gregory A. Cox, Ph.D. CONTRACTING ORGANIZATION: The Jackson Laboratory...REPORT TYPE Annual 3. DATES COVERED 1 MAR 2011 - 30 APR 2012 4. TITLE AND SUBTITLE Translational Research for Muscular Dystrophy 5a. CONTRACT

Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

PubMed

Hightower, Rylie M; Alexander, Matthew S

2018-01-01

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. © 2017 Wiley Periodicals, Inc.

Genetic Modifiers of Duchenne and Facioscapulohumeral Muscular Dystrophies

PubMed Central

Hightower, Rylie M.; Alexander, Matthew S.

2017-01-01

Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing (NGS) has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost, have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes including age of loss of ambulation, steroid-responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. Here we review and highlight recent findings on genetic modifiers of Duchenne and Facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. PMID:28877560

Wide-field fundus autofluorescence abnormalities and visual function in patients with cone and cone-rod dystrophies.

PubMed

Oishi, Maho; Oishi, Akio; Ogino, Ken; Makiyama, Yukiko; Gotoh, Norimoto; Kurimoto, Masafumi; Yoshimura, Nagahisa

2014-05-20

To evaluate the clinical utility of wide-field fundus autofluorescence (FAF) in patients with cone dystrophy and cone-rod dystrophy. Sixteen patients with cone dystrophy (CD) and 41 patients with cone-rod dystrophy (CRD) were recruited at one institution. The right eye of each patient was included for analysis. We obtained wide-field FAF images using a ultra-widefield retinal imaging device and measured the area of abnormal FAF. The association between the area of abnormal FAF and the results of visual acuity measurements, kinetic perimetry, and electroretinography (ERG) were investigated. The mean age of the participants was 51.4 ± 17.4 years, and the mean logarithm of the minimum angle of resolution was 1.00 ± 0.57. The area of abnormal FAF correlated with the scotoma measured by the Goldman perimetry I/4e isopter (ρ = 0.79, P < 0.001). The area also correlated with amplitudes of the rod ERG (ρ = -0.63, P < 0.001), combined ERG a-wave (ρ = -0.72, P < 0.001), combined ERG b-wave (ρ = -0.66, P < 0.001), cone ERG (ρ = -0.44, P = 0.001), and flicker ERG (ρ = -0.47, P < 0.001). The extent of abnormal FAF reflects the severity of functional impairment in patients with cone-dominant retinal dystrophies. Fundus autofluorescence measurements are useful for predicting retinal function in these patients. Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.

Quantitative tissue parameters of Achilles tendon and plantar fascia in healthy subjects using a handheld myotonometer.

PubMed

Orner, Sarah; Kratzer, Wolfgang; Schmidberger, Julian; Grüner, Beate

2018-01-01

The aim of the study was to examine the quantitative tissue properties of the Achilles tendon and plantar fascia using a handheld, non-invasive MyotonPRO device, in order to generate normal values and examine the biomechanical relationship of both structures. Prospective study of a large, healthy sample population. The study sample included 207 healthy subjects (87 males and 120 females) for the Achilles tendon and 176 healthy subjects (73 males and 103 females) for the plantar fascia. For the correlations of the tissue parameters of the Achilles tendon and plantar fascia an intersection of both groups was formed which included 150 healthy subjects (65 males and 85 females). All participants were measured in a prone position. Consecutive measurements of the Achilles tendon and plantar fascia were performed by MyotonPRO device at defined sites. For the left and right Achilles tendons and plantar fasciae all five MyotonPRO parameters (Frequency [Hz], Decrement, Stiffness [N/m], Creep and Relaxation Time [ms]) were calculated of healthy males and females. The correlation of the tissue parameters of the Achilles tendon and plantar fascia showed a significant positive correlation of all parameters on the left as well as on the right side. The MyotonPRO is a feasible device for easy measurement of passive tissue properties of the Achilles tendon and plantar fascia in a clinical setting. The generated normal values of the Achilles tendon and plantar fascia are important for detecting abnormalities in patients with Achilles tendinopathy or plantar fasciitis in the future. Biomechanically, both structures are positively correlated. This may provide new aspects in the diagnostics and therapy of plantar fasciitis and Achilles tendinopathy. Copyright © 2017 Elsevier Ltd. All rights reserved.

At the Crossroads of Clinical and Preclinical Research for Muscular Dystrophy-Are We Closer to Effective Treatment for Patients?

PubMed

Gawlik, Kinga I

2018-05-16

Among diseases affecting skeletal muscle, muscular dystrophy is one of the most devastating and complex disorders. The term 'muscular dystrophy' refers to a heterogeneous group of genetic diseases associated with a primary muscle defect that leads to progressive muscle wasting and consequent loss of muscle function. Muscular dystrophies are accompanied by numerous clinical complications and abnormalities in other tissues that cause extreme discomfort in everyday life. The fact that muscular dystrophy often takes its toll on babies and small children, and that many patients die at a young age, adds to the cruel character of the disease. Clinicians all over the world are facing the same problem: they have no therapy to offer except for symptom-relieving interventions. Patients, their families, but also clinicians, are in urgent need of an effective cure. Despite advances in genetics, increased understanding of molecular mechanisms underlying muscle disease, despite a sweeping range of successful preclinical strategies and relative progress of their implementation in the clinic, therapy for patients is currently out of reach. Only a greater comprehension of disease mechanisms, new preclinical studies, development of novel technologies, and tight collaboration between scientists and physicians can help improve clinical treatment. Fortunately, inventiveness in research is rapidly extending the limits and setting new standards for treatment design. This review provides a synopsis of muscular dystrophy and considers the steps of preclinical and clinical research that are taking the muscular dystrophy community towards the fundamental goal of combating the traumatic disease.

[Treatment with sympathetic intravenous block with reserpine in work-related reflex sympathetic dystrophy].

PubMed

Morros, C; Cedo, F

1994-01-01

To assess the results obtained in treatment of sympathetic reflex dystrophy by sympathetic endovenous blockades with reserpine in working patients. We reviewed 170 diagnoses of sympathetic reflex dystrophy in 165 patients. One hundred seven were located in the foot, 13 were in the knee and 50 were in the hand. All were treated once a week for 3 weeks with local sympathetic endovenous blocks with reserpine (1 mg in the upper extremity and 1.5 mg in the lower extremity). We analyzed the location, etiology, course, X-rays, gammagrams, psychological state, other treatments, associated conditions, number of blocks received and side effects. The results were classified as excellent, good, fair and nil. We particularly reviewed sympathetic reflex dystrophy associated to Colles' fractures. Five hundred forty endovenous sympathetic blocks with reserpine were performed. Results obtained were excellent in 57 (34%) patients, good in 77 (45%), fair in 29 (17%) and nil in 7 (4%). Sympathetic reflex dystrophy leads to loss of 215 +/- 91 working days. In patients with Colles' fracture without sympathetic reflex dystrophy the loss is 96 +/- 31 days, although this period lengthens to 115 +/- 15 days if the two conditions are associated in stage I and to loss of 193 +/- 71 days if the association is in stage II. Results of treating sympathetic reflex dystrophy with sympathetic endovenous blocks with reserpine are satisfactory, particularly when diagnosis and treatment are early, clearly demonstrating the usefulness of this technique in workplace medicine.

Vitelliform dystrophies: Prevalence in Olmsted County, Minnesota, United States.

PubMed

Dalvin, Lauren A; Pulido, Jose S; Marmorstein, Alan D

2017-01-01

Vitelliform dystrophies are a group of macular degenerative diseases characterized by round yellow lesions in the macula. While often idiopathic, vitelliform dystrophies include inherited maculopathies such as Best disease and some cases of pattern dystrophy. The prevalence of vitelliform dystrophies in the United States has not been reported. This study examined the prevalence of vitelliform dystrophies in Olmsted County, Minnesota. The Rochester Epidemiology Project database was used to identify all cases of vitelliform or pattern dystrophy in Olmsted County from 1 January 2000-31 December 2014. Overall, 27 patients had true vitelliform lesions, indicating a prevalence of 1 in 5500. Of these, two had genetically confirmed Best disease, and an additional five to seven carried a diagnosis of Best disease, which chart reviews confirmed as probable cases; 18-20 patients had adult-onset vitelliform macular dystrophy. The prevalence of Best disease was 1 in 16,500 to 1 in 21,000. Adult-onset vitelliform macular dystrophy was found in 1 in 7400 to 1 in 8200. Vitelliform dystrophies affect 1 in 5500 individuals in Olmsted County. While the values in this study provide good estimates for the prevalence of Best disease versus adult-onset vitelliform macular dystrophy, the results are limited by dependence on diagnoses made by other ophthalmologists and underutilization of genetic testing. Thus, these diseases should be thought of as at least as prevalent as reported here. As therapies for Best disease and other macular degenerative diseases are quickly becoming a reality, genetic testing should be employed as the gold standard for diagnosis of these diseases.

Brain natriuretic peptide is not predictive of dilated cardiomyopathy in Becker and Duchenne muscular dystrophy patients and carriers.

PubMed

Schade van Westrum, Steven; Dekker, Lukas; de Haan, Rob; Endert, Erik; Ginjaar, Ieke; de Visser, Marianne; van der Kooi, Anneke

2013-07-16

Cardiomyopathy is reported in Duchenne and Becker muscle dystrophy patients and female carriers. Brain Natriuretic peptide (BNP) is a hormone produced mainly by ventricular cardiomyocytes and its production is up regulated in reaction to increased wall stretching. N-terminal-proBNP (NT-proBNP) has been shown to be a robust laboratory parameter to diagnose and monitor cardiac failure, and it may be helpful to screen for asymptomatic left ventricular dysfunction. Therefore we tested whether NT-proBNP can distinguish patients with Duchenne or Becker muscular dystrophy patients and carriers of a dystrophin mutation with a dilated cardiomyopathy from those without. In a cohort of Duchenne and Becker muscle dystrophy patients (n = 143) and carriers (n = 219) NT-proBNP was measured, and echocardiography was performed to diagnose dilated cardiomyopathy (DCM). In total sixty-one patients (17%) fulfilled the criteria for DCM, whereas 283 patients (78%) had an elevated NT-pro BNP. The sensitivity of NT-proBNP for DCM in patients or carriers was 85%, the specificity 23%, area under the ROC-curve = 0.56. In the specified subgroups there was also no association. Measurement of NT-pro BNP in patients suffering from Duchenne or Becker muscular dystrophy and carriers does not distinguish between those with and without dilated cardiomyopathy.

Complementary and alternative medicine for Duchenne and Becker muscular dystrophies: characteristics of users and caregivers.

PubMed

Zhu, Yong; Romitti, Paul A; Conway, Kristin M; Andrews, Jennifer; Liu, Ke; Meaney, F John; Street, Natalie; Puzhankara, Soman; Druschel, Charlotte M; Matthews, Dennis J

2014-07-01

Complementary and alternative medicine is frequently used in the management of chronic pediatric diseases, but little is known about its use by those with Duchenne or Becker muscular dystrophy. Complementary and alternative medicine use by male patients with Duchenne or Becker muscular dystrophy and associations with characteristics of male patients and their caregivers were examined through interviews with 362 primary caregivers identified from the Muscular Dystrophy Surveillance, Tracking, and Research Network. Overall, 272 of the 362 (75.1%) primary caregivers reported that they had used any complementary and alternative medicine for the oldest Muscular Dystrophy Surveillance, Tracking, and Research Network male in their family. The most commonly reported therapies were from the mind-body medicine domain (61.0%) followed by those from the biologically based practice (39.2%), manipulative and body-based practice (29.3%), and whole medical system (6.9%) domains. Aquatherapy, prayer and/or blessing, special diet, and massage were the most frequently used therapies. Compared with nonusers, male patients who used any therapy were more likely to have an early onset of symptoms and use a wheel chair; their caregivers were more likely to be non-Hispanic white. Among domains, associations were observed with caregiver education and family income (mind-body medicines [excluding prayer and/or blessing only] and whole medical systems) and Muscular Dystrophy Surveillance, Tracking, and Research Network site (biologically based practices and mind-body medicines [excluding prayer and/or blessing only]). Complementary and alternative medicine use was common in the management of Duchenne and Becker muscular dystrophies among Muscular Dystrophy Surveillance, Tracking, and Research Network males. This widespread use suggests further study to evaluate the efficacy of integrating complementary and alternative medicine into treatment regimens for Duchenne and Becker muscular dystrophies. Copyright © 2014 Elsevier Inc. All rights reserved.

In vivo laser confocal microscopy findings in patients with map-dot-fingerprint (epithelial basement membrane) dystrophy.

PubMed

Kobayashi, Akira; Yokogawa, Hideaki; Sugiyama, Kazuhisa

2012-01-01

The purpose of this study was to investigate pathological changes of the corneal cell layer in patients with map-dot-fingerprint (epithelial basement membrane) dystrophy by in vivo laser corneal confocal microscopy. Two patients were evaluated using a cornea-specific in vivo laser scanning confocal microscope (Heidelberg Retina Tomograph 2 Rostock Cornea Module, HRT 2-RCM). The affected corneal areas of both patients were examined. Image analysis was performed to identify corneal epithelial and stromal deposits correlated with this dystrophy. Variously shaped (linear, multilaminar, curvilinear, ring-shape, geographic) highly reflective materials were observed in the "map" area, mainly in the basal epithelial cell layer. In "fingerprint" lesions, multiple linear and curvilinear hyporeflective lines were observed. Additionally, in the affected corneas, infiltration of possible Langerhans cells and other inflammatory cells was observed as highly reflective Langerhans cell-like or dot images. Finally, needle-shaped materials were observed in one patient. HRT 2-RCM laser confocal microscopy is capable of identifying corneal microstructural changes related to map-dot-fingerprint corneal dystrophy in vivo. The technique may be useful in elucidating the pathogenesis and natural course of map-dot-fingerprint corneal dystrophy and other similar basement membrane abnormalities.

Fat embolism after fractures in Duchenne muscular dystrophy: an underdiagnosed complication? A systematic review.

PubMed

Feder, David; Koch, Miriam Eva; Palmieri, Beniamino; Fonseca, Fernando Luiz Affonso; Carvalho, Alzira Alves de Siqueira

2017-01-01

Duchenne muscular dystrophy is the most frequent lethal genetic disease. Several clinical trials have established both the beneficial effect of steroids in Duchenne muscular dystrophy and the well-known risk of side effects associated with their daily use. For many years it has been known that steroids associated with ambulation loss lead to obesity and also damage the bone structure resulting in the bone density reduction and increased incidence of bone fractures and fat embolism syndrome, an underdiagnosed complication after fractures. Fat embolism syndrome is characterized by consciousness disturbance, respiratory failure and skin rashes. The use of steroids in Duchenne muscular dystrophy may result in vertebral fractures, even without previous trauma. Approximately 25% of patients with Duchenne muscular dystrophy have a long bone fracture, and 1% to 22% of fractures have a chance to develop fat embolism syndrome. As the patients with Duchenne muscular dystrophy have progressive cardiac and respiratory muscle dysfunction, the fat embolism may be unnoticed clinically and may result in increased risk of death and major complications. Different treatments and prevention measures of fat embolism have been proposed; however, so far, there is no efficient therapy. The prevention, early diagnosis and adequate symptomatic treatment are of paramount importance. The fat embolism syndrome should always be considered in patients with Duchenne muscular dystrophy presenting with fractures, or an unexplained and sudden worsening of respiratory and cardiac symptoms.

Fat embolism after fractures in Duchenne muscular dystrophy: an underdiagnosed complication? A systematic review

PubMed Central

Feder, David; Koch, Miriam Eva; Palmieri, Beniamino; Fonseca, Fernando Luiz Affonso; Carvalho, Alzira Alves de Siqueira

2017-01-01

Duchenne muscular dystrophy is the most frequent lethal genetic disease. Several clinical trials have established both the beneficial effect of steroids in Duchenne muscular dystrophy and the well-known risk of side effects associated with their daily use. For many years it has been known that steroids associated with ambulation loss lead to obesity and also damage the bone structure resulting in the bone density reduction and increased incidence of bone fractures and fat embolism syndrome, an underdiagnosed complication after fractures. Fat embolism syndrome is characterized by consciousness disturbance, respiratory failure and skin rashes. The use of steroids in Duchenne muscular dystrophy may result in vertebral fractures, even without previous trauma. Approximately 25% of patients with Duchenne muscular dystrophy have a long bone fracture, and 1% to 22% of fractures have a chance to develop fat embolism syndrome. As the patients with Duchenne muscular dystrophy have progressive cardiac and respiratory muscle dysfunction, the fat embolism may be unnoticed clinically and may result in increased risk of death and major complications. Different treatments and prevention measures of fat embolism have been proposed; however, so far, there is no efficient therapy. The prevention, early diagnosis and adequate symptomatic treatment are of paramount importance. The fat embolism syndrome should always be considered in patients with Duchenne muscular dystrophy presenting with fractures, or an unexplained and sudden worsening of respiratory and cardiac symptoms. PMID:29066903

Guidelines for the Perianesthesia Care of the Duchenne Muscular Dystrophy/Becker Muscular Dystrophy Patient.

PubMed

Alliod, Barbara A; Ash, Rebecca A

2016-12-01

More patients suffering with Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are presenting to perianesthesia settings for emergent and nonemergent treatment and care. A group of collaborative health care providers at Rush University Medical Center in Chicago developed a multidisciplinary DMD/BMD Task Force to study this disorder and create a set of guidelines to aid those engaging in the planning, execution of care, and recovery of this unique population in the perianesthesia setting. Attention to detail, well-executed preplanning, meticulous awareness of the patient, and prearranged implementation and intervention has proven to offset potential problems and complications and is the key to a successful perianesthesia period. Copyright © 2016 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.

Limb-girdle muscular dystrophy subtypes: First-reported cohort from northeastern China

PubMed Central

Mahmood, Omar Abdulmonem; Jiang, Xinmei; Zhang, Qi

2013-01-01

The relative frequencies of different subtypes of limb-girdle muscular dystrophies vary widely among different populations. We estimated the percentage of limb-girdle muscular dystrophy subtypes in Chinese people based on 68 patients with limb-girdle muscular dystrophy from the Myology Clinic, Neurology Department, First Hospital of Jilin University, China. A diagnosis of calpainopathy was made in 12 cases (17%), and dysferlin deficiency in 10 cases (15%). Two biopsies revealed α-sarcoglycan deficiency (3%), and two others revealed a lack of caveolin-3 (3%). A diagnosis of unclassified limb-girdle muscular dystrophy was made in the remaining patients (62%). The appearances of calpain 3- and dysferlin-deficient biopsies were similar, though rimmed vacuoles were unique to dysferlinopathy, while inflammatory infiltrates were present in both these limb-girdle muscular dystrophy type 2D biopsies. Macrophages were detected in seven dysferlinopathy biopsies. The results of this study suggest that the distribution of limb-girdle muscular dystrophy subtypes in the Han Chinese population is similar to that reported in the West. The less necrotic, regenerating and inflammatory appearance of limb-girdle muscular dystrophy type 2A, but with more lobulated fibers, supports the idea that calpainopathy is a less active, but more chronic disease than dysferlinopathy. Unusual features indicated an extended limb-girdle muscular dystrophy disease spectrum. The use of acid phosphatase stain should be considered in suspected dysferlinopathies. To the best of our knowledge, this is the first report to define the relative proportions of the various forms of limb-girdle muscular dystrophy in China, based on protein testing. PMID:25206500

Recurrent Corneal Erosions in Corneal Dystrophies: a Review of the Pathogenesis, Differential Diagnosis, and Therapy.

PubMed

Omari, Amro A; Mian, Shahzad I

2018-06-01

Recurrent corneal erosions in corneal dystrophies are visually significant and bothersome to patients. The goal of this article is to review the pathogenesis, differential diagnosis, and management of recurrent corneal erosions in corneal dystrophies. Forty-eight articles and 1 textbook recently published on corneal erosions in corneal dystrophies were reviewed. The findings on the pathogenesis and clinical characteristics of erosions in each dystrophy were summarized. Any contradicting opinions for which the literature was unclear were either omitted or recorded as lacking strong evidence. The epithelial-stromal complex plays an important role in the pathogenesis of erosions in corneal dystrophies. The clinical features of each corneal dystrophy guide their diagnosis and management. A better understanding of the pathogenesis and clinical features of erosions in corneal dystrophies can lead to better clinical outcomes. Georg Thieme Verlag KG Stuttgart · New York.

Prevalence and Characteristics of Chinese Patients With Duchenne and Becker Muscular Dystrophy: A Territory Wide Collaborative Study in Hong Kong.

PubMed

Chan, Sophelia H S; Lo, Ivan F M; Cherk, Sharon W W; Cheng, Wai Wai; Fung, Eva L W; Yeung, Wai Lan; Ngan, Mary; Lee, Wing Cheong; Kwong, Ling; Wong, Suet Na; Ma, Che Kwan; Tai, Shuk Mui; Ng, Grace S F; Wu, Shun Ping; Wong, Virginia C N

2015-01-01

The aim of this collaborative study on Duchenne muscular dystrophy and Becker muscular dystrophy is to determine the prevalence and to develop data on such patients as a prelude to the development of registry in Hong Kong. Information on clinical and molecular findings, and patient care, was systematically collected in 2011 and 2012 from all Pediatric Neurology Units in Hong Kong. Ninety patients with dystrophinopathy were identified, and 83% has Duchenne muscular dystrophy. The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per 10 000 males aged 0 to 24 years. Among the Duchenne group, we observed a higher percentage (40.6%) of point mutations with a lower percentage (45.3%) of exon deletions in our patients when compared with overseas studies. Although we observed similar percentage of Duchenne group received scoliosis surgery, ventilation support, and cardiac treatment when compared with other countries, the percentage (25%) of steroid use is lower.

Prevalence and Characteristics of Chinese Patients With Duchenne and Becker Muscular Dystrophy

PubMed Central

Lo, Ivan F. M.; Cherk, Sharon W. W.; Cheng, Wai Wai; Fung, Eva L. W.; Yeung, Wai Lan; Ngan, Mary; Lee, Wing Cheong; Kwong, Ling; Wong, Suet Na; Ma, Che Kwan; Tai, Shuk Mui; Ng, Grace S. F.; Wu, Shun Ping; Wong, Virginia C. N.

2015-01-01

The aim of this collaborative study on Duchenne muscular dystrophy and Becker muscular dystrophy is to determine the prevalence and to develop data on such patients as a prelude to the development of registry in Hong Kong. Information on clinical and molecular findings, and patient care, was systematically collected in 2011 and 2012 from all Pediatric Neurology Units in Hong Kong. Ninety patients with dystrophinopathy were identified, and 83% has Duchenne muscular dystrophy. The overall prevalence of dystrophinopathy in Hong Kong in 2010 is 1.03 per 10 000 males aged 0 to 24 years. Among the Duchenne group, we observed a higher percentage (40.6%) of point mutations with a lower percentage (45.3%) of exon deletions in our patients when compared with overseas studies. Although we observed similar percentage of Duchenne group received scoliosis surgery, ventilation support, and cardiac treatment when compared with other countries, the percentage (25%) of steroid use is lower. PMID:28503591

[Posterior polymorphous dystrophy, case report and literature review].

PubMed

Mendoza-Adam, G; Hernandez-Camarena, J C; Valdez-García, J E

2015-09-01

Posterior Polymorphous Dystrophy (DPP) is a rare posterior corneal dystrophy that is genetically transmitted as autosomal dominant. Corneal structures affected in this dystrophy are Descemet membrane and the endothelium. A case is presented on a 47 years old woman with no relevant history, with typical findings of DPP (vesicular and band lesions at the endothelium and posterior Descemet). To our knowledge there are no reported cases of DPP in Latin-American patients in the literature. The clinical manifestations in our patient were found to be very similar to the cases reported in other populations. Copyright © 2014 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing.

PubMed

Saveliev, Alexander; Everett, Christopher; Sharpe, Tammy; Webster, Zoë; Festenstein, Richard

2003-04-24

Gene repression is crucial to the maintenance of differentiated cell types in multicellular organisms, whereas aberrant silencing can lead to disease. The organization of DNA into chromatin and heterochromatin is implicated in gene silencing. In chromatin, DNA wraps around histones, creating nucleosomes. Further condensation of chromatin, associated with large blocks of repetitive DNA sequences, is known as heterochromatin. Position effect variegation (PEV) occurs when a gene is located abnormally close to heterochromatin, silencing the affected gene in a proportion of cells. Here we show that the relatively short triplet-repeat expansions found in myotonic dystrophy and Friedreich's ataxia confer variegation of expression on a linked transgene in mice. Silencing was correlated with a decrease in promoter accessibility and was enhanced by the classical PEV modifier heterochromatin protein 1 (HP1). Notably, triplet-repeat-associated variegation was not restricted to classical heterochromatic regions but occurred irrespective of chromosomal location. Because the phenomenon described here shares important features with PEV, the mechanisms underlying heterochromatin-mediated silencing might have a role in gene regulation at many sites throughout the mammalian genome and modulate the extent of gene silencing and hence severity in several triplet-repeat diseases.

GFP-based fluorescence assay for CAG repeat instability in cultured human cells.

PubMed

Santillan, Beatriz A; Moye, Christopher; Mittelman, David; Wilson, John H

2014-01-01

Trinucleotide repeats can be highly unstable, mutating far more frequently than point mutations. Repeats typically mutate by addition or loss of units of the repeat. CAG repeat expansions in humans trigger neurological diseases that include myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. In human cells, diverse mechanisms promote CAG repeat instability, and in mice, the mechanisms of instability are varied and tissue-dependent. Dissection of mechanistic complexity and discovery of potential therapeutics necessitates quantitative and scalable screens for repeat mutation. We describe a GFP-based assay for screening modifiers of CAG repeat instability in human cells. The assay exploits an engineered intronic CAG repeat tract that interferes with expression of an inducible GFP minigene. Like the phenotypes of many trinucleotide repeat disorders, we find that GFP function is impaired by repeat expansion, in a length-dependent manner. The intensity of fluorescence varies inversely with repeat length, allowing estimates of repeat tract changes in live cells. We validate the assay using transcription through the repeat and engineered CAG-specific nucleases, which have previously been reported to induce CAG repeat instability. The assay is relatively fast and should be adaptable to large-scale screens of chemical and shRNA libraries.

GFP-Based Fluorescence Assay for CAG Repeat Instability in Cultured Human Cells

PubMed Central

Santillan, Beatriz A.; Moye, Christopher; Mittelman, David; Wilson, John H.

2014-01-01

Trinucleotide repeats can be highly unstable, mutating far more frequently than point mutations. Repeats typically mutate by addition or loss of units of the repeat. CAG repeat expansions in humans trigger neurological diseases that include myotonic dystrophy, Huntington disease, and several spinocerebellar ataxias. In human cells, diverse mechanisms promote CAG repeat instability, and in mice, the mechanisms of instability are varied and tissue-dependent. Dissection of mechanistic complexity and discovery of potential therapeutics necessitates quantitative and scalable screens for repeat mutation. We describe a GFP-based assay for screening modifiers of CAG repeat instability in human cells. The assay exploits an engineered intronic CAG repeat tract that interferes with expression of an inducible GFP minigene. Like the phenotypes of many trinucleotide repeat disorders, we find that GFP function is impaired by repeat expansion, in a length-dependent manner. The intensity of fluorescence varies inversely with repeat length, allowing estimates of repeat tract changes in live cells. We validate the assay using transcription through the repeat and engineered CAG-specific nucleases, which have previously been reported to induce CAG repeat instability. The assay is relatively fast and should be adaptable to large-scale screens of chemical and shRNA libraries. PMID:25423602

Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene.

PubMed

Ishizaki, Masatoshi; Fujimoto, Akiko; Ueyama, Hidetsugu; Nishida, Yasuto; Imamura, Shigehiro; Uchino, Makoto; Ando, Yukio

2015-01-01

We herein present a report of three patients with Becker muscular dystrophy in the same family who developed complete atrioventricular block or ventricular tachycardia with severe cardiomyopathy. Our cases became unable to walk in their teens, and were introduced to mechanical ventilation due to respiratory muscle weakness in their twenties and thirties. In all three cases, a medical device such as a permanent cardiac pacemaker or an implantable cardiac defibrillator was considered to be necessary. The duplication of exons 3-4 in the dystrophin gene was detected in two of the patients. In patients with Becker muscular dystrophy, complete atrioventricular block or ventricular tachycardia within a family has rarely been reported. Thus attention should be paid to the possibility of severe arrhythmias in the severe phenotype of Becker muscular dystrophy.

Wasting Mechanisms in Muscular Dystrophy

PubMed Central

Shin, Jonghyun; Tajrishi, Marjan M.; Ogura, Yuji; Kumar, Ashok

2013-01-01

Muscular dystrophy is a group of more than 30 different clinical genetic disorders that are characterized by progressive skeletal muscle wasting and degeneration. Primary deficiency of specific extracellular matrix, sarcoplasmic, cytoskeletal, or nuclear membrane protein results in several secondary changes such as sarcolemmal instability, calcium influx, fiber necrosis, oxidative stress, inflammatory response, breakdown of extracellular matrix, and eventually fibrosis which leads to loss of ambulance and cardiac and respiratory failure. A number of molecular processes have now been identified which hasten disease progression in human patients and animal models of muscular dystrophy. Accumulating evidence further suggests that aberrant activation of several signaling pathways aggravate pathological cascades in dystrophic muscle. Although replacement of defective gene with wild-type is paramount to cure, management of secondary pathological changes has enormous potential to improving the quality of life and extending lifespan of muscular dystrophy patients. In this article, we have reviewed major cellular and molecular mechanisms leading to muscle wasting in muscular dystrophy. PMID:23669245

Recurrent Fat Embolic Strokes in a Patient With Duchenne Muscular Dystrophy With Long Bone Fractures and a Patent Foramen Ovale.

