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.

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

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 ...

Novel mutations in the CHST6 gene associated with macular corneal dystrophy in southern India.

PubMed

Warren, John F; Aldave, Anthony J; Srinivasan, M; Thonar, Eugene J; Kumar, Abha B; Cevallos, Vicky; Whitcher, John P; Margolis, Todd P

2003-11-01

To further characterize the role of the carbohydrate sulfotransferase (CHST6) gene in macular corneal dystrophy (MCD) through identification of causative mutations in a cohort of affected patients from southern India. Genomic DNA was extracted from buccal epithelium of 75 patients (51 families) with MCD, 33 unaffected relatives, and 48 healthy volunteers. The coding region of the CHST6 gene was evaluated by means of polymerase chain reaction amplification and direct sequencing. Subtyping of MCD into types I and II was performed by measuring serum levels of antigenic keratan sulfate. Seventy patients were classified as having type I MCD, and 5 patients as having type II MCD. Analysis of the CHST6 coding region in patients with type I MCD identified 11 homozygous missense mutations (Leu22Arg, His42Tyr, Arg50Cys, Arg50Leu, Ser53Leu, Arg97Pro, Cys102Tyr, Arg127Cys, Arg205Gln, His249Pro, and Glu274Lys), 2 compound heterozygous missense mutations (Arg93His and Ala206Thr), 5 homozygous deletion mutations (delCG707-708, delC890, delA1237, del1748-1770, and delORF), and 2 homozygous replacement mutations (ACCTAC 1273 GGT, and GCG 1304 AT). One patient with type II MCD was heterozygous for the C890 deletion mutation, whereas 4 possessed no CHST6 coding region mutations. A variety of previously unreported mutations in the coding region of the CHST6 gene are associated with type I MCD in a cohort of patients in southern India. An improved understanding of the genetic basis of MCD allows for earlier, more accurate diagnosis of affected individuals, and may provide the foundation for the development of novel disease treatments.

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.

Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism

PubMed Central

Meola, Giovanni; Cardani, Rosanna

2015-01-01

Abstract 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) is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) is caused by a (CCTG)n expansion in CNBP. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders. The pathogenesis of DM is explained by a common RNA gain-of-function mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. However additional pathogenic mechanism like changes in gene expression, modifier genes, protein translation and micro-RNA metabolism may also contribute to disease pathology and to clarify the phenotypic differences between these two types of myotonic dystrophies. This review is an update on the latest findings specific to DM2, including explanations for the differences in clinical manifestations and pathophysiology between the two forms of myotonic dystrophies. PMID:27858759

[Myotonic dystrophy - a new insight into a well-known disease].

PubMed

Lusakowska, Anna; Sułek-Piatkowska, Anna

2010-01-01

Myotonic dystrophy (DM), the most common dystrophy in adults, is an autosomal dominant disease characterized by a variety of multisystemic features. Two genetically distinct forms of DM are identified - type 1 (DM1), the classic form first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is caused by trinucleotide expansion of CTG in the myotonic dystrophy protein kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in the zinc finger protein 9 gene was identified. Both mutations are dynamic and are located in non-coding parts of the genes. Phenotype variability of DM1 and DM2 is caused by a molecular mechanism due to mutated RNA toxicity. This paper reviews the clinical features of both types of myotonic dystrophies and summarizes current views on pathogenesis of myotonic dystrophy.

Sleep-Wake Cycle and Daytime Sleepiness in the Myotonic Dystrophies

PubMed Central

Romigi, A.; Albanese, M.; Liguori, C.; Placidi, F.; Marciani, M. G.; Massa, R.

2013-01-01

Myotonic dystrophy is the most common type of muscular dystrophy in adults and is characterized by progressive myopathy, myotonia, and multiorgan involvement. Two genetically distinct entities have been identified, myotonic dystrophy type 1 (DM1 or Steinert's Disease) and myotonic dystrophy type 2 (DM2). Myotonic dystrophies are strongly associated with sleep dysfunction. Sleep disturbances in DM1 are common and include sleep-disordered breathing (SDB), periodic limb movements (PLMS), central hypersomnia, and REM sleep dysregulation (high REM density and narcoleptic-like phenotype). Interestingly, drowsiness in DM1 seems to be due to a central dysfunction of sleep-wake regulation more than SDB. To date, little is known regarding the occurrence of sleep disorders in DM2. SDB (obstructive and central apnoea), REM sleep without atonia, and restless legs syndrome have been described. Further polysomnographic, controlled studies are strongly needed, particularly in DM2, in order to clarify the role of sleep disorders in the myotonic dystrophies. PMID:26316996

Epiretinal membrane: a treatable cause of visual disability in myotonic dystrophy type 1.

PubMed

Kersten, Hannah M; Roxburgh, Richard H; Child, Nicholas; Polkinghorne, Philip J; Frampton, Chris; Danesh-Meyer, Helen V

2014-01-01

A wide range of ocular abnormalities have been documented to occur in patients with myotonic dystrophy type 1. The objectives of this study were to investigate the macular and optic nerve morphology using optical coherence tomography in patients with myotonic dystrophy type 1. A total of 30 myotonic dystrophy type 1 patients and 28 controls were recruited for participation. All participants underwent a thorough ophthalmologic examination, including spectral-domain optical coherence tomography of the macula and retinal nerve fibre layer. Images were reviewed by a retinal specialist ophthalmologist, masked to the diagnosis of the participants. Average macular thickness was significantly greater in the myotonic dystrophy group compared to controls [327.3 μm vs. 308.5 μm (p < 0.001)]. Macular thickness was significantly greater (p < 0.005) in five of the nine macular regions. The increase in macular thickness was due to the increased prevalence of epiretinal membranes in the myotonic dystrophy patient group (p = 0.0002): 48.2 % of myotonic dystrophy patient eyes had evidence of epiretinal membrane, compared with 12.5 % of control eyes. Examination revealed that 56.7 % of myotonic dystrophy patients had an epiretinal membrane in at least one eye. Visual acuity was reduced due to the presence of epiretinal membrane in six patient eyes and none of the control eyes. The presence of an epiretinal membrane was significantly correlated with increasing age in the patient group. We report an increased prevalence of epiretinal membrane in the myotonic dystrophy type 1 group. This may be a previously under-recognised form of visual impairment in this group. Epiretinal membranes can be treated surgically. We suggest that, in addition to a comprehensive clinical examination, optical coherence tomography examination is implemented as part of an ophthalmological assessment for the myotonic dystrophy type 1 patient with reduced visual acuity.

Immunophenotypes of macular corneal dystrophy in India and correlation with mutations in CHST6.

PubMed

Sultana, Afia; Klintworth, Gordon K; Thonar, Eugene J-M A; Vemuganti, Geeta K; Kannabiran, Chitra

2009-01-01

To determine the immunophenotypes of macular corneal dystrophy (MCD) in Indian patients and to correlate them with mutations in the carbohydrate 6-sulfotransferase (CHST6) gene. Sixty-four patients from 53 families with MCD that were previously screened for mutations in CHST6 were included in an immunophenotype analysis. Antigenic keratan sulfate (AgKS) in serum as well as corneal tissue was evaluated in 31 families. Only cornea was evaluated in 11 families, and only serum was evaluated in 11 families. AgKS was detected in formalin-fixed, paraffin-embedded corneal sections by immunohistochemistry and in serum by ELISA using a monoclonal antibody against sulfated forms of KS in patients with MCD as well as normal controls. Analysis of corneal and/or serum AgKS disclosed MCD type I (27 families), MCD type IA (5 families), and MCD type II (3 families) in the cases studied. An additional 10 families were either MCD type I or MCD type IA since only serum AgKS data were available. Seven families manifested atypical immunophenotypes since the corneal AgKS expression was either of MCD type I or MCD type IA, but serum AgKS levels ranged from 19 ng/ml to 388 ng/ml. More than one immunophenotype was detected amongst siblings in two families. Each immunophenotype was associated with mutational heterogeneity in CHST6. MCD type I was the predominant immunophenotype in the Indian population studied followed by MCD type IA and then MCD type II. We detected further immunophenotypic heterogeneity by finding atypical patterns of AgKS reactivity in a subset of families. There were no simple correlations between immunophenotypes and specific mutations in CHST6, suggesting that factors other than CHST6 mutations may be contributing to the immunophenotypes in MCD.

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

Changes in Muscle Metabolism are Associated with Phenotypic Variability in Golden Retriever Muscular Dystrophy




PubMed Central

Nghiem, Peter P.; Bello, Luca; Stoughton, William B.; López, Sara Mata; Vidal, Alexander H.; Hernandez, Briana V.; Hulbert, Katherine N.; Gourley, Taylor R.; Bettis, Amanda K.; Balog-Alvarez, Cynthia J.; Heath-Barnett, Heather; Kornegay, Joe N.

2017-01-01

Duchenne muscular dystrophy (DMD) is an X-chromosome-linked disorder and the most common monogenic disease in people. Affected boys are diagnosed at a young age, become non-ambulatory by their early teens, and succumb to cardiorespiratory failure by their thirties. Despite being a monogenic condition resulting from mutations in the DMD gene, affected boys have noteworthy phenotypic variability. Efforts have identified genetic modifiers that could modify disease progression and be pharmacologic targets. Dogs affected with golden retriever muscular dystrophy (GRMD) have absent dystrophin and demonstrate phenotypic variability at the functional, histopathological, and molecular level. Our laboratory is particularly interested in muscle metabolism changes in dystrophin-deficient muscle. We identified several metabolic alterations, including myofiber type switching from fast (type II) to slow (type I), reduced glycolytic enzyme expression, reduced and morphologically abnormal mitochondria, and differential AMP-kinase phosphorylation (activation) between hypertrophied and wasted muscle. We hypothesize that muscle metabolism changes are, in part, responsible for phenotypic variability in GRMD. Pharmacological therapies aimed at modulating muscle metabolism can be tested in GRMD dogs for efficacy. PMID:28955176

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

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

Survey of Canadian Myotonic Dystrophy Patients' Access to Computer Technology.

PubMed

Climans, Seth A; Piechowicz, Christine; Koopman, Wilma J; Venance, Shannon L

2017-09-01

Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.

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

Immunophenotypes of macular corneal dystrophy in India and correlation with mutations in CHST6

PubMed Central

Klintworth, Gordon K.; Thonar, Eugene J-M.A.; Vemuganti, Geeta K.; Kannabiran, Chitra

2009-01-01

Purpose To determine the immunophenotypes of macular corneal dystrophy (MCD) in Indian patients and to correlate them with mutations in the carbohydrate 6-sulfotransferase (CHST6) gene. Methods Sixty-four patients from 53 families with MCD that were previously screened for mutations in CHST6 were included in an immunophenotype analysis. Antigenic keratan sulfate (AgKS) in serum as well as corneal tissue was evaluated in 31 families. Only cornea was evaluated in 11 families, and only serum was evaluated in 11 families. AgKS was detected in formalin-fixed, paraffin-embedded corneal sections by immunohistochemistry and in serum by ELISA using a monoclonal antibody against sulfated forms of KS in patients with MCD as well as normal controls. Results Analysis of corneal and/or serum AgKS disclosed MCD type I (27 families), MCD type IA (5 families), and MCD type II (3 families) in the cases studied. An additional 10 families were either MCD type I or MCD type IA since only serum AgKS data were available. Seven families manifested atypical immunophenotypes since the corneal AgKS expression was either of MCD type I or MCD type IA, but serum AgKS levels ranged from 19 ng/ml to 388 ng/ml. More than one immunophenotype was detected amongst siblings in two families. Each immunophenotype was associated with mutational heterogeneity in CHST6. Conclusions MCD type I was the predominant immunophenotype in the Indian population studied followed by MCD type IA and then MCD type II. We detected further immunophenotypic heterogeneity by finding atypical patterns of AgKS reactivity in a subset of families. There were no simple correlations between immunophenotypes and specific mutations in CHST6, suggesting that factors other than CHST6 mutations may be contributing to the immunophenotypes in MCD. PMID:19204788

The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.

PubMed

David, G; Giunti, P; Abbas, N; Coullin, P; Stevanin, G; Horta, W; Gemmill, R; Weissenbach, J; Wood, N; Cunha, S; Drabkin, H; Harding, A E; Agid, Y; Brice, A

1996-12-01

Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II.

The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.

PubMed Central

David, G.; Giunti, P.; Abbas, N.; Coullin, P.; Stevanin, G.; Horta, W.; Gemmill, R.; Weissenbach, J.; Wood, N.; Cunha, S.; Drabkin, H.; Harding, A. E.; Agid, Y.; Brice, A.

1996-01-01

Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II. PMID:8940279

Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H

PubMed Central

Kudryashova, Elena; Kramerova, Irina; Spencer, Melissa J.

2012-01-01

Mutations in the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) are responsible for the disease limb-girdle muscular dystrophy 2H (LGMD2H). Previously, we generated Trim32 knockout mice (Trim32–/– mice) and showed that they display a myopathic phenotype accompanied by neurogenic features. Here, we used these mice to investigate the muscle-specific defects arising from the absence of TRIM32, which underlie the myopathic phenotype. Using 2 models of induced atrophy, we showed that TRIM32 is dispensable for muscle atrophy. Conversely, TRIM32 was necessary for muscle regrowth after atrophy. Furthermore, TRIM32-deficient primary myoblasts underwent premature senescence and impaired myogenesis due to accumulation of PIAS4, an E3 SUMO ligase and TRIM32 substrate that was previously shown to be associated with senescence. Premature senescence of myoblasts was also observed in vivo in an atrophy/regrowth model. Trim32–/– muscles had substantially fewer activated satellite cells, increased PIAS4 levels, and growth failure compared with wild-type muscles. Moreover, Trim32–/– muscles exhibited features of premature sarcopenia, such as selective type II fast fiber atrophy. These results imply that premature senescence of muscle satellite cells is an underlying pathogenic feature of LGMD2H and reveal what we believe to be a new mechanism of muscular dystrophy associated with reductions in available satellite cells and premature sarcopenia. PMID:22505452

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

Mapping recessive ophthalmic diseases: linkage of the locus for Usher syndrome type II to a DNA marker on chromosome 1q.

PubMed

Lewis, R A; Otterud, B; Stauffer, D; Lalouel, J M; Leppert, M

1990-06-01

Usher syndrome is a heterogeneous group of autosomal recessive disorders that combines variably severe congenital neurosensory hearing impairment with progressive night-blindness and visual loss similar to that in retinitis pigmentosa. Usher syndrome type I is distinguished by profound congenital (preverbal) deafness and retinal disease with onset in the first decade of life. Usher syndrome type II is characterized by partial hearing impairment and retinal dystrophy that occurs in late adolescence or early adulthood. The chromosomal assignment and the regional localization of the genetic mutation(s) causing the Usher syndromes are unknown. We analyzed a panel of polymorphic genomic markers for linkage to the disease gene among six families with Usher syndrome type I and 22 families with Usher syndrome type II. Significant linkage was established between Usher syndrome type II and the DNA marker locus THH33 (D1S81), which maps to chromosome 1q. The most likely location of the disease gene is at a map distance of 9 cM from THH33 (lod score 6.5). The same marker failed to show linkage in families segregating an allele for Usher syndrome type I. These data confirm the provisional assignment of the locus for Usher syndrome type II to the distal end of chromosome 1q and demonstrate that the clinical heterogeneity between Usher types I and II is caused by mutational events at different genetic loci. Regional localization has the potential to improve carrier detection and to provide antenatal diagnosis in families at risk for the disease.

Early-onset facioscapulohumeral muscular dystrophy type 1 with some atypical features.

PubMed

Dorobek, Małgorzata; van der Maarel, Silvère M; Lemmers, Richard J L F; Ryniewicz, Barbara; Kabzińska, Dagmara; Frants, Rune R; Gawel, Malgorzata; Walecki, Jerzy; Hausmanowa-Petrusewicz, Irena

2015-04-01

Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy). © The Author(s) 2014.

Mechanistic aspects of the formation of α-dystroglycan and therapeutic research for the treatment of α-dystroglycanopathy: A review.

PubMed

Taniguchi-Ikeda, Mariko; Morioka, Ichiro; Iijima, Kazumoto; Toda, Tatsushi

2016-10-01

α-Dystroglycanopathy, an autosomal recessive disease, is associated with the development of a variety of diseases, including muscular dystrophy. In humans, α-dystroglycanopathy includes various types of congenital muscular dystrophy such as Fukuyama type congenital muscular dystrophy (FCMD), muscle eye brain disease (MEB), and the Walker Warburg syndrome (WWS), and types of limb girdle muscular dystrophy 2I (LGMD2I). α-Dystroglycanopathy share a common etiology, since it is invariably caused by gene mutations that are associated with the O-mannose glycosylation pathway of α-dystroglycan (α-DG). α-DG is a central member of the dystrophin glycoprotein complex (DGC) family in peripheral membranes, and the proper glycosylation of α-DG is essential for it to bind to extracellular matrix proteins, such as laminin, to cell components. The disruption of this ligand-binding is thought to result in damage to cell membrane integration, leading to the development of muscular dystrophy. Clinical manifestations of α-dystroglycanopathy frequently include mild to severe alterations in the central nervous system and optical manifestations in addition to muscular dystrophy. Eighteen causative genes for α-dystroglycanopathy have been identified to date, and it is likely that more will be reported in the near future. These findings have stimulated extensive and energetic investigations in this research field, and novel glycosylation pathways have been implicated in the process. At the same time, the use of gene therapy, antisense therapy, and enzymatic supplementation have been evaluated as therapeutic possibilities for some types of α-dystroglycanopathy. Here we review the molecular and clinical findings associated with α-dystroglycanopathy and the development of therapeutic approaches, by comparing the approaches with the development of Duchenne muscular dystrophy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Exome sequencing identifies a DNAJB6 mutation in a family with dominantly-inherited limb-girdle muscular dystrophy.

PubMed

Couthouis, Julien; Raphael, Alya R; Siskind, Carly; Findlay, Andrew R; Buenrostro, Jason D; Greenleaf, William J; Vogel, Hannes; Day, John W; Flanigan, Kevin M; Gitler, Aaron D

2014-05-01

Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders (the "limb-girdle" muscles), although it is a heterogeneous disorder that can present with varying symptoms. There is currently no cure. We sought to identify the genetic basis of limb-girdle muscular dystrophy type 1 in an American family of Northern European descent using exome sequencing. Exome sequencing was performed on DNA samples from two affected siblings and one unaffected sibling and resulted in the identification of eleven candidate mutations that co-segregated with the disease. Notably, this list included a previously reported mutation in DNAJB6, p.Phe89Ile, which was recently identified as a cause of limb-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6 was only found in affected individuals. Subsequent haplotype analysis indicated that this DNAJB6 p.Phe89Ile mutation likely arose independently of the previously reported mutation. Since other published mutations are located close by in the G/F domain of DNAJB6, this suggests that the area may represent a mutational hotspot. Exome sequencing provided an unbiased and effective method for identifying the genetic etiology of limb-girdle muscular dystrophy type 1 in a previously genetically uncharacterized family. This work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D. Copyright © 2014 Elsevier B.V. All rights reserved.

Late-onset Becker-type muscular dystrophy in a Border terrier dog.

PubMed

Jeandel, A; Garosi, L S; Davies, L; Guo, L T; Salgüero, R; Shelton, G D

2018-01-29

A 9-year-old Border terrier was presented to a referral hospital after a 1-year history of progressive stiffness and exercise intolerance. Neurological examination was consistent with a neuromuscular disorder. Serum creatine kinase activity was mildly elevated. A myopathy was suspected based on MRI findings and electrophysiological examination. Muscle histopathology was consistent with a severe non-inflammatory myopathy of a dystrophic type. Immunofluorescence and western blotting confirmed a dystrophinopathy with an 80-kDa truncated dystrophin fragment similar to Becker muscular dystrophy in people. To our knowledge, this is the first description of a late-onset Becker-type muscular dystrophy in a dog, and the first description of a dystrophinopathy in a Border terrier. Muscular dystrophy in dogs should not be ruled out based on late onset clinical signs and only mildly elevated creatine kinase. © 2018 British Small Animal Veterinary Association.

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.

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.

A Cross-Sectional Study of School Experiences of Boys with Duchenne and Becker Muscular Dystrophy

ERIC Educational Resources Information Center

Soim, Aida; Lamb, Molly; Campbell, Kimberly; Pandya, Shree; Peay, Holly; Howard, James F., Jr.; Fox, Deborah

2016-01-01

The objectives of this study were to investigate types of supportive school services received and factors related to provision of these services. We conducted a cross-sectional study to describe the school experience of males with Duchenne and Becker muscular dystrophies. Study subjects were identified through the Muscular Dystrophy Surveillance,…

Endocrine Therapy of Breast Cancer

DTIC Science & Technology

2006-06-01

Becker muscular dystrophy (BMD, hypomorphic for dys- trophin, n = 5), Dysferlin deficiency (putative vesicle traf- fic defect, n = 9), and Calpain III...this study. (1) Limb-girdle muscular dystrophy (LGMD, provided by Children National Medical Center, Center for Genetic Medicine): 4 diagnostic...groups, Fukutin related protein de- ficiency (FKRP) (homozygous missense for glycosylation enzyme, limb-girdle muscular dystrophy sub-type, n = 7

Bortezomib partially improves laminin α2 chain-deficient muscular dystrophy.

PubMed

Körner, Zandra; Fontes-Oliveira, Cibely C; Holmberg, Johan; Carmignac, Virginie; Durbeej, Madeleine

2014-05-01

Congenital muscular dystrophy, caused by mutations in LAMA2 (the gene encoding laminin α2 chain), is a severe and incapacitating disease for which no therapy is yet available. We have recently demonstrated that proteasome activity is increased in laminin α2 chain-deficient muscle and that treatment with the nonpharmaceutical proteasome inhibitor MG-132 reduces muscle pathology in laminin α2 chain-deficient dy(3K)/dy(3K) mice. Here, we explore the use of the selective and therapeutic proteasome inhibitor bortezomib (currently used for treatment of relapsed multiple myeloma and mantle cell lymphoma) in dy(3K)/dy(3K) mice and in congenital muscular dystrophy type 1A muscle cells. Outcome measures included quantitative muscle morphology, gene and miRNA expression analyses, proteasome activity, motor activity, and survival. Bortezomib improved several histological hallmarks of disease, partially normalized miRNA expression (miR-1 and miR-133a), and enhanced body weight, locomotion, and survival of dy(3K)/dy(3K) mice. In addition, bortezomib reduced proteasome activity in congenital muscular dystrophy type 1A myoblasts and myotubes. These findings provide evidence that the proteasome inhibitor bortezomib partially reduces laminin α2 chain-deficient muscular dystrophy. Investigation of the clinical efficacy of bortezomib administration in congenital muscular dystrophy type 1A clinical trials may be warranted. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

[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.

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.

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.

Developmental Defects in a Zebrafish Model for Muscular Dystrophies Associated with the Loss of Fukutin-Related Protein (FKRP)

ERIC Educational Resources Information Center

Thornhill, Paul; Bassett, David; Lochmuller, Hanns; Bushby, Kate; Straub, Volker

2008-01-01

A number of muscular dystrophies are associated with the defective glycosylation of [alpha]-dystroglycan and many are now known to result from mutations in a number of genes encoding putative or known glycosyltransferases. These diseases include severe forms of congenital muscular dystrophy (CMD) such as Fukuyama type congenital muscular dystrophy…

Leigh syndrome with Fukuyama congenital muscular dystrophy: a case report.

PubMed

Kondo, Hidehito; Tanda, Koichi; Tabata, Chihiro; Hayashi, Kohei; Kihara, Minako; Kizaki, Zenro; Taniguchi-Ikeda, Mariko; Mori, Masato; Murayama, Kei; Ohtake, Akira

2014-09-01

We report the first case of Leigh syndrome (LS) with Fukuyama congenital muscular dystrophy (FCMD). A neonate suffered from lactic acidosis and subsequently presented with poor feeding, muscle weakness, hypotonia, cardiopulmonary dysfunction, and hydrocephalus. He died at 17 months. The findings of brain magnetic resonance imaging indicated some specific features of both LS and FCMD, and FCMD gene mutation was detected. Decreased mitochondrial respiratory complex I and II activity was noted. Mitochondrial DNA sequencing showed no pathogenic mutation. A case with complex I+II deficiency has rarely been reported, suggesting a nuclear gene mutation. Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

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.

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

Genetics Home Reference: Fukuyama congenital muscular dystrophy

MedlinePlus

... Fujii T, Aiba H, Toda T. Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy. Brain Dev. ... for Links Data Files & API Site Map Subscribe Customer Support USA.gov Copyright Privacy Accessibility FOIA Viewers & ...

Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F.

PubMed

Peter, Angela K; Miller, Gaynor; Capote, Joana; DiFranco, Marino; Solares-Pérez, Alhondra; Wang, Emily L; Heighway, Jim; Coral-Vázquez, Ramón M; Vergara, Julio; Crosbie-Watson, Rachelle H

2017-06-06

Sarcospan (SSPN) is a transmembrane protein that interacts with the sarcoglycans (SGs) to form a tight subcomplex within the dystrophin-glycoprotein complex that spans the sarcolemma and interacts with laminin in the extracellular matrix. Overexpression of SSPN ameliorates Duchenne muscular dystrophy in murine models. Standard cloning approaches were used to identify nanospan, and nanospan-specific polyclonal antibodies were generated and validated. Biochemical isolation of skeletal muscle membranes and two-photon laser scanning microscopy were used to analyze nanospan localization in muscle from multiple murine models. Duchenne muscular dystrophy biopsies were analyzed by immunoblot analysis of protein lysates as well as indirect immunofluorescence analysis of muscle cryosections. Nanospan is an alternatively spliced isoform of sarcospan. While SSPN has four transmembrane domains and is a core component of the sarcolemmal dystrophin-glycoprotein complex, nanospan is a type II transmembrane protein that does not associate with the dystrophin-glycoprotein complex. We demonstrate that nanospan is enriched in the sarcoplasmic reticulum (SR) fractions and is not present in the T-tubules. SR fractions contain membranes from three distinct structural regions: a region flanking the T-tubules (triadic SR), a SR region across the Z-line (ZSR), and a longitudinal SR region across the M-line (LSR). Analysis of isolated murine muscles reveals that nanospan is mostly associated with the ZSR and triadic SR, and only minimally with the LSR. Furthermore, nanospan is absent from the SR of δ-SG-null (Sgcd -/- ) skeletal muscle, a murine model for limb girdle muscular dystrophy 2F. Analysis of skeletal muscle biopsies from Duchenne muscular dystrophy patients reveals that nanospan is preferentially expressed in type I (slow) fibers in both control and Duchenne samples. Furthermore, nanospan is significantly reduced in Duchenne biopsies. Alternative splicing of proteins from the SG-SSPN complex produces δ-SG3, microspan, and nanospan that localize to the ZSR and the triadic SR, where they may play a role in regulating resting calcium levels as supported by previous studies (Estrada et al., Biochem Biophys Res Commun 340:865-71, 2006). Thus, alternative splicing of SSPN mRNA generates three protein isoforms (SSPN, microspan, and nanospan) that differ in the number of transmembrane domains affecting subcellular membrane association into distinct protein complexes.

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.

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,…

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.

[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.

Analysis of ABCA4 in mixed Spanish families segregating different retinal dystrophies.

PubMed

Paloma, Eva; Coco, Rosa; Martínez-Mir, Amalia; Vilageliu, Lluïsa; Balcells, Susana; Gonzàlez-Duarte, Roser

2002-12-01

Genotype-phenotype correlations highlighted the function of ABCA4 in retinitis pigmentosa (RP),cone-rod dystrophy (CRD) and Stargardt/Fundus Flavimaculatus disease (STGD/FFM). Initial screening of ABCA4 variants showed a correlation between the type of mutation and the severity of the disease. In the present study we have undertaken mutational and haplotype analysis of ABCA4 in three mixed pedigrees segregating different retinal dystrophies. In family I, we have shown cosegregation of different ABCA4 alleles with CRD (homozygosity for L1940P) and three subtypes of STGD/FFM. The first, a mild form, consisting on fundus flavimaculatus-like distribution of flecks, but good visual acuity and absence of dark choroid, was found to cosegregate with alleles R1097C and F553L; the second, a conventional Stargardt phenotype was associated to alleles L1940P/R1097C and the third, displaying severely reduced visual acuity and dark choroid (named FFM), was associated to L1940P/F553L. In family II, segregating STGD and RP phenotypes, while the involvement of ABCA4 in STGD seems clear this is not the case for RP. Finally, in family III, also segregating STGD and RP, ABCA4 fails to explain either phenotype. Our data highlight the wide allelic heterogeneity involving this gene and support the genetic variability (beyond ABCA4) of mixed STGD/RP pedigrees. Copyright 2002 Wiley-Liss, Inc.

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

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

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.”

Myotonic dystrophy mimicking postpolio syndrome in a polio survivor.

PubMed

Lim, Jae-Young; Kim, Kyoung-Eun; Choe, Gheeyoung

2009-02-01

We describe a 38-yr-old polio survivor with newly developed weakness from myotonic dystrophy. He suffered muscle atrophy and weakness in his legs as a result of poliomyelitis at the age of 3 yrs. After a stable interval of about 30 yrs, he felt new weakness and fatigue in his legs. Electromyography revealed generalized myotonic discharges, early recruitment, and findings of chronic denervation in his left leg. Genetic testing was consistent with myotonic dystrophy type 1. A biopsy from the right gastrocnemius revealed findings of both myotonic dystrophy and chronic denervation. This case report shows the importance of considering other uncommon conditions in the differential diagnoses of postpolio syndrome.

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.

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)

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.

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

Increased Cancer Risks in Myotonic Dystrophy

PubMed Central

Win, Aung Ko; Perattur, Promilla G.; Pulido, Jose S.; Pulido, Christine M.; Lindor, Noralane M.

2012-01-01

Objective To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified. Patients and Methods A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method. Results A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; P=.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P<.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P=.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P=.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma. Conclusion Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers. PMID:22237010

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

[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.

Autosomal Dominant Retinal Dystrophies Caused by a Founder Splice Site Mutation, c.828+3A>T, in PRPH2 and Protein Haplotypes in trans as Modifiers

PubMed Central

Shankar, Suma P.; Hughbanks-Wheaton, Dianna K.; Birch, David G.; Sullivan, Lori S.; Conneely, Karen N.; Bowne, Sara J.; Stone, Edwin M.; Daiger, Stephen P.

2016-01-01

Purpose We determined the phenotypic variation, disease progression, and potential modifiers of autosomal dominant retinal dystrophies caused by a splice site founder mutation, c.828+3A>T, in the PRPH2 gene. Methods A total of 62 individuals (19 families) harboring the PRPH2 c.828+3A>T mutation, had phenotype analysis by fundus appearance, electrophysiology, and visual fields. The PRPH2 haplotypes in trans were sequenced for potential modifying variants and generalized estimating equations (GEE) used for statistical analysis. Results Several distinct phenotypes caused by the PRPH2 c.828+3A>T mutation were observed and fell into two clinical categories: Group I (N = 44) with mild pattern dystrophies (PD) and Group II (N = 18) with more severe cone-rod dystrophy (CRD), retinitis pigmentosa (RP), and central areolar chorioretinal dystrophy (CACD). The PRPH2 Gln304-Lys310-Asp338 protein haplotype in trans was found in Group I only (29.6% vs. 0%), whereas the Glu304-Lys310-Gly338 haplotype was predominant in Group II (94.4% vs. 70.4%). Generalized estimating equations analysis for PD versus the CRD/CACD/RP phenotypes in individuals over 43 years alone with the PRPH2 haplotypes in trans and age as predictors, adjusted for correlation within families, confirmed a significant effect of haplotype on severity (P = 0.03) with an estimated odds ratio of 7.16 (95% confidence interval [CI] = [2.8, 18.4]). Conclusions The PRPH2 c.828+3A>T mutation results in multiple distinct phenotypes likely modified by protein haplotypes in trans; the odds of having the CACD/RP-like phenotype (versus the PD phenotype) are 7.16 times greater with a Glu304-Lys310-Gly338 haplotype in trans. Further functional studies of the modifying haplotypes in trans and PRPH2 splice variants may offer therapeutic targets. PMID:26842753

Sulforaphane alleviates muscular dystrophy in mdx mice by activation of Nrf2.

PubMed

Sun, Chengcao; Yang, Cuili; Xue, Ruilin; Li, Shujun; Zhang, Ting; Pan, Lei; Ma, Xuejiao; Wang, Liang; Li, Dejia

2015-01-15

Sulforaphane (SFN), one of the most important isothiocyanates in the human diet, is known to have chemo-preventive and antioxidant activities in different tissues via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. However, its effects on muscular dystrophy remain unknown. This work was undertaken to evaluate the effects of SFN on Duchenne muscular dystrophy. Four-week-old mdx mice were treated with SFN by gavage (2 mg·kg body wt(-1)·day(-1) for 8 wk), and our results demonstrated that SFN treatment increased the expression and activity of muscle phase II enzymes NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 with a Nrf2-dependent manner. SFN significantly increased skeletal muscle mass, muscle force (∼30%), running distance (∼20%), and GSH-to-GSSG ratio (∼3.2-fold) of mdx mice and decreased the activities of plasma creatine phosphokinase (∼45%) and lactate dehydrogenase (∼40%), gastrocnemius hypertrophy (∼25%), myocardial hypertrophy (∼20%), and malondialdehyde levels (∼60%). Furthermore, SFN treatment also reduced the central nucleation (∼40%), fiber size variability, and inflammation and improved the sarcolemmal integrity of mdx mice. Collectively, these results show that SFN can improve muscle function and pathology and protect dystrophic muscle from oxidative damage in mdx mice associated with Nrf2 signaling pathway, which indicate Nrf2 may have clinical implications for the treatment of patients with muscular dystrophy. Copyright © 2015 the American Physiological Society.

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.

Leg Muscle Involvement in Facioscapulohumeral Muscular Dystrophy: Comparison between Facioscapulohumeral Muscular Dystrophy Types 1 and 2.

PubMed

Mair, Dorothea; Huegens-Penzel, Monika; Kress, Wolfram; Roth, Christian; Ferbert, Andreas

2017-01-01

Facioscapulohumeral muscular dystrophy (FSHD) presents with 2 genetically distinct types. We describe for the first time the MRI patterns of leg muscle involvement in type 2 and compare it with type 1. The intramuscular fat content was assessed on lower extremity axial T1-weighted MRI scans in 6 FSHD1 and 5 FSHD2 patients. Overall, the muscle involvement profile did not differ substantially between FSHD1 and FSHD2. In the thigh, the dorsomedial compartment including the semimembranosus, semitendinosus and adductor magnus was the most affected. The quadriceps was mostly spared, but isolated involvement of the rectus femoris was common. Fat infiltration in the distal soleus and the medial gastrocnemius with sparing of the lateral gastrocnemius was a common finding; involvement of the tibialis anterior was less frequent. A proximal-to-distal increase in fat content was frequently present in some muscles. Muscle involvement appears to be independent of type, confirming a similar pathophysiological pathway in FSHD1 and FSHD2. © 2016 S. Karger AG, Basel.

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.

Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy.

PubMed

Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel; Kaur, Amanjot; Sparwasser, Tim; Tidball, James G; Margeta, Marta; Spencer, Melissa J; Bluestone, Jeffrey A

2014-10-15

We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wild-type mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype, and showed increased expression of interleukin-10 (IL-10) in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-γ (IFN-γ) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooxygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD. Copyright © 2014, American Association for the Advancement of Science.

Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan.

PubMed

Carss, Keren J; Stevens, Elizabeth; Foley, A Reghan; Cirak, Sebahattin; Riemersma, Moniek; Torelli, Silvia; Hoischen, Alexander; Willer, Tobias; van Scherpenzeel, Monique; Moore, Steven A; Messina, Sonia; Bertini, Enrico; Bönnemann, Carsten G; Abdenur, Jose E; Grosmann, Carla M; Kesari, Akanchha; Punetha, Jaya; Quinlivan, Ros; Waddell, Leigh B; Young, Helen K; Wraige, Elizabeth; Yau, Shu; Brodd, Lina; Feng, Lucy; Sewry, Caroline; MacArthur, Daniel G; North, Kathryn N; Hoffman, Eric; Stemple, Derek L; Hurles, Matthew E; van Bokhoven, Hans; Campbell, Kevin P; Lefeber, Dirk J; Lin, Yung-Yao; Muntoni, Francesco

2013-07-11

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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.

Limb Girdle Muscular Dystrophy Type 2E Due to a Novel Large Deletion in SGCB Gene.

PubMed

Ghafouri-Fard, Soudeh; Hashemi-Gorji, Feyzollah; Fardaei, Majid; Miryounesi, Mohammad

2017-01-01

Autosomal recessive limb-girdle muscular dystrophies (LGMD type 2) are a group of clinically and genetically heterogeneous diseases with the main characteristics of weakness and wasting of the pelvic and shoulder girdle muscles. Among them are sarcoglycanopathies caused by mutations in at least four genes named SGCA, SGCB, SGCG and SGCD. Here we report a consanguineous Iranian family with two children affected with LGMD type 2E. Mutation analysis revealed a novel homozygous exon 2 deletion of SGCB gene in the patients with the parents being heterozygous for this deletion. This result presents a novel underlying genetic mechanism for LGMD type 2E.

Development of Refractive Errors-What Can We Learn From Inherited Retinal Dystrophies?

PubMed

Hendriks, Michelle; Verhoeven, Virginie J M; Buitendijk, Gabriëlle H S; Polling, Jan Roelof; Meester-Smoor, Magda A; Hofman, Albert; Kamermans, Maarten; Ingeborgh van den Born, L; Klaver, Caroline C W

2017-10-01

It is unknown which retinal cells are involved in the retina-to-sclera signaling cascade causing myopia. As inherited retinal dystrophies (IRD) are characterized by dysfunction of a single retinal cell type and have a high risk of refractive errors, a study investigating the affected cell type, causal gene, and refractive error in IRDs may provide insight herein. Case-control study. Study Population: Total of 302 patients with IRD from 2 ophthalmogenetic centers in the Netherlands. Reference Population: Population-based Rotterdam Study-III and Erasmus Rucphen Family Study (N = 5550). Distributions and mean spherical equivalent (SE) were calculated for main affected cell type and causal gene; and risks of myopia and hyperopia were evaluated using logistic regression. Bipolar cell-related dystrophies were associated with the highest risk of SE high myopia 239.7; odds ratio (OR) mild hyperopia 263.2, both P < .0001; SE -6.86 diopters (D) (standard deviation [SD] 6.38), followed by cone-dominated dystrophies (OR high myopia 19.5, P < .0001; OR high hyperopia 10.7, P = .033; SE -3.10 D [SD 4.49]); rod dominated dystrophies (OR high myopia 10.1, P < .0001; OR high hyperopia 9.7, P = .001; SE -2.27 D [SD 4.65]), and retinal pigment epithelium (RPE)-related dystrophies (OR low myopia 2.7; P = .001; OR high hyperopia 5.8; P = .025; SE -0.10 D [SD 3.09]). Mutations in RPGR (SE -7.63 D [SD 3.31]) and CACNA1F (SE -5.33 D [SD 3.10]) coincided with the highest degree of myopia and in CABP4 (SE 4.81 D [SD 0.35]) with the highest degree of hyperopia. Refractive errors, in particular myopia, are common in IRD. The bipolar synapse and the inner and outer segments of the photoreceptor may serve as critical sites for myopia development. Copyright © 2017 Elsevier Inc. All rights reserved.

15 CFR 8b.3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... more of the following body systems: Neurological; musculoskeletal; special sense organs; respiratory... hearing impairments, cerebral palsy, epilepsy, muscular dystrophy, multiple sclerosis, cancer, heart... postsecondary institution, or a public system of higher education; or (ii) A local educational agency (as...

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.

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.

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.

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.

Sarcolemmal alpha and gamma sarcoglycan protein deficiencies in Turkish siblings with a novel missense mutation in the alpha sarcoglycan gene.

PubMed

Diniz, Gulden; Tosun Yildirim, Hulya; Akinci, Gulcin; Hazan, Filiz; Ozturk, Aysel; Yararbas, Kanay; Tukun, Ajlan

2014-06-01

The sarcoglycan alpha gene, also known as the adhalin gene, is located on chromosome 17q21; mutations in this gene are associated with limb-girdle muscular dystrophy type 2D. We describe two Turkish siblings with findings consistent with limb-girdle muscular dystrophy type 2D. The evaluation excluded a dystrophinopathy, which is the most common form of muscular dystrophy. Both siblings had very high levels of creatinine phosphokinase and negative molecular tests for deletions and duplications of the dystrophin gene. The older boy presented at 8 years of age with an inability to climb steps and an abnormal gait. His younger brother was 5 years old and had similar symptoms. The muscle biopsy evaluation was performed only in the older brother. The muscle biopsy showed dystrophic features as well as a deficiency in the expression of two different glycoproteins: the alpha sarcoglycan and the gamma sarcoglycan. Sarcolemmal expressions of dystrophin and other sarcoglycans (beta and delta) were diffusely present. DNA analysis demonstrated the presence of previously unknown homozygous mutations [c.226 C > T (p.L76 F)] in exon 3 in the sarcoglycan alpha genes of both siblings. Similar heterozygous point mutations at the same locus were found in both parents, but the genes of beta, delta, and gamma sarcoglycan were normal in the remaining family members. We describe two siblings with limb-girdle muscular dystrophy type 2D with a novel missense mutation. These patients illustrate that the differential diagnosis of muscular dystrophies is impossible with clinical findings alone. Therefore, a muscle biopsy and DNA analysis remain essential methods for diagnosis of muscle diseases. Copyright © 2014 Elsevier Inc. All rights reserved.

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

Refined mapping of a gene responsible for Fukuyama-type congenital muscular dystrophy: Evidence for strong linkage disequilibrium

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

Toda, Tatsushi; Ikegawa, Shiro; Okui, Keiko

1994-11-01

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. After our initial mapping of the FCMD locus to chromosome 9q31-33, we further defined the locus within a region of {approximately}5 cM between loci D9S127 and CA246, by homozygosity mapping in patients born to consanguineous marriages and by recombination analyses in other families. We also found evidence for strong linkage disequilibrium between FCMD and a polymorphic microsatellite marker, mfd220, which showed no recombination and a lod score of (Z) 17.49.more » A {open_quotes}111-bp{close_quotes} allele for the mfd220 was observed in 22 (34%) of 64 FCMD chromosomes, but it was present in only 1 of 120 normal chromosomes. This allelic association with FCMD was highly significant ({chi}{sup 2} = 50.7; P < .0001). Hence, we suspect that the FCMD gene could lie within a few hundred kilobases of the mfd220 locus. 32 refs., 2 figs., 2 tabs.« less

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

Serum Osteopontin as a Novel Biomarker for Muscle Regeneration in Duchenne Muscular Dystrophy.