PubMed

Bugnitz, Christopher J; Cripe, Linda H; Lo, Warren D; Flanigan, Kevin M

2016-10-01

Individuals with Duchenne muscular dystrophy have an increased risk of long bone fractures. Such fractures are sometimes associated with brain dysfunction due to fat embolism syndrome, although this syndrome has seldom been documented in muscular dystrophy patients. We describe a child with Duchenne muscular dystrophy who developed fat embolism syndrome with neurological dysfunction following multiple long bone fractures. He experienced recurrent cerebral infarctions that probably resulted from embolization through a patent foramen ovale. The patent foramen ovale was closed by an occluder device in the cardiac catheterization laboratory, and he did not experience further infarctions. Fat embolism with ischemic cerebral infarction can occur in individuals with Duchenne muscular dystrophy following long bone fractures. In this setting it is important to identify and close atrial level shunts in order to prevent additional infarctions. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo laser confocal microscopy findings in patients with map-dot-fingerprint (epithelial basement membrane) dystrophy

PubMed Central

Kobayashi, Akira; Yokogawa, Hideaki; Sugiyama, Kazuhisa

2012-01-01

Background: The purpose of this study was to investigate pathological changes of the corneal cell layer in patients with map-dot-fingerprint (epithelial basement membrane) dystrophy by in vivo laser corneal confocal microscopy. Methods: Two patients were evaluated using a cornea-specific in vivo laser scanning confocal microscope (Heidelberg Retina Tomograph 2 Rostock Cornea Module, HRT 2-RCM). The affected corneal areas of both patients were examined. Image analysis was performed to identify corneal epithelial and stromal deposits correlated with this dystrophy. Results: Variously shaped (linear, multilaminar, curvilinear, ring-shape, geographic) highly reflective materials were observed in the “map” area, mainly in the basal epithelial cell layer. In “fingerprint” lesions, multiple linear and curvilinear hyporeflective lines were observed. Additionally, in the affected corneas, infiltration of possible Langerhans cells and other inflammatory cells was observed as highly reflective Langerhans cell-like or dot images. Finally, needle-shaped materials were observed in one patient. Conclusion: HRT 2-RCM laser confocal microscopy is capable of identifying corneal microstructural changes related to map-dot-fingerprint corneal dystrophy in vivo. The technique may be useful in elucidating the pathogenesis and natural course of map-dot-fingerprint corneal dystrophy and other similar basement membrane abnormalities. PMID:22888214

Near-infrared fundus autofluorescence in subclinical best vitelliform macular dystrophy.

PubMed

Parodi, Maurizio Battaglia; Iacono, Pierluigi; Del Turco, Claudia; Bandello, Francesco

2014-12-01

To describe fundus autofluorescence (FAF) on short-wavelength FAF and near-infrared FAF in the subclinical form of Best vitelliform macular dystrophy. Cross-sectional prospective study. Patients affected by the subclinical form of Best vitelliform macular dystrophy (positive testing for BEST1 gene mutation, fully preserved best-corrected visual acuity, normal fundus appearance) were recruited. Each patient underwent a complete ophthalmologic examination, including electro-oculogram (EOG), short-wavelength FAF, near-infrared FAF, spectral-domain OCT (SD OCT), and microperimetry. Main outcome measure was the identification of abnormal FAF patterns. Forty-six patients showing mutations in the BEST1 gene were examined. Forty patients presented a bilateral Best vitelliform macular dystrophy, 2 patients showed a unilateral Best vitelliform macular dystrophy, and 4 patients had a bilateral subclinical form. Patients with the unilateral form (2 eyes) and patients with the subclinical form (8 eyes) were analyzed. Three BEST1 sequence variants were identified: c.73C>T (p.Arg25Trp), c.28G>A (p.Ala10Thr), and c.652C>G (p.Arg218Gly). Short-wavelength FAF was normal in all eyes. Near-infrared FAF detected a pattern consisting of a central hypo-autofluorescence surrounded by a round area of hyper-autofluorescence. A bilateral reduced EOG response was detected in 1 patient. SD OCT revealed a thicker, well-defined, and more reflective interdigitation zone in 2 patients (4 eyes, 40%). Microperimetry of the central 10 degrees revealed a slight, diffuse reduction of retinal sensitivity. Mean retinal sensitivity within the central 2 and 4 degrees was lower and matched the hypo-autofluorescent area detected on near-infrared FAF. Additional relative scotomata were detected within the 10-degree area. No change in clinical, functional, or FAF pattern was found over the follow-up. Subclinical Best vitelliform macular dystrophy is characterized by the absence of biomicroscopic fundus abnormality and fully preserved visual acuity, but shows an abnormal near-infrared FAF pattern, with central hypo-autofluorescence. Copyright © 2014 Elsevier Inc. All rights reserved.

Pathogenic mutations of TGFBI and CHST6 genes in Chinese patients with Avellino, lattice, and macular corneal dystrophies.

PubMed

Huo, Ya-nan; Yao, Yu-feng; Yu, Ping

2011-09-01

To investigate gene mutations associated with three different types of corneal dystrophies (CDs), and to establish a phenotype-genotype correlation. Two patients with Avellino corneal dystrophy (ACD), four patients with lattice corneal dystrophy type I (LCD I) from one family, and three patients with macular corneal dystrophy type I (MCD I) were subjected to both clinical and genetic examinations. Slit lamp examination was performed for all the subjects to assess their corneal phenotypes. Genomic DNA was extracted from peripheral blood leukocytes. The coding regions of the human transforming growth factor β-induced (TGFBI) gene and carbohydrate sulfotransferase 6 (CHST6) gene were amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. DNA samples from 50 healthy volunteers were used as controls. Clinical examination showed three different phenotypes of CDs. Genetic examination identified that two ACD subjects were associated with homozygous R124H mutation of TGFBI, and four LCD I subjects were all associated with R124C heterozygous mutation. One MCD I subject was associated with a novel S51X homozygous mutation in CHST6, while the other two MCD I subjects harbored a previously reported W232X homozygous mutation. Our study highlights the prevalence of codon 124 mutations in the TGFBI gene among the Chinese ACD and LCD I patients. Moreover, we found a novel mutation among MCD I patients.

High-Pressure Transvenous Perfusion of the Upper Extremity in Human Muscular Dystrophy: A Safety Study with 0.9% Saline.

PubMed

Fan, Zheng; Kocis, Keith; Valley, Robert; Howard, James F; Chopra, Manisha; Chen, Yasheng; An, Hongyu; Lin, Weili; Muenzer, Joseph; Powers, William

2015-09-01

We evaluated safety and feasibility of high-pressure transvenous limb perfusion in an upper extremity of adult patients with muscular dystrophy, after completing a similar study in a lower extremity. A dose escalation study of single-limb perfusion with 0.9% saline was carried out in nine adults with muscular dystrophies under intravenous analgesia. Our study demonstrates that it is feasible and definitely safe to perform high-pressure transvenous perfusion with 0.9% saline up to 35% of limb volume in the upper extremities of young adults with muscular dystrophy. Perfusion at 40% limb volume is associated with short-lived physiological changes in peripheral nerves without clinical correlates in one subject. This study provides the basis for a phase 1/2 clinical trial using pressurized transvenous delivery into upper limbs of nonambulatory patients with Duchenne muscular dystrophy. Furthermore, our results are applicable to other conditions such as limb girdle muscular dystrophy as a method for delivering regional macromolecular therapeutics in high dose to skeletal muscles of the upper extremity.

Improved Muscle Function in Duchenne Muscular Dystrophy through L-Arginine and Metformin: An Investigator-Initiated, Open-Label, Single-Center, Proof-Of-Concept-Study.

PubMed

Hafner, Patricia; Bonati, Ulrike; Erne, Beat; Schmid, Maurice; Rubino, Daniela; Pohlman, Urs; Peters, Thomas; Rutz, Erich; Frank, Stephan; Neuhaus, Cornelia; Deuster, Stefanie; Gloor, Monika; Bieri, Oliver; Fischmann, Arne; Sinnreich, Michael; Gueven, Nuri; Fischer, Dirk

2016-01-01

Altered neuronal nitric oxide synthase function in Duchenne muscular dystrophy leads to impaired mitochondrial function which is thought to be one cause of muscle damage in this disease. The study tested if increased intramuscular nitric oxide concentration can improve mitochondrial energy metabolism in Duchenne muscular dystrophy using a novel therapeutic approach through the combination of L-arginine with metformin. Five ambulatory, genetically confirmed Duchenne muscular dystrophy patients aged between 7–10 years were treated with L-arginine (3 x 2.5 g/d) and metformin (2 x 250 mg/d) for 16 weeks. Treatment effects were assessed using mitochondrial protein expression analysis in muscular biopsies, indirect calorimetry, Dual-Energy X-Ray Absorptiometry, quantitative thigh muscle MRI, and clinical scores of muscle performance. There were no serious side effects and no patient dropped out. Muscle biopsy results showed pre-treatment a significantly reduced mitochondrial protein expression and increased oxidative stress in Duchenne muscular dystrophy patients compared to controls. Post-treatment a significant elevation of proteins of the mitochondrial electron transport chain was observed as well as a reduction in oxidative stress. Treatment also decreased resting energy expenditure rates and energy substrate use shifted from carbohydrates to fatty acids. These changes were associated with improved clinical scores. In conclusion pharmacological stimulation of the nitric oxide pathway leads to improved mitochondria function and clinically a slowing of disease progression in Duchenne muscular dystrophy. This study shall lead to further development of this novel therapeutic approach into a real alternative for Duchenne muscular dystrophy patients. ClinicalTrials.gov NCT02516085.

Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review.

PubMed

Cup, Edith H; Pieterse, Allan J; Ten Broek-Pastoor, Jessica M; Munneke, Marten; van Engelen, Baziel G; Hendricks, Henk T; van der Wilt, Gert J; Oostendorp, Rob A

2007-11-01

To summarize and critically appraise the available evidence on exercise therapy and other types of physical therapies for patients with neuromuscular diseases (NMD). Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews, Medline, CINAHL, EMBASE (Rehabilitation and Physical Medicine), and reference lists of reviews and articles. Randomized clinical trials (RCTs), controlled clinical trials (CCTs), and other designs were included. Study participants had to have any of the following types of NMD: motoneuron diseases, disorders of the motor nerve roots or peripheral nerves, neuromuscular transmission disorders, or muscle diseases. All types of exercise therapy and other physical therapy modalities were included. Outcome measures had to be at the level of body functions, activities, or participation according to the definitions of the International Classification of Functioning, Disability and Health (ICF). Two reviewers independently decided on inclusion or exclusion of articles and rated the methodologic quality of the studies included. All RCTs, CCTs, and other designs only if of sufficient methodologic quality were included in a best evidence synthesis. A level of evidence was attributed for each subgroup of NMD and each type of intervention. Initially 58 studies were included: 12 RCTs, 5 CCTs, and 41 other designs. After methodologic assessment, 19 other designs were excluded from further analysis. There is level II evidence ("likely to be effective") for strengthening exercises in combination with aerobic exercises for patients with muscle disorders. Level III evidence ("indications of effectiveness") was found for aerobic exercises in patients with muscle disorders and for the combination of muscle strengthening and aerobic exercises in a heterogeneous group of muscle disorders. Finally, there is level III evidence for breathing exercises for patients with myasthenia gravis and for patients with myotonic muscular dystrophy. Adverse effects of exercise therapy were negligible. The available evidence is limited, but relevant for clinicians. Future studies should be preferably multicentered, and use an international classification of the variables of exercise therapy and an ICF core set for NMD in order to improve comparability of results.

Temporalis muscle hypertrophy and reduced skull eccentricity in Duchenne muscular dystrophy.

PubMed

Straathof, C S M; Doorenweerd, N; Wokke, B H A; Dumas, E M; van den Bergen, J C; van Buchem, M A; Hendriksen, J G M; Verschuuren, J J G M; Kan, H E

2014-10-01

Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P < .0001), whereas the shape of the skull was significantly rounder compared to controls. Temporal muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship. © The Author(s) 2014.

Correlation of ultra-widefield fundus autofluorescence patterns with the underlying genotype in retinal dystrophies and retinitis pigmentosa.

PubMed

Trichonas, George; Traboulsi, Elias I; Ehlers, Justis P

2017-01-01

Ultra-widefield fundus autofluorescence (UW-FAF) allows the characterization of the peripheral retinal features of vitreoretinal diseases. The purpose of this study was to examine possible genotypic/phenotypic correlations of UW-FAF patterns in patients with a variety of retinal dystrophies and retinitis pigmentosa (RP). An IRB-approved retrospective consecutive case series study was performed of genetically characterized retinal dystrophy or RP patients who underwent UW-FAF imaging. UW-FAF was performed with the Optos 200Tx system. Clinical variables, genotypic analysis, and phenotypic characteristics were reviewed. Seventeen patients were identified who had identified mutations in retinal dystrophy or RP genes and who also had undergone UW-FAF. Three patients had X-linked RP with RPGR mutations. Six patients had autosomal dominant RP (four with RHO mutations and one with a PRPF31 mutation, and one with RDS/PRPH2 mutation). Four patients had autosomal recessive RP (four with USH2A mutations). Three patients had Leber Congenital Amaurosis (LCA) with mutations including CRB1, CEP290, and RPGRIP1. Macular hyperautofluorescence was noted in all patients. A ring of hyperautofluorescence was clear in patients with RHO and USH2A mutations, and patients with USH2A mutations demonstrated a second ring of hyperautofluorescence. In the periphery, patients with RHO or RPGR mutations exhibited hyperautofluorescence with patchy areas of hypoautofluorescence. Patients with USH2A mutations had a distinctive pattern of diffuse and homogeneous peripheral hypoautofluorescence. UW-FAF may provide important information to facilitate diagnosis and further research is needed to better characterize this technology as an imaging biomarker for genotype association in retinal dystrophies and RP.

Physiology of respiratory disturbances in muscular dystrophies

PubMed Central

Lo Mauro, Antonella

2016-01-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. Key points A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination. In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia. Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness. Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase. The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. Educational aims To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy. To understand the impact of respiratory disturbances in patients with muscular dystrophy. To provide a brief description of the main forms of muscular dystrophy with their respiratory implications. PMID:28210319

Physiology of respiratory disturbances in muscular dystrophies.

PubMed

Lo Mauro, Antonella; Aliverti, Andrea

2016-12-01

Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. To understand the mechanisms leading to respiratory disturbances in patients with muscular dystrophy.To understand the impact of respiratory disturbances in patients with muscular dystrophy.To provide a brief description of the main forms of muscular dystrophy with their respiratory implications.

Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

ERIC Educational Resources Information Center

Palmer, Phyllis M.; Neel, Amy T.; Sprouls, Gwyneth; Morrison, Leslie

2010-01-01

Purpose: This prospective investigation evaluates oral weakness and its impact on swallow function, weight, and quality of life in patients with oculopharyngeal muscular dystrophy (OPMD). Method: Intraoral pressure, swallow pressure, and endurance were measured using an Iowa Oral Performance Instrument in participants with OPMD and matched…

Serum creatinine level: a supplemental index to distinguish Duchenne muscular dystrophy from Becker muscular dystrophy.

PubMed

Zhang, Huili; Zhu, Yuling; Sun, Yiming; Liang, Yingyin; Li, Yaqin; Zhang, Yu; Deng, Langhui; Wen, Xingxuan; Zhang, Cheng

2015-01-01

To improve assessment of dystrophinopathy, the aim of this study was to identify whether serum creatinine (Crn) level reflects disease severity. Biochemical, Vignos score, and genetic data were collected on 212 boys with dystrophinopathy. Serum Crn level had a strong inverse correlation with Vignos score by simple correlation (r = -0.793) and partial correlation analysis after adjustment for age, height, and weight (r = -0.791; both P < 0.01). Serum Crn level was significantly higher in patients with in-frame than out-of-frame mutations (Z = -4.716,  P < 0.01) and in Becker muscular dystrophy (BMD) patients than Duchenne muscular dystrophy (DMD) patients at ages 4, 5, 7, and 9 yr (all P < 0.0125). After adjusting for age, height, and weight, BMD patients still had a significantly higher serum Crn level than DMD patients (β = 7.140,  t = 6.277,  P < 0.01). Serum Crn level reflected disease severity and may serve as a supplemental index to distinguish DMD from BMD in clinical practice.

Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch.

PubMed

Waddell, Leigh B; Lemckert, Frances A; Zheng, Xi F; Tran, Jenny; Evesson, Frances J; Hawkes, Joanne M; Lek, Angela; Street, Neil E; Lin, Peihui; Clarke, Nigel F; Landstrom, Andrew P; Ackerman, Michael J; Weisleder, Noah; Ma, Jianjie; North, Kathryn N; Cooper, Sandra T

2011-04-01

Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex.

Mild and severe muscular dystrophy caused by a single {gamma}-sarcoglycan mutation

DOE Office of Scientific and Technical Information (OSTI.GOV)

McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W.

1996-11-01

Autosomal recessive muscular dystrophy is genetically heterogeneous. One form of this disorder, limb-girdle muscular dystrophy type 2C (LGMD 2C), is prevalent in northern Africa and has been shown to be associated with a single mutation in the gene encoding the dystrophin-associated protein {gamma}-sarcoglycan. The previous mutation analysis of {gamma}-sarcoglycan required the availability of muscle biopsies. To establish a mutation assay for genomic DNA, the intron-exon structure of the {gamma}-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding {gamma}-sarcoglycan. We studied a group of Brazilian muscular dystrophy patients for mutations in the {gamma}-sarcoglycan gene. Thesemore » patients were selected on the basis of autosomal inheritance and/or the presence of normal dystrophin and/or deficiency of {alpha}-sarcoglycan immunostaining. Four of 19 patients surveyed had a single, homozygous mutation in the {gamma}-sarcoglycan gene. The mutation identified in these patients, all of African-Brazilian descent, is identical to that seen in the North African population, suggesting that even patients of remote African descent may carry this mutation. The phenotype in these patients varied considerably. Of four families with an identical mutation, three have a severe Duchenne-like muscular dystrophy. However, one family has much milder symptoms, suggesting that other loci may be present that modify the severity of the clinical course resulting from {gamma}-sarcoglycan gene mutations. 19 refs., 5 figs., 3 tabs.« less

Pathogenic mutations of TGFBI and CHST6 genes in Chinese patients with Avellino, lattice, and macular corneal dystrophies

PubMed Central

Huo, Ya-nan; Yao, Yu-feng; Yu, Ping

2011-01-01

Objective: To investigate gene mutations associated with three different types of corneal dystrophies (CDs), and to establish a phenotype-genotype correlation. Methods: Two patients with Avellino corneal dystrophy (ACD), four patients with lattice corneal dystrophy type I (LCD I) from one family, and three patients with macular corneal dystrophy type I (MCD I) were subjected to both clinical and genetic examinations. Slit lamp examination was performed for all the subjects to assess their corneal phenotypes. Genomic DNA was extracted from peripheral blood leukocytes. The coding regions of the human transforming growth factor β-induced (TGFBI) gene and carbohydrate sulfotransferase 6 (CHST6) gene were amplified by polymerase chain reaction (PCR) and subjected to direct sequencing. DNA samples from 50 healthy volunteers were used as controls. Results: Clinical examination showed three different phenotypes of CDs. Genetic examination identified that two ACD subjects were associated with homozygous R124H mutation of TGFBI, and four LCD I subjects were all associated with R124C heterozygous mutation. One MCD I subject was associated with a novel S51X homozygous mutation in CHST6, while the other two MCD I subjects harbored a previously reported W232X homozygous mutation. Conclusions: Our study highlights the prevalence of codon 124 mutations in the TGFBI gene among the Chinese ACD and LCD I patients. Moreover, we found a novel mutation among MCD I patients. PMID:21887843

Elevated TGF β2 serum levels in Emery-Dreifuss muscular dystrophy: implications for myocyte and tenocyte differentiation and fibrogenic processes.

PubMed

Bernasconi, Pia; Carboni, Nicola; Ricci, Giulia; Siciliano, Gabriele; Politano, Luisa; Maggi, Lorenzo; Mongini, Tiziana; Vercelli, Liliana; Rodolico, Carmelo; Biagini, Elena; Boriani, Giuseppe; Ruggiero, Lucia; Santoro, Lucio; Schena, Elisa; Prencipe, Sabino; Evangelisti, Camilla; Pegoraro, Elena; Morandi, Lucia; Columbaro, Marta; Lanzuolo, Chiara; Sabatelli, Patrizia; Cavalcante, Paola; Cappelletti, Cristina; Bonne, Gisèle; Muchir, Antoine; Lattanzi, Giovanna

2018-04-25

Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss muscular dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

[Analysis of TGFBI gene mutation in a Chinese family affected with Reis-Bucklers corneal dystrophy].

PubMed

Guan, Tao; Zhang, Lingjie; Xu, Dejian; Wu, Haijian; Zheng, Libin

2017-10-10

To analyze the clinical features and TGFBI gene mutation in a Chinese family affected with Reis-Bucklers corneal dystrophy. Genomic DNA was extracted from 53 members including 9 patients from the family. The 17 exons and splice region of introns of the TGFBI gene were amplified by PCR and directly sequenced. All family members were subjected to ophthalmologic examination. A heterozygous mutation (R124L) was found in exon 4 of the TGFBI gene among all patients from the family. The same mutation was not found among unaffected family members. The inheritance pattern of the family was identified as autosomal dominant, and the Reis-Bucklers corneal dystrophy in the family was diagnosed as the geographic type. The R124L mutation of the TGFBI gene probably underlies the pathogenesis of Reis-Bucklers corneal dystrophy in this Chinese family. Molecular genetic approach is useful for the proper diagnosis of this type of corneal dystrophy.

Cardiomyopathy in becker muscular dystrophy: Overview.

PubMed

Ho, Rady; Nguyen, My-Le; Mather, Paul

2016-06-26

Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.

Adult patient with Becker dystrophy undergoing orthopedic surgery: an anesthesia challenge.

PubMed

Parish, Masoud; Farzin, Haleh

2018-01-01

Muscular dystrophies are considered to be a series of neuromuscular diseases with genetic causes and are characterized by progressive muscle weakness and degeneration of the skeletal muscle. The case of an adult man with Becker dystrophy referred for repair of the patella tendon tearing and patella fracture is described. He underwent successful surgery using total intravenous anesthesia without any complications.

Anti-gravity training improves walking capacity and postural balance in patients with muscular dystrophy.

PubMed

Berthelsen, Martin Peter; Husu, Edith; Christensen, Sofie Bouschinger; Prahm, Kira Philipsen; Vissing, John; Jensen, Bente Rona

2014-06-01

Recent studies in patients with muscular dystrophies suggest positive effects of aerobic and strength training. These studies focused training on using bicycle ergometers and conventional strength training, which precludes more severely affected patients from participating, because of their weakness. We investigated the functional effects of combined aerobic and strength training in patients with Becker and limb-girdle muscular dystrophies with knee muscle strength levels as low as 3% of normal strength. Eight patients performed 10 weeks of aerobic and strength training on an anti-gravity treadmill, which offered weight support up to 80% of their body weight. Six minute walking distance, dynamic postural balance, and plasma creatine kinase were assessed 10 weeks prior to training, immediately before training and after 10 weeks of training. Training elicited an improvement of walking distance by 8±2% and dynamic postural balance by 13±4%, indicating an improved physical function. Plasma creatine kinase remained unchanged. These results provide evidence that a combination of aerobic and strength training during anti-gravity has the potential to safely improve functional ability in severely affected patients with Becker and limb-girdle muscular dystrophies. Copyright © 2014 Elsevier B.V. All rights reserved.

Diagnostic support for selected neuromuscular diseases using answer-pattern recognition and data mining techniques: a proof of concept multicenter prospective trial.

PubMed

Grigull, Lorenz; Lechner, Werner; Petri, Susanne; Kollewe, Katja; Dengler, Reinhard; Mehmecke, Sandra; Schumacher, Ulrike; Lücke, Thomas; Schneider-Gold, Christiane; Köhler, Cornelia; Güttsches, Anne-Katrin; Kortum, Xiaowei; Klawonn, Frank

2016-03-08

Diagnosis of neuromuscular diseases in primary care is often challenging. Rare diseases such as Pompe disease are easily overlooked by the general practitioner. We therefore aimed to develop a diagnostic support tool using patient-oriented questions and combined data mining algorithms recognizing answer patterns in individuals with selected neuromuscular diseases. A multicenter prospective study for the proof of concept was conducted thereafter. First, 16 interviews with patients were conducted focusing on their pre-diagnostic observations and experiences. From these interviews, we developed a questionnaire with 46 items. Then, patients with diagnosed neuromuscular diseases as well as patients without such a disease answered the questionnaire to establish a database for data mining. For proof of concept, initially only six diagnoses were chosen (myotonic dystrophy and myotonia (MdMy), Pompe disease (MP), amyotrophic lateral sclerosis (ALS), polyneuropathy (PNP), spinal muscular atrophy (SMA), other neuromuscular diseases, and no neuromuscular disease (NND). A prospective study was performed to validate the automated malleable system, which included six different classification methods combined in a fusion algorithm proposing a final diagnosis. Finally, new diagnoses were incorporated into the system. In total, questionnaires from 210 individuals were used to train the system. 89.5 % correct diagnoses were achieved during cross-validation. The sensitivity of the system was 93-97 % for individuals with MP, with MdMy and without neuromuscular diseases, but only 69 % in SMA and 81 % in ALS patients. In the prospective trial, 57/64 (89 %) diagnoses were predicted correctly by the computerized system. All questions, or rather all answers, increased the diagnostic accuracy of the system, with the best results reached by the fusion of different classifier methods. Receiver operating curve (ROC) and p-value analyses confirmed the results. A questionnaire-based diagnostic support tool using data mining methods exhibited good results in predicting selected neuromuscular diseases. Due to the variety of neuromuscular diseases, additional studies are required to measure beneficial effects in the clinical setting.

Skeletal Muscle Metabolism in Duchenne and Becker Muscular Dystrophy-Implications for Therapies.

PubMed

Heydemann, Ahlke

2018-06-20

The interactions between nutrition and metabolism and skeletal muscle have long been known. Muscle is the major metabolic organ—it consumes more calories than other organs—and therefore, there is a clear need to discuss these interactions and provide some direction for future research areas regarding muscle pathologies. In addition, new experiments and manuscripts continually reveal additional highly intricate, reciprocal interactions between metabolism and muscle. These reciprocal interactions include exercise, age, sex, diet, and pathologies including atrophy, hypoxia, obesity, diabetes, and muscle myopathies. Central to this review are the metabolic changes that occur in the skeletal muscle cells of muscular dystrophy patients and mouse models. Many of these metabolic changes are pathogenic (inappropriate body mass changes, mitochondrial dysfunction, reduced adenosine triphosphate (ATP) levels, and increased Ca 2+ ) and others are compensatory (increased phosphorylated AMP activated protein kinase (pAMPK), increased slow fiber numbers, and increased utrophin). Therefore, reversing or enhancing these changes with therapies will aid the patients. The multiple therapeutic targets to reverse or enhance the metabolic pathways will be discussed. Among the therapeutic targets are increasing pAMPK, utrophin, mitochondrial number and slow fiber characteristics, and inhibiting reactive oxygen species. Because new data reveals many additional intricate levels of interactions, new questions are rapidly arising. How does muscular dystrophy alter metabolism, and are the changes compensatory or pathogenic? How does metabolism affect muscular dystrophy? Of course, the most profound question is whether clinicians can therapeutically target nutrition and metabolism for muscular dystrophy patient benefit? Obtaining the answers to these questions will greatly aid patients with muscular dystrophy.

GPR56-Related Polymicrogyria: Clinicoradiologic Profile of 4 Patients.

PubMed

Desai, Neelu A; Udani, Vrajesh

2015-11-01

Bilateral frontoparietal polymicrogyria is an autosomal recessive cortical malformation associated with abnormalities of neuronal migration, white matter changes, and mild brainstem and cerebellar abnormalities. Affected patients present with delayed milestones, intellectual disability, epilepsy, ataxia, and eye movement abnormalities. The clinicoradiologic profile resembles congenital muscular dystrophy. However, no muscle disease or characteristic eye abnormalities of congenial muscular dystrophy are detected in these children. GPR56 is the only confirmed gene associated with bilateral frontoparietal polymicrogyria. Antenatal diagnosis is possible if the index case is genetically confirmed. Four patients from different Indian families with a distinct clinicoradiologic profile resembling congenital muscular dystrophy with mutations in the GPR56 gene are described. © The Author(s) 2015.

Usefulness of sugammadex in a patient with Becker muscular dystrophy and dilated cardiomyopathy.

PubMed

Shimauchi, Tsukasa; Yamaura, Ken; Sugibe, Sayaka; Hoka, Sumio

2014-09-01

A 54-year-old patient with Becker muscular dystrophy and dilated cardiomyopathy underwent laparoscopic cholecystectomy under total intravenous anesthesia. Muscle relaxation was induced by rocuronium (0.4 mg/kg body weight) under train-of-four (TOF) ratio monitoring. The TOF ratio was 0 at intubation, and 0.2 at the end of surgery. Residual muscle relaxant activity was successfully reversed by sugammadex (2 mg/kg body weight) without any hemodynamic adverse effects (TOF ratio 1.0 at extubation). The clinical and hemodynamic findings suggest that sugammadex can be safely used in patients with Becker muscular dystrophy and dilated cardiomyopathy. Copyright © 2014. Published by Elsevier B.V.

Phase 3 Extension Study of Ataluren (PTC124) in Patients With Nonsense Mutation Dystrophinopathy

ClinicalTrials.gov

2018-01-16

Muscular Dystrophy, Duchenne; Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn

Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy

ERIC Educational Resources Information Center

Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.

2007-01-01

The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly…

Cardiomyopathy in becker muscular dystrophy: Overview

PubMed Central

Ho, Rady; Nguyen, My-Le; Mather, Paul

2016-01-01

Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed. PMID:27354892

Study of light scattering using C-Quant® in patients with Fuchs' endothelial dystrophy: A pilot study.