PubMed

Kuraoka, Mutsuki; Kimura, En; Nagata, Tetsuya; Okada, Takashi; Aoki, Yoshitsugu; Tachimori, Hisateru; Yonemoto, Naohiro; Imamura, Michihiro; Takeda, Shin'ichi

2016-05-01

Duchenne muscular dystrophy is a lethal X-linked muscle disorder. We have already reported that osteopontin (OPN), an inflammatory cytokine and myogenic factor, is expressed in the early dystrophic phase in canine X-linked muscular dystrophy in Japan, a dystrophic dog model. To further explore the possibility of OPN as a new biomarker for disease activity in Duchenne muscular dystrophy, we monitored serum OPN levels in dystrophic and wild-type dogs at different ages and compared the levels to other serum markers, such as serum creatine kinase, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1. Serum OPN levels in the dystrophic dogs were significantly elevated compared with those in wild-type dogs before and 1 hour after a cesarean section birth and at the age of 3 months. The serum OPN level was significantly correlated with the phenotypic severity of dystrophic dogs at the period corresponding to the onset of muscle weakness, whereas other serum markers including creatine kinase were not. Immunohistologically, OPN was up-regulated in infiltrating macrophages and developmental myosin heavy chain-positive regenerating muscle fibers in the dystrophic dogs, whereas serum OPN was highly elevated. OPN expression was also observed during the synergic muscle regeneration process induced by cardiotoxin injection. In conclusion, OPN is a promising biomarker for muscle regeneration in dystrophic dogs and can be applicable to boys with Duchenne muscular dystrophy. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Differentiation of C2C12 myoblasts expressing lamin A mutated at a site responsible for Emery-Dreifuss muscular dystrophy is improved by inhibition of the MEK-ERK pathway and stimulation of the PI3-kinase pathway

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

Favreau, Catherine; Delbarre, Erwan; Courvalin, Jean-Claude

2008-04-01

Mutation R453W in A-type lamins, that are major nuclear envelope proteins, generates Emery-Dreifuss muscular dystrophy. We previously showed that mouse myoblasts expressing R453W-lamin A incompletely exit the cell cycle and differentiate into myocytes with a low level of multinucleation. Here we attempted to improve differentiation by treating these cells with a mixture of PD98059, an extracellular-regulated kinase (ERK) kinase (also known as mitogen-activated kinase, MEK) inhibitor, and insulin-like growth factor-II, an activator of phosphoinositide 3-kinase. We show that mouse myoblasts expressing R453W-lamin A were sensitive to the drug treatment as shown by (i) an increase in multinucleation, (ii) downregulation ofmore » proliferation markers (cyclin D1, hyperphosphorylated Rb), (iii) upregulation of myogenin, and (iv) sustained activation of p21 and cyclin D3. However, nuclear matrix anchorage of p21 and cyclin D3 in a complex with hypophosphorylated Rb that is critical to trigger cell cycle arrest and myogenin induction was deficient and incompletely restored by drug treatment. As the turn-over of R453W-lamin A at the nuclear envelope was greatly enhanced, we propose that R453W-lamin A impairs the capacity of the nuclear lamina to serve as scaffold for substrates of the MEK-ERK pathway and for MyoD-induced proteins that play a role in the differentiation process.« less

Myotonic Dystrophy Initially Presenting as Tachycardiomyopathy Successful Catheter Ablation of Atrial Flutter

PubMed Central

Asbach, S.; Gutleben, K. J.; Dahlem, P.; Brachmann, J.; Nölker, G.

2010-01-01

Myotonic dystrophy is a genetic muscular disease that is frequently associated with cardiac arrhythmias. Bradyarrhythmias, such as sinus bradycardia and atrioventricular block, are more common than tachyarrhythmias. Rarely, previously undiagnosed patients with myotonic dystrophy initially present with a tachyarrhythmia. We describe the case of a 14-year-old boy, who was admitted to the hospital with clinical signs and symptoms of decompensated heart failure and severely reduced left ventricular function. Electrocardiography showed common-type atrial flutter with 2 : 1 conduction resulting in a heart rate of 160 bpm. Initiation of medical therapy for heart failure as well as electrical cardioversion led to a marked clinical improvement. Catheter ablation of atrial flutter was performed to prevent future cardiac decompensations and to prevent development of tachymyopathy. Left ventricular function normalized during followup. Genetic analysis confirmed the clinical suspicion of myotonic dystrophy as known in other family members in this case. PMID:20871860

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.

Transplantation of human umbilical cord-derived mesenchymal stems cells for the treatment of Becker muscular dystrophy in affected pedigree members.

PubMed

Li, Pang; Cui, Kai; Zhang, Bo; Wang, Zhendan; Shen, Yangyang; Wang, Xiangyu; Zhang, Jianbo; Tong, Feng; Li, Sheng

2015-04-01

The regeneration of muscle tissue has been achieved using multipotent mesenchymal stem cells in mouse models of injured skeletal muscle. In the present study, the utility of multipotent human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the treatment of Becker muscular dystrophy (BMD), a genetic disease where muscle tissue fails to regenerate, was examined in members from a pedigree affected by BMD. The disease status was evaluated in 4 affected pedigree members (II1, II2, II3 and III2; aged 50, 46, 42 and 6 years, respectively). The transplantation of the hUC‑MSCs (performed on 3 patients, I2, II3 and III2) was performed by infusion with an intravenous drip over a 30‑min period, and the patients were evaluated at 1, 3, 4 and 12 weeks following the procedure. The evaluation was based on physical characteristics, as well as on molecular testing for serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels and a histological examination of muscle biopsies. The patients suffered no adverse reactions in response to the transplantation of the hUC‑MSCs. At 1 week following transplantation all 3 patients showed improvement in the muscle force of the limbs, muscle size and daily activity. The walking gait of patient III2 had improved by 1 week post-transplantation and reached a normal status by 12 weeks. Serum CK and LDH levels were decreased relative to the baseline levels. A histological examination of muscle biopsies displayed no obvious tissue regeneration. In conclusion, the treatment of patients with BMD using hUC-MSCs was safe and of therapeutic benefit that lasted for up to 12 weeks. hUC-MSCs are, therefore, a potential cell therapy-based treatment option for patients with muscular dystrophies.

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.

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

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.

National Organizations Raising Public Consciousness. Part II.

ERIC Educational Resources Information Center

Exceptional Parent, 1980

1980-01-01

Statements of seven national organizations (Muscular Dystrophy Association, Spina Bifida Association of America, National Easter Seal Society, International Association of Parents of the Deaf, American Foundation for the Blind, Down's Syndrome Congress, and the National Society for Autistic Children) about raising community awareness of issues…

Genetics Home Reference: Fuchs endothelial dystrophy

MedlinePlus

... a protein that is part of type VIII collagen. Type VIII collagen is largely found within the cornea, surrounding the endothelial cells. Specifically, type VIII collagen is a major component of a tissue at ...

The Role of a Novel Myosin Isoform in Prostate Cancer Metastasis

DTIC Science & Technology

2013-10-01

of unconventional myosin function and targeting, Annu. Rev. Cell Dev. Biol. 27 (2011) 133–155. [42] W. Kliche, S. Fujita- Becker , M. Kollmar, D.J...tissue-specific diseases (laminopathies), including Emery–Dreifuss muscular dystrophy , Dunnigan-type familial partial lipodystrophy (FPLD), and...structure of the C-terminal domain of lamin A/C, mutated in muscular dystrophies , cardiomyopathy, and partial lipodystrophy. Structure 10, 811–823

Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies

PubMed Central

Rouillon, Jérémy; Poupiot, Jérôme; Zocevic, Aleksandar; Amor, Fatima; Léger, Thibaut; Garcia, Camille; Camadro, Jean-Michel; Wong, Brenda; Pinilla, Robin; Cosette, Jérémie; Coenen-Stass, Anna M.L.; Mcclorey, Graham; Roberts, Thomas C.; Wood, Matthew J.A.; Servais, Laurent; Udd, Bjarne; Voit, Thomas; Richard, Isabelle; Svinartchouk, Fedor

2015-01-01

Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of α-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter-individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders. PMID:26060189

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.

Muscular dystrophy in the Japanese Spitz: an inversion disrupts the DMD and RPGR genes.

PubMed

Atencia-Fernandez, Sabela; Shiel, Robert E; Mooney, Carmel T; Nolan, Catherine M

2015-04-01

An X-linked muscular dystrophy, with deficiency of full-length dystrophin and expression of a low molecular weight dystrophin-related protein, has been described in Japanese Spitz dogs. The aim of this study was to identify the causative mutation and develop a specific test to identify affected cases and carrier animals. Gene expression studies in skeletal muscle of an affected animal indicated aberrant expression of the Duchenne muscular dystrophy (dystrophin) gene and an anomaly in intron 19 of the gene. Genome-walking experiments revealed an inversion that interrupts two genes on the X chromosome, the Duchenne muscular dystrophy gene and the retinitis pigmentosa GTPase regulator gene. All clinically affected dogs and obligate carriers that were tested had the mutant chromosome, and it is concluded that the inversion is the causative mutation for X-linked muscular dystrophy in the Japanese Spitz breed. A PCR assay that amplifies mutant and wild-type alleles was developed and proved capable of identifying affected and carrier individuals. Unexpectedly, a 7-year-old male animal, which had not previously come to clinical attention, was shown to possess the mutant allele and to have a relatively mild form of the disease. This observation indicates phenotypic heterogeneity in Japanese Spitz muscular dystrophy, a feature described previously in humans and Golden Retrievers. With the availability of a simple, fast and accurate test for Japanese Spitz muscular dystrophy, detection of carrier animals and selected breeding should help eliminate the mutation from the breed. © 2015 Stichting International Foundation for Animal Genetics.

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.

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.

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.

A personal overview of causalgia and other reflex dystrophies.

PubMed Central

Shumacker, H B

1985-01-01

This is a personal assessment of true major causalgia and the other reflex dystrophies, related but distinctly separate entities. The clinical picture of causalgia differs only in minor respects from that described by Mitchell over 120 years ago. Its management has, however, been clarified, largely through the extensive experiences of World War II. It is readily recognized and can be treated effectively by sympathetic blocks or sympathectomy together with active exercise. The other reflex dystrophies are far less understood. They appear to have a similar pattern in their early phase and to respond well to a program of exercise and control of edema--a regimen which, because of pain and paresis, cannot be carried out without sympathetic blocks or occasionally sympathectomy. When not recognized early and treated properly, the sympatomatology usually changes dramatically and treatment differs. Often control of edema and active use of the affected part are all that is necessary. Sometimes, in addition to these measures, sympathetic blocks or sympathectomy is required. Guidelines found useful in management are outlined. Puzzling features are discussed. PMID:3977427

Mutation in the Auxiliary Calcium-Channel Subunit CACNA2D4 Causes Autosomal Recessive Cone Dystrophy

PubMed Central

Wycisk, Katharina Agnes; Zeitz, Christina; Feil, Silke; Wittmer, Mariana; Forster, Ursula; Neidhardt, John; Wissinger, Bernd; Zrenner, Eberhart; Wilke, Robert; Kohl, Susanne; Berger, Wolfgang

2006-01-01

Retinal signal transmission depends on the activity of high voltage–gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the α2δ type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C→A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy. PMID:17033974

Autonomic, locomotor and cardiac abnormalities in a mouse model of muscular dystrophy: targeting the renin-angiotensin system.

PubMed

Sabharwal, Rasna; Chapleau, Mark W

2014-04-01

New Findings What is the topic of this review? This symposium report summarizes autonomic, cardiac and skeletal muscle abnormalities in sarcoglycan-δ-deficient mice (Sgcd-/-), a mouse model of limb girdle muscular dystrophy, with emphasis on the roles of autonomic dysregulation and activation of the renin-angiotensin system at a young age. What advances does it highlight? The contributions of the autonomic nervous system and the renin-angiotensin system to the pathogenesis of muscular dystrophy are highlighted. Results demonstrate that autonomic dysregulation precedes and predicts later development of cardiac dysfunction in Sgcd-/- mice and that treatment of young Sgcd-/- mice with the angiotensin type 1 receptor antagonist losartan or with angiotensin-(1-7) abrogates the autonomic dysregulation, attenuates skeletal muscle pathology and increases spontaneous locomotor activity. Muscular dystrophies are a heterogeneous group of genetic muscle diseases characterized by muscle weakness and atrophy. Mutations in sarcoglycans and other subunits of the dystrophin-glycoprotein complex cause muscular dystrophy and dilated cardiomyopathy in animals and humans. Aberrant autonomic signalling is recognized in a variety of neuromuscular disorders. We hypothesized that activation of the renin-angiotensin system contributes to skeletal muscle and autonomic dysfunction in mice deficient in the sarcoglycan-δ (Sgcd) gene at a young age and that this early autonomic dysfunction contributes to the later development of left ventricular (LV) dysfunction and increased mortality. We demonstrated that young Sgcd-/- mice exhibit histopathological features of skeletal muscle dystrophy, decreased locomotor activity and severe autonomic dysregulation, but normal LV function. Autonomic regulation continued to deteriorate in Sgcd-/- mice with age and was accompanied by LV dysfunction and dilated cardiomyopathy at older ages. Autonomic dysregulation at a young age predicted later development of LV dysfunction and higher mortality in Sgcd-/- mice. Treatment of Sgcd-/- mice with the angiotensin type 1 receptor blocker losartan for 8-9 weeks, beginning at 3 weeks of age, decreased fibrosis and oxidative stress in skeletal muscle, increased locomotor activity and prevented autonomic dysfunction. Chronic infusion of the counter-regulatory peptide angiotensin-(1-7) resulted in similar protection. We conclude that activation of the renin-angiotensin system, at a young age, contributes to skeletal muscle and autonomic dysfunction in muscular dystrophy. We speculate that the latter is mediated via abnormal sensory nerve and/or cytokine signalling from dystrophic skeletal muscle to the brain and contributes to age-related LV dysfunction, dilated cardiomyopathy, arrhythmias and premature death. Therefore, correcting the early autonomic dysregulation and renin-angiotensin system activation may provide a novel therapeutic approach in muscular dystrophy.

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.

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.

Severe dystrophy in DiGeorge syndrome

PubMed Central

Rózsai, Barnabás; Kiss, Ákos; Csábi, Györgyi; Czakó, Márta; Decsi, Tamás

2009-01-01

We present the case history of a 3-year-old girl who was examined because of severe dystrophy. In the background, cow’s milk allergy was found, but her body weight was unchanged after eliminating milk from her diet. Other types of malabsorption were excluded. Based on nasal regurgitation and facial dysmorphisms, the possibility of DiGeorge syndrome was suspected and was confirmed by fluorescence in situ hybridization. The authors suggest a new feature associated with DiGeorge syndrome. PMID:19294771

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

Myotonic Dystrophy Family Registry

ClinicalTrials.gov

2016-03-28

Myotonic Dystrophy; Congenital Myotonic Dystrophy; Myotonic Dystrophy 1; Myotonic Dystrophy 2; Dystrophia Myotonica; Dystrophia Myotonica 1; Dystrophia Myotonica 2; Myotonia Dystrophica; Myotonic Dystrophy, Congenital; Myotonic Myopathy, Proximal; PROMM (Proximal Myotonic Myopathy); Proximal Myotonic Myopathy; Steinert Disease; Steinert Myotonic Dystrophy; Steinert's Disease; Myotonia Atrophica

Translational Studies of GALGT2 Gene Therapy for Duchenne Muscular Dystrophy

DTIC Science & Technology

2014-10-01

myofibers has been demonstrated to protect both wild type and dystrophic muscles from injury and to inhibit the development of muscular dystrophy in...dose for functional muscle correction after rAAVrh74.MCK.GALGT2 treatment in mdx mouse muscle . The second thing we have learned is that the MHCK7...post- treatment showed very low levels of sustained muscle transduction, however, co-injection of rAAVrh74.MHCK7.GALGT2 with an equivalent dose of

[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.

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.

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

Preliminary diffusion tensor imaging studies in limb-girdle muscular dystrophies

NASA Astrophysics Data System (ADS)

Hidalgo-Tobon, S.; Hernandez-Salazar, G.; Vargas-Cañas, S.; Marrufo-Melendez, O.; Solis-Najera, S.; Taboada-Barajas, J.; Rodriguez, A. O.; Delgado-Hernandez, R.

2012-10-01

Limb-girdle muscular dystrophies (LGMD) are a group of autosomal dominantly or recessively inherited muscular dystrophies that also present with primary proximal (limb-girdle) muscle weakness. This type of dystrophy involves the shoulder and pelvic girdles, distinct phenotypic or clinical characteristics are recognized. Imaging experiments were conducted on a 1.5T GE scanner (General Electric Medical Systems. Milwaukee. USA), using a combination of two eight-channel coil array. Diffusion Tensor Imaging (DTI) data were acquired using a SE-EPI sequence, diffusion weighted gradients were applied along 30 non-collinear directions with a b-value=550 s/mm2. The connective tissue content does not appear to have a significant effect on the directionality of the diffusion, as assessed by fractional anisotropy. The fibers of the Sartorius muscle and gracilis showed decreased number of tracts, secondary to fatty infiltration and replacement of connective tissue and muscle mass loss characteristic of the underlying pathology. Our results demonstrated the utility of non-invasive MRI techniques to characterize the muscle pathology, through quantitative and qualitative methods such as the FA values and tractrography.

Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy

PubMed Central

Villalta, S. Armando; Rosenthal, Wendy; Martinez, Leonel; Kaur, Amanjot; Sparwasser, Tim; Tidball, James G.; Margeta, Marta; Spencer, Melissa J.; Bluestone, Jeffrey A.

2016-01-01

We examined the hypothesis that regulatory T cells (Tregs) modulate muscle injury and inflammation in the mdx mouse model of Duchenne muscular dystrophy (DMD). Although Tregs were largely absent in the muscle of wildtype mice and normal human muscle, they were present in necrotic lesions, displayed an activated phenotype and showed increased expression of interleukin (IL)-10 in dystrophic muscle from mdx mice. Depletion of Tregs exacerbated muscle injury and the severity of muscle inflammation, which was characterized by an enhanced interferon-gamma (IFNγ) response and activation of M1 macrophages. To test the therapeutic value of targeting Tregs in muscular dystrophy, we treated mdx mice with IL-2/anti-IL-2 complexes (IL-2c), and found that Tregs and IL-10 concentrations were increased in muscle, resulting in reduced expression of cyclooygenase-2 and decreased myofiber injury. These findings suggest that Tregs modulate the progression of muscular dystrophy by suppressing type 1 inflammation in muscle associated with muscle fiber injury, and highlight the potential of Treg-modulating agents as therapeutics for DMD. PMID:25320234

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

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

Molecular and Genetic Studies of Congenital Myopathies

ClinicalTrials.gov

2018-03-21

Central Core Disease; Centronuclear Myopathy; Congenital Fiber Type Disproportion; Multiminicore Disease; Myotubular Myopathy; Nemaline Myopathy; Rigid Spine Muscular Dystrophy; Undefined Congenital Myopathy

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.

Progressive muscle proteome changes in a clinically relevant pig model of Duchenne muscular dystrophy.

PubMed

Fröhlich, Thomas; Kemter, Elisabeth; Flenkenthaler, Florian; Klymiuk, Nikolai; Otte, Kathrin A; Blutke, Andreas; Krause, Sabine; Walter, Maggie C; Wanke, Rüdiger; Wolf, Eckhard; Arnold, Georg J

2016-09-16

Duchenne muscular dystrophy (DMD) is caused by genetic deficiency of dystrophin and characterized by massive structural and functional changes of skeletal muscle tissue, leading to terminal muscle failure. We recently generated a novel genetically engineered pig model reflecting pathological hallmarks of human DMD better than the widely used mdx mouse. To get insight into the hierarchy of molecular derangements during DMD progression, we performed a proteome analysis of biceps femoris muscle samples from 2-day-old and 3-month-old DMD and wild-type (WT) pigs. The extent of proteome changes in DMD vs. WT muscle increased markedly with age, reflecting progression of the pathological changes. In 3-month-old DMD muscle, proteins related to muscle repair such as vimentin, nestin, desmin and tenascin C were found to be increased, whereas a large number of respiratory chain proteins were decreased in abundance in DMD muscle, indicating serious disturbances in aerobic energy production and a reduction of functional muscle tissue. The combination of proteome data for fiber type specific myosin heavy chain proteins and immunohistochemistry showed preferential degeneration of fast-twitch fiber types in DMD muscle. The stage-specific proteome changes detected in this large animal model of clinically severe muscular dystrophy provide novel molecular readouts for future treatment trials.

Survey Study and Records Review of Treatment Outcomes in Freeman-Sheldon Syndrome

ClinicalTrials.gov

2018-03-30

Freeman-Sheldon Syndrome; Arthrogryposis Distal Type 2A; Whistling Face Syndrome; Craniocarpotarsal Dysplasia; Craniocarpotarsal Dystrophy; Freeman-Sheldon Syndrome Variant; Sheldon-Hall Syndrome; Arthrogryposis Distal Type 2B; Gordon Syndrome; Arthrogryposis Distal Type 3; Arthrogryposis Distal Type 1; Arthrogryposis, Distal, Type 1A; Arthrogryposis Distal Type 1B; Arthrogryposis, Distal; Craniofacial Abnormalities; Arthrogryposis

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.

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.

Autoimmune polyglandular syndromes: interplay between the immune and the endocrine systems leading to a diverse set of clinical diseases and new insights into immune regulation.

PubMed

Lebovitz, Harold E

2013-06-01

During the last 50 years, three major classes of autoimmune polyglandular syndromes (APSs) have been defined, and their characteristics and heritability have been delineated. Simultaneously, studies of the immunologic bases of these syndromes provided fundamental information in understanding immune regulation. Genetic analyses of patients and their families with APS type 1 (autoimmune polyendocrinopathy candidiasis, ectodermal dystrophy) identified the autoimmune regulator (AIRE) gene, which drives the expression of peripheral tissue-specific antigens in thymic cells and is critical in the development of self-tolerance. Mutations in this gene cause APS type 1. In contrast, studies in APS type 2 have been instrumental in understanding the role of human leukocyte antigen type II and related molecules in the pathogenesis of polygenetic autoimmune diseases such as type 1A diabetes. Immune dysfunction polyendocrinopathy, enteropathy, X-linked syndrome, which is caused by mutations in the forkhead box P3 gene, has been a model for studying regulatory T cell biology. The APSs epitomize the synergies that the merger of clinical and basic science can achieve. This is the environment that George Eisenbarth was able to create at the Barbara Davis Center for Diabetes.

Dysferlin mediates membrane tubulation and links T-tubule biogenesis to muscular dystrophy.

PubMed

Hofhuis, Julia; Bersch, Kristina; Büssenschütt, Ronja; Drzymalski, Marzena; Liebetanz, David; Nikolaev, Viacheslav O; Wagner, Stefan; Maier, Lars S; Gärtner, Jutta; Klinge, Lars; Thoms, Sven

2017-03-01

The multi-C2 domain protein dysferlin localizes to the plasma membrane and the T-tubule system in skeletal muscle; however, its physiological mode of action is unknown. Mutations in the DYSF gene lead to autosomal recessive limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Here, we show that dysferlin has membrane tubulating capacity and that it shapes the T-tubule system. Dysferlin tubulates liposomes, generates a T-tubule-like membrane system in non-muscle cells, and links the recruitment of phosphatidylinositol 4,5-bisphosphate to the biogenesis of the T-tubule system. Pathogenic mutant forms interfere with all of these functions, indicating that muscular wasting and dystrophy are caused by the dysferlin mutants' inability to form a functional T-tubule membrane system. © 2017. Published by The Company of Biologists Ltd.

Stem Cell Differentiation Toward the Myogenic Lineage for Muscle Tissue Regeneration: A Focus on Muscular Dystrophy.

PubMed

Ostrovidov, Serge; Shi, Xuetao; Sadeghian, Ramin Banan; Salehi, Sahar; Fujie, Toshinori; Bae, Hojae; Ramalingam, Murugan; Khademhosseini, Ali

2015-12-01

Skeletal muscle tissue engineering is one of the important ways for regenerating functionally defective muscles. Among the myopathies, the Duchenne muscular dystrophy (DMD) is a progressive disease due to mutations of the dystrophin gene leading to progressive myofiber degeneration with severe symptoms. Although current therapies in muscular dystrophy are still very challenging, important progress has been made in materials science and in cellular technologies with the use of stem cells. It is therefore useful to review these advances and the results obtained in a clinical point of view. This article focuses on the differentiation of stem cells into myoblasts, and their application in muscular dystrophy. After an overview of the different stem cells that can be induced to differentiate into the myogenic lineage, we introduce scaffolding materials used for muscular tissue engineering. We then described some widely used methods to differentiate different types of stem cell into myoblasts. We highlight recent insights obtained in therapies for muscular dystrophy. Finally, we conclude with a discussion on stem cell technology. We discussed in parallel the benefits brought by the evolution of the materials and by the expansion of cell sources which can differentiate into myoblasts. We also discussed on future challenges for clinical applications and how to accelerate the translation from the research to the clinic in the frame of DMD.

[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.

Failure to up-regulate transcription of genes necessary for muscle adaptation underlies limb girdle muscular dystrophy 2A (calpainopathy)

PubMed Central

Kramerova, Irina; Ermolova, Natalia; Eskin, Ascia; Hevener, Andrea; Quehenberger, Oswald; Armando, Aaron M.; Haller, Ronald; Romain, Nadine; Nelson, Stanley F.; Spencer, Melissa J.

2016-01-01

Limb girdle muscular dystrophy 2A is due to loss-of-function mutations in the Calpain 3 (CAPN3) gene. Our previous data suggest that CAPN3 helps to maintain the integrity of the triad complex in skeletal muscle. In Capn3 knock-out mice (C3KO), Ca2+ release and Ca2+/calmodulin kinase II (CaMKII) signaling are attenuated. We hypothesized that calpainopathy may result from a failure to transmit loading-induced Ca2+-mediated signals, necessary to up-regulate expression of muscle adaptation genes. To test this hypothesis, we compared transcriptomes of muscles from wild type (WT) and C3KO mice subjected to endurance exercise. In WT mice, exercise induces a gene signature that includes myofibrillar, mitochondrial and oxidative lipid metabolism genes, necessary for muscle adaptation. C3KO muscles fail to activate the same gene signature. Furthermore, in agreement with the aberrant transcriptional profile, we observe a commensurate functional defect in lipid metabolism whereby C3KO muscles fail to release fatty acids from stored triacylglycerol. In conjunction with the defects in oxidative metabolism, C3KO mice demonstrate reduced exercise endurance. Failure to up-regulate genes in C3KO muscles is due, in part, to decreased levels of PGC1α, a transcriptional co-regulator that orchestrates the muscle adaptation response. Destabilization of PGC1α is attributable to decreased p38 MAPK activation via diminished CaMKII signaling. Thus, we elucidate a pathway downstream of Ca2+-mediated CaMKII activation that is dysfunctional in C3KO mice, leading to reduced transcription of genes involved in muscle adaptation. These studies identify a novel mechanism of muscular dystrophy: a blunted transcriptional response to muscle loading resulting in chronic failure to adapt and remodel. PMID:27005420

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.

Abnormal Collagen Metabolism in Cultured Skin Fibroblasts from Patients with Duchenne Muscular Dystrophy

NASA Astrophysics Data System (ADS)

Rodemann, H. Peter; Bayreuther, Klaus

1984-08-01

Total collagen synthesis is decreased by about 29% (P < 0.01) in skin fibroblasts established in vitro from male patients with Duchenne muscular dystrophy (DMD) as compared with that in normal male skin fibroblasts in vitro. The reduction in collagen synthesis is associated with an approximately 2-fold increase in collagen degradation in DMD fibroblasts. Correlated to these alterations in the metabolism of collagen, DMD fibroblasts express a significantly higher hydroxyproline/proline ratio (DMD: 1.36-1.45; P < 0.01) than do normal fibroblasts (controls: 0.86-0.89). The increased hydroxylation of proline residues of collagen (composed of type I and type III) could be the cause for the enhanced degradation of collagen in DMD fibroblasts.

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.

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

Functions of fukutin, a gene responsible for Fukuyama type congenital muscular dystrophy, in neuromuscular system and other somatic organs.

PubMed

Yamamoto, Tomoko; Shibata, Noriyuki; Saito, Yoshiaki; Osawa, Makiko; Kobayashi, Makio

2010-06-01

Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disease, exhibiting muscular dystrophy, and central nervous system (CNS) and ocular malformations. It is included in alpha-dystroglycanopathy, a group of muscular dystrophy showing reduced glycosylation of alpha-dystroglycan. alpha-Dystroglycan is one of the components of dystrophin-glycoprotein complex linking extracellular and intracellular proteins. The sugar chains of alpha-dystroglycan are receptors for extracellular matrix proteins such as laminin. Fukutin, a gene responsible for FCMD, is presumably related to the glycosylation of alpha-dystroglycan like other causative genes of alpha-dystroglycanopathy. The CNS lesion of FCMD is characterized by cobblestone lissencephaly, associated with decreased glycosylation of alpha-dystroglycan in the glia limitans where the basement membrane is formed. Astrocytes whose endfeet form the glia limitans seem to be greatly involved in the genesis of the CNS lesion. Fukutin is probably necessary for astrocytic function. Other components of the CNS may also need fukutin, such as migration and synaptic function in neurons. However, roles of fukutin in oligodendroglia, microglia, leptomeninges and capillaries are unknown at present. Fukutin is expressed in various somatic organs as well, and appears to work differently between epithelial cells and astrocytes. In the molecular level, since the dystrophin-glycoprotein complex is linked to cell signaling pathways involving c-src and c-jun, fukutin may be able to affect cell proliferation/survival. Fukutin was localized in the nucleus on cancer cell lines. With the consideration that mutations of fukutin give rise to wide spectrum of the clinical phenotype, more unknown functions of fukutin besides the glycosylation of alpha-dystroglycan can be suggested. Trials for novel treatments including gene therapy are in progress in muscular dystrophies. Toward effective therapies with minimal side effects, precise evaluation of the pathomechanism of FCMD and the function of fukutin would be required.

Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner

PubMed Central

Randolph, Matthew E; Luo, Qingwei; Ho, Justin; Vest, Katherine E; Sokoloff, Alan J; Pavlath, Grace K

2014-01-01

The inability to swallow, or dysphagia, is a debilitating and life-threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild-type mice depending on the particular muscle analysed. Furthermore, wild-type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild-type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild-type A10 PABPN1 was protective against age-related muscle atrophy in the laryngopharynx and prevented the development of age-related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region-dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia. PMID:25326455

Health services received by individuals with duchenne/becker muscular dystrophy.

PubMed

Pandya, Shree K; Campbell, Kim A; Andrews, Jennifer G; Meaney, F John; Ciafaloni, Emma

2016-02-01

Anecdotal reports from families and care providers suggest a wide variation in services received by individuals with Duchenne/Becker muscular dystrophy (DBMD). We documented the type and frequency of health services received by individuals with DBMD using the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) interview data released in June 2012. Interviews with eligible caregivers from 5 sites (Arizona, Colorado, Georgia, Iowa, and western New York) were conducted from April 2007 to March 2012. Two hundred ninety-six caregivers (66% of those contactable) participated in the interview. There were significant differences among sites in the specialists seen and services received. Concurrence with cardiac recommendations was higher than that with respiratory recommendations. The results of this survey support and quantify the anecdotal reports from families and care providers regarding the disparities in services received by individuals with DBMD. It remains to be determined whether these differences affect outcomes. © 2015 Wiley Periodicals, Inc.

Muscle ERRγ mitigates Duchenne muscular dystrophy via metabolic and angiogenic reprogramming.

PubMed

Matsakas, Antonios; Yadav, Vikas; Lorca, Sabina; Narkar, Vihang

2013-10-01

Treatment of Duchenne muscular dystrophy (DMD) by replacing mutant dystrophin or restoring dystrophin-associated glycoprotein complex (DAG) has been clinically challenging. Instead, identifying and targeting muscle pathways deregulated in DMD will provide new therapeutic avenues. We report that the expression of nuclear receptor estrogen-related receptor-γ (ERRγ), and its metabolic and angiogenic targets are down-regulated (50-85%) in skeletal muscles of mdx mice (DMD model) vs. wild-type mice. Corelatively, oxidative myofibers, muscle vasculature, and exercise tolerance (33%) are decreased in mdx vs. wild-type mice. Overexpressing ERRγ selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERRγ enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33-66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERRγ pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERRγ did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERRγ. In summary, ERRγ-dependent metabolic and angiogenic gene program is defective in DMD, and we demonstrate that its restoration is a potential strategy for treating muscular dystrophy.

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.

Morphological and functional analyses of skeletal muscles from an immunodeficient animal model of limb-girdle muscular dystrophy type 2E.

PubMed

Giovannelli, Gaia; Giacomazzi, Giorgia; Grosemans, Hanne; Sampaolesi, Maurilio

2018-02-24

Limb-girdle muscular dystrophy type 2E (LGMD2E) is caused by mutations in the β-sarcoglycan gene, which is expressed in skeletal, cardiac, and smooth muscles. β-Sarcoglycan-deficient (Sgcb-null) mice develop severe muscular dystrophy and cardiomyopathy with focal areas of necrosis. In this study we performed morphological (histological and cellular characterization) and functional (isometric tetanic force and fatigue) analyses in dystrophic mice. Comparison studies were carried out in 1-month-old (clinical onset of the disease) and 7-month-old control mice (C57Bl/6J, Rag2/γc-null) and immunocompetent and immunodeficient dystrophic mice (Sgcb-null and Sgcb/Rag2/γc-null, respectively). We found that the lack of an immunological system resulted in an increase of calcification in striated muscles without impairing extensor digitorum longus muscle performance. Sgcb/Rag2/γc-null muscles showed a significant reduction of alkaline phosphate-positive mesoangioblasts. The immunological system counteracts skeletal muscle degeneration in the murine model of LGMD2E. Muscle Nerve, 2018. © 2018 The Authors. Muscle & Nerve Published by Wiley Periodicals, Inc.

R124C mutation of the betaIGH3 gene leads to remarkable phenotypic variability in a Greek four-generation family with lattice corneal dystrophy type 1.

PubMed

Hellenbroich, Y; Tzivras, G; Neppert, B; Schwinger, E; Zühlke, C

2001-01-01

Five autosomal dominantly inherited corneal dystrophies are caused by missense mutations in the betaIGH3 gene on chromosome 5q31. Here we describe the clinical features and the analysis of the betaIGH3 gene in a Greek four-generation family with lattice corneal dystrophy type 1 (CDL1). Sequencing of the betaIGH3 cDNA from an affected family member revealed the R124C mutation. More recent data indicate that this is probably a mutation hot spot in CDL1. We could not find a common haplotype with another CDL1 family with the R124C mutation demonstrating that this mutation occurs independently in different families. The clinical course of the disease showed a remarkable variability between the affected family members. To investigate a possible role between the phenotypic variability and apolipoprotein E (ApoE), which co-localises with amyloid deposits in CDL1, we determined the ApoE genotype of all family members. The resulting data revealed no association with the variable clinical course. Copyright 2001 S. Karger AG, Basel

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.

[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.

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

Comparative Study of Anterior Eye Segment Measurements with Spectral Swept-Source and Time-Domain Optical Coherence Tomography in Eyes with Corneal Dystrophies

PubMed Central

Teper, Sławomir J.; Janiszewska, Dominika A.; Lyssek-Boron, Anita; Dobrowolski, Dariusz; Koprowski, Robert; Wylegala, Edward

2015-01-01

Purpose. To compare anterior eye segment measurements and morphology obtained with two optical coherence tomography systems (TD OCT, SS OCT) in eyes with corneal dystrophies (CDs). Methods. Fifty healthy volunteers (50 eyes) and 54 patients (96 eyes) diagnosed with CD (epithelial basement membrane dystrophy, EBMD = 12 eyes; Thiel-Behnke CD = 6 eyes; lattice CD TGFBI type = 15 eyes; granular CD type 1 = 7 eyes, granular CD type 2 = 2 eyes; macular CD = 23 eyes; and Fuchs endothelial CD = 31 eyes) were recruited for the study. Automated and manual central corneal thickness (aCCT, mCCT), anterior chamber depth (ACD), and nasal and temporal trabecular iris angle (nTIA, tTIA) were measured and compared with Bland-Altman plots. Results. Good agreement between the TD and SS OCT measurements was demonstrated for mCCT and aCCT in normal individuals and for mCCT in the CDs group. The ACD, nTIA, and tTIA measurements differed significantly in both groups. TBCD, LCD, and FECD caused increased CCT. MCD caused significant corneal thinning. FECD affected all analyzed parameters. Conclusions. Better agreement between SS OCT and TD OCT measurements was demonstrated in normal individuals compared to the CDs group. OCT provides comprehensive corneal deposits analysis and demonstrates the association of CD with CCT, ACD, and TIA measurements. PMID:26457303

Comparative Study of Anterior Eye Segment Measurements with Spectral Swept-Source and Time-Domain Optical Coherence Tomography in Eyes with Corneal Dystrophies.

PubMed

Nowinska, Anna K; Teper, Sławomir J; Janiszewska, Dominika A; Lyssek-Boron, Anita; Dobrowolski, Dariusz; Koprowski, Robert; Wylegala, Edward

2015-01-01

To compare anterior eye segment measurements and morphology obtained with two optical coherence tomography systems (TD OCT, SS OCT) in eyes with corneal dystrophies (CDs). Fifty healthy volunteers (50 eyes) and 54 patients (96 eyes) diagnosed with CD (epithelial basement membrane dystrophy, EBMD = 12 eyes; Thiel-Behnke CD = 6 eyes; lattice CD TGFBI type = 15 eyes; granular CD type 1 = 7 eyes, granular CD type 2 = 2 eyes; macular CD = 23 eyes; and Fuchs endothelial CD = 31 eyes) were recruited for the study. Automated and manual central corneal thickness (aCCT, mCCT), anterior chamber depth (ACD), and nasal and temporal trabecular iris angle (nTIA, tTIA) were measured and compared with Bland-Altman plots. Good agreement between the TD and SS OCT measurements was demonstrated for mCCT and aCCT in normal individuals and for mCCT in the CDs group. The ACD, nTIA, and tTIA measurements differed significantly in both groups. TBCD, LCD, and FECD caused increased CCT. MCD caused significant corneal thinning. FECD affected all analyzed parameters. Better agreement between SS OCT and TD OCT measurements was demonstrated in normal individuals compared to the CDs group. OCT provides comprehensive corneal deposits analysis and demonstrates the association of CD with CCT, ACD, and TIA measurements.

Deletion of Galgt2 (B4Galnt2) Reduces Muscle Growth in Response to Acute Injury and Increases Muscle Inflammation and Pathology in Dystrophin-Deficient Mice

PubMed Central

Xu, Rui; Singhal, Neha; Serinagaoglu, Yelda; Chandrasekharan, Kumaran; Joshi, Mandar; Bauer, John A.; Janssen, Paulus M.L.; Martin, Paul T.

2016-01-01

Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2−/−mdx). Galgt2−/− mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. PMID:26435413

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.

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

Potent pro-inflammatory and pro-fibrotic molecules, osteopontin and galectin-3, are not major disease modulators of laminin α2 chain-deficient muscular dystrophy

PubMed Central

Gawlik, Kinga I.; Holmberg, Johan; Svensson, Martina; Einerborg, Mikaela; Oliveira, Bernardo M. S.; Deierborg, Tomas; Durbeej, Madeleine

2017-01-01

A large number of human diseases are caused by chronic tissue injury with fibrosis potentially leading to organ failure. There is a need for more effective anti-fibrotic therapies. Congenital muscular dystrophy type 1A (MDC1A) is a devastating form of muscular dystrophy caused by laminin α2 chain-deficiency. It is characterized with early inflammation and build-up of fibrotic lesions, both in patients and MDC1A mouse models (e.g. dy3K/dy3K). Despite the enormous impact of inflammation on tissue remodelling in disease, the inflammatory response in MDC1A has been poorly described. Consequently, a comprehensive understanding of secondary mechanisms (impaired regeneration, enhanced fibrosis) leading to deterioration of muscle phenotype in MDC1A is missing. We have monitored inflammatory processes in dy3K/dy3K muscle and created mice deficient in laminin α2 chain and osteopontin or galectin-3, two pro-inflammatory and pro-fibrotic molecules drastically increased in dystrophic muscle. Surprisingly, deletion of osteopontin worsened the phenotype of dy3K/dy3K mice and loss of galectin-3 did not reduce muscle pathology. Our results indicate that osteopontin could even be a beneficial immunomodulator in MDC1A. This knowledge is essential for the design of future therapeutic interventions for muscular dystrophies that aim at targeting inflammation, especially that osteopontin inhibition has been suggested for Duchenne muscular dystrophy therapy. PMID:28281577

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.

A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.

PubMed

Vissing, John; Barresi, Rita; Witting, Nanna; Van Ghelue, Marijke; Gammelgaard, Lise; Bindoff, Laurence A; Straub, Volker; Lochmüller, Hanns; Hudson, Judith; Wahl, Christoph M; Arnardottir, Snjolaug; Dahlbom, Kathe; Jonsrud, Christoffer; Duno, Morten

2016-08-01

Limb girdle muscular dystrophy type 2A is the most common limb girdle muscular dystrophy form worldwide. Although strict recessive inheritance is assumed, patients carrying a single mutation in the calpain 3 gene (CAPN3) are reported. Such findings are commonly attributed to incomplete mutation screening. In this investigation, we report 37 individuals (age range: 21-85 years, 21 females and 16 males) from 10 families in whom only one mutation in CAPN3 could be identified; a 21-bp, in-frame deletion (c.643_663del21). This mutation co-segregated with evidence of muscle disease and autosomal dominant transmission in several generations. Evidence of muscle disease was indicated by muscle pain, muscle weakness and wasting, significant fat replacement of muscles on imaging, myopathic changes on muscle biopsy and loss of calpain 3 protein on western blotting. Thirty-one of 34 patients had elevated creatine kinase or myoglobin. Muscle weakness was generally milder than observed in limb girdle muscular dystrophy type 2A, but affected the same muscle groups (proximal leg, lumbar paraspinal and medial gastrocnemius muscles). In some cases, the weakness was severely disabling. The 21-bp deletion did not affect mRNA maturation. Calpain 3 expression in muscle, assessed by western blot, was below 15% of normal levels in the nine mutation carriers in whom this could be tested. Haplotype analysis in four families from three different countries suggests that the 21-bp deletion is a founder mutation. This study provides strong evidence that heterozygosity for the c.643_663del21 deletion in CAPN3 results in a dominantly inherited muscle disease. The normal expression of mutated mRNA and the severe loss of calpain 3 on western blotting, suggest a dominant negative effect with a loss-of-function mechanism affecting the calpain 3 homodimer. This renders patients deficient in calpain 3 as in limb girdle muscular dystrophy type 2A, albeit in a milder form in most cases. Based on findings in 10 families, our study indicates that a dominantly inherited pattern of calpainopathy exists, and should be considered in the diagnostic work-up and genetic counselling of patients with calpainopathy and single-allele aberrations in CAPN3. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

Genetics Home Reference: Laing distal myopathy

MedlinePlus

... Muscular Dystrophy Association: Facts About Rare Muscular Dystrophies (PDF) Muscular Dystrophy Canada Muscular Dystrophy UK National Organization for Rare Disorders (NORD): Distal Myopathy Resource list ...

Muscular dystrophy - resources

MedlinePlus

Resources - muscular dystrophy ... The following organizations are good resources for information on muscular dystrophy : Muscular Dystrophy Association -- www.mda.org National Institute of Neurological Disorders and Stroke -- www.ninds.nih. ...

Vitelliform dystrophy and pattern dystrophy of the retinal pigment epithelium: concomitant presence in a family.

PubMed Central

Giuffrè, G; Lodato, G

1986-01-01

We describe three siblings presenting unusual pigmented dystrophic lesions of the fovea. The first sibling showed macroreticular dystrophy associated with butterfly shaped dystrophy in one eye and associated with vitelliform cyst in the other eye. The second showed the atrophic outcome of a vitelliform cyst with development of subretinal neovascular membrane in one eye and a radial pigmented macular dystrophy in the other eye. The third sibling had bilateral macular vitelliform lesions. This vitelliform patterned dystrophy of the retinal pigment epithelium may represent a new form that should be classified near Best's disease and the pattern dystrophies. Images PMID:3718916

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 ...

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.

Gastrobronchial fistula following minimally invasive esophagectomy for esophageal cancer in a patient with myotonic dystrophy: Case report

PubMed Central

Hugin, Silje; Johnson, Egil; Johannessen, Hans-Olaf; Hofstad, Bjørn; Olafsen, Kjell; Mellem, Harald

2015-01-01

Introduction Myotonic dystrophies are inherited multisystemic diseases characterized by musculopathy, cardiac arrythmias and cognitive disorders. These patients are at increased risk for fatal post-surgical complications from pulmonary hypoventilation. We present a case with myotonic dystrophy and esophageal cancer who had a minimally invasive esophagectomy complicated with gastrobronchial fistulisation. Presentation of case A 44-year-old male with myotonic dystrophy type 1 and esophageal cancer had a minimally invasive esophagectomy performed instead of open surgery in order to reduce the risk for pulmonary complications. At day 15 respiratory failure occurred from a gastrobronchial fistula between the right intermediary bronchus (defect 7–8 mm) and the esophagogastric anastomosis (defect 10 mm). In order to minimize large leakage of air into the gastric conduit the anastomosis was stented and ventilation maintained at low airway pressures. His general condition improved and allowed extubation at day 29 and stent removal at day 35. Bronchoscopy confirmed that the fistula was healed. The patient was discharged from hospital at day 37 without further complications. Discussion The fistula was probably caused by bronchial necrosis from thermal injury during close dissection using the Ligasure instrument. Fistula treatment by non-surgical intervention was considered safer than surgery which could be followed by potentially life-threatening respiratory complications. Indications for stenting of gastrobronchial fistulas will be discussed. Conclusions Minimally invasive esophagectomy was performed instead of open surgery in a myotonic dystrophy patient as these patients are particularly vulnerable to respiratory complications. Gastrobronchial fistula, a major complication, was safely treated by stenting and low airway pressure ventilation. PMID:26520033

[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)

[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.