PubMed

Castaño-Martín, B; Gros-Otero, J; Martínez, J; Teus, M

2017-11-01

The purpose of this study was to determine the light scattering in patients with Fuchs' endothelial dystrophy without clinically significant corneal oedema, and evaluate its relationship with endothelial cell count, corneal thickness, and corneal biomechanical parameters. The values of light scattering were measured by C-Quant ® (Oculus Optikgeräte GmbH, Germany) in 32 eyes of 17 patients diagnosed with Fuchs' endothelial dystrophy without clinically significant corneal oedema. Corneal biomechanical properties were determined using ORA (ocular response) and Corvis ST ® (tonometry). A light scattering value outside the normal range was observed in 93.8% of eyes studied. No statistically significant association (P>.05) was found between the values of the measured light scattering by C-Quant ® and endothelial count, pachymetry, or corneal biomechanical properties. In this study, changes were found in the values of light scattering values of patients with corneal Fuchs' endothelial dystrophy. This change does not appear to correlate significantly with disease severity. Copyright © 2017 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

Fighting Against Disuse of the Masticatory System in Duchenne Muscular Dystrophy: A Pilot Study Using Chewing Gum.

PubMed

van Bruggen, H Willemijn; van den Engel-Hoek, Lenie; Steenks, Michel H; van der Bilt, Andries; Bronkhorst, Ewald M; Creugers, Nico H J; de Groot, Imelda J M; Kalaykova, Stanimira I

2015-10-01

Duchenne muscular dystrophy patients report masticatory problems. The aim was to determine the efficacy of mastication training in Duchenne muscular dystrophy using chewing gum for 4 weeks. In all, 17 patients and 17 healthy age-matched males participated. The masticatory performance was assessed using a mixing ability test and measuring anterior bite force before, shortly after and 1 month after the training. In the patient group the masticatory performance improved and remained after 1-month follow-up, no significant changes in anterior maximum bite force was observed after mastication training. In the healthy subject the bite force increased and remained at the 1-month follow-up; no significant differences in masticatory performance were observed. Mastication training by using sugar-free chewing gum in Duchenne muscular dystrophy patients improved their masticatory performance. Since bite force did not improve, the working mechanism of the improvement in chewing may relate to changes of the neuromuscular function and coordination, resulting in improvement of skills in performing mastication. © The Author(s) 2015.

The muscular dystrophies associated with central nervous system lesions: a brief review from a standpoint of the localization and function of causative genes.

PubMed

Yamamoto, Tomoko; Hiroi, Atsuko; Osawa, Makiko; Shibata, Noriyuki

2014-01-01

The muscular dystrophies have been traditionally classified based mainly on clinical manifestation and mode of inheritance. Owing to the discoveries of causative genes, new terminologies derived from each gene, such as dystrophinopathy, α-dystroglycanopathy, sarcoglycanopathy and fukutinopathy, have also become common. Mutations of each gene may cause several clinical phenotypes. Some muscular dystrophies accompany central nervous system (CNS) lesions, especially in the congenital muscular dystrophies. Cobblestone lissencephaly (type II lissencephaly) is a well-known CNS malformation observed in severe forms of α-dystroglycanopathy. Moreover, CNS involvement has been reported in other muscular dystrophies, such as Duchenne muscular dystrophy. In this review, genes related to the muscular dystrophies associated with CNS lesions are briefly described along with the molecular characteristics of each gene and the pathomechanism of the CNS lesions. Understanding of both the clinicopathological characteristics of these CNS lesions and their molecular mechanisms is important for the diagnosis, care of patients, and development of new therapeutic strategies.

LAMA2-related myopathy: Frequency among congenital and limb-girdle muscular dystrophies.

PubMed

Løkken, Nicoline; Born, Alfred Peter; Duno, Morten; Vissing, John

2015-10-01

Muscular dystrophy caused by LAMA2-gene mutations is an autosomal recessive disease typically presenting as a severe, early-onset congenital muscular dystrophy (CMD). However, milder cases with a limb-girdle type muscular dystrophy (LGMD) have been described. In this study, we assessed the frequency and phenotypic spectrum of LAMA2-related muscular dystrophy in CMD (n = 18) and LGMD2 (n = 128) cohorts identified in the last 15 years in eastern Denmark. The medical history, brain-MRI, muscle pathology, muscle laminin-α2 expression, and genetic analyses were assessed. Molecular genetics revealed 2 pathogenic LAMA2 mutations in 5 of 18 CMD and 3 of 128 LGMD patients, corresponding to a LAMA2-mutation frequency of 28% in the CMD and 2.3% in the LGMD cohorts, respectively. This study demonstrates a wide clinical spectrum of LAMA2-related muscular dystrophy and its prevalence in an LGMD2 cohort, which indicates that LAMA2 muscular dystrophy should be included in the LGMD2 nomenclature. © 2015 Wiley Periodicals, Inc.

Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): case definition in surveillance for childhood-onset Duchenne/Becker muscular dystrophy.

PubMed

Mathews, Katherine D; Cunniff, Chris; Kantamneni, Jiji R; Ciafaloni, Emma; Miller, Timothy; Matthews, Dennis; Cwik, Valerie; Druschel, Charlotte; Miller, Lisa; Meaney, F John; Sladky, John; Romitti, Paul A

2010-09-01

The Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) is a multisite collaboration to determine the prevalence of childhood-onset Duchenne/Becker muscular dystrophy and to characterize health care and health outcomes in this population. MD STARnet uses medical record abstraction to identify patients with Duchenne/Becker muscular dystrophy born January 1, 1982 or later who resided in 1 of the participating sites. Critical diagnostic elements of each abstracted record are reviewed independently by >4 clinicians and assigned to 1 of 6 case definition categories (definite, probable, possible, asymptomatic, female, not Duchenne/Becker muscular dystrophy) by consensus. As of November 2009, 815 potential cases were reviewed. Of the cases included in analysis, 674 (82%) were either ''definite'' or ''probable'' Duchenne/Becker muscular dystrophy. These data reflect a change in diagnostic testing, as case assignment based on genetic testing increased from 67% in the oldest cohort (born 1982-1987) to 94% in the cohort born 2004 to 2009.

Rapidly progressive heart failure requiring transplantation in muscular dystrophy: a need for frequent screening.

PubMed

Pick, Justin M; Ellis, Zachary D; Alejos, Juan C; Chang, Anthony C

2017-11-01

Fukuyama congenital muscular dystrophy weakens both skeletal and cardiac muscles, but the rate of cardiomyopathic progression can accelerate faster than that of skeletal muscles. A 14-year-old boy with Fukuyama congenital muscular dystrophy presented with mild skeletal myopathy but severe cardiomyopathy requiring heart transplantation within 1 year of declining heart function. These patients need frequent screening regardless of musculoskeletal symptoms.

Physiotherapy, based on the Bobath concept, may influence the gait pattern in persons with limb-girdle muscle dystrophy: a multiple case series study.

PubMed

Oygard, Kjellaug; Haestad, Helge; Jørgensen, Lone

2011-03-01

 There are few studies on possible effects of physiotherapy for adults with muscular dystrophy. The aim of this study was to examine if treatment based on the Bobath concept may influence specific gait parameters in some of these patients.   A single-subject experimental design with A-B-A-A phases was used, and four patients, three with limb-girdle muscular dystrophy (LGMD) and one with fascioscapulohumeral muscular dystrophy (FSHD), were included. The patients had 1 hour of individually tailored physiotherapy at each working day for a period of 3 weeks. Step length, step width and gait velocity were measured during the A-B-A-A phases by use of an electronic walkway. Walking distance and endurance were measured by use of the '6 minute walk test'.  . The three LGMD patients, who initially walked with a wide base of support, had a narrower, velocity-adjusted step width after treatment, accompanied with the same or even longer step length. These changes lasted throughout follow-up. Moreover, two of the patients were able to walk a longer distance within 6 minutes after the treatment period. The fourth patient (with FSHD) had a normal step width at baseline, which did not change during the study.   The results indicate that physiotherapy treatment based on the Bobath concept may influence the gait pattern in patients with LGMD. However, in order to evaluate the effectiveness of physiotherapy to patients with muscular dystrophies, we call for larger studies and controlled trials. Copyright © 2010 John Wiley & Sons, Ltd.

Heterogeneity in macular corneal dystrophy.

PubMed

Edward, D P; Yue, B Y; Sugar, J; Thonar, E J; SunderRaj, N; Stock, E L; Tso, M O

1988-11-01

Macular corneal dystrophy is an autosomal recessive disorder in which abnormal deposits in the corneal stroma have been identified. We examined the corneal buttons of 12 patients, who had clinical features of macular dystrophy, by histochemical staining, transmission electron microscopy, and immunohistochemical techniques. All corneas exhibited positive staining with Muller Mowry's colloidal iron. Using monoclonal antibodies 1/20/5-D-4, J-10, J-19, and J-36 that recognize specific sites on the sulfated keratan sulfate molecule, we stained corneal sections by an avidin-biotin-peroxidase complex method and identified two groups of macular corneal dystrophy. One group consisting of four corneas reacted positively with all four antibodies, and the other group consisting of eight corneas did not react with any of the antibodies used. These results confirmed those recently presented by Yang et al that there may be subgroups of macular dystrophy that can be identified by immunohistochemical methods. Also, serum levels of sulfated keratan sulfate were determined in seven patients. One patient who displayed a normal level of serum keratan sulfate had positive corneal immunoreactivity. Of the six patients who lacked serum keratan sulfate, four showed negative and two had positive corneal immunostaining, suggesting at least three subgroups in the disease. An attempt was made to correlate the clinical features, histochemical-staining characteristics, and ultrastructural morphology with the immunoreactivity to keratan sulfate antibodies, but no correlations could be made.

The experiences of patients with Duchenne muscular dystrophy in facing and learning about their clinical conditions.

PubMed

Fujino, Haruo; Iwata, Yuko; Saito, Toshio; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Imura, Osamu

2016-01-01

Patients experience extreme difficulty when facing an intractable genetic disease. Herein, we examine the experiences of patients with Duchenne muscular dystrophy in facing and learning about their disease. A total of seven patients with Duchenne muscular dystrophy (age range: 20-48) participated. We conducted in-depth interviews with them about how they learned of their disease and how their feelings regarding the disease changed over time. Transcribed data were analysed using thematic analysis. The following themes emerged from this analysis: "experiences before receiving the diagnosis," "experiences when they learned of their condition and progression of the disease," "supports," and "desired explanations." Anxiety and worry were most pronounced when they had to transition to using wheelchairs or respirators due to disease progression; indeed, such transitions affect the patients psychological adjustment. In such times, support from significant others in their lives helped patients adjust.

Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non‐syndromic corneal endothelial dystrophy

PubMed Central

Desir, Julie; Moya, Graciela; Reish, Orit; Van Regemorter, Nicole; Deconinck, Hilde; David, Karen L; Meire, Françoise M; Abramowicz, Marc J

2007-01-01

Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non‐syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. PMID:17220209

Congenital myotonic myopathy in the miniature schnauzer: an autosomal recessive trait.

PubMed

Vite, C H; Melniczek, J; Patterson, D; Giger, U

1999-01-01

Myotonia is a clinical sign characterized by a delay in skeletal muscle relaxation following electrical or mechanical stimulation. A series of related miniature schnauzer dogs with congenital myotonic myopathy were studied. A composite pedigree of six affected litters and the results of a planned breeding between two affected animals are consistent with an autosomal recessive mode of inheritance.

Sarcoidosis: nail dystrophy without underlying bone changes.

PubMed

Wakelin, S H; James, M P

1995-06-01

Sarcoidosis is a chronic granulomatous disease of unknown origin that affects multiple organs and may present with a variety of skin lesions. Involvement of the nails is rare and almost invariably associated with underlying bone disease. We describe a patient with sarcoid nail dystrophy in whom this diagnosis was confirmed by a proximal nail fold biopsy. Radiologic investigation did not show evidence of an associated bone dystrophy in this case.

Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beggs, A.H.; Neumann, P.E.; Anderson, M.S.

1992-01-15

Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative tomore » Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.« less

Cognitive behavioural therapy for reducing fatigue in post-polio syndrome and in facioscapulohumeral dystrophy: A comparison.

PubMed

Koopman, Fieke S; Brehm, Merel A; Beelen, Anita; Voet, Nicole; Bleijenberg, Gijs; Geurts, Alexander; Nollet, Frans

2017-07-07

Cognitive behavioural therapy does not reduce fatigue in post-polio syndrome, but is effective in facioscapulohumeral dystrophy. This difference in efficacy might be explained by a different role of cognitions in these conditions. To compare fatigue-related cognitions between patients with post-polio syndrome and facio-scapulohumeral dystrophy. Patients with post-polio syndrome (n = 21) and facioscapulohumeral dystrophy (n = 24) allocated to a cognitive behavioural therapy intervention in 2 identical trials. Assessed cognitions included: sense of control over fatigue; catastrophizing; acceptance; focusing on fatigue; and perceived social support. Group differences in cognitions (independent t-tests or Mann-Whitney U tests) and group differences in the association of cognitions with fatigue (linear regression models) were studied. No differences in cognitions were found between the 2 groups (p > 0.18). Furthermore, there were no cognition-by-group interaction effects, except for "perceived social support", for which a different association with fatigue was found between the 2 groups (p = 0.01). However, univariate models revealed no associations per group. Fatigue-related cognitions in severely fatigued patients with post-polio syndrome are not clearly different from that in facioscapulohumeral dystrophy. Thus, the lack of efficacy of cognitive behavioural therapy in post-polio syndrome cannot be attributed to unique cognitive characteristics of this population.

Dropped head congenital muscular dystrophy caused by de novo mutations in LMNA.

PubMed

Karaoglu, Pakize; Quizon, Nicolas; Pergande, Matthias; Wang, Haicui; Polat, Ayşe Ipek; Ersen, Ayca; Özer, Erdener; Willkomm, Lena; Hiz Kurul, Semra; Heredia, Raúl; Yis, Uluç; Selcen, Duygu; Çirak, Sebahattin

2017-04-01

Dropped head syndrome is an easily recognizable clinical presentation of Lamin A/C-related congenital muscular dystrophy. Patients usually present in the first year of life with profound neck muscle weakness, dropped head, and elevated serum creatine kinase. Two patients exhibited head drop during infancy although they were able to sit independently. Later they developed progressive axial and limb-girdle weakness. Creatine kinase levels were elevated and muscle biopsies of both patients showed severe dystrophic changes. The distinctive clinical hallmark of the dropped head led us to the diagnosis of Lamin A/C-related congenital muscular dystrophy, with a pathogenic de novo mutation p.Glu31del in the head domain of the Lamin A/C gene in both patients. Remarkably, one patient also had a central involvement with white matter changes on brain magnetic resonance imaging. Lamin A/C-related dropped-head syndrome is a rapidly progressive congenital muscular dystrophy and may lead to loss of ambulation, respiratory insufficiency, and cardiac complications. Thus, the genetic diagnosis of dropped-head syndrome as L-CMD and the implicated clinical care protocols are of vital importance for these patients. This disease may be underdiagnosed, as only a few genetically confirmed cases have been reported. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Collaborative goal setting with adults attending physiotherapy at a specialist neuromuscular centre: is it always appropriate? A cross-sectional survey.

PubMed

Hartley, S E; Stockley, R C

2016-12-01

Collaborative goal setting is an integral component of treatment planning for adults with neuromuscular disorders (NMD). However, due to the unique challenges for these individuals, identifying a process for goal setting that is advantageous for all can be problematic. This study aimed to evaluate collaborative goal setting at a specialist NMD centre, as reported by service users attending physiotherapy. It also aimed to generate discussion about collaborative goal setting and the practice of goal setting in adults with NMD in order to inform future practice. Specialist NMD community-based centre in the UK. One hundred and four adults with NMD who attended the centre. Cross-sectional survey. Thematic and content analyses of goals set were performed alongside demographic data collection. One hundred and four patients (34 females) with a range of neuromuscular conditions - including Becker, facioscapularhumeral, limb girdle, Duchenne and myotonic muscular dystrophies - completed the survey. Thirty-six respondents (37%) stated that they had set goals with the physiotherapist, whilst 62 (63%) stated that they had not set goals with the physiotherapist. Respondents' goals were grouped into four themes: symptom management, maintenance, improving physical condition, and learning to live with the condition. Readiness to take part in collaborative goal setting is unique to each individual. Physiotherapists need to be skilful in supporting adults with NMD through the goal-setting process until they are capable of sharing responsibility. Setting personal goals to improve emotional well-being may help to develop confidence to take more control of their situation, hence facilitating skills in self-management. Copyright © 2015 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.

Treatment of cataplexy in Niemann-Pick disease type C with the use of miglustat.

PubMed

Zarowski, Marcin; Steinborn, Barbara; Gurda, Barbara; Dvorakova, Lenka; Vlaskova, Hana; Kothare, Sanjeev V

2011-01-01

Cataplexy is the sudden muscle weakness brought on by strong emotions, particularly joking, laughter, or anger. Cataplexy may involve only certain group of muscles or the entire voluntary musculature. In rare cases, symptoms of cataplexy can be seen during the course of some inherited diseases (Niemann-Pick type C (NPC), Prader-Willi syndrome, myotonic dystrophy, Norrie disease). We report the successful use of miglustat, a reversible inhibitor of the enzyme glucosylceramide synthase, approved for use in Gaucher's disease, and which catalyses the first step in the biosynthesis of most glycosphingolipid, in a boy with NPC with cataplexy. A 9-year-old boy was admitted for assessments of frequent "drop attacks" while laughing. The filipin fluorescence tests of cultured skin fibroblasts revealed massive accumulation of unesterified cholesterol, confirming the diagnosis of NPC disease. Molecular studies confirmed the diagnosis of NPC too. After approval from the bioethics committee, miglustat was initiated on the child at 100mg three times a day. Cataplectic attacks disappeared completely after 6 months on treatment, and patient continues to be in remission from the cataplectic attacks at 16 months follow-up. There was no further progression of neurological signs or symptoms or splenomegaly, with some improvement in cognitive function as well as social, affective and attention problems, up-gaze, and gait. Miglustat was well tolerated with no side effects observed. In summary, this is the first report of miglustat treatment of cataplexy in NPC. Long-term follow-up for continuing efficacy and tolerability in a larger cohort with NPC is needed to substantiate our observation. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

PubMed Central

Morgenthaler, Timothy I.; Kapur, Vishesh K.; Brown, Terry; Swick, Todd J.; Alessi, Cathy; Aurora, R. Nisha; Boehlecke, Brian; Chesson, Andrew L.; Friedman, Leah; Maganti, Rama; Owens, Judith; Pancer, Jeffrey; Zak, Rochelle

2007-01-01

These practice parameters pertain to the treatment of hypersomnias of central origin. They serve as both an update of previous practice parameters for the therapy of narcolepsy and as the first practice parameters to address treatment of other hypersomnias of central origin. They are based on evidence analyzed in the accompanying review paper. The specific disorders addressed by these parameters are narcolepsy (with cataplexy, without cataplexy, due to medical condition and unspecified), idiopathic hypersomnia (with long sleep time and without long sleep time), recurrent hypersomnia and hypersomnia due to medical condition. Successful treatment of hypersomnia of central origin requires an accurate diagnosis, individual tailoring of therapy to produce the fullest possible return of normal function, and regular follow-up to monitor response to treatment. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for excessive sleepiness associated with narcolepsy, while tricyclic antidepressants and fluoxetine are effective treatments for cataplexy, sleep paralysis, and hypnagogic hallucinations; but the quality of published clinical evidence supporting them varies. Scheduled naps can be beneficial to combat sleepiness in narcolepsy patients. Based on available evidence, modafinil is an effective therapy for sleepiness due to idiopathic hypersomnia, Parkinson's disease, myotonic dystrophy, and multiple sclerosis. Based on evidence and/or long history of use in the therapy of narcolepsy committee consensus was that modafinil, amphetamine, methamphetamine, dextroamphetamine, and methylphenidate are reasonable options for the therapy of hypersomnias of central origin. Citation: Morgenthaler TI; Kapur VK; Brown T; Swick TJ; Alessi C; Aurora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J; Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. SLEEP 2007;30(12):1705-1711. PMID:18246980

Cystic dystrophy of the gastric and duodenal wall developing in heterotopic pancreas: an unrecognised entity.

PubMed Central

Fléjou, J F; Potet, F; Molas, G; Bernades, P; Amouyal, P; Fékété, F

1993-01-01

Ten patients in whom cystic dystrophy developed in a heterotopic pancreas of the duodenal (nine patients) or gastric (one patient) wall are reported. All were young or middle aged white men, only two of whom were alcoholic. The symptoms were caused by intestinal or biliary stenosis, or both, secondary to the inflammation and fibrosis. Only endosonography provided strong evidence for the diagnosis in three patients. All patients underwent surgery: a pancreaticoduodenectomy was performed in eight patients. The surgical specimen showed cystic lesions of the gut wall, occurring in inflammatory and fibrous heterotopic pancreatic tissue. The pancreas proper was normal in all patients. It is suggested that cystic dystrophy is an uncommon and serious complication of heterotopic pancreas. Similar cases associated with chronic pancreatitis of the pancreas have been observed and it is suggested that this process could be responsible for some of the chronic pancreatitis encountered in young, non-alcoholic patients. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:8097180

Homozygosity Mapping in Patients with Cone–Rod Dystrophy: Novel Mutations and Clinical Characterizations

PubMed Central

Littink, Karin W.; Koenekoop, Robert K.; van den Born, L. Ingeborgh; Collin, Rob W. J.; Moruz, Luminita; Veltman, Joris A.; Roosing, Susanne; Zonneveld, Marijke N.; Omar, Amer; Darvish, Mahshad; Lopez, Irma; Kroes, Hester Y.; van Genderen, Maria M.; Hoyng, Carel B.; Rohrschneider, Klaus; van Schooneveld, Mary J.; Cremers, Frans P. M.

2010-01-01

Purpose. To determine the genetic defect and to describe the clinical characteristics in a cohort of mainly nonconsanguineous cone–rod dystrophy (CRD) patients. Methods. One hundred thirty-nine patients with diagnosed CRD were recruited. Ninety of them were screened for known mutations in ABCA4, and those carrying one or two mutations were excluded from further research. Genome-wide homozygosity mapping was performed in the remaining 108. Known genes associated with autosomal recessive retinal dystrophies located within a homozygous region were screened for mutations. Patients in whom a mutation was detected underwent further ophthalmic examination. Results. Homozygous sequence variants were identified in eight CRD families, six of which were nonconsanguineous. The variants were detected in the following six genes: ABCA4, CABP4, CERKL, EYS, KCNV2, and PROM1. Patients carrying mutations in ABCA4, CERKL, and PROM1 had typical CRD symptoms, but a variety of retinal appearances on funduscopy, optical coherence tomography, and autofluorescence imaging. Conclusions. Homozygosity mapping led to the identification of new mutations in consanguineous and nonconsanguineous patients with retinal dystrophy. Detailed clinical characterization revealed a variety of retinal appearances, ranging from nearly normal to extensive retinal remodeling, retinal thinning, and debris accumulation. Although CRD was initially diagnosed in all patients, the molecular findings led to a reappraisal of the diagnosis in patients carrying mutations in EYS, CABP4, and KCNV2. PMID:20554613

Restricting calcium currents is required for correct fiber type specification in skeletal muscle

PubMed Central

Sultana, Nasreen; Dienes, Beatrix; Benedetti, Ariane; Tuluc, Petronel; Szentesi, Peter; Sztretye, Monika; Rainer, Johannes; Hess, Michael W.; Schwarzer, Christoph; Obermair, Gerald J.; Csernoch, Laszlo

2016-01-01

ABSTRACT Skeletal muscle excitation-contraction (EC) coupling is independent of calcium influx. In fact, alternative splicing of the voltage-gated calcium channel CaV1.1 actively suppresses calcium currents in mature muscle. Whether this is necessary for normal development and function of muscle is not known. However, splicing defects that cause aberrant expression of the calcium-conducting developmental CaV1.1e splice variant correlate with muscle weakness in myotonic dystrophy. Here, we deleted CaV1.1 (Cacna1s) exon 29 in mice. These mice displayed normal overall motor performance, although grip force and voluntary running were reduced. Continued expression of the developmental CaV1.1e splice variant in adult mice caused increased calcium influx during EC coupling, altered calcium homeostasis, and spontaneous calcium sparklets in isolated muscle fibers. Contractile force was reduced and endurance enhanced. Key regulators of fiber type specification were dysregulated and the fiber type composition was shifted toward slower fibers. However, oxidative enzyme activity and mitochondrial content declined. These findings indicate that limiting calcium influx during skeletal muscle EC coupling is important for the secondary function of the calcium signal in the activity-dependent regulation of fiber type composition and to prevent muscle disease. PMID:26965373

Msh3 is a limiting factor in the formation of intergenerational CTG expansions in DM1 transgenic mice.

PubMed

Foiry, Laurent; Dong, Li; Savouret, Cédric; Hubert, Laurence; te Riele, Hein; Junien, Claudine; Gourdon, Geneviève

2006-06-01

The CTG repeat involved in myotonic dystrophy is one of the most unstable trinucleotide repeats. However, the molecular mechanisms underlying this particular form of genetic instability-biased towards expansions-have not yet been completely elucidated. We previously showed, with highly unstable CTG repeat arrays in DM1 transgenic mice, that Msh2 is required for the formation of intergenerational and somatic expansions. To identify the partners of Msh2 in the formation of intergenerational CTG repeat expansions, we investigated the involvement of Msh3 and Msh6, partners of Msh2 in mismatch repair. Transgenic mice with CTG expansions were crossed with Msh3- or Msh6-deficient mice and CTG repeats were analysed after maternal and paternal transmissions. We demonstrated that Msh3 but not Msh6 plays also a key role in the formation of expansions over successive generation. Furthermore, the absence of one Msh3 allele was sufficient to decrease the formation of expansions, indicating that Msh3 is rate-limiting in this process. In the absence of Msh6, the frequency of expansions decreased only in maternal transmissions. However, the significantly lower levels of Msh2 and Msh3 proteins in Msh6 -/- ovaries suggest that the absence of Msh6 may have an indirect effect.

[Dynamic mutations--a newly detected category of mutations which is the basis for certain neurologic diseases].

PubMed

Mardesić, D

1995-01-01

This review offers some basic information on the discovery of a new type of mutations being the cause of some significant neurologic diseases: myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1, spinobulbar pallido-louysian muscular atrophy, fragile X syndrome and some other, up to a total of ten entities. The basis of the so-called dynamic mutations is an abnormal multiplication of a trinucleotide producing sequences of several hundreds or even thousands of identical copies in the respective gene. The result is designated as expanded or amplified trinucleotide (or triplet) repeat. These sequences are not stable, but increase (or exceptionally decrease) in length during cell multiplication in successive generations. They segregate within families with the affected members, demonstrating a significant correlation between the length of the repeat sequence, the severity of the pathologic phenotype and an inverse correlation with the age at the clinical manifestation of the disease. Thus, at least, a formal explanation for the anticipation phenomenon of the age at which the disease is manifested within a family is offered. The importance of the discovery of dynamic mutations lies in the possibility for more precise and reliable genetic counselling. The discovery has opened a lot of new questions giving a new impetus for intensive research.

Triplet repeat RNA structure and its role as pathogenic agent and therapeutic target

PubMed Central

Krzyzosiak, Wlodzimierz J.; Sobczak, Krzysztof; Wojciechowska, Marzena; Fiszer, Agnieszka; Mykowska, Agnieszka; Kozlowski, Piotr

2012-01-01

This review presents detailed information about the structure of triplet repeat RNA and addresses the simple sequence repeats of normal and expanded lengths in the context of the physiological and pathogenic roles played in human cells. First, we discuss the occurrence and frequency of various trinucleotide repeats in transcripts and classify them according to the propensity to form RNA structures of different architectures and stabilities. We show that repeats capable of forming hairpin structures are overrepresented in exons, which implies that they may have important functions. We further describe long triplet repeat RNA as a pathogenic agent by presenting human neurological diseases caused by triplet repeat expansions in which mutant RNA gains a toxic function. Prominent examples of these diseases include myotonic dystrophy type 1 and fragile X-associated tremor ataxia syndrome, which are triggered by mutant CUG and CGG repeats, respectively. In addition, we discuss RNA-mediated pathogenesis in polyglutamine disorders such as Huntington's disease and spinocerebellar ataxia type 3, in which expanded CAG repeats may act as an auxiliary toxic agent. Finally, triplet repeat RNA is presented as a therapeutic target. We describe various concepts and approaches aimed at the selective inhibition of mutant transcript activity in experimental therapies developed for repeat-associated diseases. PMID:21908410

[Current status of the predictive genetic testing for hereditary neurological diseases in Shinshu University Hospital].

PubMed

Tanaka, Keiko; Sekijima, Yoshiki; Yoshida, Kunihiro; Mizuuchi, Asako; Yamashita, Hiromi; Tamai, Mariko; Ikeda, Shu-ichi; Fukushima, Yoshimitsu

2013-01-01

The current status of predictive genetic testing for late-onset hereditary neurological diseases in Japan is largely unknown. In this study, we analyzed data from 73 clients who visited the Division of Clinical and Molecular Genetics, Shinshu University Hospital, for the purpose of predictive genetic testing. The clients consisted of individuals with family histories of familial amyloid polyneuropathy (FAP; n=30), Huntington's disease (HD; n=16), spinocerebellar degeneration (SCD; n=14), myotonic dystrophy type 1 (DM1; n=9), familial amyotrophic lateral sclerosis type 1 (ALS1; n=3), and Alzheimer's disease (AD; n=1). Forty-nine of the 73 (67.1%) clients were in their twenties or thirties. Twenty-seven of the 73 (37.0%) clients visited a medical institution within 3 months after becoming aware of predictive genetic testing. The most common reason for requesting predictive genetic testing was a need for certainty or to reduce uncertainty and anxiety. The decision-making about marriage and having a child was also a main reason in clients in the twenties and thirties. The numbers of clients who actually underwent predictive genetic testing was 22 of 30 (73.3%) in FAP, 3 of 16 (18.8%) in HD, 6 of 10 (60.0%) in SCD, 7 of 9 (77.8%) in DM1, and 0 of 3 (0%) in ALS1 (responsible gene of the disease was unknown in 4 SCD patients and an AD patient). The percentage of test usage was lower in untreatable diseases such as HD and SCD than that in FAP, suggesting that many clients changed their way of thinking on the significance of testing through multiple genetic counseling sessions. In addition, it was obvious that existence of disease-modifying therapy promoted usage of predictive genetic testing in FAP. Improvement of genetic counseling system to manage predictive genetic testing is necessary, as consultation concerning predictive genetic testing is the main motivation to visit genetic counseling clinic in many at-risk clients.