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.

YAC and cosmid contigs encompassing the Fukuyama-type congenital muscular dystrophy (FCMD) candidate region on 9q31

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

Miyake, Masashi; Nakahori, Yutaka; Matsushita, Ikumi

1997-03-01

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common form of childhood muscular dystrophy in Japan, is an autosomal recessive severe muscular dystrophy associated with an anomaly of the brain. We had mapped the FCMD gene to an approximately 5-cM interval between D9S127 and D9S2111 on 9q31-q33 and had also found evidence for linkage disequilibrium between FCMD and D9S306 in this candidate region. Through further analysis, we have defined another marker, D9S172, which showed stronger linkage disequilibrium than D9S306. A yeast artificial chromosome (YAC) contig spanning 3.5 Mb, which includes this D9S306-D9S172 interval on 9q31, has been constructed by amore » combination of sequence-tagged site, Alu-PCR, and restriction mapping. Also, cosmid clones subcloned from the YAC were assembled into three contigs, one of which contains D9S2107, which showed the strongest linkage disequilibrium with FCMD. These contigs also allowed us to order the markers as follows: cen-D9S127-({approximately}800 kb)-D9S306 (identical to D9S53)-({approximately}700 kb)-A107XF9-({approximately}500 kb)-D9S172-({approximately}30 kb)-D9S299 (identical to D9S774)-({approximately}120 kb)-WI2269-tel. Thus, we have constructed the first high-resolution physical map of the FCMD candidate region. The YAC and cosmid contigs established here will be a crucial resource for identification of the FCMD gene and other genes in this region. 37 refs., 7 figs., 2 tabs.« less

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.

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

Mouse Regenerating Myofibers Detected as False-Positive Donor Myofibers with Anti-Human Spectrin

PubMed Central

Rozkalne, Anete; Adkin, Carl; Meng, Jinhong; Lapan, Ariya; Morgan, Jennifer E.

2014-01-01

Abstract Stem cell transplantation is being tested as a potential therapy for a number of diseases. Stem cells isolated directly from tissue specimens or generated via reprogramming of differentiated cells require rigorous testing for both safety and efficacy in preclinical models. The availability of mice with immune-deficient background that carry additional mutations in specific genes facilitates testing the efficacy of cell transplantation in disease models. The muscular dystrophies are a heterogeneous group of disorders, of which Duchenne muscular dystrophy is the most severe and common type. Cell-based therapy for muscular dystrophy has been under investigation for several decades, with a wide selection of cell types being studied, including tissue-specific stem cells and reprogrammed stem cells. Several immune-deficient mouse models of muscular dystrophy have been generated, in which human cells obtained from various sources are injected to assess their preclinical potential. After transplantation, the presence of engrafted human cells is detected via immunofluorescence staining, using antibodies that recognize human, but not mouse, proteins. Here we show that one antibody specific to human spectrin, which is commonly used to evaluate the efficacy of transplanted human cells in mouse muscle, detects myofibers in muscles of NOD/Rag1nullmdx5cv, NOD/LtSz-scid IL2Rγnull mice, or mdx nude mice, irrespective of whether they were injected with human cells. These “reactive” clusters are regenerating myofibers, which are normally present in dystrophic tissue and the spectrin antibody is likely recognizing utrophin, which contains spectrin-like repeats. Therefore, caution should be used in interpreting data based on detection of single human-specific proteins, and evaluation of human stem cell engraftment should be performed using multiple human-specific labeling strategies. PMID:24152287

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

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase

PubMed Central

Cozzoli, Anna; Liantonio, Antonella; Conte, Elena; Cannone, Maria; Massari, Ada Maria; Giustino, Arcangela; Scaramuzzi, Antonia; Pierno, Sabata; Mantuano, Paola; Capogrosso, Roberta Francesca; Camerino, Giulia Maria

2014-01-01

Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers. PMID:25080489

Angiotensin II modulates mouse skeletal muscle resting conductance to chloride and potassium ions and calcium homeostasis via the AT1 receptor and NADPH oxidase.

PubMed

Cozzoli, Anna; Liantonio, Antonella; Conte, Elena; Cannone, Maria; Massari, Ada Maria; Giustino, Arcangela; Scaramuzzi, Antonia; Pierno, Sabata; Mantuano, Paola; Capogrosso, Roberta Francesca; Camerino, Giulia Maria; De Luca, Annamaria

2014-10-01

Angiotensin II (ANG II) plays a role in muscle wasting and remodeling; however, little evidence shows its direct effects on specific muscle functions. We presently investigated the acute in vitro effects of ANG II on resting ionic conductance and calcium homeostasis of mouse extensor digitorum longus (EDL) muscle fibers, based on previous findings that in vivo inhibition of ANG II counteracts the impairment of macroscopic ClC-1 chloride channel conductance (gCl) in the mdx mouse model of muscular dystrophy. By means of intracellular microelectrode recordings we found that ANG II reduced gCl in the nanomolar range and in a concentration-dependent manner (EC50 = 0.06 μM) meanwhile increasing potassium conductance (gK). Both effects were inhibited by the ANG II receptors type 1 (AT1)-receptor antagonist losartan and the protein kinase C inhibitor chelerythrine; no antagonism was observed with the AT2 antagonist PD123,319. The scavenger of reactive oxygen species (ROS) N-acetyl cysteine and the NADPH-oxidase (NOX) inhibitor apocynin also antagonized ANG II effects on resting ionic conductances; the ANG II-dependent gK increase was blocked by iberiotoxin, an inhibitor of calcium-activated potassium channels. ANG II also lowered the threshold for myofiber and muscle contraction. Both ANG II and the AT1 agonist L162,313 increased the intracellular calcium transients, measured by fura-2, with a two-step pattern. These latter effects were not observed in the presence of losartan and of the phospholipase C inhibitor U73122 and the in absence of extracellular calcium, disclosing a Gq-mediated calcium entry mechanism. The data show for the first time that the AT1-mediated ANG II pathway, also involving NOX and ROS, directly modulates ion channels and calcium homeostasis in adult myofibers. Copyright © 2014 the American Physiological Society.

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

Limb girdle muscular dystrophy type 2G with myopathic-neurogenic motor unit potentials and a novel muscle image pattern.

PubMed

Cotta, Ana; Paim, Julia Filardi; da-Cunha-Junior, Antonio Lopes; Neto, Rafael Xavier; Nunes, Simone Vilela; Navarro, Monica Magalhaes; Valicek, Jaquelin; Carvalho, Elmano; Yamamoto, Lydia U; Almeida, Camila F; Braz, Shelida Vasconcelos; Takata, Reinaldo Issao; Vainzof, Mariz

2014-01-01

Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C > T in the TCAP gene. This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis.

What Are the Types of Muscular Dystrophy?

MedlinePlus

... or sitting position Waddle when walking Have difficulty running and jumping Have calf muscles that appear large ... that causes shoulders to appear slanted and shoulder blades to appear "winged" Impaired reflexes only at the ...

Types of Leukodystrophies

MedlinePlus

... Leukoencephalopathy (RNASET2 related) Elongation of Very Long-Chain Fatty Acids-4 (ELOVL4; Pseudo-Sjogren-Larsson) Extensive Cerebral White ... with Adult Onset Dementia and Abnormal Glycolipid Storage Fatty Acid 2-Hydroxylase Deficiency Fucosidosis Fukuyama Congential Muscular Dystrophy ...

Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-α-glucosidase

PubMed Central

Amalfitano, A.; McVie-Wylie, A. J.; Hu, H.; Dawson, T. L.; Raben, N.; Plotz, P.; Chen, Y. T.

1999-01-01

This report demonstrates that a single intravenous administration of a gene therapy vector can potentially result in the correction of all affected muscles in a mouse model of a human genetic muscle disease. These results were achieved by capitalizing both on the positive attributes of modified adenovirus-based vectoring systems and receptor-mediated lysosomal targeting of enzymes. The muscle disease treated, glycogen storage disease type II, is a lysosomal storage disorder that manifests as a progressive myopathy, secondary to massive glycogen accumulations in the skeletal and/or cardiac muscles of affected individuals. We demonstrated that a single intravenous administration of a modified Ad vector encoding human acid α-glucosidase (GAA) resulted in efficient hepatic transduction and secretion of high levels of the precursor GAA proenzyme into the plasma of treated animals. Subsequently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed. As a result, systemic decreases (and correction) of the glycogen accumulations in a variety of muscle tissues was demonstrated. This model can potentially be expanded to include the treatment of other lysosomal enzyme disorders. Lessons learned from systemic genetic therapy of muscle disorders also should have implications for other muscle diseases, such as the muscular dystrophies. PMID:10430861

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.

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.

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.

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.

'Laminopathies': A wide spectrum of human diseases

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

Worman, Howard J.; Bonne, Gisele; Universite Pierre et Marie Curie-Paris 6, Faculte de medecine, Paris F-75013

2007-06-10

Mutations in genes encoding the intermediate filament nuclear lamins and associated proteins cause a wide spectrum of diseases sometimes called 'laminopathies.' Diseases caused by mutations in LMNA encoding A-type lamins include autosomal dominant Emery-Dreifuss muscular dystrophy and related myopathies, Dunnigan-type familial partial lipodystrophy, Charcot-Marie-Tooth disease type 2B1 and developmental and accelerated aging disorders. Duplication in LMNB1 encoding lamin B1 causes autosomal dominant leukodystrophy and mutations in LMNB2 encoding lamin B2 are associated with acquired partial lipodystrophy. Disorders caused by mutations in genes encoding lamin-associated integral inner nuclear membrane proteins include X-linked Emery-Dreifuss muscular dystrophy, sclerosing bone dysplasias, HEM/Greenberg skeletal dysplasiamore » and Pelger-Huet anomaly. While mutations and clinical phenotypes of 'laminopathies' have been carefully described, data explaining pathogenic mechanisms are only emerging. Future investigations will likely identify new 'laminopathies' and a combination of basic and clinical research will lead to a better understanding of pathophysiology and the development of therapies.« less

Inherited Retinal Degenerative Disease Registry

ClinicalTrials.gov

2017-09-13

Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

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

Genetics Home Reference: lattice corneal dystrophy type I

MedlinePlus

... have recurrent corneal erosions, which are caused by separation of particular layers of the cornea from one ... intricate network that forms in the spaces between cells and provides structural support to tissues. The protein ...

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus.

PubMed

Torres, Manuel; Jimenez, Sebastian; Sanchez-Varo, Raquel; Navarro, Victoria; Trujillo-Estrada, Laura; Sanchez-Mejias, Elisabeth; Carmona, Irene; Davila, Jose Carlos; Vizuete, Marisa; Gutierrez, Antonia; Vitorica, Javier

2012-11-22

Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer's patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.

Loss of Drosophila A-type lamin C initially causes tendon abnormality including disintegration of cytoskeleton and nuclear lamina in muscular defects.

PubMed

Uchino, Ryo; Nonaka, Yu-Ki; Horigome, Tuneyoshi; Sugiyama, Shin; Furukawa, Kazuhiro

2013-01-01

Lamins are the major components of nuclear envelope architecture, being required for both the structural and informational roles of the nuclei. Mutations of lamins cause a spectrum of diseases in humans, including muscular dystrophy. We report here that the loss of the A-type lamin gene, lamin C in Drosophila resulted in pupal metamorphic lethality caused by tendon defects, matching the characteristics of human A-type lamin revealed by Emery-Dreifuss muscular dystrophy (EDMD). In tendon cells lacking lamin C activity, overall cell morphology was affected and organization of the spectraplakin family cytoskeletal protein Shortstop which is prominently expressed in tendon cells gradually disintegrated, notably around the nucleus and in a manner correlating well with the degradation of musculature. Furthermore, lamin C null mutants were efficiently rescued by restoring lamin C expression to shortstop-expressing cells, which include tendon cells but exclude skeletal muscle cells. Thus the critical function of A-type lamin C proteins in Drosophila musculature is to maintain proper function and morphology of tendon cells. Copyright © 2012 Elsevier Inc. All rights reserved.

Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation 1 as augmentation therapeutic strategy approaches in muscular dystrophy.

PubMed

Afzal, Ehsan; Zakeri, Saba; Keyhanvar, Peyman; Bagheri, Meisam; Mahjoubi, Parvin; Asadian, Mahtab; Omoomi, Nogol; Dehqanian, Mohammad; Ghalandarlaki, Negar; Darvishmohammadi, Tahmineh; Farjadian, Fatemeh; Golvajoee, Mohammad Sadegh; Afzal, Shadi; Ghaffari, Maryam; Cohan, Reza Ahangari; Gravand, Amin; Ardestani, Mehdi Shafiee

2013-01-01

[Corrected] Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion - like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation.

Nanolipodendrosome-loaded glatiramer acetate and myogenic differentiation 1 as augmentation therapeutic strategy approaches in muscular dystrophy

PubMed Central

Afzal, Ehsan; Zakeri, Saba; Keyhanvar, Peyman; Bagheri, Meisam; Mahjoubi, Parvin; Asadian, Mahtab; Omoomi, Nogol; Dehqanian, Mohammad; Ghalandarlaki, Negar; Darvishmohammadi, Tahmineh; Farjadian, Fatemeh; Golvajoee, Mohammad Sadegh; Afzal, Shadi; Ghaffari, Maryam; Cohan, Reza Ahangari; Gravand, Amin; Ardestani, Mehdi Shafiee

2013-01-01

Backgrond Muscular dystrophies consist of a number of juvenile and adult forms of complex disorders which generally cause weakness or efficiency defects affecting skeletal muscles or, in some kinds, other types of tissues in all parts of the body are vastly affected. In previous studies, it was observed that along with muscular dystrophy, immune inflammation was caused by inflammatory cells invasion – like T lymphocyte markers (CD8+/CD4+). Inflammatory processes play a major part in muscular fibrosis in muscular dystrophy patients. Additionally, a significant decrease in amounts of two myogenic recovery factors (myogenic differentation 1 [MyoD] and myogenin) in animal models was observed. The drug glatiramer acetate causes anti-inflammatory cytokines to increase and T helper (Th) cells to induce, in an as yet unknown mechanism. MyoD recovery activity in muscular cells justifies using it alongside this drug. Methods In this study, a nanolipodendrosome carrier as a drug delivery system was designed. The purpose of the system was to maximize the delivery and efficiency of the two drug factors, MyoD and myogenin, and introduce them as novel therapeutic agents in muscular dystrophy phenotypic mice. The generation of new muscular cells was analyzed in SW1 mice. Then, immune system changes and probable side effects after injecting the nanodrug formulations were investigated. Results The loaded lipodendrimer nanocarrier with the candidate drug, in comparison with the nandrolone control drug, caused a significant increase in muscular mass, a reduction in CD4+/CD8+ inflammation markers, and no significant toxicity was observed. The results support the hypothesis that the nanolipodendrimer containing the two candidate drugs will probably be an efficient means to ameliorate muscular degeneration, and warrants further investigation. PMID:23966782

Protein and genetic diagnosis of limb girdle muscular dystrophy type 2A: The yield and the pitfalls.

PubMed

Fanin, Marina; Angelini, Corrado

2015-08-01

Limb girdle muscular dystrophy type 2A (LGMD2A) is the most frequent form of LGMD worldwide. Comprehensive clinical assessment and laboratory testing is essential for diagnosis of LGMD2A. Muscle immunoblot analysis of calpain-3 is the most useful tool to direct genetic testing, as detection of calpain-3 deficiency has high diagnostic value. However, calpain-3 immunoblot testing lacks sensitivity in about 30% of cases due to gene mutations that inactivate the enzyme. The best diagnostic strategy should be determined on a case-by-case basis, depending on which tissues are available, and which molecular and/or genetic methods are adopted. In this work we survey the current knowledge, advantages, limitations, and pitfalls of protein testing and mutation detection in LGMD2A and provide an update of genetic epidemiology. © 2015 Wiley Periodicals, Inc.

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.

Clinical, pathological, and genetic features of limb-girdle muscular dystrophy type 2A with new calpain 3 gene mutations in seven patients from three Japanese families.

PubMed

Kawai, H; Akaike, M; Kunishige, M; Inui, T; Adachi, K; Kimura, C; Kawajiri, M; Nishida, Y; Endo, I; Kashiwagi, S; Nishino, H; Fujiwara, T; Okuno, S; Roudaut, C; Richard, I; Beckmann, J S; Miyoshi, K; Matsumoto, T

1998-11-01

We report on the clinical, pathological, and genetic features of 7 patients with limb-girdle muscular dystrophy type 2A (LGMD2A) from three Japanese families. The mean age of onset was 9.7+/-3.1 years (mean+/-SD), and loss of ambulance occurred at 38.5+/-2.1 years. Muscle atrophy was predominant in the pelvic and shoulder girdles, and proximal limb muscles. Muscle pathology revealed dystrophic changes. In two families, an identical G to C mutation at position 1080 the in calpain 3 gene was identified, and a frameshift mutation (1796insA) was found in the third family. The former mutation results in a W360R substitution in the proteolytic site of calpain 3, and the latter in a deletion of the Ca2+-binding domain.

Electric injury, Part II: Specific injuries.

PubMed

Fish, R M

2000-01-01

Electric injury can cause disruption of cardiac rhythm and breathing, burns, fractures, dislocations, rhabdomyolysis, eye and ear injury, oral and gastrointestinal injury, vascular damage, disseminated intravascular coagulation, peripheral and spinal cord injury, and Reflex Sympathetic Dystrophy. Secondary trauma from falls, fires, flying debris, and inhalation injury can complicate the clinical picture. Diagnostic and treatment considerations for electric injuries are described in this article, which is the second part of a three-part series on electric injuries.

[New international classification of corneal dystrophies and clinical landmarks].

PubMed

Lisch, W; Seitz, B

2008-07-01

The International Committee on Classification of Corneal Dystrophies, briefly IC (3)D, was founded with the sponsorship of the American Cornea Society and the American Academy of Ophthalmology in July 2005. This committee consists of 17 corneal experts (1) from USA, Asia and Europe. The goal of this group was to develop a new, internationally accepted classification of corneal dystrophies (CD) based on modern clinical, histological and genetical knowledge. The aim of the new classification should be to avoid wrong interpretations and misnomers of the different forms of CD. The IC (3)D extensive manuscript is in press as Supplement publication in the journal "Cornea". The 25 different CD are divided in four categories by clinical and genetical knowledge. Additionally, templates for each type of CD are included. Finally, many typical color slit-lamp photos are presented in the publication together with essential references and current genetical results in tabular form. As members of IC (3)D the authors present a clinical landmark survey of the different corneal dystrophies. The ophthalmologist is the first to examine and to diagnose a new patient with a probable CD at the slit-lamp. Our elaborated table of landmarks is supposed to be a "bridge" for the ophthalmologist to precisely define the corneal opacities of a presumed CD. This "bridge" makes it easier for them to study the IC (3)D Supplement publication and to get more information including adequate differential diagnosis.

Inherited neuroaxonal dystrophy in dogs causing lethal, fetal-onset motor system dysfunction and cerebellar hypoplasia

PubMed Central

Fyfe, John C.; Al-Tamimi, Raba' A.; Castellani, Rudy J.; Rosenstein, Diana; Goldowitz, Daniel; Henthorn, Paula S.

2010-01-01

Neuroaxonal dystrophy in brainstem, spinal cord tracts, and spinal nerves accompanied by cerebellar hypoplasia was observed in a colony of laboratory dogs. Fetal akinesia was documented by ultrasonographic examination. At birth, affected puppies exhibited stereotypical positioning of limbs, scoliosis, arthrogryposis, pulmonary hypoplasia, and respiratory failure. Regional hypoplasia in the central nervous system was apparent grossly, most strikingly as underdeveloped cerebellum and spinal cord. Histopathologic abnormalities included swollen axons and spheroids in brainstem and spinal cord tracts; reduced cerebellar foliation, patchy loss of Purkinje cells, multifocal thinning of the external granular cell layer, and loss of neurons in the deep cerebellar nuclei; spheroids and loss of myelinated axons in spinal roots and peripheral nerves; increased myocyte apoptosis in skeletal muscle; and fibrofatty connective tissue proliferation around joints. Breeding studies demonstrated that the canine disorder is a fully penetrant, simple autosomal recessive trait. The disorder demonstrated a type and distribution of lesions homologous to that of human infantile neuroaxonal dystrophy (INAD), most commonly caused by mutations of PLA2G6, but alleles of informative markers flanking the canine PLA2G6 locus did not associate with the canine disorder. Thus, fetal-onset neuroaxonal dystrophy in dogs, a species with well-developed genome mapping resources, provides a unique opportunity for additional disease gene discovery and understanding of this pathology. PMID:20653033

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

Modulation of Stem Cell Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration after Injury

DTIC Science & Technology

2011-03-01

Duchenne muscular dystrophy (DMD). To examine whether counteracting myostatin, a negative regulator of muscle mass and a pro-lipofibrotic factor...extracellular matrix, and fat, characterizes muscle dystrophy , and in particular Duchenne muscular dystrophy (DMD) (1,2), as seen also in its animal model...stem cells (MDSC) into myogenic as opposed to lipofibrogenic lineages is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). To

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.

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.

Phenomics in Autoimmune and Inflammatory Diseases

ClinicalTrials.gov

2016-12-12

Healthy Volunteer; Rheumatoid Arthritis; Ankylosing Spondylitis; Systemic Lupus Erythematosus/Antiphospholipid Syndrome; FMF; Cryopyrin-Associated Periodic Syndromes /TNF-receptor Associated Periodic Syndrome; Vasculitis; Uveitis; Myositis; Crohn's Disease; Ulcerative Rectocolitis; Type 1 Diabetes; Unclassified IAD Knee and/or Hip Arthritis, Muscular Dystrophy

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.

Three Wishes and Psychological Functioning in Boys with Duchenne Muscular Dystrophy

PubMed Central

NEREO, NANCY E.; HINTON, VERONICA J.