[Survey on the attitude toward genetic testing of neurologists certified by the Japanese Society of Neurology].

PubMed

Yoshida, Kunihiro; Ohata, Takako; Muto, Kaori; Tsuchiya, Atsushi; Sawada, Jinichi; Hazama, Takanori; Ikeda, Shu-Ichi; Toda, Tatsushi

2013-01-01

To clarify the attitude toward genetic testing for neuromuscular diseases, a questionnaire was sent to 4,762 neurologists certified by the Japanese Society of Neurology. By December 21, 2011, 1,493 questionnaires (31.4%) were returned. Of these, 1,233 (82.6%) had experienced genetic testing, but only 396 (26.5%) had referred to the guideline for genetic testing of the Japanese Society of Neurology (2009). The numbers of respondents who were positive, or more positive than negative for genetic testing for myotonic dystrophy type 1 (DM1), Huntington's disease (HD), and familial amyloid polyneuropathy (FAP) were 753 (50.4%), 915 (61.3%), and 980 (65.6%), respectively. The predominant reason for a positive attitude toward genetic testing was to confirm or exclude the diagnosis. Conversely, the predominant reason for a negative attitude toward genetic testing differed between the diseases. For DM1, it was to confirm the diagnosis without genetic testing. For HD, it was that genetic testing would not result in effective prevention or therapy. In FAP, it was that post-testing psychosocial support for the patient and their family was difficult. Common to DM1, HD, and FAP, a significant number of respondents (approximately 60%) felt it difficult to explain the negative aspects that might occur after the disclosure of test results. Concerning predictive or prenatal genetic testing, most respondents referred at-risk individuals to specialized genetic counseling clinics. In general, neurologists are likely to conduct genetic testing properly in consideration not only of the characteristics of the diseases but also of the circumstances of each patient and his or her family. To support neurologists who are involved in genetic testing, the guidelines should be more easily accessible. Many respondents wanted information on the institutions that provide genetic counseling and testing; however, financial support to such institutions is indispensable for fulfilling this requirement.

Small RNAome profiling from human skeletal muscle: novel miRNAs and their targets associated with cancer cachexia.

PubMed

Narasimhan, Ashok; Ghosh, Sunita; Stretch, Cynthia; Greiner, Russell; Bathe, Oliver F; Baracos, Vickie; Damaraju, Sambasivarao

2017-06-01

MicroRNAs (miRs) are small non-coding RNAs that regulate gene (mRNA) expression. Although the pathological role of miRs have been studied in muscle wasting conditions such as myotonic and muscular dystrophy, their roles in cancer cachexia (CC) are still emerging. The objectives are (i) to profile human skeletal muscle expressed miRs; (ii) to identify differentially expressed (DE) miRs between cachectic and non-cachectic cancer patients; (iii) to identify mRNA targets for the DE miRs to gain mechanistic insights; and (iv) to investigate if miRs show potential prognostic and predictive value. Study subjects were classified based on the international consensus diagnostic criteria for CC. Forty-two cancer patients were included, of which 22 were cachectic cases and 20 were non-cachectic cancer controls. Total RNA isolated from muscle biopsies were subjected to next-generation sequencing. A total of 777 miRs were profiled, and 82 miRs with read counts of ≥5 in 80% of samples were retained for analysis. We identified eight DE miRs (up-regulated, fold change of ≥1.4 at P < 0.05). A total of 191 potential mRNA targets were identified for the DE miRs using previously described human skeletal muscle mRNA expression data (n = 90), and a majority of them were also confirmed in an independent mRNA transcriptome dataset. Ingenuity pathway analysis identified pathways related to myogenesis and inflammation. qRT-PCR analysis of representative miRs showed similar direction of effect (P < 0.05), as observed in next-generation sequencing. The identified miRs also showed prognostic and predictive value. In all, we identified eight novel miRs associated with CC. © 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.

Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies.

PubMed

Lee, Kristy; Garg, Seema

2015-04-01

Inherited eye disorders are a significant cause of vision loss. Genetic testing can be particularly helpful for patients with inherited retinal dystrophies because of genetic heterogeneity and overlapping phenotypes. The need to identify a molecular diagnosis for retinal dystrophies is particularly important in the era of developing novel gene therapy-based treatments, such as the RPE65 gene-based clinical trials and others on the horizon, as well as recent advances in reproductive options. The introduction of massively parallel sequencing technologies has significantly advanced the identification of novel gene candidates and has expanded the landscape of genetic testing. In a relatively short time clinical medicine has progressed from limited testing options to a plethora of choices ranging from single-gene testing to whole-exome sequencing. This article outlines currently available genetic testing and factors to consider when selecting appropriate testing for patients with inherited retinal dystrophies.

Psychometric properties of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy: a Rasch analysis.

PubMed

Landfeldt, Erik; Mayhew, Anna; Straub, Volker; Bushby, Katharine; Lochmüller, Hanns; Lindgren, Peter

2017-12-18

To explore the psychometric properties of the full 22-item English (UK and US) version of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy. Caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States, recruited through the TREAT-NMD network, completed the Zarit Caregiver Burden Interview online. The psychometric properties of the Zarit Caregiver Burden Interview were examined using Rasch analysis. A total of 475 caregivers completed the Zarit Caregiver Burden Interview. Model misfit was identified for 9 of 22 items (mean item fit residual 0.061, SD: 2.736) and 13 of 22 items displayed disordered thresholds. The overall item-trait interaction chi-square value was 499 (198 degrees of freedom, p < 0.001). The mean person fit residual was estimated at -0.213 (SD: 1.235). The Person Separation Index and Cronbach's α were estimated at 0.902 and 0.914, respectively. Item dependency was low and we found no significant differential item functioning by country or sex. Our Rasch analysis shows that the Zarit Caregiver Burden Interview fails to fully operationalize a quantitative conceptualization of caregiver burden among caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States. Further research is needed to understand the psychometric properties of the Zarit Caregiver Burden Interview in other populations and settings. Implications for Rehabilitation Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers. The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden. Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy. Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.

Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet): Case Definition in Surveillance for Childhood-Onset Duchenne/Becker Muscular Dystrophy

PubMed Central

Mathews, Katherine D.; Cunniff, Chris; Kantamneni, Jiji R.; Ciafaloni, Emma; Miller, Timothy; Matthews, Dennis; Cwik, Valerie; Druschel, Charlotte; Miller, Lisa; Meaney, F. John; Sladky, John; Romitti, Paul A.

2013-01-01

The Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) is a multisite collaboration to determine the prevalence of childhood-onset Duchenne/Becker muscular dystrophy and to characterize health care and health outcomes in this population. MD STARnet uses medical record abstraction to identify patients with Duchenne/Becker muscular dystrophy born January 1, 1982 or later who resided in one of the participating sites. Critical diagnostic elements of each abstracted record are reviewed independently by ≥4 clinicians and assigned to 1 of 6 case definition categories (definite, probable, possible, asymptomatic, female, not Duchenne/Becker muscular dystrophy) by consensus. As of November 2009, 815 potential cases were reviewed. Of the cases included in analysis, 674 (82%) were either “definite” or “probable” Duchenne/Becker muscular dystrophy. These data reflect a change in diagnostic testing, as case assignment based on genetic testing increased from 67% in the oldest cohort (born 1982–1987) to 94% in the cohort born 2004–2009. PMID:20817884

Immortalized pathological human myoblasts: towards a universal tool for the study of neuromuscular disorders

PubMed Central

2011-01-01

Background Investigations into both the pathophysiology and therapeutic targets in muscle dystrophies have been hampered by the limited proliferative capacity of human myoblasts. Isolation of reliable and stable immortalized cell lines from patient biopsies is a powerful tool for investigating pathological mechanisms, including those associated with muscle aging, and for developing innovative gene-based, cell-based or pharmacological biotherapies. Methods Using transduction with both telomerase-expressing and cyclin-dependent kinase 4-expressing vectors, we were able to generate a battery of immortalized human muscle stem-cell lines from patients with various neuromuscular disorders. Results The immortalized human cell lines from patients with Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, congenital muscular dystrophy, and limb-girdle muscular dystrophy type 2B had greatly increased proliferative capacity, and maintained their potential to differentiate both in vitro and in vivo after transplantation into regenerating muscle of immunodeficient mice. Conclusions Dystrophic cellular models are required as a supplement to animal models to assess cellular mechanisms, such as signaling defects, or to perform high-throughput screening for therapeutic molecules. These investigations have been conducted for many years on cells derived from animals, and would greatly benefit from having human cell models with prolonged proliferative capacity. Furthermore, the possibility to assess in vivo the regenerative capacity of these cells extends their potential use. The innovative cellular tools derived from several different neuromuscular diseases as described in this report will allow investigation of the pathophysiology of these disorders and assessment of new therapeutic strategies. PMID:22040608

[Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy].

PubMed

Silva, Helga Cristina Almeida da; Hiray, Marcia; Vainzof, Mariz; Schmidt, Beny; Oliveira, Acary Souza Bulle; Amaral, José Luiz Gomes do

2017-05-31

Duchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia. Male patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels - CK), with CK values of 7,779-29,040IU.L -1 (normal 174IU.L -1 ). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy. On preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

What Can DuchenneConnect Teach Us About Treating Duchenne Muscular Dystrophy?

PubMed Central

Wang, Richard T; Nelson, Stanley F

2015-01-01

Purpose of Review This review aims to describe the benefits and limitations of using the DuchenneConnect patient registry to provide information particularly in regard to active treatment choices in Duchenne muscular dystrophy and their impact on disease progression. Recent findings Clinical trials and natural history studies are difficult for rare diseases like Duchenne muscular dystrophy. Using an online patient self-report survey model, DuchenneConnect provides relevant data that are difficult to gather in other ways. Validation of the overall dataset is supported by comparable mutational spectrum relative to other cohorts and demonstrated beneficial effect of corticosteroid use in prolonging ambulation. These types of analyses are provocative and allow multivariate analyses across the breadth of patient and physician medication and supplement practices. Because the data is self-reported and online, the barrier to participation is low and great potential exists for novel directions of further research in a highly participatory forum. Summary Patient registries for Duchenne and Becker muscular dystrophy are powerful tools for monitoring patient outcomes, comparing treatments options, and relating information between patients, researchers and clinicians. DuchenneConnect is an online patient self-report registry for individuals with DBMD that facilitates aggregation of treatment modalities, outcomes and genotype data and has played a vital role in furthering DBMD research, particularly in the US, in a highly participatory and low cost manner. PMID:26356412

Congenital Muscle Disease Study of Patient and Family Reported Medical Information

ClinicalTrials.gov

2017-05-05

Congenital Muscular Dystrophy (Including Unspecified/Undiagnosed); Dystroglycanopathy; Congenital Fiber Type Disproportion; Rigid Spine Muscular Dystrophy; Congenital Myopathy (Including Unspecified/Undiagnosed); Collagen VI CMD (Ullrich CMD, Intermediate, Bethlem Myopathy); Laminin Alpha 2 Related Congenital Muscular Dystrophy; LAMA2-CMD/Merosin Deficient/MDC1A; Walker-Warburg Syndrome; Muscle-Eye-Brain Disease; Fukuyama/Fukutin Related Muscular Dystrophy; Integrin Alpha 7 Deficiency; Integrin Alpha 9 Deficiency; LMNA-CMD/Lamin A/C/Laminopathy; SEPN1-Related Myopathy; Bethlem Myopathy; Actin Aggregation Myopathy; Cap Disease; Central Core Disease; Centronuclear Myopathy; Core Rod Myopathy; Hyaline Body Myopathy; Multiminicore Myopathy; Myotubular Myopathy; Nemaline Myopathy; Tubular Aggregate Myopathy; Zebra Body Myopathy; Reducing Body Myopathy; Spheroid Body Myopathy; LGMD1B (LMNA); LGMD1E (DES); LGMD2G (TCAP); LGMD2H (TRIM32); LGMD2I (FKRP); LGMD2J (TTN); LGMD2K (POMT1); LGMD2M (FKTN); LGMD2N (POMT2); LGMD2O (POMGnT1); LGMD2P (DAG1); LGMD2Q (PLEC1); LGMD2R (DES); LGMD2S (TRAPPC11); LGMD2T (GMPPB); LGMD2U (ISPD); LGMD2V (GAA); Ullrich Congenital Muscular Dystrophy; Titinopathy; Choline Kinase B Receptor; Emery-Dreifuss Muscular Dystrophy; RYR1 Related Myopathy; SYNE1/Nesprin Related Muscular Dystrophy; Telethonin Related Muscular Dystrophy (TCAP/Titin-Cap); Congenital Myasthenic Syndrome; Escobar Syndrome; Myofibrillar Myopathy; Malignant Hyperthermia; Alpha-Dystroglycan Related Muscular Dystrophy (DAG1, DPM1, DPM2, DPM3, FKRP, FKTN); Alpha-Dystroglycan Related Muscular Dystrophy (GAA, ISPD, LARGE, POMT1, POMT2, POMGnT1); Alpha-Dystroglycan Related Muscular Dystrophy (Unspecified/Undiagnosed/Other)

More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1995-11-06

This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

Serum Creatinine Distinguishes Duchenne Muscular Dystrophy from Becker Muscular Dystrophy in Patients Aged ≤3 Years: A Retrospective Study.

PubMed

Wang, Liang; Chen, Menglong; He, Ruojie; Sun, Yiming; Yang, Juan; Xiao, Lulu; Cao, Jiqing; Zhang, Huili; Zhang, Cheng

2017-01-01

Here, we investigated correlations between serum creatinine (SCRN) levels and clinical phenotypes of dystrophinopathy in young patients. Sixty-eight patients with dystrophinopathy at the Neuromuscular Clinic, The First Affiliated Hospital, Sun Yat-sen University, were selected for this study. The diagnosis of dystrophinopathy was based on clinical manifestation, biochemical changes, and molecular analysis. Some patients underwent muscle biopsies; SCRN levels were tested when patients were ≤3 years old, and reading frame changes were analyzed. Each patient was followed up, and motor function and clinical phenotype were assessed when the same patients were ≥4 years old. Our findings indicated that in young patients, lower SCRN levels were associated with increased disease severity ( p  < 0.01) and that SCRN levels were the highest in patients exhibiting mild Becker muscular dystrophy (BMD) ( p  < 0.001) and the lowest in patients with Duchenne muscular dystrophy (DMD) ( p  < 0.01) and were significantly higher in patients carrying in-frame mutations than in patients carrying out-of-frame mutations ( p  < 0.001). SCRN level cutoff values for identifying mild BMD [18 µmol/L; area under the curve (AUC): 0.947; p  < 0.001] and DMD (17 µmol/L; AUC: 0.837; p  < 0.001) were established. These results suggest that SCRN might be a valuable biomarker for distinguishing DMD from BMD in patients aged ≤3 years and could assist in the selection of appropriate treatment strategies.

Serum Creatinine Distinguishes Duchenne Muscular Dystrophy from Becker Muscular Dystrophy in Patients Aged ≤3 Years: A Retrospective Study

PubMed Central

Wang, Liang; Chen, Menglong; He, Ruojie; Sun, Yiming; Yang, Juan; Xiao, Lulu; Cao, Jiqing; Zhang, Huili; Zhang, Cheng

2017-01-01

Here, we investigated correlations between serum creatinine (SCRN) levels and clinical phenotypes of dystrophinopathy in young patients. Sixty-eight patients with dystrophinopathy at the Neuromuscular Clinic, The First Affiliated Hospital, Sun Yat-sen University, were selected for this study. The diagnosis of dystrophinopathy was based on clinical manifestation, biochemical changes, and molecular analysis. Some patients underwent muscle biopsies; SCRN levels were tested when patients were ≤3 years old, and reading frame changes were analyzed. Each patient was followed up, and motor function and clinical phenotype were assessed when the same patients were ≥4 years old. Our findings indicated that in young patients, lower SCRN levels were associated with increased disease severity (p < 0.01) and that SCRN levels were the highest in patients exhibiting mild Becker muscular dystrophy (BMD) (p < 0.001) and the lowest in patients with Duchenne muscular dystrophy (DMD) (p < 0.01) and were significantly higher in patients carrying in-frame mutations than in patients carrying out-of-frame mutations (p < 0.001). SCRN level cutoff values for identifying mild BMD [18 µmol/L; area under the curve (AUC): 0.947; p < 0.001] and DMD (17 µmol/L; AUC: 0.837; p < 0.001) were established. These results suggest that SCRN might be a valuable biomarker for distinguishing DMD from BMD in patients aged ≤3 years and could assist in the selection of appropriate treatment strategies. PMID:28533764

Pharmacological rescue of the dystrophin-glycoprotein complex in Duchenne and Becker skeletal muscle explants by proteasome inhibitor treatment.

PubMed

Assereto, Stefania; Stringara, Silvia; Sotgia, Federica; Bonuccelli, Gloria; Broccolini, Aldobrando; Pedemonte, Marina; Traverso, Monica; Biancheri, Roberta; Zara, Federico; Bruno, Claudio; Lisanti, Michael P; Minetti, Carlo

2006-02-01

In this report, we have developed a novel method to identify compounds that rescue the dystrophin-glycoprotein complex (DGC) in patients with Duchenne or Becker muscular dystrophy. Briefly, freshly isolated skeletal muscle biopsies (termed skeletal muscle explants) from patients with Duchenne or Becker muscular dystrophy were maintained under defined cell culture conditions for a 24-h period in the absence or presence of a specific candidate compound. Using this approach, we have demonstrated that treatment with a well-characterized proteasome inhibitor, MG-132, is sufficient to rescue the expression of dystrophin, beta-dystroglycan, and alpha-sarcoglycan in skeletal muscle explants from patients with Duchenne or Becker muscular dystrophy. These data are consistent with our previous findings regarding systemic treatment with MG-132 in a dystrophin-deficient mdx mouse model (Bonuccelli G, Sotgia F, Schubert W, Park D, Frank PG, Woodman SE, Insabato L, Cammer M, Minetti C, and Lisanti MP. Am J Pathol 163: 1663-1675, 2003). Our present results may have important new implications for the possible pharmacological treatment of Duchenne or Becker muscular dystrophy in humans.

Multifocal electroretinography in patients with Stargardt's macular dystrophy

PubMed Central

Kretschmann, U; Seeliger, M; Ruether, K; Usui, T; Apfelstedt-Sylla, E; Zrenner, E

1998-01-01

AIMS—To describe the topography of multifocal electroretinograms (ERGs) and to explore its diagnostic value in patients with Stargardt's macular dystrophy (SMD).
METHODS—51 patients with SMD were examined by means of the m-sequence technique to characterise the topography of electroretinographic responses in the central visual field. The results were compared with data from 30 normal volunteers.
RESULTS—In 49 of 51 patients with SMD, macular electroretinographic activity was markedly diminished or non-detectable. Towards more peripheral areas, ERG responses of the SMD patients approached those of normals. Implicit times were not markedly delayed at any eccentricity.
CONCLUSION—In contrast with Ganzfeld electroretinography, multifocal electroretinography is useful to detect foveal dysfunction in SMD. Areas of dysfunction were found to be usually larger than expected from psychophysical measurements and morphological alteration. In early stages of the disease it was possible to detect foveal dysfunction, even in patients lacking morphological fundus changes and with good visual acuity.

 Keywords: Stargardt's macular dystrophy; fundus flavimaculatus; electroretinography PMID:9602623

Cardiac considerations in the operative management of the patient with Duchenne or Becker muscular dystrophy.

PubMed

Cripe, Linda H; Tobias, Joseph D

2013-09-01

Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) is a progressive multisystem neuromuscular disorder. In addition to the skeletal muscle, the myocardium in the DMD/BMD patient is dystrophin deficient which results in a progressive cardiomyopathy. The myopathic myocardium poses significant risk of increased morbidity and mortality at the time of major surgical procedures. Careful attention must be given to the DMD/BMD patient during the intraoperative and postoperative period. Anesthesia selection is critical and anesthetics should be avoided which have been shown to be harmful in this patient population. Preanesthesia assessment should include cardiac consultation and detailed preoperative evaluation. Intraoperative management needs to insure that the weakened myocardium is not compromised by physiologic changes such as hypotension or major fluid shifts. Finally, attention to the cardiac status of the patient must continue into the postoperative period. The surgical care of the DMD/BMD patient requires a multispecialty approach to insure operative success. © 2013 John Wiley & Sons Ltd.

Cystic dystrophy of the duodenal wall is not always associated with chronic pancreatitis

PubMed Central

Pezzilli, Raffaele; Santini, Donatella; Calculli, Lucia; Casadei, Riccardo; Morselli-Labate, Antonio Maria; Imbrogno, Andrea; Fabbri, Dario; Taffurelli, Giovanni; Ricci, Claudio; Corinaldesi, Roberto

2011-01-01

Cystic dystrophy of the duodenal wall is a rare form of the disease which was described in 1970 by French authors who reported the presence of focal pancreatic disease localized in an area comprising the C-loop of the duodenum and the head of the pancreas. German authors have defined this area as a “groove”. We report our recent experience on cystic dystrophy of the paraduodenal space and systematically review the data in the literature regarding the alterations of this space. A MEDLINE search of papers published between 1966 and 2010 was carried out and 59 papers were considered for the present study; there were 19 cohort studies and 40 case reports. The majority of patients having groove pancreatitis were middle aged. Mean age was significantly higher in patients having groove carcinoma. The diagnosis of cystic dystrophy of the duodenal wall can now be assessed by multidetector computer tomography, magnetic resonance imaging and endoscopic ultrasonography. These latter two techniques may also add more information on the involvement of the remaining pancreatic gland not involved by the duodenal malformation and they may help in differentiating “groove pancreatitis” from “groove adenocarcinoma”. In conclusion, chronic pancreatitis involving the entire pancreatic gland was present in half of the patients with cystic dystrophy of the duodenal wall and, in the majority of them, the pancreatitis had calcifications. PMID:22110260

[Myostatin blockade therapy for muscular atrophy].

PubMed

Sunada, Yoshihide

2011-11-01

Myostatin, a member of the muscle-specific transforming growth factor (TGF)-β family, negatively regulates skeletal muscle growth. It inhibits muscle stem cell proliferation and differentiation and attenuates adult muscle fiber protein accretion, resulting in decreased skeletal muscle mass. As such, it has been considered a therapeutic target of muscular dystrophy. Notably, administration of a blocking antibody against myostatin ameliorated the pathophysiology of dystrophin-deficient mdx mice. Although a clinical trial of anti-myostatin antibody MYO-029 failed to achieve a significant outcome in patients with muscular dystrophies, various distinct approaches have been taken to establish anti-myostatin therapy, including myostatin decoy receptor ACE-031, small-molecule inhibitors against the myostatin receptor, and myostatin short intertering RNA with collagen-derived carrier particles. The clinical application of anti-myostatin therapeutics in treatment of patients with muscular dystrophy needs further evaluation for safety and specification of the target disease types among the various muscular dystrophies. In addition, myostatin inhibition could be effective for muscle-wasting conditions other than muscular dystrophy- for instance, steroid-induced myopathy, mitochondrial myopathy, or sarcopenia in elderly patients. Moreover, considerable evidence shows that myostatin regulates energy metabolism and that its inhibition can significantly attenuate the progression of obesity and diabetes. It may also be applicable for the prevention of metabolic syndrome. Thus, safe and potent anti-myostatin therapy will have a wide variety of applications in modern medicine.

The prevalence of Usher syndrome and other retinal dystrophy-hearing impairment associations.

PubMed

Rosenberg, T; Haim, M; Hauch, A M; Parving, A

1997-05-01

The study was undertaken to procure population-based prevalence data on the various types of Usher syndrome and other retinal dystrophy-hearing impairment associations. The medical files on 646 patients with a panretinal pigmentary dystrophy aged 20-49 years derived from the Danish Retinitis Pigmentosa (RP) register were scrutinised. The data were supplemented by a prior investigation on hearing ability in a part of the study population. After exclusion of patients with possibly extrinsic causes of hearing impairments, 118 patients, including 89 cases of Usher syndrome were allocated to one of five clinically defined groups. We calculated the following prevalence rates: Usher syndrome type I: 1.5/100,000, Usher syndrome type II: 2.2/100,000, and Usher syndrome type III: 0.1/100,000 corresponding to a 2:3 ratio between Usher syndrome type I and II. The overall prevalence rate of Usher syndrome was estimated to 5/100,000 in the Danish population, devoid of genetic isolates. The material comprised 11 cases with retinal dystrophy, hearing impairment, and additional syndromic features. Finally, 18 subjects with various retinal dystrophy-hearing impairment associations without syndromic features were identified, corresponding to a prevalence rate of 0.8/100,000. This group had a significant overrepresentation of X-linked RP, including two persons harboring a mutation in the retinitis pigmentosa GTP-ase regulator (RPGR) gene.

Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies.

PubMed

Janghra, Narinder; Morgan, Jennifer E; Sewry, Caroline A; Wilson, Francis X; Davies, Kay E; Muntoni, Francesco; Tinsley, Jonathon

2016-01-01

Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section. Our aim was to develop robust and reproducible staining and imaging protocols to quantify sarcolemmal utrophin levels, sarcolemmal dystrophin complex members and numbers of regenerating fibres within a biopsy section. We quantified sarcolemmal utrophin in mature and regenerating fibres and the percentage of regenerating muscle fibres, in muscle biopsies from Duchenne, the milder Becker muscular dystrophy and controls. Fluorescent immunostaining followed by image analysis was performed to quantify utrophin intensity and β-dystrogylcan and ɣ -sarcoglycan intensity at the sarcolemma. Antibodies to fetal and developmental myosins were used to identify regenerating muscle fibres allowing the accurate calculation of percentage regeneration fibres in the biopsy. Our results indicate that muscle biopsies from Becker muscular dystrophy patients have fewer numbers of regenerating fibres and reduced utrophin intensity compared to muscle biopsies from Duchenne muscular dystrophy patients. Of particular interest, we show for the first time that the percentage of regenerating muscle fibres within the muscle biopsy correlate with the clinical severity of Becker and Duchenne muscular dystrophy patients from whom the biopsy was taken. The ongoing development of these tools to quantify sarcolemmal utrophin and muscle regeneration in muscle biopsies will be invaluable for assessing utrophin modulator activity in future clinical trials.

Muscle MRI findings in facioscapulohumeral muscular dystrophy.

PubMed

Gerevini, Simonetta; Scarlato, Marina; Maggi, Lorenzo; Cava, Mariangela; Caliendo, Giandomenico; Pasanisi, Barbara; Falini, Andrea; Previtali, Stefano Carlo; Morandi, Lucia

2016-03-01

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. Muscle MRI identifies a specific pattern of muscle involvement in FSHD patients. Muscle MRI may predict FSHD in asymptomatic and severely affected patients. Muscle MRI of upper girdle better predicts FSHD. Muscle MRI may differentiate FSHD from other forms of muscular dystrophy. Muscle MRI may show the involvement of non-clinical testable muscles.

Long-term follow-up for efficacy and safety of treatment of retinitis pigmentosa with valproic acid.

PubMed

Bhalla, Sheena; Joshi, Deval; Bhullar, Shaminder; Kasuga, Daniel; Park, Yeonhee; Kay, Christine N

2013-07-01

The purpose of this study was to determine the long-term efficacy and safety of valproic acid (VPA) treatment in patients with pigmentary retinal dystrophies. A retrospective chart review was conducted on 31 patients with a diagnosis of pigmentary retinal dystrophy prescribed VPA at a single centre. Visual field (VF), visual acuity (VA), length of treatment, liver enzymes and side effects were analysed. VF areas were defined using Goldmann VF (GVF) tracings recorded before, during and after VPA treatment using the V4e isopter for each eye. Using custom software, planimetric areas of VF were calculated. Five of the patients (10 eyes) had two Goldmann VF tracings, allowing comparison between baseline and follow-up VF. After 9.8 months of VPA, VF decreased by 0.145 cm(2) (26.478%) (p=0.432). For 22 of the patients (41 eyes), VA data was available, and logarithm of the minimum angle of resolution (logMAR) score changed by 0.056 log units (representing a decline in VA) after 14.9 months on VPA (p=0.002). Twelve patients (38.7%) reported negative side effects related to VPA use. VPA plays a complex role in patients with pigmentary retinal dystrophies and may be associated with VA and field decline as well as adverse side effects. Physicians should use caution with using VPA for pigmentary retinal dystrophies.

Cardiac consequences to skeletal muscle-centric therapeutics for Duchenne muscular dystrophy.

PubMed

Townsend, DeWayne; Yasuda, Soichiro; Chamberlain, Jeffrey; Metzger, Joseph M

2009-02-01

Duchenne muscular dystrophy (DMD) is a fatal disease of muscle deterioration. Duchenne muscular dystrophy affects all striated muscles in the body, including the heart. Recent advances in palliative care, largely directed at improving respiratory function, have extended life but paradoxically further unmasked emergent heart disease in DMD patients. New experimental strategies have shown promise in restoring dystrophin in the skeletal muscles of dystrophin- deficient animals. These strategies often have little or no capacity for restitution of dystrophin in the hearts of these animals. This article draws on both clinical data and recent experimental data to posit that effective skeletal muscle restricted therapies for DMD will paradoxically heighten cardiomyopathy and heart failure in these patients.

The importance of genetic diagnosis for Duchenne muscular dystrophy

PubMed Central

Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

2016-01-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

PubMed

LeBoeuf, Nicole; Garg, Amit; Worobec, Sophie

2007-01-01

The autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is characterized by the presence of chronic mucocutaneous candidiasis, adrenal insufficiency, and hypoparathyroidism. Almost all patients have skin or nail findings early in the course of the disease. Therefore, the dermatologist is in the unique position of being able to identify patients with this syndrome early in its course and to facilitate careful monitoring of potentially lethal complications.

Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing.

PubMed

Xu, Yan; Guan, Liping; Xiao, Xueshan; Zhang, Jianguo; Li, Shiqiang; Jiang, Hui; Jia, Xiaoyun; Yang, Jianhua; Guo, Xiangming; Yin, Ye; Wang, Jun; Zhang, Qingjiong

2015-01-01

Mutations in 60 known genes were previously identified by exome sequencing in 79 of 157 families with retinitis pigmentosa (RP). This study analyzed variants in 129 genes associated with other forms of hereditary retinal dystrophy in the same cohort. Apart from the 73 genes previously analyzed, a further 129 genes responsible for other forms of hereditary retinal dystrophy were selected based on RetNet. Variants in the 129 genes determined by whole exome sequencing were selected and filtered by bioinformatics analysis. Candidate variants were confirmed by Sanger sequencing and validated by analysis of available family members and controls. A total of 90 candidate variants were present in the 129 genes. Sanger sequencing confirmed 83 of the 90 variants. Analysis of family members and controls excluded 76 of these 83 variants. The remaining seven variants were considered to be potential pathogenic mutations; these were c.899A>G, c.1814C>G, and c.2107C>T in BBS2; c.1073C>T and c.1669C>T in INPP5E; and c.3582C>G and c.5704-5C>G in CACNA1F. Six of these seven mutations were novel. The mutations were detected in five unrelated patients without a family history, including three patients with homozygous or compound heterozygous mutations in BBS2 and INPP5E, and two patients with hemizygous mutations in CACNA1F. None of the patients had mutations in the genes associated with autosome dominant retinal dystrophy. Only a small portion of patients with RP, about 3% (5/157), had causative mutations in the 129 genes associated with other forms of hereditary retinal dystrophy.

Genetic diagnosis of Duchenne and Becker muscular dystrophy using next-generation sequencing technology: comprehensive mutational search in a single platform.

PubMed

Lim, Byung Chan; Lee, Seungbok; Shin, Jong-Yeon; Kim, Jong-Il; Hwang, Hee; Kim, Ki Joong; Hwang, Yong Seung; Seo, Jeong-Sun; Chae, Jong Hee

2011-11-01

Duchenne muscular dystrophy or Becker muscular dystrophy might be a suitable candidate disease for application of next-generation sequencing in the genetic diagnosis because the complex mutational spectrum and the large size of the dystrophin gene require two or more analytical methods and have a high cost. The authors tested whether large deletions/duplications or small mutations, such as point mutations or short insertions/deletions of the dystrophin gene, could be predicted accurately in a single platform using next-generation sequencing technology. A custom solution-based target enrichment kit was designed to capture whole genomic regions of the dystrophin gene and other muscular-dystrophy-related genes. A multiplexing strategy, wherein four differently bar-coded samples were captured and sequenced together in a single lane of the Illumina Genome Analyser, was applied. The study subjects were 25 16 with deficient dystrophin expression without a large deletion/duplication and 9 with a known large deletion/duplication. Nearly 100% of the exonic region of the dystrophin gene was covered by at least eight reads with a mean read depth of 107. Pathogenic small mutations were identified in 15 of the 16 patients without a large deletion/duplication. Using these 16 patients as the standard, the authors' method accurately predicted the deleted or duplicated exons in the 9 patients with known mutations. Inclusion of non-coding regions and paired-end sequence analysis enabled accurate identification by increasing the read depth and providing information about the breakpoint junction. The current method has an advantage for the genetic diagnosis of Duchenne muscular dystrophy and Becker muscular dystrophy wherein a comprehensive mutational search may be feasible using a single platform.

Contact lens fitting in a patient with Alport syndrome and posterior polymorphous corneal dystrophy: a case report.

PubMed

Rosa, Juliana Maria da Silva; Andrade Sobrinho, Marcelo Vicente de; Lipener, César

2016-02-01

Alport Syndrome is a hereditary disease that is caused by a gene mutation and affects the production of collagen in basement membranes; this condition causes hemorrhagic nephritis associated with deafness and ocular changes. The X-linked form of this disease is the most common and mainly affects males. Typical ocular findings are dot-and-fleck retinopathy, anterior lenticonus, and posterior polymorphous corneal dystrophy. Some cases involving polymorphous corneal dystrophy and corneal ectasia have been previously described. Here we present a case report of a 33-year-old female with Alport syndrome, posterior polymorphous corneal dystrophy, and irregular astigmatism, whose visual acuity improved with a rigid gas permeable contact lens.

Cardiac function in muscular dystrophy associates with abdominal muscle pathology.

PubMed

Gardner, Brandon B; Swaggart, Kayleigh A; Kim, Gene; Watson, Sydeaka; McNally, Elizabeth M

The muscular dystrophies target muscle groups differentially. In mouse models of muscular dystrophy, notably the mdx model of Duchenne Muscular Dystrophy, the diaphragm muscle shows marked fibrosis and at an earlier age than other muscle groups, more reflective of the histopathology seen in human muscular dystrophy. Using a mouse model of limb girdle muscular dystrophy, the Sgcg mouse, we compared muscle pathology across different muscle groups and heart. A cohort of nearly 200 Sgcg mice were studied using multiple measures of pathology including echocardiography, Evans blue dye uptake and hydroxyproline content in multiple muscle groups. Spearman rank correlations were determined among echocardiographic and pathological parameters. The abdominal muscles were found to have more fibrosis than other muscle groups, including the diaphragm muscle. The abdominal muscles also had more Evans blue dye uptake than other muscle groups. The amount of diaphragm fibrosis was found to correlate positively with fibrosis in the left ventricle, and abdominal muscle fibrosis correlated with impaired left ventricular function. Fibrosis in the abdominal muscles negatively correlated with fibrosis in the diaphragm and right ventricles. Together these data reflect the recruitment of abdominal muscles as respiratory muscles in muscular dystrophy, a finding consistent with data from human patients.

At the Crossroads of Clinical and Preclinical Research for Muscular Dystrophy—Are We Closer to Effective Treatment for Patients?

PubMed Central

Gawlik, Kinga I.

2018-01-01

Among diseases affecting skeletal muscle, muscular dystrophy is one of the most devastating and complex disorders. The term ‘muscular dystrophy’ refers to a heterogeneous group of genetic diseases associated with a primary muscle defect that leads to progressive muscle wasting and consequent loss of muscle function. Muscular dystrophies are accompanied by numerous clinical complications and abnormalities in other tissues that cause extreme discomfort in everyday life. The fact that muscular dystrophy often takes its toll on babies and small children, and that many patients die at a young age, adds to the cruel character of the disease. Clinicians all over the world are facing the same problem: they have no therapy to offer except for symptom-relieving interventions. Patients, their families, but also clinicians, are in urgent need of an effective cure. Despite advances in genetics, increased understanding of molecular mechanisms underlying muscle disease, despite a sweeping range of successful preclinical strategies and relative progress of their implementation in the clinic, therapy for patients is currently out of reach. Only a greater comprehension of disease mechanisms, new preclinical studies, development of novel technologies, and tight collaboration between scientists and physicians can help improve clinical treatment. Fortunately, inventiveness in research is rapidly extending the limits and setting new standards for treatment design. This review provides a synopsis of muscular dystrophy and considers the steps of preclinical and clinical research that are taking the muscular dystrophy community towards the fundamental goal of combating the traumatic disease. PMID:29772730

Electrolysis for corneal opacities in a young patient with superficial variant of granular corneal dystrophy (Reis-Bücklers corneal dystrophy).

PubMed

Kamoi, Mizuka; Mashima, Yukihiko; Kawashima, Motoko; Tsubota, Kazuo

2005-06-01

To report the efficacy of electrolysis as a treatment of corneal opacities in a young patient with the superficial variant of granular corneal dystrophy. Interventional case report. An 11-year-old boy presented with subepithelial opacities in both eyes. His visual acuity was 0.2 in the left eye; he received corneal electrolysis under topical anesthesia. The electrolysis, which required only 5 minutes, resulted in the disappearance of the subepithelial opacities. His visual acuity improved to 0.4 on the next day and was 1.0 eight months later. The corneal curvature and thickness were not altered by the electrolysis. Corneal electrolysis proved to be an effective treatment for subepithelial opacities, and we recommend electrolysis as an effective and simple treatment for young patients with SGCD.

[Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

PubMed

Magot, A; Mercier, S; Péréon, Y

2015-12-01

Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Genetic analysis of CHST6 and TGFBI in Turkish patients with corneal dystrophies: Five novel variations in CHST6

PubMed Central

Yaylacioglu Tuncay, Fulya; Kayman Kurekci, Gülsüm; Guntekin Ergun, Sezen; Pasaoglu, Ozge Tugce; Akata, Rustu Fikret; Dincer, Pervin Rukiye

2016-01-01

Purpose To identify pathogenic variations in carbohydrate sulfotransferase 6 (CHST6) and transforming growth factor, beta-induced (TGFBI) genes in Turkish patients with corneal dystrophy (CD). Methods In this study, patients with macular corneal dystrophy (MCD; n = 18), granular corneal dystrophy type 1 (GCD1; n = 12), and lattice corneal dystrophy type 1 (LCD1; n = 4), as well as 50 healthy controls, were subjected to clinical and genetic examinations. The level of antigenic keratan sulfate (AgKS) in the serum samples of patients with MCD was determined with enzyme-linked immunosorbent assay (ELISA) to immunophenotypically subtype the patients as MCD type I and MCD type II. DNA was isolated from venous blood samples from the patients and controls. Variations were analyzed with DNA sequencing in the coding region of CHST6 in patients with MCD and exons 4 and 12 in TGFBI in patients with LCD1 and GCD1. Clinical characteristics and the detected variations were evaluated to determine any existing genotype–phenotype correlations. Results The previously reported R555W mutation in TGFBI was detected in 12 patients with GCD1, and the R124C mutation in TGFBI was detected in four patients with LCD1. Serum AgKS levels indicated that 12 patients with MCD were in subgroup I, and five patients with MCD were in subgroup II. No genetic variation was detected in the coding region of CHST6 for three patients with MCD type II. In other patients with MCD, three previously reported missense variations (c. 1A>T, c.738C>G, and c.631 C>T), three novel missense variations (c.164 T>C, c.526 G>A, c. 610 C>T), and two novel frameshift variations (c.894_895 insG and c. 462_463 delGC) were detected. These variations did not exist in the control chromosomes, 1000 Genomes, and dbSNP. Conclusions This is the first molecular analysis of TGFBI and CHST6 in Turkish patients with different types of CD. We detected previously reported, well-known hot spot mutations in TGFBI in the patients with GCD1 and LCD1. Eight likely pathogenic variations in CHST6, five of them novel, were reported in patients with MCD, which enlarges the mutational spectrum of MCD. PMID:27829782

Genetic analysis of CHST6 and TGFBI in Turkish patients with corneal dystrophies: Five novel variations in CHST6.

PubMed

Yaylacioglu Tuncay, Fulya; Kayman Kurekci, Gülsüm; Guntekin Ergun, Sezen; Pasaoglu, Ozge Tugce; Akata, Rustu Fikret; Dincer, Pervin Rukiye

2016-01-01

To identify pathogenic variations in carbohydrate sulfotransferase 6 ( CHST6 ) and transforming growth factor, beta-induced ( TGFBI ) genes in Turkish patients with corneal dystrophy (CD). In this study, patients with macular corneal dystrophy (MCD; n = 18), granular corneal dystrophy type 1 (GCD1; n = 12), and lattice corneal dystrophy type 1 (LCD1; n = 4), as well as 50 healthy controls, were subjected to clinical and genetic examinations. The level of antigenic keratan sulfate (AgKS) in the serum samples of patients with MCD was determined with enzyme-linked immunosorbent assay (ELISA) to immunophenotypically subtype the patients as MCD type I and MCD type II. DNA was isolated from venous blood samples from the patients and controls. Variations were analyzed with DNA sequencing in the coding region of CHST6 in patients with MCD and exons 4 and 12 in TGFBI in patients with LCD1 and GCD1. Clinical characteristics and the detected variations were evaluated to determine any existing genotype-phenotype correlations. The previously reported R555W mutation in TGFBI was detected in 12 patients with GCD1, and the R124C mutation in TGFBI was detected in four patients with LCD1. Serum AgKS levels indicated that 12 patients with MCD were in subgroup I, and five patients with MCD were in subgroup II. No genetic variation was detected in the coding region of CHST6 for three patients with MCD type II. In other patients with MCD, three previously reported missense variations (c. 1A>T, c.738C>G, and c.631 C>T), three novel missense variations (c.164 T>C, c.526 G>A, c. 610 C>T), and two novel frameshift variations (c.894_895 insG and c. 462_463 delGC) were detected. These variations did not exist in the control chromosomes, 1000 Genomes, and dbSNP. This is the first molecular analysis of TGFBI and CHST6 in Turkish patients with different types of CD. We detected previously reported, well-known hot spot mutations in TGFBI in the patients with GCD1 and LCD1. Eight likely pathogenic variations in CHST6 , five of them novel, were reported in patients with MCD, which enlarges the mutational spectrum of MCD.

[Evaluation of fundus autofluorescence in hereditary retinal diseases using Heidelberg Retina Angiograph2].

PubMed

Côco, Monique; Baba, Natalia Tamie; Sallum, Juliana Maria Ferraz

2007-01-01

To define characteristics of the fundus autofluorescence examination, verifying usefulness in the diagnosis and care of hereditary retinal diseases. 28 patients, adults, divided equally into four groups with diagnoses of Stargardt macular dystrophy, cone dystrophy, retinitis pigmentosa and healthy volunteers for the establishment of the normality pattern. An average of nine images with the filter for fluorescein angiography was obtained for the formation of the image autofluorescence using Heidelberg Retina Angiograph2. The images of each group of patients were analyzed to verify common characteristics. The fundus autofluorescence of healthy volunteers showed the foveal area darker than the surrounding retina. The images of Stargardt macular dystrophy, in general, presented an oval central lesion, with reduced autofluorescence. The main alterations of the autofluorescence in patients with cone dystrophy were reduced foveal autofluorescence with a parafoveal ring of increased autofluorescence. In general, the images of retinitis pigmentosa showed outlying pigments with reduced autofluorescence, and of the foveal area, in some cases disorganization or reduced autofluorescence. The study showed the existence of patterns of fundus autofluorescence in the hereditary retinal diseases that allow the diagnosis and better interpretation of the pathogenesis of these diseases.

Dystrophin Immunity in Duchenne’s Muscular Dystrophy

PubMed Central

Mendell, Jerry R.; Campbell, Katherine; Rodino-Klapac, Louise; Sahenk, Zarife; Shilling, Chris; Lewis, Sarah; Bowles, Dawn; Gray, Steven; Li, Chengwen; Galloway, Gloria; Malik, Vinod; Coley, Brian; Clark, K. Reed; Li, Juan; Xiao, Xiao; Samulski, Jade; McPhee, Scott W.; Samulski, R. Jude; Walker, Christopher M.

2010-01-01

SUMMARY We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne’s muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence of transgene expression even when the functional protein was not visualized in skeletal muscle. Circulating dystrophin-specific T cells were unexpectedly detected in two patients before vector treatment. Revertant dystrophin fibers, which expressed functional, truncated dystrophin from the deleted endogenous gene after spontaneous in-frame splicing, contained epitopes targeted by the autoreactive T cells. The potential for T-cell immunity to self and nonself dystrophin epitopes should be considered in designing and monitoring experimental therapies for this disease. (Funded by the Muscular Dystrophy Association and others; ClinicalTrials.gov number, NCT00428935.) PMID:20925545

[Two cases of Duchenne muscular dystrophy over 40 years after onset].

PubMed

Ishizaki, Masatoshi; Ueyama, Hidetsugu; Masuda, Teruaki; Nishida, Yasuto; Imamura, Shigehiro; Ando, Yukio

2013-01-01

We report two 45 year old men with Duchenne muscular dystrophy. Case 1 showed a deleted exon 50 of the dystrophin gene by MLPA analysis, and Case 2 showed deleted exons 46-52. Both patients presented with severe weakness of the skeletal muscles and respiratory dysfunction, while cardiac involvement was mild and cognitive function was almost normal. The patients are able to shop at a mall, participate in activities, and attend hobbies, although they are bedridden with artificial respiration through tracheotomy. With the progress of the respiratory care and cardiac protective therapy, the prognosis of Duchenne muscular dystrophy has improved remarkably. At present, it is possible to survive over 40 years with maintenance of quality of life, if cardiac damage is not severe.

Rhabdomyolysis associated with human parvovirus B19 infection in a patient with Fukuyama-type congenital muscular dystrophy.

PubMed

Ishikawa, Aki; Yoto, Yuko; Ohya, Kazuhiro; Tsugawa, Takeshi; Tsutsumi, Hiroyuki

2014-07-01

Patients with Fukuyama-type congenital muscular dystrophy sometimes experience transient exacerbations of muscle weakness. We took care of a 9-year-old boy with Fukuyama-type congenital muscular dystrophy who presented with acute respiratory failure and decreased exercise ability with marked elevation of serum creatine kinase indicating rhabdomyolysis. At that time, his younger sister suffered from erythema infectiosum. Although he had no particular symptoms, he was tested and proven to have acute human parvovirus B19 infection based on detection of anti-B19 IgM and parvovirus B19 DNA in his serum. His acute rhabdomyolysis was possibly triggered by human parvovirus B19 infection. © The Author(s) 2013.

[Current status and future prospects of research on Fukuyama muscular dystrophy].

PubMed

Toda, Tatsushi

2015-08-01

Fukuyama congenital muscular dystrophy(FCMD) is a second common childhood muscular dystrophy in Japan. All FCMD patients have ancestral insertion of the SVA retrotransposal element into fukutin. We show that aberrant mRNA splicing induced by SVA exon-trapping caused FCMD. Introduction of 3 cocktailed antisense oligonucleotides(AONs) targeting around these splice sites prevented pathogenic splicing in FCMD patient cells and model mice, and normalized protein production and functions of Fukutin as well as O-glycosylation of α-dystroglycan. We show the promise of splicing modulation therapy as the first radical clinical treatment for FCMD in the near future. We also show that fukutin is prerequisite to ameliorate muscular dystrophic phenotype by myofiber-selective LARGE expression. Recent advances in FCMD are discussed.

Decreased cerebral perfusion in Duchenne muscular dystrophy patients.

PubMed

Doorenweerd, Nathalie; Dumas, Eve M; Ghariq, Eidrees; Schmid, Sophie; Straathof, Chiara S M; Roest, Arno A W; Wokke, Beatrijs H; van Zwet, Erik W; Webb, Andrew G; Hendriksen, Jos G M; van Buchem, Mark A; Verschuuren, Jan J G M; Asllani, Iris; Niks, Erik H; van Osch, Matthias J P; Kan, Hermien E

2017-01-01

Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 ± 6.4 and 47.8 ± 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume. Copyright © 2016 Elsevier B.V. All rights reserved.

Reliability, validity and description of timed performance of the Jebsen-Taylor Test in patients with muscular dystrophies.

PubMed

Artilheiro, Mariana Cunha; Fávero, Francis Meire; Caromano, Fátima Aparecida; Oliveira, Acary de Souza Bulle; Carvas, Nelson; Voos, Mariana Callil; Sá, Cristina Dos Santos Cardoso de

2017-12-08

The Jebsen-Taylor Test evaluates upper limb function by measuring timed performance on everyday activities. The test is used to assess and monitor the progression of patients with Parkinson disease, cerebral palsy, stroke and brain injury. To analyze the reliability, internal consistency and validity of the Jebsen-Taylor Test in people with Muscular Dystrophy and to describe and classify upper limb timed performance of people with Muscular Dystrophy. Fifty patients with Muscular Dystrophy were assessed. Non-dominant and dominant upper limb performances on the Jebsen-Taylor Test were filmed. Two raters evaluated timed performance for inter-rater reliability analysis. Test-retest reliability was investigated by using intraclass correlation coefficients. Internal consistency was assessed using the Cronbach alpha. Construct validity was conducted by comparing the Jebsen-Taylor Test with the Performance of Upper Limb. The internal consistency of Jebsen-Taylor Test was good (Cronbach's α=0.98). A very high inter-rater reliability (0.903-0.999), except for writing with an Intraclass correlation coefficient of 0.772-1.000. Strong correlations between the Jebsen-Taylor Test and the Performance of Upper Limb Module were found (rho=-0.712). The Jebsen-Taylor Test is a reliable and valid measure of timed performance for people with Muscular Dystrophy. Copyright © 2017 Associação Brasileira de Pesquisa e Pós-Graduação em Fisioterapia. Publicado por Elsevier Editora Ltda. All rights reserved.

Bilateral nanophthalmos and pigmentary retinal dystrophy--an unusual syndrome.

PubMed

Proença, Helena; Castanheira-Dinis, A; Monteiro-Grillo, M

2006-09-01

To report the clinical picture of the rare association of nanophthalmos and pigmentary retinal dystrophy and its cataract surgery outcome. We report a case of a 60-year-old female who presented with bilateral slowly progressive visual loss. The patient presented with bilateral light perception visual acuity, exotropia, brunescent cataract hindering fundus examination and hypodontia. Ultrasonography revealed bilateral nanophthalmos. A visual-evoked potential was also performed preoperatively. Cataract surgery with +40D IOL implantation was uneventful. Postoperative fundus examination revealed pigmentary retinal dystrophy, confirmed by electrophysiologic tests. Glycosaminoglycan urinary excretion was normal. Congenital bilateral nanophthalmos may rarely be associated with pigmentary retinal dystrophy. We suggest thorough preoperative evaluation in nanophthalmic eyes for the exclusion of significant features concerning visual prognosis.

Bilateral nanophthalmos, pigmentary retinal dystrophy, and angle closure glaucoma--a new syndrome?

PubMed Central

Ghose, S; Sachdev, M S; Kumar, H

1985-01-01

An unusual case of bilateral nanophthalmos with pigmentary retinal dystrophy and angle closure glaucoma is presented. This is probably the first published report of the established association of all these three entities in the same patient. The aetiological possibilities and clinical significance are discussed. Images PMID:4016062

Axillary Brachial Plexus Blockade for the Reflex Sympathetic Dystrophy Syndrome.

ERIC Educational Resources Information Center

Ribbers, G. M.; Geurts, A. C. H.; Rijken, R. A. J.; Kerkkamp, H. E. M.

1997-01-01

Reflex sympathetic dystrophy syndrome (RSD) is a neurogenic pain syndrome characterized by pain, vasomotor and dystrophic changes, and often motor impairments. This study evaluated the effectiveness of brachial plexus blockade with local anaesthetic drugs as a treatment for this condition. Three patients responded well; three did not. (DB)

Pupillometer-based objective chromatic perimetry in normal eyes and patients with retinal photoreceptor dystrophies.

PubMed

Skaat, Alon; Sher, Ifat; Kolker, Andrew; Elyasiv, Sivan; Rosenfeld, Elkana; Mhajna, Mohamad; Melamed, Shlomo; Belkin, Michael; Rotenstreich, Ygal

2013-04-17

To evaluate a novel objective perimetry using multifocal chromatic pupil light reflex in normal participants and patients with photoreceptor dysfunction, and to relate this new technique with subjective dark-adapted chromatic Goldmann perimetry. Thirty-two eyes of 17 retinitis pigmentosa (RP) or cone-rod dystrophy patients and 20 eyes of 12 healthy individuals were tested. A computerized infrared video pupillometer was used to record changes in pupil diameter in response to short- and long-wavelength stimuli (peak 485 and 640 nm, respectively; light intensity 40 cd/m(2)) at 13 different points of the 30° visual field (VF), under background illumination of 2.7 cd/m(2). The pupillary response (PR) of patients was compared with PR obtained from normal control participants. In 11 patients, the pupillary responses were also compared with their findings on dark-adapted chromatic Goldmann perimetry. Significantly reduced pupillary responses were obtained in RP patients in response to the short-wavelength stimulus in nearly all perimetric locations (P < 0.03). By contrast, in response to the long-wavelength stimulus, RP patients demonstrated significantly reduced PR mostly in peripheral locations (P ≤ 0.02). In a cone-rod dystrophy patient, the PR to both long- and short-wavelength stimuli was significantly lower in the scotoma area identified by the dark-adapted chromatic Goldmann perimetry. In all patients that were tested by the chromatic Goldmann, minimal PR was recorded in areas that were nondetected in the chromatic Goldmann perimetry. This study demonstrates the potential feasibility of using pupillometer-based chromatic perimetry for objectively assessing VF defects and retinal function in patients with retinal dystrophies. (ClinicalTrials.gov number, NCT01021982.).

Creatine kinase response to high-intensity aerobic exercise in adult-onset muscular dystrophy.

PubMed

Andersen, Søren P; Sveen, Marie-Louise; Hansen, Regitze S; Madsen, Karen L; Hansen, Jonas B; Madsen, Mads; Vissing, John

2013-12-01

We investigated the effect of high-intensity exercise on plasma creatine kinase (CK) in patients with muscular dystrophies. Fourteen patients with Becker (BMD), facioscapulohumeral (FSHD), or limb-girdle type 2 (LGMD2) muscular dystrophy, and 8 healthy subjects performed 5 cycling tests: an incremental max test, and tests at 65%, 75%, 85%, and 95% of maximal oxygen uptake (VO2max ). Heart rate and oxygen consumption were measured during the tests, and plasma CK was measured before, immediately after, and 24 hours after exercise. All subjects were able to perform high-intensity exercise at the different levels. In patients with LGMD2 and FSHD, CK normalized 24 hours after exercise compared with the pre-exercise value, whereas those with BMD and healthy controls had elevated CK values 24 hours after exercise. The findings suggest that high-intensity exercise is generally well tolerated in patients with LGMD2 and FSHD, whereas those with BMD may be more prone to exercise-induced damage. Copyright © 2013 Wiley Periodicals, Inc.

Focal Choroidal Excavation in Best Vitelliform Macular Dystrophy: Case Report

PubMed Central

Esfahani, Mohammad Riazi; Esfahani, Hamid Riazi; Mahmoudi, Alireza; Johari, Mohammad Karim

2015-01-01

Focal choroidal excavation (FCE) was first reported as a choroidal posteriorly excavated zone without any scleral change. Choroidal excavation also divided into conforming and nonconforming type. Numerous reports demonstrated association between FCE and other disease such as choroidal neovascularization and central serous choroidoretinopathy. Here, we report a rare case of FCE in a patient with Best disease. The patient was diagnosed by spectoral domain optical coherence tomography (SD-OCT). To the best of our knowledge, our patient is the second report of choroidal excavation in Best vitelliform macular dystrophy. PMID:26155505

Tissue engineering the mechanosensory circuit of the stretch reflex arc: sensory neuron innervation of intrafusal muscle fibers.

PubMed

Rumsey, John W; Das, Mainak; Bhalkikar, Abhijeet; Stancescu, Maria; Hickman, James J

2010-11-01

The sensory circuit of the stretch reflex arc, composed of specialized intrafusal muscle fibers and type Ia proprioceptive sensory neurons, converts mechanical information regarding muscle length and stretch to electrical action potentials and relays them to the central nervous system. Utilizing a non-biological substrate, surface patterning photolithography and a serum-free medium formulation a co-culture system was developed that facilitated functional interactions between intrafusal muscle fibers and sensory neurons. The presence of annulospiral wrappings (ASWs) and flower-spray endings (FSEs), both physiologically relevant morphologies in sensory neuron-intrafusal fiber interactions, were demonstrated and quantified using immunocytochemistry. Furthermore, two proposed components of the mammalian mechanosensory transduction system, BNaC1 and PICK1, were both identified at the ASWs and FSEs. To verify functionality of the mechanoreceptor elements the system was integrated with a MEMS cantilever device, and Ca(2+) currents were imaged along the length of an axon innervating an intrafusal fiber when stretched by cantilever deflection. This system provides a platform for examining the role of this mechanosensory complex in the pathology of myotonic and muscular dystrophies, peripheral neuropathy, and spasticity inducing diseases like Parkinson's. These studies will also assist in engineering fine motor control for prosthetic devices by improving our understanding of mechanosensitive feedback. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Myotonin protein-kinase [AGC]n trinucleotide repeat in seven nonhuman primates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Novelli, G.; Sineo, L.; Pontieri, E.

Myotonic dystrophy (DM) is due to a genomic instability of a trinucleotide [AGC]n motif, located at the 3{prime} UTR region of a protein-kinase gene (myotonin protein kinase, MT-PK). The [AGC] repeat is meiotically and mitotically unstable, and it is directly related to the manifestations of the disorder. Although a gene dosage effect of the MT-PK has been demonstrated n DM muscle, the mechanism(s) by which the intragenic repeat expansion leads to disease is largely unknown. This non-standard mutational event could reflect an evolutionary mechanism widespread among animal genomes. We have isolated and sequenced the complete 3{prime}UTR region of the MT-PKmore » gene in seven primates (macaque, orangutan, gorilla, chimpanzee, gibbon, owl monkey, saimiri), and examined by comparative sequence nucleotide analysis the [AGC]n intragenic repeat and the surrounding nucleotides. The genomic organization, including the [AGC]n repeat structure, was conserved in all examined species, excluding the gibbon (Hylobates agilis), in which the [AGC]n upstream sequence (GGAA) is replaced by a GA dinucleotide. The number of [AGC]n in the examined species ranged between 7 (gorilla) and 13 repeats (owl monkeys), with a polymorphism informative content (PIC) similar to that observed in humans. These results indicate that the 3{prime}UTR [AGC] repeat within the MT-PK gene is evolutionarily conserved, supporting that this region has important regulatory functions.« less

[Understanding people with Steinert’s disease to better care for them.

PubMed

Lecordier, Didier; Cartron, Emmanuelle; Jovic, Ljiljana

2017-12-01

the lifestyles of people with myotonic dystrophy type 1 (DM1) are poorly understood and yet their consideration is essential for effective long-term care. The nursing care provided in the reference centers integrates the diversity clinic of this disease in interdisciplinary care, but it is more complicated from a relational point of view. The objective of this qualitative study was to understand the ways of living for a person with DM1, his body and the coping strategies developed. this research in social sciences and nursing is based on a problem of care and is based on an ethnosociological problematization. the aim is to make visible the evolution of the body affected by Steinert’s disease, participating in the construction of the body pattern and the social identity of the person, which allows him to maintain himself in a “normal” daily life as long as possible but can reach limits imposing him radical reorientations in his life. These results are discussed in the light of a framework of analysis based on the four levels of reading of the body proposed by Nicolas Vonarx: the “material body” ; the “capable body”, the “body feeling” and the “knowing/judging body” ; “socializing body” will be proposed to discuss the place the body takes for people living with a DM1 when it comes to living within a normative society.