2007-01-01

This study examined Three Wishes (a projective technique commonly used with children) in boys with Duchenne muscular dystrophy (DMD), a fatal, progressive illness (n = 74). A reliable and parsimonious scoring system was developed to code wish type. Probands’ responses were compared with unaffected siblings (n = 32) and a male comparison group (n = 43). Contrary to what was expected, the DMD group did not make significantly more health-related wishes than their siblings or the comparison group. Further, no association between health-related wishes and problem behaviors was observed in the DMD group. These findings indicate that, despite increased stressors, boys with DMD present wishes similar to those of their healthy peers. PMID:12692454

Corneal dystrophies

PubMed Central

Klintworth, Gordon K

2009-01-01

The term corneal dystrophy embraces a heterogenous group of bilateral genetically determined non-inflammatory corneal diseases that are restricted to the cornea. The designation is imprecise but remains in vogue because of its clinical value. Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies), the corneal stroma (stromal corneal dystrophies), or Descemet membrane and the corneal endothelium (posterior corneal dystrophies). Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Knowledge about the responsible genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage diseases (mucopolysaccharidoses, lipidoses, mucolipidoses), and several skin diseases (X-linked ichthyosis, keratosis follicularis spinolosa decalvans). The management of the corneal dystrophies varies with the specific disease. Some are treated medically or with methods that excise or ablate the abnormal corneal tissue, such as deep lamellar endothelial keratoplasty (DLEK) and phototherapeutic keratectomy (PTK). Other less debilitating or asymptomatic dystrophies do not warrant treatment. The prognosis varies from minimal effect on the vision to corneal blindness, with marked phenotypic variability. PMID:19236704

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

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

Systems Biology of Glucocorticoids in Muscle Disease

DTIC Science & Technology

2010-10-01

Introduction Duchenne muscular dystrophy (DMD) is the most common and incurable muscular dystrophy of childhood. Muscle regeneration fails with...SUBJECT TERMS Duchenne Muscular dystrophy , Glucocorticoids, Systems biology, Drug mechanism 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION...better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant proposal is led by Dr. Eric Hoffman, and it

Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy

ClinicalTrials.gov

2018-05-16

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

An elderly-onset limb girdle muscular dystrophy type 1B (LGMD1B) with pseudo-hypertrophy of paraspinal muscles.

PubMed

Furuta, Mitsuru; Sumi-Akamaru, Hisae; Takahashi, Masanori P; Hayashi, Yukiko K; Nishino, Ichizo; Mochizuki, Hideki

2016-09-01

Mutations in LMNA, encoding A-type lamins, lead to diverse disorders, collectively called "laminopathies," which affect the striated muscle, cardiac muscle, adipose tissue, skin, peripheral nerve, and premature aging. We describe a patient with limb-girdle muscular dystrophy type 1B (LGMD1B) carrying a heterozygous p.Arg377His mutation in LMNA, in whom skeletal muscle symptom onset was at the age of 65 years. Her weakness started at the erector spinae muscles, which showed marked pseudo-hypertrophy even at the age of 72 years. Her first episode of syncope was at 44 years; however, aberrant cardiac conduction was not revealed until 60 years. The p.Arg377His mutation has been previously reported in several familial LMNA-associated myopathies, most of which showed muscle weakness before the 6th decade. This is the first report of pseudo-hypertrophy of paravertebral muscles in LMNA-associated myopathies. The pseudo-hypertrophy of paravertebral muscles and the elderly-onset of muscle weakness make this case unique and reportable. Copyright © 2016 Elsevier B.V. All rights reserved.

Autologous intramuscular transplantation of engineered satellite cells induces exosome-mediated systemic expression of Fukutin-related protein and rescues disease phenotype in a murine model of limb-girdle muscular dystrophy type 2I.

PubMed

Frattini, Paola; Villa, Chiara; De Santis, Francesca; Meregalli, Mirella; Belicchi, Marzia; Erratico, Silvia; Bella, Pamela; Raimondi, Manuela Teresa; Lu, Qilong; Torrente, Yvan

2017-10-01

α-Dystroglycanopathies are a group of muscular dystrophies characterized by α-DG hypoglycosylation and reduced extracellular ligand-binding affinity. Among other genes involved in the α-DG glycosylation process, fukutin related protein (FKRP) gene mutations generate a wide range of pathologies from mild limb girdle muscular dystrophy 2I (LGMD2I), severe congenital muscular dystrophy 1C (MDC1C), to Walker-Warburg Syndrome and Muscle-Eye-Brain disease. FKRP gene encodes for a glycosyltransferase that in vivo transfers a ribitol phosphate group from a CDP -ribitol present in muscles to α-DG, while in vitro it can be secreted as monomer of 60kDa. Consistently, new evidences reported glycosyltransferases in the blood, freely circulating or wrapped within vesicles. Although the physiological function of blood stream glycosyltransferases remains unclear, they are likely released from blood borne or distant cells. Thus, we hypothesized that freely or wrapped FKRP might circulate as an extracellular glycosyltransferase, able to exert a "glycan remodelling" process, even at distal compartments. Interestingly, we firstly demonstrated a successful transduction of MDC1C blood-derived CD133+ cells and FKRP L276IKI mouse derived satellite cells by a lentiviral vector expressing the wild-type of human FKRP gene. Moreover, we showed that LV-FKRP cells were driven to release exosomes carrying FKRP. Similarly, we observed the presence of FKRP positive exosomes in the plasma of FKRP L276IKI mice intramuscularly injected with engineered satellite cells. The distribution of FKRP protein boosted by exosomes determined its restoration within muscle tissues, an overall recovery of α-DG glycosylation and improved muscle strength, suggesting a systemic supply of FKRP protein acting as glycosyltransferase. © The Author 2017. Published by Oxford University Press.

Advanced Gene Therapy for Treatment of Cardiomyopathy and Respiratory Insufficiency in Duchenne Muscular Dystrophy

DTIC Science & Technology

2014-09-01

TITLE: Advanced Gene Therapy for Treatment of Cardiomyopathy and Respiratory Insufficiency in Duchenne Muscular Dystrophy PRINCIPAL...Advanced Gene Therapy for Treatment of Cardiomyopathy and Respiratory Insufficiency in Duchenne Muscular Dystrophy 5a. CONTRACT NUMBER 5b. GRANT...effective recombinant AAV vector serotype 9 delivery system for the treatment of cardiorespiratory dysfunction in Duchenne Muscular Dystrophy . 2

Physical Activity in Boys With Duchenne Muscular Dystrophy Is Lower and Less Demanding Compared to Healthy Boys.

PubMed

Heutinck, Lotte; Kampen, Nadine van; Jansen, Merel; Groot, Imelda J M de

2017-04-01

This study describes the amount of physical activity and perception of physical activity in boys with Duchenne muscular dystrophy (DMD) compared to healthy boys. A questionnaire described 6 domains of physical activity. Four Duchenne muscular dystrophy subgroups were made: early and late ambulatory, nonambulatory with relative good, or limited arm function. Eighty-four boys with Duchenne muscular dystrophy (15.0 ± 6.4 years) and 198 healthy boys (14.0 ± 4.3 years) participated. Daily activities were more passive for boys with Duchenne muscular dystrophy. Physical activity was less and low demanding compared to healthy boys. It decreased with disease severity ( P < .05), whereas screen time increased ( P < .05). Benefits of physical activity in boys with Duchenne muscular dystrophy were having fun and making friends. Barriers were lack of sport facilities and insufficient health. This study helps to quantify poor engagement in physical activity by boys with Duchenne muscular dystrophy, and demonstrates factors that contribute to it. Suggestions to stimulate physical activity are made.

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.

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.

[Encopresis revealing myotonic dystrophy in 2 children].

PubMed

Avez-Couturier, J; Michaud, L; Cuisset, J-M; Lamblin, M-D; Dolhem, P; Turck, D; Vallée, L; Gottrand, F

2009-05-01

Gastrointestinal symptoms are very frequent in myotonic dystrophy but largely unrecognized. They can be the revealing factors of the disease. We report 2 cases of 10 and 17-year-old children with persistent encopresis starting at the age of 3 and 5 years in spite of laxative treatment. Neurological examination and anorectal manometry provided the diagnosis of myotonic dystrophy. Procainamide treatment was introduced and the digestive symptoms improved. Any child with encopresis should have complete evaluation to rule out the diagnosis of myotonic dystrophy and physicians should look for upper and/or lower gastrointestinal symptoms in every patient with myotonic dystrophy.

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

A homozygous mutation in the stem II domain of RNU4ATAC causes typical Roifman syndrome.

PubMed

Dinur Schejter, Yael; Ovadia, Adi; Alexandrova, Roumiana; Thiruvahindrapuram, Bhooma; Pereira, Sergio L; Manson, David E; Vincent, Ajoy; Merico, Daniele; Roifman, Chaim M

2017-01-01

Roifman syndrome (OMIM# 616651) is a complex syndrome encompassing skeletal dysplasia, immunodeficiency, retinal dystrophy and developmental delay, and is caused by compound heterozygous mutations involving the Stem II region and one of the other domains of the RNU4ATAC gene. This small nuclear RNA gene is essential for minor intron splicing. The Canadian Centre for Primary Immunodeficiency Registry and Repository were used to derive patient information as well as tissues. Utilising RNA sequencing methodologies, we analysed samples from patients with Roifman syndrome and assessed intron retention. We demonstrate that a homozygous mutation in Stem II is sufficient to cause the full spectrum of features associated with typical Roifman syndrome. Further, we demonstrate the same pattern of aberration in minor intron retention as found in cases with compound heterozygous mutations.

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.

Translational Research for Muscular Dystrophy

DTIC Science & Technology

2014-05-01

year of work was awarded to allow completion of our transgenic analysis of Becker -like muscular dystrophy rescue experiments, allow completion of the D2... Dystrophy PRINCIPAL INVESTIGATOR: Gregory A. Cox, Ph.D. CONTRACTING ORGANIZATION: The Jackson Laboratory Bar Harbor, ME 04609-1523...April 2014 4. TITLE AND SUBTITLE Translational Research for Muscular Dystrophy 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-1-0330 5c

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

Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

PubMed Central

2012-01-01

Background Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions. PMID:23173743

Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation

PubMed Central

Merrick, Deborah; Stadler, Lukas Kurt Josef; Larner, Dean; Smith, Janet

2009-01-01

SUMMARY Examination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3−/−) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD-1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3−/− mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3−/− and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3−/− and mdx mutants have cardiac defects. In cav-3−/− mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3−/− mutants. In double mutant (mdxcav-3+/−) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3+/−), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients. PMID:19535499

Retinitis pigmentosa and allied conditions today: a paradigm of translational research

PubMed Central

2010-01-01

Monogenic human retinal dystrophies are a group of disorders characterized by progressive loss of photoreceptor cells leading to visual handicap. Retinitis pigmentosa is a type of retinal dystrophy where degeneration of rod photoreceptors occurs at the early stages. At present, there are no available effective therapies to maintain or improve vision in patients affected with retinitis pigmentosa, but post-genomic studies are allowing the development of potential therapeutic approaches. This review summarizes current knowledge on genes that have been identified to be responsible for retinitis pigmentosa, the involvement of these genes in the different forms of the disorder, the role of the proteins encoded by these genes in retinal function, the utility of genotyping, and current efforts to develop novel therapies. PMID:20519033

Early Events in the Amyloid Formation of the A546T Mutant of Transforming Growth Factor β-Induced Protein in Corneal Dystrophies Compared to the Nonfibrillating R555W and R555Q Mutants.

PubMed

Koldsø, Heidi; Andersen, Ole Juul; Nikolajsen, Camilla Lund; Scavenius, Carsten; Sørensen, Charlotte S; Underhaug, Jarl; Runager, Kasper; Nielsen, Niels Chr; Enghild, Jan J; Schiøtt, Birgit

2015-09-15

The human transforming growth factor β-induced protein (TGFBIp) is involved in several types of corneal dystrophies where protein aggregation and amyloid fibril formation severely impair vision. Most disease-causing mutations are located in the last of four homologous fasciclin-1 (FAS1) domains of the protein, and it has been shown that when isolated, the fourth FAS1 domain (FAS1-4) mimics the behavior of full-length TGFBIp. In this study, we use molecular dynamics simulations and principal component analysis to study the wild-type FAS1-4 domain along with three disease-causing mutations (R555W, R555Q, and A546T) to decipher any internal difference in dynamical properties of the domains that may explain their varied stabilities and aggregation properties. In addition, we use a protein-protein docking method in combination with chemical cross-linking experiments and mass spectrometry of the cross-linked species to obtain information about interaction faces between identical FAS1-4 domains. The results show that the pathogenic mutations A546T and R555W affect the packing in the hydrophobic core of FAS1-4 in different directions. We further show that the FAS1-4 monomers associate using their β-rich regions, consistent with peptides observed to be part of the amyloid fibril core in lattice corneal dystrophy patients.

Mutation in transforming growth factor beta induced protein associated with granular corneal dystrophy type 1 reduces the proteolytic susceptibility through local structural stabilization.

PubMed

Underhaug, Jarl; Koldsø, Heidi; Runager, Kasper; Nielsen, Jakob Toudahl; Sørensen, Charlotte S; Kristensen, Torsten; Otzen, Daniel E; Karring, Henrik; Malmendal, Anders; Schiøtt, Birgit; Enghild, Jan J; Nielsen, Niels Chr

2013-12-01

Hereditary mutations in the transforming growth factor beta induced (TGFBI) gene cause phenotypically distinct corneal dystrophies characterized by protein deposition in cornea. We show here that the Arg555Trp mutant of the fourth fasciclin 1 (FAS1-4) domain of the protein (TGFBIp/keratoepithelin/βig-h3), associated with granular corneal dystrophy type 1, is significantly less susceptible to proteolysis by thermolysin and trypsin than the WT domain. High-resolution liquid-state NMR of the WT and Arg555Trp mutant FAS1-4 domains revealed very similar structures except for the region around position 555. The Arg555Trp substitution causes Trp555 to be buried in an otherwise empty hydrophobic cavity of the FAS1-4 domain. The first thermolysin cleavage in the core of the FAS1-4 domain occurs on the N-terminal side of Leu558 adjacent to the Arg555 mutation. MD simulations indicated that the C-terminal end of helix α3' containing this cleavage site is less flexible in the mutant domain, explaining the observed proteolytic resistance. This structural change also alters the electrostatic properties, which may explain increased propensity of the mutant to aggregate in vitro with 2,2,2-trifluoroethanol. Based on our results we propose that the Arg555Trp mutation disrupts the normal degradation/turnover of corneal TGFBIp, leading to accumulation and increased propensity to aggregate through electrostatic interactions. © 2013.

Mutation in Transforming Growth Factor Beta Induced protein associated with Granular Corneal Dystrophy Type 1 Reduces the Proteolytic Susceptibility through Local Structural Stabilization#

PubMed Central

Underhaug, Jarl; Koldsø, Heidi; Runager, Kasper; Nielsen, Jakob Toudahl; Sørensen, Charlotte S.; Kristensen, Torsten; Otzen, Daniel E.; Karring, Henrik; Malmendal, Anders; Schiøtt, Birgit; Enghild, Jan J.; Nielsen, Niels Chr.

2014-01-01

Hereditary mutations in the transforming growth factor beta induced (TGFBI) gene cause phenotypically distinct corneal dystrophies characterized by protein deposition in cornea. We show here that the Arg555Trp mutant of the fourth fasciclin 1 (FAS1-4) domain of the protein (TGFBIp/keratoepithelin/βig-h3), associated with granular corneal dystrophy type 1, is significantly less susceptible to proteolysis by thermolysin and trypsin than the WT domain. High-resolution liquid-state NMR of the WT and Arg555Trp mutant FAS1-4 domains revealed very similar structures except for the region around position 555. The Arg555Trp substitution causes Trp555 to be buried in an otherwise empty hydrophobic cavity of the FAS1-4 domain. The first thermolysin cleavage in the core of the FAS1-4 domain occurs on the N-terminal side of Leu558 adjacent to the Arg555 mutation. MD simulations indicated that the C-terminal end of helix α3′ containing this cleavage site is less flexible in the mutant domain, explaining the observed proteolytic resistance. This structural change also alters the electrostatic properties, which may explain increased propensity of the mutant to aggregate in vitro with 2,2,2-trifluoroethanol. Based on our results we propose that the Arg555Trp mutation disrupts the normal degradation/turnover of corneal TGFBIp, leading to accumulation and increased propensity to aggregate through electrostatic interactions. PMID:24129074

Limb-Girdle Muscular Dystrophy (LGMD)

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

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

Reue, K.; Rehnmark, S.; Cohen, R.D.

1997-07-01

Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and thesemore » droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.« less

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

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

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

NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy

PubMed Central

Goody, Michelle F.; Kelly, Meghan W.; Reynolds, Christine J.; Khalil, Andre; Crawford, Bryan D.; Henry, Clarissa A.

2012-01-01

Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex– or integrin alpha7–deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies. PMID:23109907

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

Hydrogel biomaterials and their therapeutic potential for muscle injuries and muscular dystrophies

PubMed Central

Lev, Rachel

2018-01-01

Muscular diseases such as muscular dystrophies and muscle injuries constitute a large group of ailments that manifest as muscle weakness, atrophy or fibrosis. Although cell therapy is a promising treatment option, the delivery and retention of cells in the muscle is difficult and prevents sustained regeneration needed for adequate functional improvements. Various types of biomaterials with different physical and chemical properties have been developed to improve the delivery of cells and/or growth factors for treating muscle injuries. Hydrogels are a family of materials with distinct advantages for use as cell delivery systems in muscle injuries and ailments, including their mild processing conditions, their similarities to natural tissue extracellular matrix, and their ability to be delivered with less invasive approaches. Moreover, hydrogels can be made to completely degrade in the body, leaving behind their biological payload in a process that can enhance the therapeutic process. For these reasons, hydrogels have shown great potential as cell delivery matrices. This paper reviews a few of the hydrogel systems currently being applied together with cell therapy and/or growth factor delivery to promote the therapeutic repair of muscle injuries and muscle wasting diseases such as muscular dystrophies. PMID:29343633

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

[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.

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.

A rare subclinical or mild type of Becker muscular dystrophy caused by a single exon 48 deletion of the dystrophin gene.

PubMed

Zimowski, Janusz G; Pilch, Jacek; Pawelec, Magdalena; Purzycka, Joanna K; Kubalska, Jolanta; Ziora-Jakutowicz, Karolina; Dudzińska, Magdalena; Zaremba, Jacek

2017-08-01

In the material of 227 families with Becker muscular dystrophy (BMD), we found nine non-consanguineous families with 17 male individuals carrying a rare mutation-a single exon 48 deletion of the dystrophin gene-who were affected with a very mild or subclinical form of BMD. They were usually detected thanks to accidental findings of elevated serum creatine phosphokinase (sCPK). A thorough clinical analysis of the carriers, both children (12) and adults (5), revealed in some of them muscle hypotonia (10/17) and/or very mild muscle weakness (9/17), as well as decreased tendon reflexes (6/17). Adults, apart from very mild muscle weakness and calf hypertrophy in some, had no significant abnormalities on neurological assessments and had good exercise tolerance. Parents of the children carriers of the exon 48 deletion are usually unaware of their children being affected, and possibly at risk of developing life-threatening cardiomyopathy. The same concerns the adult male carriers. Therefore, the authors postulate undertaking preventive measures such as cascade screening of the relatives of the probands. Newborn screening programmes of Duchenne muscular dystrophy (DMD)/BMD based on sCPK marked increase may be considered.

Genetics Home Reference: limb-girdle muscular dystrophy

MedlinePlus

... age of onset, and features of limb-girdle muscle dystrophy vary among the many subtypes of this condition ... occurs in some people with limb-girdle muscular dystrophy . Weakening of the heart muscle (cardiomyopathy) occurs in some forms of limb-girdle ...

What is muscular dystrophy? Forty years of progressive ignorance.

PubMed

Dubowitz, V

2000-01-01

This lecture traces recent advances in knowledge of the muscular dystrophies, as well as their increasing complexity. They are described through the eyes of the author from his first exposure to and complete ignorance of the disease in the late 1950s, through the advent of modern techniques, to the molecular genetic revolution, with the recognition of individual genes and proteins for disorders within the muscular dystrophy umbrella. There initially seemed to be a logical sequence of linked membrane proteins from dystrophin in Duchenne and Becker dystrophy, through the dystrophin-associated glycoproteins (sarcoglycans) in some of the limb girdle muscular dystrophies (LGMD), to the extracellular matrix protein merosin (alpha-2 laminin) in congenital muscular dystrophy (CMD). The first spoke in the wheel came with the discovery of a calcium activated protease enzyme, calpain 3, in one form of LGMD, and subsequently another novel non-membrane protein, dysferlin, in another. There are currently at least eight distinct genetic forms of LGMD alone, and another eight separate genetic entities in the CMD group. This has highlighted our ignorance of the pathogenesis of the muscular dystrophies in relation to a diverse array of protein deficiencies. To compound things further, the X-linked and dominant forms of Emery-Dreifuss muscular dystrophy have recently been linked to emerin and lamin A/C, respectively, two proteins of the nuclear membrane, opening up yet another new ballpark of discovery.

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.

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.

Mini-dystrophin restores L-type calcium currents in skeletal muscle of transgenic mdx mice

PubMed Central

Friedrich, O; Both, M; Gillis, J M; Chamberlain, J S; Fink, RHA

2004-01-01

L-type calcium currents (iCa) were recorded using the two-microelectrode voltage-clamp technique in single short toe muscle fibres of three different mouse strains: (i) C57/SV129 wild-type mice (wt); (ii) mdx mice (an animal model for Duchenne muscular dystrophy; and (iii) transgenically engineered mini-dystrophin (MinD)-expressing mdx mice. The activation and inactivation properties of iCa were examined in 2- to 18-month-old animals. Ca2+ current densities at 0 mV in mdx fibres increased with age, but were always significantly smaller compared to age-matched wild-type fibres. Time-to-peak (TTP) of iCa was prolonged in mdx fibres compared to wt fibres. MinD fibres always showed similar TTP and current amplitudes compared to age-matched wt fibres. In all three genotypes, the voltage-dependent inactivation and deactivation of iCa were similar. Intracellular resting calcium concentration ([Ca2+]i) and the distribution of dihydropyridine binding sites were also not different in young animals of all three genotypes, whereas iCa was markedly reduced in mdx fibres. We conclude, that dystrophin influences L-type Ca2+ channels via a direct or indirect linkage which may be disrupted in mdx mice and may be crucial for proper excitation–contraction coupling initiating Ca2+ release from the sarcoplasmic reticulum. This linkage seems to be fully restored in the presence of mini-dystrophin. PMID:14594987

Congenital muscle dystrophy and diet consistency affect mouse skull shape differently.