R-loops: targets for nuclease cleavage and repeat instability.

PubMed

Freudenreich, Catherine H

2018-01-11

R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias. Recently, it was found that R-loops at an expanded CAG/CTG repeat tract cause DNA breaks as well as repeat instability (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Two factors were identified as causing R-loop-dependent breaks at CAG/CTG tracts: deamination of cytosines and the MutLγ (Mlh1-Mlh3) endonuclease, defining two new mechanisms for how R-loops can generate DNA breaks (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Following R-loop-dependent nicking, base excision repair resulted in repeat instability. These results have implications for human repeat expansion diseases and provide a paradigm for how RNA:DNA hybrids can cause genome instability at structure-forming DNA sequences. This perspective summarizes mechanisms of R-loop-induced fragility at G-rich repeats and new links between DNA breaks and repeat instability.

[Anaesthetic management of patients with Steinert myotonia: two case reports].

PubMed

Mahr, A; Attof, Y; Flamens, C; Bastien, O; Lehot, J-J

2009-02-01

Steinert disease, the most common myopathy in adults, is a challenge for anaesthesiologists and critical care physicians during the perioperative time. The risk of myotonic crisis, malign hyperthermia and the increased sensitivity to anaesthetic drugs shouldn't be forgotten. On contrary, Steinert disease is rarely revealed in the postoperative period. It should be evoked in case of postoperative pulmonary complications such as difficult weaning with neurological symptoms like hypotonia or muscular weakness.

Clinical characteristics and current therapies for inherited retinal degenerations.

PubMed

Sahel, José-Alain; Marazova, Katia; Audo, Isabelle

2014-10-16

Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

PubMed Central

Sahel, José-Alain; Marazova, Katia; Audo, Isabelle

2015-01-01

Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307–316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod–cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone–rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances. PMID:25324231

COUP-TFII regulates satellite cell function and muscular dystrophy.

PubMed

Xie, Xin; Tsai, Sophia Y; Tsai, Ming-Jer

2016-10-03

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle-wasting disease caused by mutations in the dystrophin gene. Although dystrophin deficiency in myofiber triggers the disease's pathological changes, the degree of satellite cell (SC) dysfunction defines disease progression. Here, we have identified chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) hyperactivity as a contributing factor underlying muscular dystrophy in a dystrophin-deficient murine model of DMD. Ectopic expression of COUP-TFII in murine SCs led to Duchenne-like dystrophy in the muscles of control animals and exacerbated degenerative myopathies in dystrophin-deficient mice. COUP-TFII-overexpressing mice exhibited regenerative failure that was attributed to deficient SC proliferation and myoblast fusion. Mechanistically, we determined that COUP-TFII coordinated a regenerative program through combined regulation of multiple promyogenic factors. Furthermore, inhibition of COUP-TFII preserved SC function and counteracted the muscle weakness associated with Duchenne-like dystrophy in the murine model, suggesting that targeting COUP-TFII is a potential treatment for DMD. Together, our findings reveal a regulatory role of COUP-TFII in the development of muscular dystrophy and open up a potential therapeutic opportunity for managing disease progression in patients with DMD.

[Central Nervous Involvement in Patients with Fukuyama Congenital Muscular Dystrophy].

PubMed

Ishigaki, Keiko

2016-02-01

Fukuyama congenital muscular dystrophy (FCMD), the second most common muscular dystrophy in the Japanese population, is an autosomal recessive disorder caused by mutations in the fukutin (FKTN) gene. The main features of FCMD are a combination of infantile-onset hypotonia, generalized muscle weakness, eye abnormalities and central nervous system involvement with mental retardation and seizures associated with cortical migration defects. The FKTN gene product is thought to be necessary for maintaining migrating neurons in an immature state during migration, and for supporting migration via α-dystroglycan in the central nervous system. Typical magnetic resonance imaging findings in FCMD patients are cobblestone lissencephaly and cerebellar cystic lesions. White matter abnormalities with hyperintensity on T(2)-weighted images are seen especially in younger patients and those with severe phenotypes. Most FCMD patients are mentally retarded and the level is moderate to severe, with IQs ranging from 30 to 50. In our recent study, 62% of patients developed seizures. Among them, 71% had only febrile seizures, 6% had afebrile seizures from the onset, and 22% developed afebrile seizures following febrile seizures. Most patients had seizures that were controllable with just 1 type of antiepileptic drug, but 18% had intractable seizures that must be treated with 3 medications.

Drusen in patient-derived hiPSC-RPE models of macular dystrophies

PubMed Central

Galloway, Chad A.; Dalvi, Sonal; Hung, Sandy S. C.; MacDonald, Leslie A.; Latchney, Lisa R.; Wong, Raymond C. B.; Guymer, Robyn H.; Williams, David S.; Chung, Mina M.; Gamm, David M.; Pébay, Alice; Hewitt, Alex W.; Singh, Ruchira

2017-01-01

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby’s fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich “drusen-like” composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE–ECM interface. PMID:28878022

Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

PubMed Central

Raman, Subha V; Hor, Kan N; Mazur, Wojciech; Halnon, Nancy J; Kissel, John T; He, Xin; Tran, Tam; Smart, Suzanne; McCarthy, Beth; Taylor, Michael D; Jefferies, John L; Rafael-Fortney, Jill A; Lowe, Jeovanna; Roble, Sharon L; Cripe, Linda H

2015-01-01

Summary Background Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. Methods In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Findings Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ΔEcc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. Interpretation In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. Funding BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health. PMID:25554404

Contractile properties are disrupted in Becker muscular dystrophy, but not in limb girdle type 2I.

PubMed

Løkken, Nicoline; Hedermann, Gitte; Thomsen, Carsten; Vissing, John

2016-09-01

We investigated whether a linear relationship between muscle strength and cross-sectional area (CSA) is preserved in calf muscles of patients with Becker muscular dystrophy (BMD, n = 14) and limb-girdle type 2I muscular dystrophy (LGMD2I, n = 11), before and after correcting for muscle fat infiltration. The Dixon magnetic resonance imaging technique was used to quantify fat and calculate a fat-free contractile CSA. Strength was assessed by dynamometry. Muscle strength/CSA relationships were significantly lower in patients versus controls. The strength/contractile-CSA relationship was still severely lowered in BMD, but was almost normalized in LGMD2I. Our findings suggest close to intact contractile properties in LGMD2I, which are severely disrupted in BMD. Ann Neurol 2016;80:466-471. © 2016 American Neurological Association.

Macular hole-associated retinal detachment in Best vitelliform dystrophy: Series of two cases and literature review

PubMed Central

Tewari, Ruchir; Kumar, Vinod; Ravani, Raghav; Dubey, Devashish; Chandra, Parijat; Kumar, Atul

2018-01-01

Two eyes of 2 patients with macular hole-associated retinal detachment in clinically diagnosed vitelliruptive stage of Best vitelliform dystrophy were surgically managed by 25-gauge sutureless pars plana vitrectomy, internal limiting membrane (ILM) peeling with inverted ILM flap, and short-acting (SF6) gas tamponade. The patients were assessed with respect to best-corrected visual acuity, color fundus photographs, shortwave fundus autofluorescence, and swept source optical coherence tomography. Surgical intervention led to Type 1 closure of macular hole, resolution of retinal detachment, and improvement in vision in both patients. PMID:29676326

[Kurschmann-Steinert myotonic dystrophia and Adams-Stoke attacks. Successful treatment of arrhythmia by means of pacemaker implantation].

PubMed

Bieler, M; Sefidpar, M; Engel, U R; Reutter, F W

1976-11-20

The case is reported of a 39-year-old male with Steinert's dystrophia myotonica complicated by cardiac arrhythmias manifested by high-degree a-v block with Stokes-Adams attacks. Implantation of a demand-type cardiac pacemaker brought prompt relief from cardiac symptoms and the patient was able to resume work. The pathologico-anatomical findings in dystrophia myotonica are discussed, together with their possible connection with the type of arrhythmias described.

Novel mutations of the carbohydrate sulfotransferase-6 (CHST6) gene causing macular corneal dystrophy in India.

PubMed

Sultana, Afia; Sridhar, Mittanamalli S; Jagannathan, Aparna; Balasubramanian, Dorairajan; Kannabiran, Chitra; Klintworth, Gordon K

2003-12-22

Macular corneal dystrophy (MCD) is an autosomal recessive disorder characterized by progressive central haze, confluent punctate opacities and abnormal deposits in the cornea. It is caused by mutations in the carbohydrate sulfotransferase-6 (CHST6) gene, encoding corneal N-acetyl glucosamine-6-O-sulfotransferase (C-GlcNAc-6-ST). We screened the CHST6 gene for mutations in Indian families with MCD, in order to determine the range of pathogenic mutations. Genomic DNA was isolated from peripheral blood leukocytes of patients with MCD and normal controls. The coding regions of the CHST6 gene were amplified using three pairs of primers and amplified products were directly sequenced. We identified 22 (5 nonsense, 5 frameshift, 2 insertion, and 10 missense) mutations in 36 patients from 31 families with MCD, supporting the conclusion that loss of function of this gene is responsible for this corneal disease. Seventeen of these mutations are novel. These data highlight the allelic heterogeneity of macular corneal dystrophy in Indian patients.

Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study.

PubMed

McDonald, Craig M; Henricson, Erik K; Abresch, Richard T; Duong, Tina; Joyce, Nanette C; Hu, Fengming; Clemens, Paula R; Hoffman, Eric P; Cnaan, Avital; Gordish-Dressman, Heather

2018-02-03

Glucocorticoid treatment is recommended as a standard of care in Duchenne muscular dystrophy; however, few studies have assessed the long-term benefits of this treatment. We examined the long-term effects of glucocorticoids on milestone-related disease progression across the lifespan and survival in patients with Duchenne muscular dystrophy. For this prospective cohort study, we enrolled male patients aged 2-28 years with Duchenne muscular dystrophy at 20 centres in nine countries. Patients were followed up for 10 years. We compared no glucocorticoid treatment or cumulative treatment duration of less than 1 month versus treatment of 1 year or longer with regard to progression of nine disease-related and clinically meaningful mobility and upper limb milestones. We used Kaplan-Meier analyses to compare glucocorticoid treatment groups for time to stand from supine of 5 s or longer and 10 s or longer, and loss of stand from supine, four-stair climb, ambulation, full overhead reach, hand-to-mouth function, and hand function. Risk of death was also assessed. This study is registered with ClinicalTrials.gov, number NCT00468832. 440 patients were enrolled during two recruitment periods (2006-09 and 2012-16). Time to all disease progression milestone events was significantly longer in patients treated with glucocorticoids for 1 year or longer than in patients treated for less than 1 month or never treated (log-rank p<0·0001). Glucocorticoid treatment for 1 year or longer was associated with increased median age at loss of mobility milestones by 2·1-4·4 years and upper limb milestones by 2·8-8·0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones by 2·1-2·7 years in comparison with prednisone or prednisolone (log-rank p<0·012). 45 patients died during the 10-year follow-up. 39 (87%) of these deaths were attributable to Duchenne-related causes in patients with known duration of glucocorticoids usage. 28 (9%) deaths occurred in 311 patients treated with glucocorticoids for 1 year or longer compared with 11 (19%) deaths in 58 patients with no history of glucocorticoid use (odds ratio 0·47, 95% CI 0·22-1·00; p=0·0501). In patients with Duchenne muscular dystrophy, glucocorticoid treatment is associated with reduced risk of losing clinically meaningful mobility and upper limb disease progression milestones across the lifespan as well as reduced risk of death. US Department of Education/National Institute on Disability and Rehabilitation Research; US Department of Defense; National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases; and Parent Project Muscular Dystrophy. Copyright © 2018 Elsevier Ltd. All rights reserved.

[Diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy: experience and recommendations for Mexico. Administración del Patrimonio de la Beneficencia Pública. Asociación de Distrofia Muscular de Occidente].

PubMed

Vázquez-Cárdenas, Norma A; Ibarra-Hernández, Francisco; López-Hernández, Luz B; Escobar-Cedillo, Rosa E; Ruano-Calderón, Luis A; Gómez-Díaz, Benjamín; García-Calderón, Noemí; Carriedo-Dávila, M Fernanda; Rojas-Hurtado, Liliana G; Luna-Padrón, Emilia; Coral-Vázquez, Ramón M

2013-11-16

Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The long-term steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy.

A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss.

PubMed

Servián-Morilla, Emilia; Takeuchi, Hideyuki; Lee, Tom V; Clarimon, Jordi; Mavillard, Fabiola; Area-Gómez, Estela; Rivas, Eloy; Nieto-González, Jose L; Rivero, Maria C; Cabrera-Serrano, Macarena; Gómez-Sánchez, Leonardo; Martínez-López, Jose A; Estrada, Beatriz; Márquez, Celedonio; Morgado, Yolanda; Suárez-Calvet, Xavier; Pita, Guillermo; Bigot, Anne; Gallardo, Eduard; Fernández-Chacón, Rafael; Hirano, Michio; Haltiwanger, Robert S; Jafar-Nejad, Hamed; Paradas, Carmen

2016-11-01

Skeletal muscle regeneration by muscle satellite cells is a physiological mechanism activated upon muscle damage and regulated by Notch signaling. In a family with autosomal recessive limb-girdle muscular dystrophy, we identified a missense mutation in POGLUT1 (protein O-glucosyltransferase 1), an enzyme involved in Notch posttranslational modification and function. In vitro and in vivo experiments demonstrated that the mutation reduces O-glucosyltransferase activity on Notch and impairs muscle development. Muscles from patients revealed decreased Notch signaling, dramatic reduction in satellite cell pool and a muscle-specific α-dystroglycan hypoglycosylation not present in patients' fibroblasts. Primary myoblasts from patients showed slow proliferation, facilitated differentiation, and a decreased pool of quiescent PAX7 + cells. A robust rescue of the myogenesis was demonstrated by increasing Notch signaling. None of these alterations were found in muscles from secondary dystroglycanopathy patients. These data suggest that a key pathomechanism for this novel form of muscular dystrophy is Notch-dependent loss of satellite cells. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Comparison of Serum rAAV Serotype-Specific Antibodies in Patients with Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Inclusion Body Myositis, or GNE Myopathy.

PubMed

Zygmunt, Deborah A; Crowe, Kelly E; Flanigan, Kevin M; Martin, Paul T

2017-09-01

Recombinant adeno-associated virus (rAAV) is a commonly used gene therapy vector for the delivery of therapeutic transgenes in a variety of human diseases, but pre-existing serum antibodies to viral capsid proteins can greatly inhibit rAAV transduction of tissues. Serum was assayed from patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), inclusion body myositis (IBM), and GNE myopathy (GNE). These were compared to serum from otherwise normal human subjects to determine the extent of pre-existing serum antibodies to rAAVrh74, rAAV1, rAAV2, rAAV6, rAAV8, and rAAV9. In almost all cases, patients with measurable titers to one rAAV serotype showed titers to all other serotypes tested, with average titers to rAAV2 being highest in all instances. Twenty-six percent of all young normal subjects (<18 years old) had measurable rAAV titers to all serotypes tested, and this percentage increased to almost 50% in adult normal subjects (>18 years old). Fifty percent of all IBM and GNE patients also had antibody titers to all rAAV serotypes, while only 18% of DMD and 0% of BMD patients did. In addition, serum-naïve macaques treated systemically with rAAVrh74 could develop cross-reactive antibodies to all other serotypes tested at 24 weeks post treatment. These data demonstrate that most DMD and BMD patients should be amenable to vascular rAAV-mediated treatment without the concern of treatment blockage by pre-existing serum rAAV antibodies, and that serum antibodies to rAAVrh74 are no more common than those for rAAV6, rAAV8, or rAAV9.

Osteopontin--a fibrosis-related marker--in dilated cardiomyopathy in patients with Emery-Dreifuss muscular dystrophy.

PubMed

Niebroj-Dobosz, Irena; Madej-Pilarczyk, Agnieszka; Marchel, Michał; Sokołowska, Beata; Hausmanowa-Petrusewicz, Irena

2011-12-01

As osteopontin (OPN) may be assumed to have diagnostic/prognostic value in heart diseases, it is worth assessing whether it is also involved in the pathogenesis and can be applied in the diagnosis of the dilated cardiomyopathy (DCM) in Emery-Dreifuss muscular dystrophy (EDMD). Serum levels of osteopontin were quantified by means of sandwich immunoassay in 25 EDMD patients (10 laminopathies AD-EDMD and 15 emerinopathies--X-EDMD), eight carriers of X-EDMD, nine disease controls (patients with dystrophinopathy) and 20 age-matched healthy controls. The levels of circulating OPN were elevated in all AD-EDMD and X-linked EDMD patients, as well as in X-EDMD carriers and patients suffering progressive muscular dystrophy. There was no correlation between the osteopontin level and different cardiac parameters, including left-ventricular end-diastolic diameter, left atrial diameter, the left ventricular ejection fraction and the CK-MB level. There was a slight negative correlation with the ages of the patients. The presented results indicate that assessments of circulating OPN levels may help to identify EDMD patients at risk of dilated cardiomyopathy and might be therefore included among the set of biomarkers referred to with a view to appropriate early cardiologic diagnosis and therapy being commenced with in time.

Allelic heterogeneity of the carbohydrate sulfotransferase-6 gene in patients with macular corneal dystrophy.

PubMed

Sultana, A; Sridhar, M S; Klintworth, G K; Balasubramanian, D; Kannabiran, C

2005-11-01

Allelic heterogeneity of the carbohydrate sulfotransferase-6 gene in patients with macular corneal dystrophy. Macular corneal dystrophy (MCD) is an autosomal recessive disorder characterized by grayish white opacities in the cornea. It is caused by mutations in the carbohydrate sulfotransferase-6 (CHST6) gene, which codes for the enzyme corneal N-acetylglucosamine-6-sulfotransferase. This enzyme catalyzes the sulfation of keratan sulfate, an important component of corneal proteoglycans. We screened 31 patients from 26 families with MCD for mutations in the coding region of the CHST6 gene. Twenty-six different mutations were identified, of which 14 mutations are novel. The novel mutations are one nonsense mutation found in one patient (Trp2Ter), one frameshift (insertion plus deletion) mutation in two patients (His335fs), and 12 missense mutations (Leu3Met, Ser54Phe, Val56Arg, Ala73Thr, Ser98Leu, Cys165Trp, Ser167Phe, Phe178Cys, Leu193Pro, Pro204Arg, Arg272Ser, and Arg334Cys) in 11 patients. These data demonstrate a high degree of allelic heterogeneity of the CHST6 gene in patient populations with MCD from Southern India, where this disease may have a relatively higher prevalence than in outbred communities.

Corneal electrolysis for recurrence of corneal stromal dystrophy after keratoplasty

PubMed Central

Mashima, Y; Kawai, M; Yamada, M

2002-01-01

Aims: To evaluate corneal electrolysis as a treatment for recurrent diffuse corneal opacities at the host-graft interface of the stroma or at the subepithelial region in two types of granular corneal dystrophy (GCD). Methods: Recurrence developed at the host-graft interface of the stroma after lamellar keratoplasty in a patient with Avellino corneal dystrophy (ACD). At surgery, the deep aspect of the graft in this patient was partially separated from host tissue to expose the deposits, with one third of the host-graft junction left intact. The graft was everted, and electrolysis was applied directly to remove the deposits attached to both surfaces of the host and the graft. Then the graft was returned to its place and sutured. In two patients with homozygous ACD and one patient with the superficial variant of GCD, diffuse subepithelial opacities developed following penetrating keratoplasty. Electrolysis was applied directly to the corneal surface. Results: Deposits at the host-graft interface of the stroma and in the subepithelial region disappeared following treatment, and vision recovered in all patients. Conclusions: This method is a simple, easy, and inexpensive way to remove deposits that recur after lamellar or penetrating keratoplasty. PMID:11864880

Corneal electrolysis for recurrence of corneal stromal dystrophy after keratoplasty.

PubMed

Mashima, Y; Kawai, M; Yamada, M

2002-03-01

To evaluate corneal electrolysis as a treatment for recurrent diffuse corneal opacities at the host-graft interface of the stroma or at the subepithelial region in two types of granular corneal dystrophy (GCD). Recurrence developed at the host-graft interface of the stroma after lamellar keratoplasty in a patient with Avellino corneal dystrophy (ACD). At surgery, the deep aspect of the graft in this patient was partially separated from host tissue to expose the deposits, with one third of the host-graft junction left intact. The graft was everted, and electrolysis was applied directly to remove the deposits attached to both surfaces of the host and the graft. Then the graft was returned to its place and sutured. In two patients with homozygous ACD and one patient with the superficial variant of GCD, diffuse subepithelial opacities developed following penetrating keratoplasty. Electrolysis was applied directly to the corneal surface. Deposits at the host-graft interface of the stroma and in the subepithelial region disappeared following treatment, and vision recovered in all patients. This method is a simple, easy, and inexpensive way to remove deposits that recur after lamellar or penetrating keratoplasty.

Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene.

PubMed

Fishman, G A; Stone, E M; Grover, S; Derlacki, D J; Haines, H L; Hockey, R R

1999-04-01

To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene. Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene. Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene. Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change. A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of a Gly1961Glu change in exon 42 of the ABCR gene. The identification of correlations between specific mutations in the ABCR gene and clinical phenotypes will better facilitate the counseling of patients on their visual prognosis. This information will also likely be important for future therapeutic trials in patients with Stargardt dystrophy.

Contractility and supersensitivity to adrenaline in dystrophic muscle.

PubMed Central

Takamori, M

1975-01-01

In the adductor pollicis muscle of patients with limb-girdle and facioscapulohumeral muscular dystrophies and possible carriers of Duchenne type muscular dystrophy, abnormal active state properties were found at the time when there was no alteration of needle electromyography and evoked muscle action potentials. Adrenaline induced a marked reduction of incomplete tetanus via beta receptors without change in neuromuscular transmission. PMID:1151415

Infrared imaging enhances retinal crystals in Bietti's crystalline dystrophy.

PubMed

Brar, Vikram S; Benson, William H

2015-01-01

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti's crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time.

Proteomics identification of differentially expressed proteins in the muscle of dysferlin myopathy patients.

PubMed

De la Torre, Carolina; Illa, Isabel; Faulkner, Georgine; Soria, Laura; Robles-Cedeño, Rene; Dominguez-Perles, Raul; De Luna, Noemí; Gallardo, Eduard

2009-04-01

The muscular dystrophies are a large and heterogeneous group of neuromuscular disorders that can be classified according to the mode of inheritance, the clinical phenotype and the molecular defect. To better understand the pathological mechanisms of dysferlin myopathy we compared the protein-expression pattern in the muscle biopsies of six patients with this disease with six patients with limb girdle muscular dystrophy 2A, five with facioscapulohumeral dystrophy and six normal control subjects. To investigate differences in the expression levels of skeletal muscle proteins we used 2-DE and MS. Western blot or immunohistochemistry confirmed relevant results. The study showed specific increase expression of proteins involved in fast-to-slow fiber type conversion (ankyrin repeat protein 2), type I predominance (phosphorylated forms of slow troponin T), sarcomere stabilization (actinin-associated LIM protein), protein ubiquitination (TRIM 72) and skeletal muscle differentiation (Rho-GDP-dissociation inhibitor ly-GDI) in dysferlin myopathy. As anticipated, we also found differential expression of proteins common to all the muscular dystrophies studied. This comparative proteomic analysis suggests that in dysferlin myopathy (i) the type I fiber predominance is an active process of fiber type conversion rather than a selective loss of type II fibers and (ii) the dysregulation of proteins involved in muscle differentiation further confirms the role of dysferlin in this process. Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shomrat, R.; Gluck, E.; Legum, C.

1994-02-15

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and themore » remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.« less

[Propofol anesthesia for a patient with progressive muscular dystrophy].

PubMed

Egi, Moritoki; Tokioka, Hiroaki; Chikai, Takashi; Fukushima, Tomihiro; Ishizu, Tomoko; Tanaka, Toshiaki; Kosogabe, Yoshinori

2002-02-01

We gave propofol anesthesia to a patient with limb-girdle type of progressive muscular dystrophy. A 42 year-old male was to have skin graft for third degree burn. His respiratory function test showed %VC of 73.6% and %FEV1.0 of 107.6%. Arterial blood gas data were within normal ranges. He was anesthetized with propofol, fentanyl, vecuronium and nitrous oxide. During position change, Wenckebach type of second degree AV block occurred. AV block returned to sinus rhythm easily by injection of ephedrine hydrochloride and atropine sulfate, and reduction of propofol infusion rate. There were no perioperative respiratory complications and no clinical manifestations of malignant hyperthermia. Propofol anesthesia is suitable for limb-girdle type of progressive muscular dystrophy, because of very little possibility of triggering malignant hyperthermia, rapid awaking, minimal residual effects of the respiratory system, and easiness in controlling anesthetic depth.

Generation of induced pluripotent stem cells from a Becker muscular dystrophy patient carrying a deletion of exons 45-55 of the dystrophin gene (CCMi002BMD-A-9 ∆45-55).

PubMed

Gowran, Aoife; Spaltro, Gabriella; Casalnuovo, Federica; Vigorelli, Vera; Spinelli, Pietro; Castiglioni, Elisa; Rovina, Davide; Paganini, Stefania; Di Segni, Marina; Gervasini, Cristina; Nigro, Patrizia; Pompilio, Giulio

2018-04-01

Becker muscular dystrophy (BMD) is a dystrophinopathy caused by mutations in the dystrophin gene on chromosome Xp21. BMD mutations result in truncated semi-functional dystrophin isoforms. Consequently, less severe clinical symptoms become apparent later in life compared to Duchenne muscular dystrophy. Dermal fibroblasts from a BMD patient were electroporated with episomal plasmids containing reprogramming factors to create the induced pluripotent stem cell line: CCMi002BMD-A-9 that showed pluripotent markers, were karyotypically normal and capable of trilineage differentiation. MLPA analyses performed on DNA extracted from CCMi002BMD-A-9 showed an in-frame deletion of exons 45 to 55 (CCMi002BMD-A-9 Δ45-55). Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

High-Resolution Adaptive Optics Retinal Image Analysis at Early Stage Central Areolar Choroidal Dystrophy With PRPH2 Mutation.

PubMed

Gocho, Kiyoko; Akeo, Keiichiro; Itoh, Naoko; Kameya, Shuhei; Hayashi, Takaaki; Katagiri, Satoshi; Gekka, Tamaki; Ohkuma, Yasuhiro; Tsuneoka, Hiroshi; Takahashi, Hiroshi

2016-12-01

To report the clinical features of Japanese patients at Stage 1 and 2 of central areolar choroidal dystrophy (CACD). Five family members had comprehensive ophthalmic examinations including adaptive optics (AO) retinal imaging. Mutation analysis of the PRPH2 gene was performed by Sanger sequencing. The protocol conformed to the tenets of the Declaration of Helsinki and was approved by the institutional review board of The Jikei University School of Medicine. Four family members had a heterozygous PRPH2 mutation, p.R172Q; however, one member with a mutation did not show any ophthalmological abnormalities. Two patients had mild parafoveal retinal dystrophy and a reduction of cone density determined by AO analysis. The results indicate that the parafoveal cone photoreceptors can be affected even at the early stage of CACD. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:1115-1126.]. Copyright 2016, SLACK Incorporated.

Cardiac treatment in neuro-muscular diseases.

PubMed

Nigro, G; Politano, L; Passamano, L; Palladino, A; De Luca, F; Nigro, Ge; Comi, L I

2006-12-01

The authors have been treating heart involvement in muscle dystrophy since 1978. However, this study aimed to define recent therapeutic protocols, evaluating the results of cardiac treatment, performed between 1st February 2004 and 31st July, 2006. In this period, 100 Becker, 136 Duchenne, 44 Limb-girdle and 116 Steinert patients were treated. In that same period, a large group of MD patients refusing cardiac therapy have also been followed. All patients had previously been classified in the appropriate stage of cardiomyopathy and examined at least twice every year and even every week if presenting heart failure. The results show the usefulness of the recent protocols of treatment of cardiac involvement in muscle dystrophy patients.

Advances in genetic therapeutic strategies for Duchenne muscular dystrophy.

PubMed

Guiraud, Simon; Chen, Huijia; Burns, David T; Davies, Kay E

2015-12-01

What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X-linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene-replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re-establish muscle function. © 2015 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

Propofol-induced violent coughing in a patient with Becker's muscular dystrophy

PubMed Central

Jain, Amit

2011-01-01

Propofol anesthesia is often associated with decreased incidence of gagging, coughing or laryngospasm, and provides intense suppression on airway reflex during tracheal intubation and laryngeal mask airway insertion. Propofol pretreatment is also effective in reducing the occurrence of opioid-induced coughing. These benefits are often attributed to bronchodilator and sedative effects of propofol. However, severe coughing following sedative doses of 1% propofol has not been reported so far. We report a rare case of violent coughing following low-dose propofol infusion in a patient with Becker's muscular dystrophy. PMID:21845012

Secondary Conditions Among Males With Duchenne or Becker Muscular Dystrophy.

PubMed

Latimer, Rebecca; Street, Natalie; Conway, Kristin Caspers; James, Kathy; Cunniff, Christopher; Oleszek, Joyce; Fox, Deborah; Ciafaloni, Emma; Westfield, Christina; Paramsothy, Pangaja

2017-06-01

Duchenne and Becker muscular dystrophy are X-linked neuromuscular disorders characterized by progressive muscle degeneration. Despite the involvement of multiple systems, secondary conditions among affected males have not been comprehensively described. Two hundred nine caregivers of affected males (aged 3-31 years) identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network completed a mailed survey that included questions about secondary conditions impacting multiple body functions. The 5 most commonly reported conditions in males with Duchenne were cognitive deficits (38.4%), constipation (31.7%), anxiety (29.3%), depression (27.4%), and obesity (19.5%). Higher frequencies of anxiety, depression, and kidney stones were found among nonambulatory males compared to ambulatory males. Attention-deficit hyperactivity disorder (ADHD) was more common in ambulatory than nonambulatory males. These data support clinical care recommendations for monitoring of patients with Duchenne or Becker muscular dystrophy by a multidisciplinary team to prevent and treat conditions that may be secondary to the diagnosis.

TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins.

PubMed

Zamiri, Bita; Reddy, Kaalak; Macgregor, Robert B; Pearson, Christopher E

2014-02-21

Certain DNA and RNA sequences can form G-quadruplexes, which can affect genetic instability, promoter activity, RNA splicing, RNA stability, and neurite mRNA localization. Amyotrophic lateral sclerosis and frontotemporal dementia can be caused by expansion of a (GGGGCC)n repeat in the C9orf72 gene. Mutant r(GGGGCC)n- and r(GGCCCC)n-containing transcripts aggregate in nuclear foci, possibly sequestering repeat-binding proteins such as ASF/SF2 and hnRNPA1, suggesting a toxic RNA pathogenesis, as occurs in myotonic dystrophy. Furthermore, the C9orf72 repeat RNA was recently demonstrated to undergo the noncanonical repeat-associated non-AUG translation (RAN translation) into pathologic dipeptide repeats in patient brains, a process that is thought to depend upon RNA structure. We previously demonstrated that the r(GGGGCC)n RNA forms repeat tract length-dependent G-quadruplex structures that bind the ASF/SF2 protein. Here we show that the cationic porphyrin (5,10,15,20-tetra(N-methyl-4-pyridyl) porphyrin (TMPyP4)), which can bind some G-quadruplex-forming sequences, can bind and distort the G-quadruplex formed by r(GGGGCC)8, and this ablates the interaction of either hnRNPA1 or ASF/SF2 with the repeat. These findings provide proof of concept that nucleic acid binding small molecules, such as TMPyP4, can distort the secondary structure of the C9orf72 repeat, which may beneficially disrupt protein interactions, which may ablate either protein sequestration and/or RAN translation into potentially toxic dipeptides. Disruption of secondary structure formation of the C9orf72 RNA repeats may be a viable therapeutic avenue, as well as a means to test the role of RNA structure upon RAN translation.

Characterization of conservative somatic instability of the CAG repeat region in Huntington`s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schaefer, F.V.; Calikoglu, A.S.; Whetsell, L.H.

1994-09-01

Instability and enlargement of a CAG repeat region at the beginning of the huntingtin gene (IT-15) has been linked with Huntington`s disease. The CAG repeat size shows a highly significant correlation with age-of-onset of clinicial features in individuals with 40 or more repeats who have Huntington disease. The clinical status of nonsymptomatic individuals with 30 to 39 CAG repeats is considered ambiguous. In order to define more carefully the nature of the HD expansion instability, we examined patients in our HD population using a discriminating fluorescence-based PCR approach. The degree of somatic mutation increases with both earlier age of onsetmore » and the size of the inherited allele. A single prominent band one repeat larger than the index peak was typical in individuals with 40-41 CAG repeats. Three to four larger bands are typically discerned in individuals with 50 or more repeats. In an extreme example, an individual with approximately 95 repeats had at least 8 prominent bands. Plotting the degree of somatic mutation relative to the size of the HD allele shows somatic mutation activity increases with size. By this approach 40-60% of the alleles in a 40-41 CAG repeat HD loci is represented in the primary allele. In contrast, the primary allele represents a relatively minor proportion of the total alleles for expansions greater than 50 CAG repeats (10-20%). The limited range of somatic mutation suggest that the instability is restricted to very early stages of embryogenesis before tissue development diverges or that persistent somatic instability occurs at a slow rate. Therefore, the properties of somatic instability in Huntington`s disease have aspects that are both in common but also different from that found in other trinucleotide repeat expanding diseases such as myotonic muscular dystrophy and fragile X syndrome.« less

[Complete atrioventricular block in Duchenne muscular dystrophy].

PubMed

Kuru, Satoshi; Tanahashi, Tamotsu; Matsumoto, Shinjirou; Kitamura, Tetsuya; Konagaya, Masaaki

2012-01-01

We report a case of complete atrioventricular (AV) block in a 40-year-old patient with Duchenne muscular dystrophy (DMD). While he was bed-ridden and required mechanical ventilation, his cardiac involvement was mild. He had the deletion of exon 45-52 in the dystrophin gene. He underwent transient complete AV block and came to require pacemaker implantation due to recurrence of complete AV block ten days after the first attack. Electrophysiological study revealed mild prolonged AH and HV interval. Although DMD patients with AV block have been rarely reported so far, attention should be paid to AV block for patients who prolonged their lives.

Anesthesia and Duchenne or Becker muscular dystrophy: review of 117 anesthetic exposures.

PubMed

Segura, Leal G; Lorenz, Jessica D; Weingarten, Toby N; Scavonetto, Federica; Bojanić, Katarina; Selcen, Duygu; Sprung, Juraj

2013-09-01

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are associated with life-threatening perioperative complications, including rhabdomyolysis, hyperkalemia, and hyperthermia. Current recommendations contraindicate use of succinylcholine and volatile anesthetics; however, the latter recommendation remains controversial. To review the perioperative outcomes of patients with DMD and BMD. We reviewed records of patients with DMD or BMD who underwent anesthetic management at our institution from January 1990 through December 2011. We identified 47 patients (DMD, 37; BMD, 10) who underwent 117 anesthetic exposures (DMD, 101; BMD, 16). Volatile anesthetic agents were used 66 times (DMD, 59; BMD, 7). One patient with undiagnosed BMD received succinylcholine and developed acute rhabdomyolysis and hyperkalemic cardiac arrest. All other major complications were attributed to the procedure (i.e., large bleeding), to preexisting comorbidities (i.e., respiratory failure, cardiac disease), or to both. Use of succinylcholine in children with dystrophinopathy is contraindicated. These patients have significant comorbidities and are frequently undergoing extensive operations; complications related to these factors can develop, as evidenced by our series. These complications may occur with use of volatile and nonvolatile anesthetics. However, because most of our patients were older than 8 years at the time of surgery, our observation cannot be generalized to younger dystrophin-deficient children. © 2013 John Wiley & Sons Ltd.

Functional outcomes in Duchenne muscular dystrophy scoliosis: comparison of the differences between surgical and nonsurgical treatment.

PubMed

Suk, Kyung Soo; Lee, Byung Ho; Lee, Hwan Mo; Moon, Seong Hwan; Choi, Young Chul; Shin, Dong Eun; Ha, Jung Won; Song, Kwang Min; Kim, Hak Sun

2014-03-05

While most studies of Duchenne muscular dystrophy scoliosis focus on technical and radiographic indices, functional status is a more important factor to consider in the management of Duchenne muscular dystrophy. The objectives of the current study were to compare the pulmonary function, radiographic outcome, and functional recovery, with use of validated questionnaires, in surgically and nonsurgically treated patients with Duchenne muscular dystrophy who have scoliosis. Sixty-six patients (forty treated surgically and twenty-six treated nonsurgically) with a minimum follow-up of two years were included in this study. Forced vital capacity, radiographic parameters (the Cobb angle, lordosis, and pelvic obliquity), and functional status, according to the modified Rancho scale and manual muscle test, were measured preoperatively and at the time of the final follow-up. The Muscular Dystrophy Spine Questionnaire (MDSQ) was completed at the final follow-up evaluation. Pulmonary function, functional scores (manual muscle test and modified Rancho scale), and radiographic measurements, except for lordosis, were similar for both groups at the time of the initial consultation (p > 0.05). At the time of the final follow-up, all radiographic parameters were significantly improved in the surgical group compared with the nonsurgical group. The mean score (and standard deviation) on the manual muscle test was not significantly different between the surgical and nonsurgical groups (23.2 ± 8.3 versus 22.8 ± 6.3; p = 0.828). The mean score on the modified Rancho scale also showed similar results in the groups (3.9 ± 0.3 and 4.04 ± 0.3, respectively; p = 0.088). The surgical group had higher mean MDSQ scores than the nonsurgical group (35.1 ± 14.7 and 26.9 ± 9.9, respectively; p = 0.008). Both groups showed a decrease in forced vital capacity at the time of the final follow-up, but the deterioration of forced vital capacity was significantly slower (p = 0.035) in the surgical group (268 ± 361 mL) than in the nonsurgical group (536 ± 323 mL). Surgery in patients who had Duchenne muscular dystrophy with scoliosis improved function and decreased the rate of deterioration of forced vital capacity compared with patients treated conservatively. However, the muscle power and forced vital capacity decreased in both groups.

[Clinical features of patients with Becker muscular dystrophy and deletions of the rod domain of dystrophin gene].

PubMed

Wang, Yanyun; Zhu, Yuling; Yang, Juan; Li, Yaqin; Sun, Jiangwen; Zhan, Yixin; Zhang, Cheng

2018-02-10

OBJECTIVE To explore the clinical features of patients carrying deletions of the rod domain of the dystrophin gene. METHODS Clinical data of 12 Chinese patients with Becker muscular dystrophy (BMD) and such deletions was reviewed. RESULTS Most patients complained of muscle weakness of lower limbs. Two patients had muscle cramps, one had increased creatine kinase (CK) level, and one had dilated cardiomyopathy. CONCLUSION Compared with DMD, the clinical features of BMD are much more variable, particularly for those carrying deletions of the rod domain of the dystrophin gene. Muscular weakness may not be the sole complaint of BMD. The diagnosis of BMD cannot be excluded by moderately elevated CK. For male patients with dilated cardiomyopathy, the possibility of BMD should be considered.

Infrared imaging enhances retinal crystals in Bietti’s crystalline dystrophy

PubMed Central

Brar, Vikram S; Benson, William H

2015-01-01

Infrared imaging dramatically increased the number of crystalline deposits visualized compared with clinical examination, standard color fundus photography, and red free imaging in patients with Bietti’s crystalline dystrophy. We believe that this imaging modality significantly improves the sensitivity with which these lesions are detected, facilitating earlier diagnosis and may potentially serve as a prognostic indicator when examined over time. PMID:25931805

Decreased Nocturnal Movements in Patients with Facioscapulohumeral Muscular Dystrophy

PubMed Central

Marca, Giacomo Della; Frusciante, Roberto; Dittoni, Serena; Vollono, Catello; Losurdo, Anna; Testani, Elisa; Scarano, Emanuele; Colicchio, Salvatore; Iannaccone, Elisabetta; Tonali, Pietro A.; Ricci, Enzo

2010-01-01

Study Objectives: Reduced mobility during sleep characterizes a variety of movement disorders and neuromuscular diseases. Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy in the general population, and people with FSHD have poor sleep quality. The aims of the present study were to evaluate nocturnal motor activity in patients with FSHD by means of videopolysomnography and to verify whether activity was associated with modifications in sleep structure. Methods: We enrolled 32 adult patients affected by genetically confirmed FSHD (18 women and 14 men, mean age 45.1 ± 13.4 years) and 32 matched control subjects, (18 women and 14 men, mean age 45.5 ± 11.4 years). Major body movements (MBM) were scored in videopolygraphic recordings in accordance with established criteria. An MBM index was calculated (number of MBM per hour of sleep). Results: The FSHD group showed a decrease in the MBM index (FSHD: 1.2 ± 1.1; control subjects: 2.3 ± 1.2, analysis of variance F = 13.672; p = 0.008). The sleep pattern of patients with FSHD, as compared with that of controls, was characterized by longer sleep latencies, shorter sleep durations, an increased percentage of wake during sleep, and a decreased percentage of rapid eye movement sleep. In the patient group, the MBM index was inversely correlated with severity of disease (Spearman test: r30 = −0.387; p < 0.05). Conclusions: The present findings suggest that patients with FSHD have a reduced number of nocturnal movements, which is related to disease severity. Reduced movement in bed may contribute to the sleep modifications observed in these patients. Citation: Marca GD; Frusciante R; Dittoni S; Vollono C; Losurdo A; Testani E; Scarano E; Colicchio S; Iannaccone E; Tonali PA; Ricci E. Decreased nocturnal movements in patients with facioscapulohumeral muscular dystrophy. J Clin Sleep Med 2010;6(3):276-280. PMID:20572422

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

PubMed

Klevering, B Jeroen; Yzer, Suzanne; Rohrschneider, Klaus; Zonneveld, Marijke; Allikmets, Rando; van den Born, L Ingeborgh; Maugeri, Alessandra; Hoyng, Carel B; Cremers, Frans P M

2004-12-01

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.

Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

PubMed

Maugeri, A; Klevering, B J; Rohrschneider, K; Blankenagel, A; Brunner, H G; Deutman, A F; Hoyng, C B; Cremers, F P

2000-10-01

The photoreceptor cell-specific ATP-binding cassette transporter gene (ABCA4; previously denoted "ABCR") is mutated, in most patients, with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients from Germany and The Netherlands with isolated CRD. Single-strand conformation-polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans.

Identification of sleep hypoventilation in young individuals with Becker muscular dystrophy: A pilot study.

PubMed

Nakamura, Yuko; Saito, Yoshiaki; Kubota, Norika; Matsumura, Wataru; Hosoda, Chika; Tamasaki-Kondo, Akiko; Nishimura, Yoko; Sunada, Yoshihide; Fukada, Masuyuki; Ohno, Takako; Maegaki, Yoshihiro; Matsuo, Masafumi; Tokita, Yasuko

2018-03-08

To report on sleep hypercapnia in Becker muscular dystrophy (BMD) at earlier stages than ever recognized. This retrospective study examined nocturnal hypercapnia in six young Becker muscular dystrophy (BMD) patients with deletions of one or more exons of DMD gene. Clinical information, consecutive data on forced vital capacity (FVC%), forced expiratory volume in one second (FEV1%), peak expiratory flow (PEF%), peak cough flow (PCF), average PCO 2 in all-night monitoring, and left ventricular ejection fraction (LVEF) were reviewed. In five BMD patients, including three who were still ambulant, nocturnal average PCO 2 was elevated to >45 mmHg at 12-31 years of age. Noninvasive positive pressure ventilation was initiated in four patients. Gradual declines in FVC% and PEF% were evident in one BMD patient with exon 3-7 deletion, whereas these functions did not change in the remaining BMD patients. PCF, FEV1%, and LVEF were less informative for the assessment of respiratory function in this patient series. Sleep hypercapnia was present in certain BMD patients, which was unexpected from the routine pulmonary function tests. Individualized assessment of nocturnal PCO 2 , partly based on the deletion types, should be further explored in the clinical practice of BMD patients. Copyright © 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Processing of double-R-loops in (CAG)·(CTG) and C9orf72 (GGGGCC)·(GGCCCC) repeats causes instability

PubMed Central

Reddy, Kaalak; Schmidt, Monika H.M.; Geist, Jaimie M.; Thakkar, Neha P.; Panigrahi, Gagan B.; Wang, Yuh-Hwa; Pearson, Christopher E.

2014-01-01

R-loops, transcriptionally-induced RNA:DNA hybrids, occurring at repeat tracts (CTG)n, (CAG)n, (CGG)n, (CCG)n and (GAA)n, are associated with diseases including myotonic dystrophy, Huntington's disease, fragile X and Friedreich's ataxia. Many of these repeats are bidirectionally transcribed, allowing for single- and double-R-loop configurations, where either or both DNA strands may be RNA-bound. R-loops can trigger repeat instability at (CTG)·(CAG) repeats, but the mechanism of this is unclear. We demonstrate R-loop-mediated instability through processing of R-loops by HeLa and human neuron-like cell extracts. Double-R-loops induced greater instability than single-R-loops. Pre-treatment with RNase H only partially suppressed instability, supporting a model in which R-loops directly generate instability by aberrant processing, or via slipped-DNA formation upon RNA removal and its subsequent aberrant processing. Slipped-DNAs were observed to form following removal of the RNA from R-loops. Since transcriptionally-induced R-loops can occur in the absence of DNA replication, R-loop processing may be a source of repeat instability in the brain. Double-R-loop formation and processing to instability was extended to the expanded C9orf72 (GGGGCC)·(GGCCCC) repeats, known to cause amyotrophic lateral sclerosis and frontotemporal dementia, providing the first suggestion through which these repeats may become unstable. These findings provide a mechanistic basis for R-loop-mediated instability at disease-associated repeats. PMID:25147206

MSH3 Promotes Dynamic Behavior of Trinucleotide Repeat Tracts In Vivo

PubMed Central

Williams, Gregory M.; Surtees, Jennifer A.

2015-01-01

Trinucleotide repeat (TNR) expansions are the underlying cause of more than 40 neurodegenerative and neuromuscular diseases, including myotonic dystrophy and Huntington’s disease, yet the pathway to expansion remains poorly understood. An important step in expansion is the shift from a stable TNR sequence to an unstable, expanding tract, which is thought to occur once a TNR attains a threshold length. Modeling of human data has indicated that TNR tracts are increasingly likely to expand as they increase in size and to do so in increments that are smaller than the repeat itself, but this has not been tested experimentally. Genetic work has implicated the mismatch repair factor MSH3 in promoting expansions. Using Saccharomyces cerevisiae as a model for CAG and CTG tract dynamics, we examined individual threshold-length TNR tracts in vivo over time in MSH3 and msh3Δ backgrounds. We demonstrate, for the first time, that these TNR tracts are highly dynamic. Furthermore, we establish that once such a tract has expanded by even a few repeat units, it is significantly more likely to expand again. Finally, we show that threshold- length TNR sequences readily accumulate net incremental expansions over time through a series of small expansion and contraction events. Importantly, the tracts were substantially stabilized in the msh3Δ background, with a bias toward contractions, indicating that Msh2-Msh3 plays an important role in shifting the expansion-contraction equilibrium toward expansion in the early stages of TNR tract expansion. PMID:25969461

Benzalkonium chloride accelerates the formation of the amyloid fibrils of corneal dystrophy-associated peptides.

PubMed

Kato, Yusuke; Yagi, Hisashi; Kaji, Yuichi; Oshika, Tetsuro; Goto, Yuji

2013-08-30

Corneal dystrophies are genetic disorders resulting in progressive corneal clouding due to the deposition of amyloid fibrils derived from keratoepithelin, also called transforming growth factor β-induced protein (TGFBI). The formation of amyloid fibrils is often accelerated by surfactants such as sodium dodecyl sulfate (SDS). Most eye drops contain benzalkonium chloride (BAC), a cationic surfactant, as a preservative substance. In the present study, we aimed to reveal the role of BAC in the amyloid fibrillation of keratoepithelin-derived peptides in vitro. We used three types of 22-residue synthetic peptides covering Leu110-Glu131 of the keratoepithelin sequence: an R-type peptide with wild-type R124, a C-type peptide with C124 associated with lattice corneal dystrophy type I, and a H-type peptide with H124 associated with granular corneal dystrophy type II. The time courses of spontaneous amyloid fibrillation and seed-dependent fibril elongation were monitored in the presence of various concentrations of BAC or SDS using thioflavin T fluorescence. BAC and SDS accelerated the fibrillation of all synthetic peptides in the absence and presence of seeds. Optimal acceleration occurred near the CMC, which suggests that the unstable and dynamic interactions of keratoepithelin peptides with amphipathic surfactants led to the formation of fibrils. These results suggest that eye drops containing BAC may deteriorate corneal dystrophies and that those without BAC are preferred especially for patients with corneal dystrophies.

A Case of Refractory Heart Failure in Becker Muscular Dystrophy Improved With Corticosteroid Therapy.

PubMed

Nakamura, Makiko; Sunagawa, Osahiko; Hokama, Ryo; Tsuchiya, Hiroyuki; Miyara, Takafumi; Taba, Yoji; Touma, Takashi

2016-09-28

The patient was a 26 year-old man who was referred to our hospital in June 2011 because of severe heart failure. At age 24 years, he was found to have Becker muscular dystrophy. He received enalapril for cardiac dysfunction; however, he had worsening heart failure and was thus referred to our hospital. Echocardiography showed enlargement of the left ventricle, with a diastolic dimension of 77 mm and ejection fraction of 19%. His condition improved temporarily after an infusion of dobutamine and milrinone. He was then administered amiodarone for ventricular tachycardia; however, he subsequently developed hemoptysis. Amiodarone was discontinued and corticosteroid pulse therapy was administered followed by oral prednisolone (PSL). His creatinine phosphokinase (CPK) level and cardiomegaly improved after the corticosteroid therapy. The PSL dose was reduced gradually, bisoprolol was introduced, and the catecholamine infusion was tapered. A cardiac resynchronization device was implanted; however, the patient's condition gradually worsened, which necessitated dobutamine infusion for heart failure. We readministered 30 mg PSL, which decreased the CPK level and improved the cardiomegaly. The dobutamine infusion was discontinued, and the patient was discharged. He was given 7.5 mg PSL as an outpatient, and he returned to normal life without exacerbation of the heart failure. There are similar reports showing that corticosteroids are effective for skeletal muscle improvement in Duchenne muscular dystrophy; however, their effectiveness for heart failure has been rarely reported. We experienced a case of Becker muscular dystrophy in which corticosteroid therapy was effective for refractory heart failure.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING.

PubMed

Hafler, Brian P

2017-03-01

Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies.

Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands.

PubMed

Xu, Yan; Xiao, Xueshan; Li, Shiqiang; Jia, Xiaoyun; Xin, Wei; Wang, Panfeng; Sun, Wenmin; Huang, Li; Guo, Xiangming; Zhang, Qingjiong

2016-08-01

Leber congenital amaurosis (LCA) is the most severe form of inherited retinal dystrophy. We have previously performed a mutational analysis of the known LCA-associated genes in probands with LCA by both Sanger and whole exome sequencing. In this study, whole exome sequencing was carried out on 66 new probabds with LCA. In conjunction with these data, the present study provides a comprehensive analysis of the spectrum and frequency of all known genes associated with retinal dystrophy in a total of 159 Chinese probands with LCA. The known genes responsible for all forms hereditary retinal dystrophy were included based on information from RetNet. The candidate variants were filtered by bioinformatics analysis and confirmed by Sanger sequencing. Potentially causative mutations were further validated in available family members. Overall, a total of 118 putative pathogenic mutations from 23 genes were identified in 56.6% (90/159) of probands. These mutations were harbored in 13 LCA-associated genes and in ten genes related to other forms of retinal dystrophy. The most frequently mutated gene in probands with LCA was GUCY2D (10.7%, 17/159). A series of mutational analyses suggests that all known genes associated with retinal dystrophy account for 56.6% of Chinese patients with LCA. A comprehensive molecular genetic analysis of Chinese patients with LCA provides an overview of the spectrum and frequency of ethno-specific mutations of all known genes, as well as indications about other unknown genes in the remaining probands who lacked identified mutations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Therapeutic strategies to address neuronal nitric oxide synthase deficiency and the loss of nitric oxide bioavailability in Duchenne Muscular Dystrophy.

PubMed

Timpani, Cara A; Hayes, Alan; Rybalka, Emma

2017-05-25

Duchenne Muscular Dystrophy is a rare and fatal neuromuscular disease in which the absence of dystrophin from the muscle membrane induces a secondary loss of neuronal nitric oxide synthase and the muscles capacity for endogenous nitric oxide synthesis. Since nitric oxide is a potent regulator of skeletal muscle metabolism, mass, function and regeneration, the loss of nitric oxide bioavailability is likely a key contributor to the chronic pathological wasting evident in Duchenne Muscular Dystrophy. As such, various therapeutic interventions to re-establish either the neuronal nitric oxide synthase protein deficit or the consequential loss of nitric oxide synthesis and bioavailability have been investigated in both animal models of Duchenne Muscular Dystrophy and in human clinical trials. Notably, the efficacy of these interventions are varied and not always translatable from animal model to human patients, highlighting a complex interplay of factors which determine the downstream modulatory effects of nitric oxide. We review these studies herein.

Co-incidence of Turner syndrome and Duchenne muscular dystrophy - an important problem for the clinician.

PubMed

Kaczorowska, Ewa; Zimowski, Janusz; Cichoń-Kotek, Monika; Mrozińska, Agnieszka; Purzycka, Joanna; Wierzba, Jolanta; Limon, Janusz; Lipska-Ziętkiewicz, Beata S

Turner syndrome is a relatively common chromosomal disorder which affects about one in 2000 live born females. Duchenne muscular dystrophy is an X-linked recessive disorder affecting 1:3600 live born males. Considering the above, the coexistence of these two diseases may occur only anecdotally. Here, we report a 4 ½ year-old female with classical 45,X Turner syndrome who also had Duchenne muscular dystrophy caused by a point mutation in the dystrophin gene (c.9055delG). The patient showed the typical phenotype of Turner syndrome including distinctive dysmorphic features (short neck, low posterior hairline, wide position of nipples), aortic coarctation and feet lymphedema. Besides, she presented with an unusually early beginning of muscular dystrophy symptoms with infantile-onset motor developmental delay, intellectual disability and early calf muscular hypertrophy. The coexistence of an X-linked recessive disorder should be considered in women affected by Turner syndrome presenting with additional atypical clinical features.

Secondary conditions among males with Duchenne or Becker muscular dystrophy

PubMed Central

Latimer, Rebecca; Street, Natalie; Conway, Kristin Caspers; James, Kathy; Cunniff, Christopher; Oleszek, Joyce; Fox, Deborah; Ciafaloni, Emma; Westfield, Christina; Paramsothy, Pangaja

2017-01-01

Duchenne and Becker muscular dystrophy are X-linked neuromuscular disorders characterized by progressive muscle degeneration. Despite the involvement of multiple systems, secondary conditions among affected males have not been comprehensively described. Two hundred and nine caregivers of affected males (aged 3–31 years) identified by the Muscular Dystrophy Surveillance, Tracking, and Research Network completed a mailed survey that included questions about secondary conditions impacting multiple body functions. The five most commonly reported conditions in males with Duchenne were cognitive deficits (38.4%), constipation (31.7%), anxiety (29.3%), depression (27.4%), and obesity (19.5%). Higher frequencies of anxiety, depression, and kidney stones, were found among non-ambulatory males compared to ambulatory males. Attention deficit hyperactivity disorder was more common in ambulatory than non-ambulatory males. These data support clinical care recommendations for monitoring of patients with Duchenne or Becker muscular dystrophy by a multidisciplinary team to prevent and treat conditions that may be secondary to the diagnosis. PMID:28393671

NMNAT1 variants cause cone and cone-rod dystrophy.

PubMed

Nash, Benjamin M; Symes, Richard; Goel, Himanshu; Dinger, Marcel E; Bennetts, Bruce; Grigg, John R; Jamieson, Robyn V

2018-03-01

Cone and cone-rod dystrophies (CD and CRD, respectively) are degenerative retinal diseases that predominantly affect the cone photoreceptors. The underlying disease gene is not known in approximately 75% of autosomal recessive cases. Variants in NMNAT1 cause a severe, early-onset retinal dystrophy called Leber congenital amaurosis (LCA). We report two patients where clinical phenotyping indicated diagnoses of CD and CRD, respectively. NMNAT1 variants were identified, with Case 1 showing an extremely rare homozygous variant c.[271G > A] p.(Glu91Lys) and Case 2 compound heterozygous variants c.[53 A > G];[769G > A] p.(Asn18Ser);(Glu257Lys). The detailed variant analysis, in combination with the observation of an associated macular atrophy phenotype, indicated that these variants were disease-causing. This report demonstrates that the variants in NMNAT1 may cause CD or CRD associated with macular atrophy. Genetic investigations of the patients with CD or CRD should include NMNAT1 in the genes examined.

The ultrasound-guided nerve blocks of abdominal wall contributed to anesthetic management of cholecystectomy in a patient with Becker muscular dystrophy without using muscle relaxants.

PubMed

Iwata, Masato; Kuzumoto, Naoya; Akasaki, Yuka; Morioka, Masayo; Nakayama, Kana; Matsuzawa, Nobuyoshi; Kimoto, Katsuhiro; Shimomura, Toshiyuki

2017-01-01

Becker muscular dystrophy (BMD) is a progressive neuromuscular disorder caused by mutations in the dystrophin gene. The sensitivity to non-depolarizing muscle relaxant in a patient with muscle dystrophy is reportedly higher than that in normal individuals, and the duration of the effect is known to be prolonged. In this report, we present the case of a 58-year-old man with BMD who underwent laparoscopic cholecystectomy for symptomatic cholelithiasis under total intravenous anesthesia without the use of muscle-relaxant drugs and supplemented with regional anesthesia. Anesthesia was induced and maintained with propofol, remifentanil, and fentanyl; ultrasound-guided bilateral rectus sheath block (RSB) and right-sided subcostal transversus abdominis plane block (TAP) were performed. The procedure required conversion to open surgery because of hard conglutination; intraoperative and postoperative periods were uneventful. Adequate analgesia was maintained after extubation because of the effect of RSB and TAP.

Application of the International Classification of Functioning, Disability and Health system to symptoms of the Duchenne and Becker muscular dystrophies.

PubMed

Conway, Kristin M; Ciafaloni, Emma; Matthews, Dennis; Westfield, Chris; James, Kathy; Paramsothy, Pangaja; Romitti, Paul A

2018-07-01

Duchenne and Becker muscular dystrophies, collectively referred to as dystrophinopathies, are X-linked recessive diseases that affect dystrophin production resulting in compromised muscle function across multiple systems. The International Classification of Functioning, Disability and Health provides a systematic classification scheme from which body functions affected by a dystrophinopathy can be identified and used to examine functional health. The infrastructure of the Muscular Dystrophy Surveillance, Tracking, and Research Network was used to identify commonly affected body functions and link selected functions to clinical surveillance data collected through medical record abstraction. Seventy-one (24 second-, 41 third- and 7 fourth-level) body function categories were selected via clinician review and consensus. Of these, 15 of 24 retained second-level categories were linked to data elements from the Muscular Dystrophy Surveillance, Tracking, and Research Network surveillance database. Our findings support continued development of a core set of body functions from the International Classification of Functioning, Disability and Health system that are representative of disease progression in dystrophinopathies and the incorporation of these functions in standardized evaluations of functional health and implementation of individualized rehabilitation care plans. Implications for Rehabilitation Duchenne and Becker muscular dystrophies, collectively referred to as dystrophinopathies, are X-linked recessive disorders that affect the production of dystrophin resulting in compromised muscle function across multiple systems. The severity and progressive nature of dystrophinopathies can have considerable impact on a patient's participation in activities across multiple life domains. Our findings support continued development of an International Classification of Functioning, Disability and Health core set for childhood-onset dystrophinopathies. A standardized dystrophinopathy International Classification of Functioning, Disability and Health documentation form can be used as a screening tool by rehabilitation professionals and for patient goal setting when developing rehabilitation plans. Patient reports of perceived functional health should be incorporated into the rehabilitation plan and therapeutic progress monitored by a standardized form.