PubMed

Spassov, Alexander; Toro-Ibacache, Viviana; Krautwald, Mirjam; Brinkmeier, Heinrich; Kupczik, Kornelius

2017-11-01

The bones of the mammalian skull respond plastically to changes in masticatory function. However, the extent to which muscle function affects the growth and development of the skull, whose regions have different maturity patterns, remains unclear. Using muscle dissection and 3D landmark-based geometric morphometrics we investigated the effect of changes in muscle function established either before or after weaning, on skull shape and muscle mass in adult mice. We compared temporalis and masseter mass and skull shape in mice with a congenital muscle dystrophy (mdx) and wild type (wt) mice fed on either a hard or a soft diet. We found that dystrophy and diet have distinct effects on the morphology of the skull and the masticatory muscles. Mdx mice show a flattened neurocranium with a more dorsally displaced foramen magnum and an anteriorly placed mandibular condyle compared with wt mice. Compared with hard diet mice, soft diet mice had lower masseter mass and a face with more gracile features as well as labially inclined incisors, suggesting reduced bite strength. Thus, while the early-maturing neurocranium and the posterior portion of the mandible are affected by the congenital dystrophy, the late-maturing face including the anterior part of the mandible responds to dietary differences irrespective of the mdx mutation. Our study confirms a hierarchical, tripartite organisation of the skull (comprising neurocranium, face and mandible) with a modular division based on development and function. Moreover, we provide further experimental evidence that masticatory loading is one of the main environmental stimuli that generate craniofacial variation. © 2017 Anatomical Society.

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.

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

Mouthpiece ventilation in Duchenne muscular dystrophy: a rescue strategy for noncompliant patients

PubMed Central

Fiorentino, Giuseppe; Annunziata, Anna; Cauteruccio, Rosa; Frega, Gianfranco Scotto di; Esquinas, Antonio

2016-01-01

ABSTRACT Objective: To evaluate mouthpiece ventilation (MPV) in patients with Duchenne muscular dystrophy (DMD) who are noncompliant with noninvasive ventilation (NIV). Methods: We evaluated four young patients with DMD who had previously refused to undergo NIV. Each patient was reassessed and encouraged to try MPV. Results: The four patients tolerated MPV well and were compliant with NIV at home. MPV proved to be preferable and more comfortable than NIV with any other type of interface. Two of the patients required overnight NIV and eventually agreed to use a nasal mask during the night. Conclusions: The advantages of MPV over other types of NIV include fewer speech problems, better appearance, and less impact on the patient, eliminating the risk of skin breakdown, gastric distension, conjunctivitis, and claustrophobia. The use of a mouthpiece interface should be always considered in patients with DMD who need to start NIV, in order to promote a positive approach and a rapid acceptance of NIV. Using MPV during the daytime makes patients feel safe and more likely to use NIV at night. In addition, MPV increases treatment compliance for those who refuse to use other types of interfaces. PMID:28117478

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.

Muscular dystrophy in a dog resembling human becker muscular dystrophy.

PubMed

Baroncelli, A B; Abellonio, F; Pagano, T B; Esposito, I; Peirone, B; Papparella, S; Paciello, O

2014-05-01

A 3-year-old, male Labrador retriever dog was presented with clinical signs of progressive exercise intolerance, bilateral elbow extension, rigidity of the forelimbs, hindlimb flexion and kyphosis. Microscopical examination of muscle tissue showed marked variability in myofibre size, replacement of muscle with mature adipose tissue and degeneration/regeneration of muscle fibres, consistent with muscular dystrophy. Immunohistochemical examination for dystrophin showed markedly reduced labelling with monoclonal antibodies specific for the rod domain and the carboxy-terminal of dystrophin, while expression of β-sarcoglycan, γ-sarcoglycan and β-dystroglycan was normal. Immunoblotting revealed a truncated dystrophin protein of approximately 135 kDa. These findings supported a diagnosis of congenital canine muscular dystrophy resembling Becker muscular dystrophy in man. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Recurrent Corneal Erosions in Epithelial Corneal Dystrophies].

PubMed

Geerling, Gerd; Lisch, Walter; Finis, David

2018-06-01

The corneal epithelium is the most important structure of the ocular optical system. Recurrent corneal erosions can result from inflammation, trauma, degeneration and dystrophies. Epithelial basement membrane dystrophy (EBMD), epithelial recurrent erosion dystrophy (ERED) and Francheschetti and Meesmann's epithelial corneal dystrophy (MECD) can all - besides other signs and symptoms - result in more or less frequent corneal erosions. The pathomechanisms involved however are different. In EBMD, corneal erosions are facultative and clinical signs are often subtle. Aberrant basement membrane structures are associated with thinning of the epithelium and can be clinically identified as maps or fingerprints. In ERED, recurrent corneal erosions are - predominantly in the first decades of life - always present. A defect in the COL17A1 gene results in a dysfunctional hemidesmosome. In MECD, punctate corneal erosions are less frequent and result from intraepithelial microcysts which open spontaneously onto the ocular surface. Usually lubricants, therapeutic contact lenses and sometimes epithelial debridement and phototherapeutic keratectomy are the mainstay for treating corneal erosions in these three dystrophies. Georg Thieme Verlag KG Stuttgart · New York.

Anti-fibrotic effect of pirfenidone in muscle derived-fibroblasts from Duchenne muscular dystrophy patients.

PubMed

Zanotti, Simona; Bragato, Cinzia; Zucchella, Andrea; Maggi, Lorenzo; Mantegazza, Renato; Morandi, Lucia; Mora, Marina

2016-01-15

Tissue fibrosis, characterized by excessive deposition of extracellular matrix proteins, is the end point of diseases affecting the kidney, bladder, liver, lung, gut, skin, heart and muscle. In Duchenne muscular dystrophy (DMD), connective fibrotic tissue progressively substitutes muscle fibers. So far no specific pharmacological treatment is available for muscle fibrosis. Among promising anti-fibrotic molecules, pirfenidone has shown anti-fibrotic and anti-inflammatory activity in animal and cell models, and has already been employed in clinical trials. Therefore we tested pirfenidone anti-fibrotic properties in an in vitro model of muscle fibrosis. We evaluated effect of pirfenidone on fibroblasts isolated from DMD muscle biopsies. These cells have been previously characterized as having a pro-fibrotic phenotype. We tested cell proliferation and migration, secretion of soluble collagens, intracellular levels of collagen type I and fibronectin, and diameter of 3D fibrotic nodules. We found that pirfenidone significantly reduced proliferation and cell migration of control and DMD muscle-derived fibroblasts, decreased extracellular secretion of soluble collagens by control and DMD fibroblasts, as well as levels of collagen type I and fibronectin, and, in DMD fibroblasts only, reduced synthesis and deposition of intracellular collagen. Furthermore, pirfenidone was able to reduce the diameter of fibrotic-nodules in our 3D model of in vitro fibrosis. These pre-clinical results indicate that pirfenidone has potential anti-fibrotic effects also in skeletal muscle fibrosis, urging further studies in in vivo animal models of muscular dystrophy in order to translate the drug into the treatment of muscle fibrosis in DMD patients. Copyright © 2015 Elsevier Inc. All rights reserved.

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.

[Ocular findings in patients with Steinert myotonic dystrophy].

PubMed

Markowska, Elzbieta; Zalewska, Renata; Mariak, Zofia; Wojnar, Małgorzata

2006-01-01

The authors present one of many myotonic dystrophies: Steinert myotonic dystrophy (Steinert disease), which is a disease occuring seldom, and causing a lot of problems during the diagnostic and treatment process. Genetic factors, results of the histopathology tests, main clinical symptoms, particularly ophtalmic manifestation are described in this article.

Rare Muscular Dystrophies: Congenital, Distal, Emery-Dreifuss and Oculopharyngeal Muscular Dystrophies

MedlinePlus

... although EDMD and OPMD can have more than one genetic cause). In most cases of muscular dystrophy, muscle mass in the affected ... categories. Many of these diseases can vary from one person to the next, and in some cases, research- ers are still in the process of ...

Curvilinear pigmentary lesions in a rod-cone dystrophy.

PubMed

Tamaki, Y; Sawa, M; Yannuzzi, L A

2005-01-01

To report a peculiar curvilinear pigmentary lesion in the peripheral fundus in a rod-cone dystrophy. Observational case report. Fundus examination of a 57-year-old woman who was known to have a generalized rod-cone dystrophy since she was 8 years old. The peripheral fundus examination revealed a curvilinear lesion which resembles a well-known finding associated with a presumed ocular histoplasmosis syndrome or multifocal choroiditis. The differential diagnosis of a peculiar curvilinear pigmentary lesion in the peripheral fundus may be expanded to include a generalized rod-cone dystrophy.

[Congenital myotonic dystrophy in a Neonatal Intensive Care Unit: case series].

PubMed

Domingues, Sara; Alves Pereira, Clara; Machado, Angela; Pereira, Sandra; Machado, Leonilde; Fraga, Carla; Oliveira, Abílio; Vale, Isabel; Quelhas, Ilídio

2014-02-01

Steinert myotonic dystrophy is a multisystemic disease, autosomal dominant, with a wide spectrum of severity and clinical manifestations. The most severe form is one that manifests in the neonatal period, called congenital myotonic dystrophy. This condition is distinguished by overall hypotonia at birth and respiratory function compromise. Complications are frequent, mainly psychomotor development delay, growth failure, food difficulties and constipation. It is associated with a poor prognosis, with an overall mortality of up to 50% of severely affected children. We present five patients with congenital myotonic dystrophy in order to describe clinical manifestations, diagnosis, treatment and prognosis. Existing data in the literature on psychomotor development, complications and prognosis of survivors with congenital myotonic dystrophy are scarce. In our case studies, we have found significant chronic psychomotor limitations.

Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.

PubMed

Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2014-02-01

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.

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.

Evaluation of MMX1902 as an Oral Treatment for Duchenne Muscular Dystrophy

DTIC Science & Technology

2016-10-01

type control mice. Further, embryonic myosin heavy chain (eMHC) staining of the diaphragm showed a significant increase in eMHC positive muscle...resulting in cardiac functional measures comparable to exercised wild-type control mice (Table 1). Further, embryonic myosin heavy chain (eMHC) staining of...and cost-driver at scale-up, and the synthesis of 10.2 grams of MMX1902 at >98% purity. What opportunities for training and professional

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

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

Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy

PubMed Central

Sarparanta, Jaakko; Jonson, Per Harald; Golzio, Christelle; Sandell, Satu; Luque, Helena; Screen, Mark; McDonald, Kristin; Stajich, Jeffrey M.; Mahjneh, Ibrahim; Vihola, Anna; Raheem, Olayinka; Penttilä, Sini; Lehtinen, Sara; Huovinen, Sanna; Palmio, Johanna; Tasca, Giorgio; Ricci, Enzo; Hackman, Peter; Hauser, Michael; Katsanis, Nicholas; Udd, Bjarne

2012-01-01

Limb-girdle muscular dystrophy type 1D (LGMD1D) was linked to 7q36 over a decade ago1, but its genetic cause has remained elusive. We have studied nine LGMD families from Finland, the U.S., and Italy, and identified four dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the ubiquitously expressed co-chaperone DNAJB6. Functional testing in vivo showed that the mutations have a dominant toxic effect mediated specifically by the cytoplasmic isoform of DNAJB6. In vitro studies demonstrated that the mutations increase the half-life of DNAJB6, extending this effect to the wild-type protein, and reduce its protective anti-aggregation effect. Further, we show that DNAJB6 interacts with members of the CASA complex, including the myofibrillar-myopathy-causing protein BAG3. Our data provide the genetic cause of LGMD1D, suggest that the pathogenesis is mediated by defective chaperone function, and highlight how mutations expressed ubiquitously can exert their effect in a tissue-, cellular compartment-, and isoform-specific manner. PMID:22366786

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.

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.

Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

ERIC Educational Resources Information Center

de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

2007-01-01

This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

Adaptive Immune Response Impairs the Efficacy of Autologous Transplantation of Engineered Stem Cells in Dystrophic Dogs

PubMed Central

Sitzia, Clementina; Farini, Andrea; Jardim, Luciana; Razini, Paola; Belicchi, Marzia; Cassinelli, Letizia; Villa, Chiara; Erratico, Silvia; Parolini, Daniele; Bella, Pamela; da Silva Bizario, Joao Carlos; Garcia, Luis; Dias-Baruffi, Marcelo; Meregalli, Mirella; Torrente, Yvan

2016-01-01

Duchenne muscular dystrophy is the most common genetic muscular dystrophy. It is caused by mutations in the dystrophin gene, leading to absence of muscular dystrophin and to progressive degeneration of skeletal muscle. We have demonstrated that the exon skipping method safely and efficiently brings to the expression of a functional dystrophin in dystrophic CD133+ cells injected scid/mdx mice. Golden Retriever muscular dystrophic (GRMD) dogs represent the best preclinical model of Duchenne muscular dystrophy, mimicking the human pathology in genotypic and phenotypic aspects. Here, we assess the capacity of intra-arterial delivered autologous engineered canine CD133+ cells of restoring dystrophin expression in Golden Retriever muscular dystrophy. This is the first demonstration of five-year follow up study, showing initial clinical amelioration followed by stabilization in mild and severe affected Golden Retriever muscular dystrophy dogs. The occurrence of T-cell response in three Golden Retriever muscular dystrophy dogs, consistent with a memory response boosted by the exon skipped-dystrophin protein, suggests an adaptive immune response against dystrophin. PMID:27506452

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.

Use of placental extract for the treatment of myopic and senile chorio-retinal dystrophies.

PubMed

Girotto, G; Malinverni, W

1982-01-01

After an examination of the literature, the authors evaluate the activity of placenta extract in 34 subjects suffering from chorio-retinal dystrophy of different types (myopic and senile) and of different degrees of anatomo-functional alteration. The parameters used for this study were visual acuity, the luminous sense, the visual field and the electrophysiological activity of the retina. The aqueous solution was administered by intramuscular route at a daily dose of 3 ml (equivalent to 1,80 g of fresh organ) during 20 days; the parameters were tested before and at the end of the treatment. The results obtained during this study show that the parameters were improved, in different degrees, by the administration of the placenta extract. This is clearly demonstrated by the significant improvement in the luminous sense.

Cardiac involvement in facio-scapulo-humeral muscular dystrophy: a family study using Thallium-201 single-photon-emission-computed tomography.

PubMed

Faustmann, P M; Farahati, J; Rupilius, B; Dux, R; Koch, M C; Reiners, C

1996-12-01

Fifteen persons from two consecutive generations of one family affected with facio-scapulo-humeral muscular dystrophy (FSHD) were clinically and neurophysiologically examined. Diagnostic muscle biopsies were obtained from two members. Linkage analysis showed that all four affected members of the family inherit the same 4q35 haplotype giving a lod score of z = +1.44. Six family members were examined by ECG at rest and under stress, by two-dimensional echocardiography, and by cardiac Thallium-201 single-photon-emission computed tomography (Tl-201-SPECT) under dobutamine stress and at rest. Abnormal reduced Tl-201 uptake in cardiac SPECT was only found in the affected members of the family. Therefore we suggest that cardiac Tl-201-SPECT abnormalities in FSHD reflect cardiomyogenic changes in this type of muscular disease.

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

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.

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

Ehlers-Danlos syndrome with lethal cardiac valvular dystrophy in males carrying a novel splice mutation in FLNA.

PubMed

Ritelli, Marco; Morlino, Silvia; Giacopuzzi, Edoardo; Carini, Giulia; Cinquina, Valeria; Chiarelli, Nicola; Majore, Silvia; Colombi, Marina; Castori, Marco

2017-01-01

Filamin A is an X-linked, ubiquitous actin-binding protein whose mutations are associated to multiple disorders with limited genotype-phenotype correlations. While gain-of-function mutations cause various bone dysplasias, loss-of-function variants are the most common cause of periventricular nodular heterotopias with variable soft connective tissue involvement, as well as X-linked cardiac valvular dystrophy (XCVD). The term "Ehlers-Danlos syndrome (EDS) with periventricular heterotopias" has been used in females with neurological, cardiovascular, integument and joint manifestations, but this nosology is still a matter of debate. We report the clinical and molecular update of an Italian family with an X-linked recessive soft connective tissue disorder and which was described, in 1975, as the first example of EDS type V of the Berlin nosology. The cutaneous phenotype of the index patient was close to classical EDS and all males died for a lethal cardiac valvular dystrophy. Whole exome sequencing identified the novel c.1829-1G>C splice variation in FLNA in two affected cousins. The nucleotide change was predicted to abolish the canonical splice acceptor site of exon 13 and to activate a cryptic acceptor site 15 bp downstream, leading to in frame deletion of five amino acid residues (p.Phe611_Gly615del). The predicted in frame deletion clusters with all the mutations previously identified in XCVD and falls within the N-terminus rod 1 domain of filamin A. Our findings expand the male-specific phenotype of FLNA mutations that now includes classical-like EDS with lethal cardiac valvular dystrophy, and offer further insights for the genotype-phenotype correlations within this spectrum. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Duchenne Muscular Dystrophy and Becker Muscular Dystrophy Confirmed by Multiplex Ligation-Dependent Probe Amplification: Genotype-Phenotype Correlation in a Large Cohort.

PubMed

Vengalil, Seena; Preethish-Kumar, Veeramani; Polavarapu, Kiran; Mahadevappa, Manjunath; Sekar, Deepha; Purushottam, Meera; Thomas, Priya Treesa; Nashi, Saraswathi; Nalini, Atchayaram

2017-01-01

Studies of cases of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) confirmed by multiplex ligation-dependent probe amplification (MLPA) have determined the clinical characteristics, genotype, and relations between the reading frame and phenotype for different countries. This is the first such study from India. A retrospective genotype-phenotype analysis of 317 MLPA-confirmed patients with DMD or BMD who visited the neuromuscular clinic of a quaternary referral center in southern India. The 317 patients comprised 279 cases of DMD (88%), 32 of BMD (10.1%), and 6 of intermediate phenotype (1.9%). Deletions accounted for 91.8% of cases, with duplications causing the remaining 8.2%. There were 254 cases of DMD (91%) with deletions and 25 (9%) due to duplications, and 31 cases (96.8%) of BMD with deletions and 1 (3.2%) due to duplication. All six cases of intermediate type were due to deletions. The most-common mutation was a single-exon deletion. Deletions of six or fewer exons constituted 68.8% of cases. The deletion of exon 50 was the most common. The reading-frame rule held in 90% of DMD and 94% of BMD cases. A tendency toward a lower IQ and earlier wheelchair dependence was observed with distal exon deletions, though a significant correlation was not found. The reading-frame rule held in 90% to 94% of children, which is consistent with reports from other parts of the world. However, testing by MLPA is a limitation, and advanced sequencing methods including analysis of the structure of mutant dystrophin is needed for more-accurate assessments of the genotype-phenotype correlation.

Deficiency of merosin in dystrophic dy mouse homologue of congenital muscular dystrophy

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

Sunada, Y.; Campbell, K.P.; Bernier, S.M.

1994-09-01

Merosin (laminin M chain) is the predominant laminin isoform in the basal lamina of striated muscle and peripheral nerve and is a native ligand for {alpha}-dystroglycan, a novel laminin receptor. Merosin is linked to the subsarcolemmal actin cytoskeleton via the dystrophin-glycoprotein complex (DGC), which plays an important role for maintenance of normal muscle function. We have mapped the mouse merosin gene, Lamm, to the region containing the dystrophia muscularis (dy) locus on chromosome 10. This suggested the possibility that a mutation in the merosin gene could be responsible for the dy mouse, an animal model for autosomal recessive muscular dystrophy,more » and prompted us to test this hypothesis. We analyzed the status of merosin expression in dy mouse by immunofluorescence and immunoblotting. In dy mouse skeletal and cardiac muscle and peripheral nerve, merosin was reduced greater than 90% as compared to control mice. However, the expression of laminin B1/B2 chains and collagen type IV was smaller to that in control mice. These findings strongly suggest that merosin deficiency may be the primary defect in the dy mouse. Furthermore, we have identified two patients afflicted with congenital muscular dystrophy with merosin deficiency, providing the basis for future studies of molecular pathogenesis and gene therapy.« less

Role of dystroglycan in limiting contraction-induced injury to the sarcomeric cytoskeleton of mature skeletal muscle.

PubMed

Rader, Erik P; Turk, Rolf; Willer, Tobias; Beltrán, Daniel; Inamori, Kei-Ichiro; Peterson, Taylor A; Engle, Jeffrey; Prouty, Sally; Matsumura, Kiichiro; Saito, Fumiaki; Anderson, Mary E; Campbell, Kevin P

2016-09-27

Dystroglycan (DG) is a highly expressed extracellular matrix receptor that is linked to the cytoskeleton in skeletal muscle. DG is critical for the function of skeletal muscle, and muscle with primary defects in the expression and/or function of DG throughout development has many pathological features and a severe muscular dystrophy phenotype. In addition, reduction in DG at the sarcolemma is a common feature in muscle biopsies from patients with various types of muscular dystrophy. However, the consequence of disrupting DG in mature muscle is not known. Here, we investigated muscles of transgenic mice several months after genetic knockdown of DG at maturity. In our study, an increase in susceptibility to contraction-induced injury was the first pathological feature observed after the levels of DG at the sarcolemma were reduced. The contraction-induced injury was not accompanied by increased necrosis, excitation-contraction uncoupling, or fragility of the sarcolemma. Rather, disruption of the sarcomeric cytoskeleton was evident as reduced passive tension and decreased titin immunostaining. These results reveal a role for DG in maintaining the stability of the sarcomeric cytoskeleton during contraction and provide mechanistic insight into the cause of the reduction in strength that occurs in muscular dystrophy after lengthening contractions.

Measuring tendon properties in mdx mice: cell viability and viscoelastic characteristics.