Characteristics of Japanese Patients with Becker Muscular Dystrophy and Intermediate Muscular Dystrophy in a Japanese National Registry of Muscular Dystrophy (Remudy): Heterogeneity and Clinical Variation.

PubMed

Mori-Yoshimura, Madoka; Mitsuhashi, Satomi; Nakamura, Harumasa; Komaki, Hirofumi; Goto, Kanako; Yonemoto, Naohiro; Takeuchi, Fumi; Hayashi, Yukiko K; Murata, Miho; Takahashi, Yuji; Nishino, Ichizo; Takeda, Shin'ichi; Kimura, En

2018-01-01

Obtaining an adequate number of patients to conduct a natural history study for rare diseases such as Becker muscular dystrophy (BMD) is difficult. The present study used data from Remudy, a national registry for neuromuscular diseases in Japan, to conduct a phenotypic analysis of BMD. We analyzed Remudy data of participants with dystrophinopathy. All participants who were aged 17 and older and were ambulant at age 13 were included in this study. Participants were divided into two groups: those with BMD who were ambulant at age 17, and those with intermediate muscular dystrophy (IMD) who lost ambulation by age 17. Frequent mutations were analyzed by age at ambulation, cardiopulmonary function, and genotype. For clinical comparisons, participants who were administered steroids were excluded. From July 2009 through September 2015, 192 participants had registered with Remudy. Mean participant age was 34.80±13.3 (range, 17-78) years, and 52.1% of participants were ambulant. Of the entire study population, 50.5% had cardiomyopathy and 35.9% had respiratory failure. Three participants required invasive ventilation and 30 required non-invasive ventilation. Nineteen of the 30 non-invasive ventilator users were part-time users. In total, 138 (71.9%) had BMD and 54 (28.1%) had IMD. The most frequent mutation was ex45_ex47del (36 participants). Among participants with frequent in-frame mutations, those with the ex45-49del mutation lost their ambulation earlier than those with the ex45_ex47del mutation. A total of 67 different exon deletions and duplications were identified in the study population. We clarified the clinical phenotypes of Japanese patients with BMD/IMD using data from Remudy. Our results suggest that not only IMD but also BMD are associated with risk of respiratory dysfunction.

Calpain 3 is important for muscle regeneration: evidence from patients with limb girdle muscular dystrophies.

PubMed

Hauerslev, Simon; Sveen, Marie-Louise; Duno, Morten; Angelini, Corrado; Vissing, John; Krag, Thomas O

2012-03-23

Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration. We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers. We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene. Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes.

Mutations in the ABCA4 (ABCR) Gene Are the Major Cause of Autosomal Recessive Cone-Rod Dystrophy

PubMed Central

Maugeri, Alessandra; Klevering, B. Jeroen; Rohrschneider, Klaus; Blankenagel, Anita; Brunner, Han G.; Deutman, August F.; Hoyng, Carel B.; Cremers, Frans P. M.

2000-01-01

The photoreceptor cell–specific ATP-binding cassette transporter gene (ABCA4; previously denoted “ABCR”) is mutated in most patients with autosomal recessive (AR) Stargardt disease (STGD1) or fundus flavimaculatus (FFM). In addition, a few cases with AR retinitis pigmentosa (RP) and AR cone-rod dystrophy (CRD) have been found to have ABCA4 mutations. To evaluate the importance of the ABCA4 gene as a cause of AR CRD, we selected 5 patients with AR CRD and 15 patients with isolated CRD, all from Germany and The Netherlands . Single-strand conformation–polymorphism analysis and sequencing revealed 19 ABCA4 mutations in 13 (65%) of 20 patients. In six patients, mutations were identified in both ABCA4 alleles; in seven patients, mutations were detected in one allele. One complex ABCA4 allele (L541P;A1038V) was found exclusively in German patients with CRD; one patient carried this complex allele homozygously, and five others were compound heterozygous. These findings suggest that mutations in the ABCA4 gene are the major cause of AR CRD. A primary role of the ABCA4 gene in STGD1/FFM and AR CRD, together with the gene's involvement in an as-yet-unknown proportion of cases with AR RP, strengthens the idea that mutations in the ABCA4 gene could be the most frequent cause of inherited retinal dystrophy in humans. PMID:10958761

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.

PubMed

Audo, Isabelle; Bujakowska, Kinga; Mohand-Saïd, Saddek; Tronche, Sophie; Lancelot, Marie-Elise; Antonio, Aline; Germain, Aurore; Lonjou, Christine; Carpentier, Wassila; Sahel, José-Alain; Bhattacharya, Shomi; Zeitz, Christina

2011-01-01

To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition. A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.

Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weiler, T.; Nylen, E.; Wrogemann, K.

1996-10-01

We report the results of our investigations of a large, inbred, aboriginal Canadian kindred with nine muscular dystrophy patients. The ancestry of all but two of the carrier parents could be traced to a founder couple, seven generations back. Seven patients presented with proximal myopathy consistent with limb girdle-type muscular dystrophy (LGMD), whereas two patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy (distal autosomal recessive muscular dystrophy) (MM). Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MM is consistent with autosomal recessive inheritance, and themore » putative locus is significantly linked (LOD scores >3.0) to six marker loci that span the region of the LGMD2B locus on chromosome 2p. Our initial hypothesis that the affected patients would all be homozygous by descent for microsatellite markers surrounding the disease locus was rejected. Rather, two different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating that there are two mutant alleles of independent origin in this kindred. There was no association, however, between the two different haplotypes and clinical variability; they do not distinguish between the LGMD and MM phenotypes. Thus, we conclude that LGMD and MM in our population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must contribute to the clinical phenotype. 37 refs., 2 figs., 2 tabs.« less

Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pegoraro, E.; Wessel, H.B.; Schwartz, L.

1994-06-01

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carries who show preferential inactivation ofmore » the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here the authors study X-inactivation patterns of 13 female dystrophinopathy patients - 10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. They show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in the assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, the results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. The results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients. 58 refs., 7 figs., 2 tabs.« less

Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

PubMed

Witting, N; Duno, M; Vissing, J

2013-01-01

Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. Copyright © 2012 Elsevier B.V. All rights reserved.

Fuchs' dystrophy associated with radial keratotomy: Lamellar or perforating keratoplasty?

PubMed

Rodriguez-Ausin, P; Antolin-Garcia, D; Santamaria Garcia, L; Blazquez-Fernandez, A-B

2017-05-01

A 70 year-old male patient with a history of radial keratotomy suffering from Fuchs' dystrophy and a cataract. The patient received a two-step surgery: lens phacoemulsification and intraocular lens implant, followed by descemet stripping automated endothelial keratoplasty in both eyes, four months later. There were no complications apart from a recurrent cystoid macular oedema in both eyes. The best corrected visual acuity was 20/40 both eyes, and the patient was satisfied. Descemet stripping automated endothelial keratoplasty may be considered as an alternative to penetrating keratoplasty in the case of endothelial dysfunction and radial keratotomy in patients with no corneal ectasia or significant stromal opacity. Copyright © 2016 Sociedad Española de Oftalmología. Publicado por Elsevier España, S.L.U. All rights reserved.

A Human Pluripotent Stem Cell Model of Facioscapulohumeral Muscular Dystrophy-Affected Skeletal Muscles.

PubMed

Caron, Leslie; Kher, Devaki; Lee, Kian Leong; McKernan, Robert; Dumevska, Biljana; Hidalgo, Alejandro; Li, Jia; Yang, Henry; Main, Heather; Ferri, Giulia; Petek, Lisa M; Poellinger, Lorenz; Miller, Daniel G; Gabellini, Davide; Schmidt, Uli

2016-09-01

: Facioscapulohumeral muscular dystrophy (FSHD) represents a major unmet clinical need arising from the progressive weakness and atrophy of skeletal muscles. The dearth of adequate experimental models has severely hampered our understanding of the disease. To date, no treatment is available for FSHD. Human embryonic stem cells (hESCs) potentially represent a renewable source of skeletal muscle cells (SkMCs) and provide an alternative to invasive patient biopsies. We developed a scalable monolayer system to differentiate hESCs into mature SkMCs within 26 days, without cell sorting or genetic manipulation. Here we show that SkMCs derived from FSHD1-affected hESC lines exclusively express the FSHD pathogenic marker double homeobox 4 and exhibit some of the defects reported in FSHD. FSHD1 myotubes are thinner when compared with unaffected and Becker muscular dystrophy myotubes, and differentially regulate genes involved in cell cycle control, oxidative stress response, and cell adhesion. This cellular model will be a powerful tool for studying FSHD and will ultimately assist in the development of effective treatments for muscular dystrophies. This work describes an efficient and highly scalable monolayer system to differentiate human pluripotent stem cells (hPSCs) into skeletal muscle cells (SkMCs) and demonstrates disease-specific phenotypes in SkMCs derived from both embryonic and induced hPSCs affected with facioscapulohumeral muscular dystrophy. This study represents the first human stem cell-based cellular model for a muscular dystrophy that is suitable for high-throughput screening and drug development. ©AlphaMed Press.

Benzalkonium Chloride Accelerates the Formation of the Amyloid Fibrils of Corneal Dystrophy-associated Peptides*

PubMed Central

Kato, Yusuke; Yagi, Hisashi; Kaji, Yuichi; Oshika, Tetsuro; Goto, Yuji

2013-01-01

Corneal dystrophies are genetic disorders resulting in progressive corneal clouding due to the deposition of amyloid fibrils derived from keratoepithelin, also called transforming growth factor β-induced protein (TGFBI). The formation of amyloid fibrils is often accelerated by surfactants such as sodium dodecyl sulfate (SDS). Most eye drops contain benzalkonium chloride (BAC), a cationic surfactant, as a preservative substance. In the present study, we aimed to reveal the role of BAC in the amyloid fibrillation of keratoepithelin-derived peptides in vitro. We used three types of 22-residue synthetic peptides covering Leu110-Glu131 of the keratoepithelin sequence: an R-type peptide with wild-type R124, a C-type peptide with C124 associated with lattice corneal dystrophy type I, and a H-type peptide with H124 associated with granular corneal dystrophy type II. The time courses of spontaneous amyloid fibrillation and seed-dependent fibril elongation were monitored in the presence of various concentrations of BAC or SDS using thioflavin T fluorescence. BAC and SDS accelerated the fibrillation of all synthetic peptides in the absence and presence of seeds. Optimal acceleration occurred near the CMC, which suggests that the unstable and dynamic interactions of keratoepithelin peptides with amphipathic surfactants led to the formation of fibrils. These results suggest that eye drops containing BAC may deteriorate corneal dystrophies and that those without BAC are preferred especially for patients with corneal dystrophies. PMID:23861389

Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy.

PubMed

Hathout, Yetrib; Brody, Edward; Clemens, Paula R; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H Lee; Williams, Steve; Gold, Larry

2015-06-09

Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases.

CLINICAL PROGRESS IN INHERITED RETINAL DEGENERATIONS: GENE THERAPY CLINICAL TRIALS AND ADVANCES IN GENETIC SEQUENCING

PubMed Central

HAFLER, BRIAN P.

2017-01-01

Purpose Inherited retinal dystrophies are a significant cause of vision loss and are characterized by the loss of photoreceptors and the retinal pigment epithelium (RPE). Mutations in approximately 250 genes cause inherited retinal degenerations with a high degree of genetic heterogeneity. New techniques in next-generation sequencing are allowing the comprehensive analysis of all retinal disease genes thus changing the approach to the molecular diagnosis of inherited retinal dystrophies. This review serves to analyze clinical progress in genetic diagnostic testing and implications for retinal gene therapy. Methods A literature search of PubMed and OMIM was conducted to relevant articles in inherited retinal dystrophies. Results Next-generation genetic sequencing allows the simultaneous analysis of all the approximately 250 genes that cause inherited retinal dystrophies. Reported diagnostic rates range are high and range from 51% to 57%. These new sequencing tools are highly accurate with sensitivities of 97.9% and specificities of 100%. Retinal gene therapy clinical trials are underway for multiple genes including RPE65, ABCA4, CHM, RS1, MYO7A, CNGA3, CNGB3, ND4, and MERTK for which a molecular diagnosis may be beneficial for patients. Conclusion Comprehensive next-generation genetic sequencing of all retinal dystrophy genes is changing the paradigm for how retinal specialists perform genetic testing for inherited retinal degenerations. Not only are high diagnostic yields obtained, but mutations in genes with novel clinical phenotypes are also identified. In the era of retinal gene therapy clinical trials, identifying specific genetic defects will increasingly be of use to identify patients who may enroll in clinical studies and benefit from novel therapies. PMID:27753762

Generation of induced pluripotent stem cells from a patient with Best Dystrophy carrying 11q12.3 (BEST1 (VMD2)) mutation.

PubMed

Hsu, Chih-Chien; Lu, Huai-En; Chuang, Jen-Hua; Ko, Yu-Ling; Tsai, Yi-Ching; Tai, Hsiao-Yun; Yarmishyn, Aliaksandr A; Hwang, De-Kuang; Wang, Mong-Lien; Yang, Yi-Ping; Chen, Shih-Jen; Peng, Chi-Hsien; Chiou, Shih-Hwa; Lin, Tai-Chi

2018-04-03

Best disease (BD), also termed Best vitelliform macular dystrophy (BVMD), is a juvenile-onset form of macular degeneration and central visual loss. In this report, we generated an induced pluripotent stem cell (iPSC) line, TVGH-iPSC-012-04, from the peripheral blood mononuclear cells of a female patient with BD by using the Sendai virus delivery system. The resulting iPSCs retained the disease-causing DNA mutation, expressed pluripotent markers and could differentiate into three germ layers. We believe that BD patient-specific iPSCs provide a powerful in vitro model for evaluating the pathological phenotypes of the disease. Copyright © 2018. Published by Elsevier B.V.

Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

PubMed

Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

2014-04-01

New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons.

Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

PubMed

Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

2013-03-01

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy?

PubMed

Bakker, H D; de Sonnaville, M L; Vreken, P; Abeling, N G; Groener, J E; Keulemans, J L; van Diggelen, O P

2001-02-01

Two new individuals with alpha-NAGA deficiency are presented. The index patient, 3 years old, has congenital cataract, slight motor retardation and secondary demyelinisation. Screening of his sibs revealed an alpha-NAGA deficiency in his 7-year-old healthy brother who had no clinical or neurological symptoms. Both sibs are homozygous for the E325K mutation, the same genotype that was found in the most severe form of alpha-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of alpha-NAGA may present as a 'non-disease' (present healthy case) and can be associated with the vegetative state (the first two patients described with alpha-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with alpha-NAGA deficiency is extreme, with a 'non-disease' (two cases) and infantile neuroaxonal dystrophy (two cases) at the opposite sides of the clinical spectrum. The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have angiokeratoma and clear vacuolisation in various cell types (three cases). These observations are difficult to reconcile with a straightforward genotype-phenotype correlation and suggest that factors or genes other than alpha-NAGA contribute to the clinical heterogeneity of the 11 patients with alpha-NAGA deficiency.

Progression and variation of fatty infiltration of the thigh muscles in Duchenne muscular dystrophy, a muscle magnetic resonance imaging study.

PubMed

Li, Wenzhu; Zheng, Yiming; Zhang, Wei; Wang, Zhaoxia; Xiao, Jiangxi; Yuan, Yun

2015-05-01

The purpose of this study was to assess the progression and variation of fatty infiltration of the thigh muscles of Duchenne muscular dystrophy patients. Muscle magnetic resonance imaging was used to measure the degree of fatty infiltration of the thigh muscles of 171 boys with Duchenne muscular dystrophy (mean age, 6.09 ± 2.30 years). Fatty infiltration was assigned using a modified Mercuri's scale 0-5 (normal-severe). The gluteus maximus and adductor magnus were affected in patients less than two years old, followed by the biceps femoris. Quadriceps and semimembranosus were first affected at the age of five to six years; the sartorius, gracilis and adductor longus remained apparently unaffected until seven years of age. Fatty infiltration of all the thigh muscles developed rapidly after seven years of age. The standard deviation of the fatty infiltration scores ranged from 2.41 to 4.87 before five years old, and from 6.84 to 11.66 between six and ten years old. This study provides evidence of highly variable degrees of fatty infiltration in children of different ages with Duchenne muscular dystrophy, and indicates that fatty infiltration progresses more quickly after seven years of age. These findings may be beneficial for the selection of therapeutic regimens and the analysis of future clinical trials. Copyright © 2015 Elsevier B.V. All rights reserved.

Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids (DELOS): a double-blind randomised placebo-controlled phase 3 trial.

PubMed

Buyse, Gunnar M; Voit, Thomas; Schara, Ulrike; Straathof, Chiara S M; D'Angelo, M Grazia; Bernert, Günther; Cuisset, Jean-Marie; Finkel, Richard S; Goemans, Nathalie; McDonald, Craig M; Rummey, Christian; Meier, Thomas

2015-05-02

Cardiorespiratory failure is the leading cause of death in Duchenne muscular dystrophy. Based on preclinical and phase 2 evidence, we assessed the efficacy and safety of idebenone in young patients with Duchenne muscular dystrophy who were not taking concomitant glucocorticoids. In a multicentre phase 3 trial in Belgium, Germany, the Netherlands, Switzerland, France, Sweden, Austria, Italy, Spain, and the USA, patients (age 10-18 years old) with Duchenne muscular dystrophy were randomly assigned in a one-to-one ratio with a central interactive web response system with a permuted block design with four patients per block to receive idebenone (300 mg three times a day) or matching placebo orally for 52 weeks. Study personnel and patients were masked to treatment assignment. The primary endpoint was change in peak expiratory flow (PEF) as percentage predicted (PEF%p) from baseline to week 52, measured with spirometry. Analysis was by intention to treat (ITT) and a modified ITT (mITT), which was prospectively defined to exclude patients with at least 20% difference in the yearly change in PEF%p, measured with hospital-based and weekly home-based spirometry. This study is registered with ClinicalTrials.gov, number NCT01027884. 31 patients in the idebenone group and 33 in the placebo group comprised the ITT population, and 30 and 27 comprised the mITT population. Idebenone significantly attenuated the fall in PEF%p from baseline to week 52 in the mITT (-3·05%p [95% CI -7·08 to 0·97], p=0·134, vs placebo -9·01%p [-13·18 to -4·84], p=0·0001; difference 5·96%p [0·16 to 11·76], p=0·044) and ITT populations (-2·57%p [-6·68 to 1·54], p=0·215, vs -8·84%p [-12·73 to -4·95], p<0·0001; difference 6·27%p [0·61 to 11·93], p=0·031). Idebenone also had a significant effect on PEF (L/min), weekly home-based PEF, FVC, and FEV1. The effect of idebenone on respiratory function outcomes was similar between patients with previous corticosteroid use and steroid-naive patients. Treatment with idebenone was safe and well tolerated with adverse event rates were similar in both groups. Nasopharyngitis and headache were the most common adverse events (idebenone, eight [25%] and six [19%] of 32 patients; placebo, nine [26%] and seven [21%] of 34 patients). Transient and mild diarrhoea was more common in the idebenone group than in the placebo group (eight [25%] vs four [12%] patients). Idebenone reduced the loss of respiratory function and represents a new treatment option for patients with Duchenne muscular dystrophy. Santhera Pharmaceuticals. Copyright © 2015 Elsevier Ltd. All rights reserved.

An epidemiological approach for the estimation of disease onset in Central Europe in central and peripheral monogenic retinal dystrophies.

PubMed

Prokofyeva, Elena; Wilke, Robert; Lotz, Gunnar; Troeger, Eric; Strasser, Torsten; Zrenner, Eberhart

2009-07-01

To study clinical patterns of disease onset in monogenic retinal dystrophies (MRD), using an epidemiological approach. Records of patients with MRD, seen at the University Eye Hospital Tuebingen from 1994 to 1999, were selected from a database and retrospectively reviewed. For analysis, patients were divided into 2 groups by predominant part of visual field (VF) involvement: group 1 (predominantly central involvement) included Stargardt disease (ST), macular dystrophy (MD), and central areolar choroidal dystrophy (CACD), and group 2 (predominantly peripheral involvement) included Bardet-Biedl syndrome (BBD), Usher syndrome (USH) I and II, and choroideremia (CHD). Age, sex, age of first diagnosis, age of visual acuity (VA) decrease and VF emergence, night blindness and photophobia onset, types of VF defects and age of its onset, color discrimination defects and best corrected VA were analyzed. Records of 259 patients were studied. Men were more prevalent than women. Mean age of the patients was 47.2 (SD = 15.6) years old. Forty-five patients in the first group and 40 in the second were first diagnosed between 21 and 30 years of age. Ninety-four patients in the first group had VA decrease before 30 years of age; in the second group, 68 patients had VA decrease onset between 21 and 40 years of age. Forty-four patients in the first group noticed VF at an age between 21 and 30 years, and 74 patients between 11 and 30 years in the second group. Central scotoma was typical for the first group, and was detected in 115 patients. Concentric constriction was typical for the second group, and was found in 81 patients. Half of patients in both groups preserved best-corrected VA in the better eye at a level of 20/40 or better; 7% in the first group and 6% in the second group were registered as legally blind according to WHO criteria, having VA <1/50 or VF <5 degrees . Diagnosis frequency was USH I and II-34%, ST-31%, MD-18%, CHD-14%, BBD-5%. An epidemiological approach to the estimation of the disease onset of various subtypes of monogenic retinal degenerations will be useful for detection of disease duration, its prognosis, rehabilitation and the researching of future treatment possibilities.

[Diagnosis and treatment of duodenal dystrophy in patients with chronic pancreatitis].

PubMed

Kriger, A G; Smirnov, A V; Berelavichus, S V; Gorin, D S; Karmazanovskiy, G G; Vetsheva, N N; Nerestyuk, Ya I; Kalinin, D V; Glotov, A V

to define optimal treatment of duodenal dystrophy in patients with chronic pancreatitis. 515 patients with chronic pancreatitis have been treated for the period 2004-2015 in A.V.Vishnevsky Institute of Surgery. Duodenal dystrophy (DD) was diagnosed in 79 (15.3%) of them. The diagnosis was confirmed by sonography, CT, MRI and endosonography. 5 patients are under observation without surgery. 74 patients were operated after previous medical therapy during 39 months on the average. Pancreatoduodenectomy was performed in 36 patients. Organ-sparing interventions were applied in 34 cases including different duodenal resections in 20 patients and pancreatic head resections in different modifications in 14 cases. 4 patients underwent palliative surgery. Chronic pancreatitis and DD were verified by morphological analysis of specimens. Long-term results were estimated in 47 patients. Median follow-up was 49.9 months. X-ray diagnostics showed that DD was combined with chronic pancreatitis in 87.3% of cases while morphological analysis revealed 93.8%. Clinical signs of DD were caused by striated pancreatitis in 69.6% and ectopic pancreatic tissue in 30.4%. Clinical manifestations of DD did not depend on its cause and were presented by symptoms of chronic pancreatitis. Postoperative complications occurred in 25 (34.7%) patients. There were 33.5% of complications after pancreatoduodenectomy and 70% after duodenal resection. 1 patient died. Overall mortality was 1,3%. In long-term period complete regression of symptoms was observed in 66% of cases, significant improvement - in 32%, absence of the effect - in 2%. Medical therapy should be preferred for patients with DD and chronic pancreatitis. Surgery is indicated in case of persistent pain, complicated course of chronic pancreatitis and duodenal obstruction. Pancreatoduodenectomy and pancreatic head resection are preferred.

Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture

PubMed Central

Woodman, Keryn G.; Coles, Chantal A.; Lamandé, Shireen R.; White, Jason D.

2016-01-01

In recent years, complementary and alternative medicine has become increasingly popular. This trend has not escaped the Duchenne Muscular Dystrophy community with one study showing that 80% of caregivers have provided their Duchenne patients with complementary and alternative medicine in conjunction with their traditional treatments. These statistics are concerning given that many supplements are taken based on purely “anecdotal” evidence. Many nutraceuticals are thought to have anti-inflammatory or anti-oxidant effects. Given that dystrophic pathology is exacerbated by inflammation and oxidative stress these nutraceuticals could have some therapeutic benefit for Duchenne Muscular Dystrophy (DMD). This review gathers and evaluates the peer-reviewed scientific studies that have used nutraceuticals in clinical or pre-clinical trials for DMD and thus separates the credible from the conjecture. PMID:27834844

Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture.

PubMed

Woodman, Keryn G; Coles, Chantal A; Lamandé, Shireen R; White, Jason D

2016-11-09

In recent years, complementary and alternative medicine has become increasingly popular. This trend has not escaped the Duchenne Muscular Dystrophy community with one study showing that 80% of caregivers have provided their Duchenne patients with complementary and alternative medicine in conjunction with their traditional treatments. These statistics are concerning given that many supplements are taken based on purely "anecdotal" evidence. Many nutraceuticals are thought to have anti-inflammatory or anti-oxidant effects. Given that dystrophic pathology is exacerbated by inflammation and oxidative stress these nutraceuticals could have some therapeutic benefit for Duchenne Muscular Dystrophy (DMD). This review gathers and evaluates the peer-reviewed scientific studies that have used nutraceuticals in clinical or pre-clinical trials for DMD and thus separates the credible from the conjecture.

Late-onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings.

PubMed

Beltran Papsdorf, Tania; Howard, James F; Chahin, Nizar

2015-11-01

The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy. © 2015 Wiley Periodicals, Inc.

Upper Girdle Imaging in Facioscapulohumeral Muscular Dystrophy

PubMed Central

Tasca, Giorgio; Monforte, Mauro; Iannaccone, Elisabetta; Laschena, Francesco; Ottaviani, Pierfrancesco; Leoncini, Emanuele; Boccia, Stefania; Galluzzi, Giuliana; Pelliccioni, Marco; Masciullo, Marcella; Frusciante, Roberto; Mercuri, Eugenio; Ricci, Enzo

2014-01-01

Background In Facioscapulohumeral muscular dystrophy (FSHD), the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment. Methods We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed. Results The trapezius (100% of the patients) and serratus anterior (85% of the patients) were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients) were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR) sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies. Conclusions The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease. PMID:24932477

Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy: A Randomized Clinical Trial.

PubMed

Silva, Marly Conceição; Magalhães, Tiago Augusto; Meira, Zilda Maria Alves; Rassi, Carlos Henrique Reis Esselin; Andrade, Amanda Cristina de Souza; Gutierrez, Paulo Sampaio; Azevedo, Clerio Francisco; Gurgel-Giannetti, Juliana; Vainzof, Mariz; Zatz, Mayana; Kalil-Filho, Roberto; Rochitte, Carlos Eduardo

2017-02-01

In Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), interventions reducing the progression of myocardial disease could affect survival. To assess the effect of early angiotensin-converting enzyme (ACE) inhibitor therapy in patients with normal left ventricular function on the progression of myocardial fibrosis (MF) identified on cardiovascular magnetic resonance (CMR). A randomized clinical trial conducted in 2 centers included 76 male patients with DMD or BMD undergoing 2 CMR studies with a 2-year interval for ventricular function and MF assessment. In a non-intent-to-treat trial, 42 patients with MF and normal left ventricular ejection fraction (LVEF) were randomized (1:1) to receive or not receive ACE inhibitor therapy. The study was conducted from June 26, 2009, to June 30, 2012. Data analysis was performed from June 30, 2013, to October 3, 2016. Randomization (1:1) to receive or not receive ACE inhibitor therapy. Primary outcome was MF progression from baseline to the 2-year CMR study. Of the 76 male patients included in the study, 70 had DMD (92%) and 6 had BMD (8%); mean (SD) age at baseline was 13.1 (4.4) years. Myocardial fibrosis was present in 55 patients (72%) and LV systolic dysfunction was identified in 13 patients (24%). Myocardial fibrosis at baseline was an independent indicator of lower LVEF at follow-up (coefficient [SE], -0.16 [0.07]; P = .03). Among patients with MF and preserved LVEF (42 [55%]), those randomized (21 patients in each arm) to receive ACE inhibitors demonstrated slower MF progression compared with the untreated group (mean [SD] increase of 3.1% [7.4%] vs 10.0% [6.2%] as a percentage of LV mass; P = .001). In multivariate analysis, ACE inhibitor therapy was an independent indicator of decreased MF progression (coefficient [SE], -4.51 [2.11]; P = .04). Patients with MF noted on CMR had a higher probability of cardiovascular events (event rate, 10 of 55 [18.2%] vs 0 of 21 [0%]; log-rank P = .04). In this 2-year, follow-up, randomized clinical trial of patients with Duchenne or Becker muscular dystrophy whose LVEF was preserved and MF was present as determined on CMR, ACE inhibitor therapy was associated with significantly slower progression of MF. The presence of MF was associated with worse patient prognosis. clinicaltrials.org Identifier: NCT02432885.

Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies

PubMed Central

Ayoglu, Burcu; Chaouch, Amina; Lochmüller, Hanns; Politano, Luisa; Bertini, Enrico; Spitali, Pietro; Hiller, Monika; Niks, Eric H; Gualandi, Francesca; Pontén, Fredrik; Bushby, Kate; Aartsma-Rus, Annemieke; Schwartz, Elena; Le Priol, Yannick; Straub, Volker; Uhlén, Mathias; Cirak, Sebahattin; ‘t Hoen, Peter A C; Muntoni, Francesco; Ferlini, Alessandra; Schwenk, Jochen M; Nilsson, Peter; Al-Khalili Szigyarto, Cristina

2014-01-01

Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. PMID:24920607