PubMed

Rizzuto, E; Musarò, A; Catizone, A; Del Prete, Z

2009-10-16

Muscular dystrophy is a genetic disorder of skeletal muscle characterized by progressive muscle weakness. Here we assessed whether muscle wasting affects cell viability and mechanical properties of extensor digitorum longus (EDL) and of tibialis anterior (TA) tendons from mdx dystrophic mice compared to wild type (WT) mice. mdx mice represent the classical animal model for human Duchenne muscular dystrophy, and show several signs of the pathology, including a decrease in specific force and an increase of fibrotic index. Cell viability of tendons was evaluated by histological analysis, and viscoelastic properties have been assessed by a rapid measurement protocol that allowed us to compute, at the same time, tissue complex compliance for all the frequencies of interest. Confocal microscopy and mechanical properties measurements revealed that mdx tendons, compared to WT ones, have an increase in the number of dead cells and a significant reduction in tissue elasticity for all the frequencies that were tested. These findings indicate a reduced quality of the tissue. Moreover, mdx tendons have an increase in the viscous response, indicating that during dynamic loading, they dissipate more energy compared to WT. Our results demonstrate that muscular dystrophy involves not only muscle wasting, but also alteration in the viscoelastic properties of tendons, suggesting a paracrine effect of altered skeletal muscle on tendinous tissue.

Reducing CTGF/CCN2 slows down mdx muscle dystrophy and improves cell therapy.

PubMed

Morales, Maria Gabriela; Gutierrez, Jaime; Cabello-Verrugio, Claudio; Cabrera, Daniel; Lipson, Kenneth E; Goldschmeding, Roel; Brandan, Enrique

2013-12-15

In Duchenne muscular dystrophy (DMD) and the mdx mouse model, the absence of the cytoskeletal protein dystrophin causes defective anchoring of myofibres to the basal lamina. The resultant myofibre degeneration and necrosis lead to a progressive loss of muscle mass, increased fibrosis and ultimately fatal weakness. Connective tissue growth factor (CTGF/CCN-2) is critically involved in several chronic fibro-degenerative diseases. In DMD, the role of CTGF might extend well beyond replacement fibrosis secondary to loss of muscle fibres, since its overexpression in skeletal muscle could by itself induce a dystrophic phenotype. Using two independent approaches, we here show that mdx mice with reduced CTGF availability do indeed have less severe muscular dystrophy. Mdx mice with hemizygous CTGF deletion (mdx-Ctgf+/-), and mdx mice treated with a neutralizing anti-CTGF monoclonal antibody (FG-3019), performed better in an exercise endurance test, had better muscle strength in isolated muscles and reduced skeletal muscle impairment, apoptotic damage and fibrosis. Transforming growth factor type-β (TGF-β), pERK1/2 and p38 signalling remained unaffected during CTGF suppression. Moreover, both mdx-Ctgf+/- and FG-3019 treated mdx mice had improved grafting upon intramuscular injection of dystrophin-positive satellite cells. These findings reveal the potential of targeting CTGF to reduce disease progression and to improve cell therapy in DMD.

Exacerbation of pathology by oxidative stress in respiratory and locomotor muscles with Duchenne muscular dystrophy.

PubMed

Lawler, John M

2011-05-01

Duchenne muscular dystrophy (DMD) is the most devastating type of muscular dystrophy, leading to progressive weakness of respiratory (e.g. diaphragm) and locomotor muscles (e.g. gastrocnemius). DMD is caused by X-linked defects in the gene that encodes for dystrophin, a key scaffolding protein of the dystroglycan complex (DCG) within the sarcolemmal cytoskeleton. As a result of a compromised dystroglycan complex, mechanical integrity is impaired and important signalling proteins (e.g. nNOS, caveolin-3) and pathways are disrupted. Disruption of the dystroglycan complex leads to high susceptibility to injury with repeated, eccentric contractions as well as inflammation, resulting in significant damage and necrosis. Chronic damage and repair cycling leads to fibrosis and weakness. While the link between inflammation with damage and weakness in the DMD diaphragm is unresolved, elevated oxidative stress may contribute to damage, weakness and possibly fibrosis. While utilization of non-specific antioxidant interventions has yielded inconsistent results, recent data suggest that NAD(P)H oxidase could play a pivotal role in elevating oxidative stress via integrated changes in caveolin-3 and stretch-activated channels (SACs). Oxidative stress may act as an amplifier, exacerbating disruption of the dystroglycan complex, upregulation of the inflammatory transcription factor NF-B, and thus functional impairment of force-generating capacity.

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.

Loss of Calpain 3 Proteolytic Activity Leads to Muscular Dystrophy and to Apoptosis-Associated Iκbα/Nuclear Factor κb Pathway Perturbation in Mice

PubMed Central

Richard, Isabelle; Roudaut, Carinne; Marchand, Sylvie; Baghdiguian, Stephen; Herasse, Muriel; Stockholm, Daniel; Ono, Yasuko; Suel, Laurence; Bourg, Nathalie; Sorimachi, Hiroyuki; Lefranc, Gérard; Fardeau, Michel; Sébille, Alain; Beckmann, Jacques S.

2000-01-01

Calpain 3 is known as the skeletal muscle–specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. It was previously shown that defects in the human calpain 3 gene are responsible for limb girdle muscular dystrophy type 2A (LGMD2A), an inherited disease affecting predominantly the proximal limb muscles. To better understand the function of calpain 3 and the pathophysiological mechanisms of LGMD2A and also to develop an adequate model for therapy research, we generated capn3-deficient mice by gene targeting. capn3-deficient mice are fully fertile and viable. Allele transmission in intercross progeny demonstrated a statistically significant departure from Mendel's law. capn3-deficient mice show a mild progressive muscular dystrophy that affects a specific group of muscles. The age of appearance of myopathic features varies with the genetic background, suggesting the involvement of modifier genes. Affected muscles manifest a similar apoptosis-associated perturbation of the IκBα/nuclear factor κB pathway as seen in LGMD2A patients. In addition, Evans blue staining of muscle fibers reveals that the pathological process due to calpain 3 deficiency is associated with membrane alterations. PMID:11134085

Rehabilitative technology use among individuals with Duchenne/Becker muscular dystrophy.

PubMed

Pandya, Shree; Andrews, Jennifer; Campbell, Kim; Meaney, F John

2016-01-01

To document use of rehabilitative technology among individuals with Duchenne/Becker muscular dystrophy (DBMD) among sites of the Muscular Dystrophy Surveillance, Tracking, and Research network (MD STARnet). Data from 362 caregivers who participated in the MD STARnet caregiver interview between April 2006 and March 2012 (54.7% response rate) were analyzed to assess the type, frequency and duration of use of assistive technology. Caregiver reports of technology use by individuals with DBMD across five MD STARnet sites in the US demonstrated significant regional differences in the proportion of individuals who had ever used night splints (36.9%-73.0%), standers (3.1%-22.2%) and scooters (10.7%-54.5%). Among individuals who used night splints 59.7% stopped using them at a mean age of 10.3 years after a mean duration of 2.9 years in spite of the current recommendation to continue using them through the non-ambulatory phase. Results of this comprehensive survey document the frequency of assistive device use by individuals with DBMD in the USA and also provides data on differences across the sites. Further research is needed to understand the reasons for and the impact of these differences on clinical outcomes and health related quality of life of individuals with DBMD.

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.

Cone rod dystrophies

PubMed Central

Hamel, Christian P

2007-01-01

Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness. PMID:17270046

Successful Gene Therapy in the RPGRIP1-deficient Dog: a Large Model of Cone–Rod Dystrophy

PubMed Central

Lhériteau, Elsa; Petit, Lolita; Weber, Michel; Le Meur, Guylène; Deschamps, Jack-Yves; Libeau, Lyse; Mendes-Madeira, Alexandra; Guihal, Caroline; François, Achille; Guyon, Richard; Provost, Nathalie; Lemoine, Françoise; Papal, Samantha; El-Amraoui, Aziz; Colle, Marie-Anne; Moullier, Philippe; Rolling, Fabienne

2014-01-01

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod–cone dystrophies but not in large models of progressive cone–rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone–rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18–72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22–29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone–rod dystrophy provides great promise for human treatment. PMID:24091916

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

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.

Meeting the Assistive Technology Needs of Students with Duchenne Muscular Dystrophy

ERIC Educational Resources Information Center

Heller, Kathryn Wolff; Mezei, Peter J.; Avant, Mary Jane Thompson

2009-01-01

Students with Duchenne muscular dystrophy (DMD) have a degenerative disease that requires ongoing changes in assistive technology (AT). The AT team needs to be knowledgeable about the disease and its progression in order to meet these students' changing needs in a timely manner. The unique needs of students with Duchenne muscular dystrophy in…

Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

PubMed Central

Ramos, Fresnida J.; Chen, Steven C.; Garelick, Michael G.; Dai, Dao-Fu; Liao, Chen-Yu; Schreiber, Katherine H.; MacKay, Vivian L.; An, Elroy H.; Strong, Randy; Ladiges, Warren C.; Rabinovitch, Peter S.; Kaeberlein, Matt; Kennedy, Brian K.

2013-01-01

Mutations in LMNA, the gene that encodes A-type lamins, cause multiple diseases including dystrophies of the skeletal muscle and fat, dilated cardiomyopathy, and progeria-like syndromes (collectively termed laminopathies). Reduced A-type lamin function, however, is most commonly associated with skeletal muscle dystrophy and dilated cardiomyopathy rather than lipodystrophy or progeria. The mechanisms underlying these diseases are only beginning to be unraveled. We report that mice deficient in Lmna, which corresponds to the human gene LMNA, have enhanced mTORC1 (mammalian target of rapamycin complex 1) signaling specifically in tissues linked to pathology, namely, cardiac and skeletal muscle. Pharmacologic reversal of elevated mTORC1 signaling by rapamycin improves cardiac and skeletal muscle function and enhances survival in mice lacking A-type lamins. At the cellular level, rapamycin decreases the number of myocytes with abnormal desmin accumulation and decreases the amount of desmin in both muscle and cardiac tissue of Lmna–/– mice. In addition, inhibition of mTORC1 signaling with rapamycin improves defective autophagic-mediated degradation in Lmna–/– mice. Together, these findings point to aberrant mTORC1 signaling as a mechanistic component of laminopathies associated with reduced A-type lamin function and offer a potential therapeutic approach, namely, the use of rapamycin-related mTORC1 inhibitors. PMID:22837538

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice.

PubMed

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain; El-Amraoui, Aziz; Petit, Christine

2012-10-15

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins-myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans-do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner-outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients.

Localization of Usher 1 proteins to the photoreceptor calyceal processes, which are absent from mice

PubMed Central

Sahly, Iman; Dufour, Eric; Schietroma, Cataldo; Michel, Vincent; Bahloul, Amel; Perfettini, Isabelle; Pepermans, Elise; Estivalet, Amrit; Carette, Diane; Aghaie, Asadollah; Ebermann, Inga; Lelli, Andrea; Iribarne, Maria; Hardelin, Jean-Pierre; Weil, Dominique; Sahel, José-Alain

2012-01-01

The mechanisms underlying retinal dystrophy in Usher syndrome type I (USH1) remain unknown because mutant mice lacking any of the USH1 proteins—myosin VIIa, harmonin, cadherin-23, protocadherin-15, sans—do not display retinal degeneration. We found here that, in macaque photoreceptor cells, all USH1 proteins colocalized at membrane interfaces (i) between the inner and outer segments in rods and (ii) between the microvillus-like calyceal processes and the outer segment basolateral region in rods and cones. This pattern, conserved in humans and frogs, was mediated by the formation of an USH1 protein network, which was associated with the calyceal processes from the early embryonic stages of outer segment growth onwards. By contrast, mouse photoreceptors lacked calyceal processes and had no USH1 proteins at the inner–outer segment interface. We suggest that USH1 proteins form an adhesion belt around the basolateral region of the photoreceptor outer segment in humans, and that defects in this structure cause the retinal degeneration in USH1 patients. PMID:23045546

Clinical features of children and adults with a muscular dystrophy using powered indoor/outdoor wheelchairs: disease features, comorbidities and complications of disability.

PubMed

Frank, Andrew Oliver; De Souza, Lorraine H

2018-05-01

To describe the clinical features of electric powered indoor/outdoor wheelchair users with a muscular dystrophy, likely to influence optimal prescription; reflecting features of muscular dystrophies, conditions secondary to disability, and comorbidities impacting on equipment provision. Cross-sectional retrospective case note review of recipients of electric powered indoor/outdoor wheelchairs provided by a specialist regional wheelchair service. Data on demography, diagnostic/clinical, and wheelchair prescription were systematically extracted. Fifty-one men and 14 women, mean age 23.7 (range 10-67, s.d. 12.95) years, were studied. Forty had Duchenne muscular dystrophy, 22 had other forms of muscular dystrophy, and three were unclassified. Twenty-seven were aged under 19. Notable clinical features included problematic pain (10), cardiomyopathy (5), and ventilatory failure (4). Features related to disability were (kypho)scoliosis (20) and edema/cellulitis (3) whilst comorbidities included back pain (5). Comparison of younger with older users revealed younger users had more features of muscular dystrophy affecting electric powered chair provision (56%) whilst older users had more comorbidity (37%). Tilt-in-space was prescribed for 81% of users, specialized seating for 55% and complex controls for 16%. Muscular dystrophy users were prescribed electric powered indoor/outdoor chairs with many additional features reflecting the consequences of profound muscle weakness. In addition to facilitating independence and participation, electric powered indoor/outdoor chairs have major therapeutic benefits. Implications for rehabilitation Powered wheelchairs have therapeutic benefits in managing muscular dystrophy pain and weakness. The use of specialized seating needs careful consideration in supporting progressive muscle weakness and the management of scoliosis. Pain, discomfort, pressure risk, and muscle fatigue may be reduced by use of tilt-in-space.

Attenuated Ca(2+) release in a mouse model of limb girdle muscular dystrophy 2A.

PubMed

DiFranco, Marino; Kramerova, Irina; Vergara, Julio L; Spencer, Melissa Jan

2016-01-01

Mutations in CAPN3 cause limb girdle muscular dystrophy type 2A (LGMD2A), a progressive muscle wasting disease. CAPN3 is a non-lysosomal, Ca-dependent, muscle-specific proteinase. Ablation of CAPN3 (calpain-3 knockout (C3KO) mice) leads to reduced ryanodine receptor (RyR1) expression and abnormal Ca2+/calmodulin-dependent protein kinase II (Ca-CaMKII)-mediated signaling. We previously reported that Ca(2+) release measured by fura2-FF imaging in response to single action potential stimulation was reduced in old C3KO mice; however, the use of field stimulation prevented investigation of the mechanisms underlying this impairment. Furthermore, our prior studies were conducted on older animals, whose muscles showed advanced muscular dystrophy, which prevented us from establishing whether impaired Ca(2+) handling is an early feature of disease. In the current study, we sought to overcome these matters by studying single fibers isolated from young wild-type (WT) and C3KO mice using a low affinity calcium dye and high intracellular ethylene glycol-bis(2-aminoethylether)-n,n,n',n'-tetraacetic acid (EGTA) to measure Ca(2+) fluxes. Muscles were subjected to both current and voltage clamp conditions. Standard and confocal fluorescence microscopy was used to study Ca(2+) release in single fibers enzymatically isolated from hind limb muscles of wild-type and C3KO mice. Two microelectrode amplifier and experiments were performed under current or voltage clamp conditions. Calcium concentration changes were detected with an impermeant low affinity dye in the presence of high EGTA intracellular concentrations, and fluxes were calculated with a single compartment model. Standard Western blotting analysis was used to measure the concentration of RyR1 and the α subunit of the dihydropyridine (αDHPR) receptors. Data are presented as mean ± SEM and compared with the Student's test with significance set at p < 0.05. We found that the peak value of Ca(2+) fluxes elicited by single action potentials was significantly reduced by 15-20 % in C3KO fibers, but the kinetics was unaltered. Ca(2+) release elicited by tetanic stimulation was also impaired in C3KO fibers. Confocal studies confirmed that Ca(2+) release was similarly reduced in all triads of C3KO mice. Voltage clamp experiments revealed a normal voltage dependence of Ca(2+) release in C3KO mice but reduced peak Ca(2+) fluxes as with action potential stimulation. These findings concur with biochemical observations of reduced RyR1 and αDHPR levels in C3KO muscles and reduced mechanical output. Confocal studies revealed a similar decrease in Ca(2+) release at all triads consistent with a homogenous reduction of functional voltage activated Ca(2+) release sites. Overall, these results suggest that decreased Ca(2+) release is an early defect in calpainopathy and may contribute to the observed reduction of CaMKII activation in C3KO mice.

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.

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.

[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.

Dystrophin Hot-Spot Mutants Leading to Becker Muscular Dystrophy Insert More Deeply into Membrane Models than the Native Protein.

PubMed

Ameziane-Le Hir, Sarah; Paboeuf, Gilles; Tascon, Christophe; Hubert, Jean-François; Le Rumeur, Elisabeth; Vié, Véronique; Raguénès-Nicol, Céline

2016-07-26

Dystrophin (DYS) is a membrane skeleton protein whose mutations lead to lethal Duchenne muscular dystrophy or to the milder Becker muscular dystrophy (BMD). One third of BMD "in-frame" exon deletions are located in the region that codes for spectrin-like repeats R16 to R21. We focused on four prevalent mutated proteins deleted in this area (called RΔ45-47, RΔ45-48, RΔ45-49, and RΔ45-51 according to the deleted exon numbers), analyzing protein/membrane interactions. Two of the mutants, RΔ45-48 and RΔ45-51, led to mild pathologies and displayed a similar triple coiled-coil structure as the full-length DYS R16-21, whereas the two others, RΔ45-47 and RΔ45-49, induced more severe pathologies and showed "fractional" structures unrelated to the normal one. To explore lipid packing, small unilamellar liposomes (SUVs) and planar monolayers were used at various initial surface pressures. The dissociation constants determined by microscale thermophoresis (MST) were much higher for the full-length DYS R161-21 than for the mutants; thus the wild type protein has weaker SUV binding. Comparing surface pressures after protein adsorption and analysis of atomic force microscopy images of mixed protein/lipid monolayers revealed that the mutants insert more into the lipid monolayer than the wild type does. In fact, in both models every deletion mutant showed more interactions with membranes than the full-length protein did. This means that mutations in the R16-21 part of dystrophin disturb the protein's molecular behavior as it relates to membranes, regardless of whether the accompanying pathology is mild or severe.

Dysferlin rescue by spliceosome-mediated pre-mRNA trans-splicing targeting introns harbouring weakly defined 3' splice sites.

PubMed

Philippi, Susanne; Lorain, Stéphanie; Beley, Cyriaque; Peccate, Cécile; Précigout, Guillaume; Spuler, Simone; Garcia, Luis

2015-07-15

The modification of the pre-mRNA cis-splicing process employing a pre-mRNA trans-splicing molecule (PTM) is an attractive strategy for the in situ correction of genes whose careful transcription regulation and full-length expression is determinative for protein function, as it is the case for the dysferlin (DYSF, Dysf) gene. Loss-of-function mutations of DYSF result in different types of muscular dystrophy mainly manifesting as limb girdle muscular dystrophy 2B (LGMD2B) and Miyoshi muscular dystrophy 1 (MMD1). We established a 3' replacement strategy for mutated DYSF pre-mRNAs induced by spliceosome-mediated pre-mRNA trans-splicing (SmaRT) by the use of a PTM. In contrast to previously established SmaRT strategies, we particularly focused on the identification of a suitable pre-mRNA target intron other than the optimization of the PTM design. By targeting DYSF pre-mRNA introns harbouring differentially defined 3' splice sites (3' SS), we found that target introns encoding weakly defined 3' SSs were trans-spliced successfully in vitro in human LGMD2B myoblasts as well as in vivo in skeletal muscle of wild-type and Dysf(-/-) mice. For the first time, we demonstrate rescue of Dysf protein by SmaRT in vivo. Moreover, we identified concordant qualities among the successfully targeted Dysf introns and targeted endogenous introns in previously reported SmaRT approaches that might facilitate a selective choice of target introns in future SmaRT strategies. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Papillorenal syndrome after Beta-interferon treatment in pregnancy.

PubMed

Gucev, Zoran S; Kirovski, Ilija; Jancevska, Aleksandra; Popjordanova, Nada; Tasic, Velibor

2009-01-01

Papillo-Renal Syndrome (PRS, or Renal-Coloboma Syndrome) is an autosomal dominant disorder, characterized by colobomatous eye defects, abnormal vascular pattern of the optic disk, renal hypoplasia, vesicoureteral reflux, high-frequency hearing loss, and sometimes central nervous system (CNS) abnormalities. The syndrome is associated with mutations in the PAX2 gene. This 11-year-old girl's mother was treated with beta-interferon (IFNbeta-1a) for multiple sclerosis (MS) during the pregnancy. The child failed to thrive in infancy and early childhood. The multicystic renal dystrophy, hypoplastic right kidney, and vesico-ureteral reflux (II-III grade) were diagnosed by ultrasound and radionucleotide renal scan. Subsequently, a morning glory anomaly and coloboma of the optic disc was discovered. Renal failure progressively followed. MRI of the head revealed a cyst of the right optic nerve. Genetic analysis revealed a mutation of the PAX2 gene (619 insG). The multicystic renal dystrophy and a cyst of the optic nerve in association with PRS syndrome have only rarely been described. The fact that this PRS patient stemmed from a pregnancy under beta-interferon treatment raises the question whether IFNbeta-1a treatment during pregnancy has influenced the manifestation or the severity of the PAX2 mutant phenotype in this child.

CINRG: Systems Biology of Glucocorticoids in Muscle Disease

DTIC Science & Technology

2012-10-01

Duchenne Muscular dystrophy , Glucocorticoids, Systems biology, Drug mechanism CINRG: Systems Biology of Glucocorticoids in Muscle Disease Zuyi Wang, Ph.D...2011-2012) for Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy ...DMD) is the most common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis

CINRG: Systems Biology of Glucocorticoids in Muscle Disease

DTIC Science & Technology

2013-10-01

Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy (DMD) is the most...common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis. Corticosteroid... muscle and enable the development of better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant

Instructional Constraints Faced by Learners with Muscular Dystrophy: A Case of Joytown Special Primary School, Thika, Kenya

ERIC Educational Resources Information Center

Wang'ang'a, Annrose Wanjiku; Wamocho, Franciscah Irangi; Kioy, Paul

2015-01-01

The purpose of this study was to investigate the instructional constraints facing learners with muscular dystrophy in Joy Town special primary school, Thika, Kenya. Descriptive design was used for this study. The target population were all the 20 learners suffering from muscular dystrophy from S.A Joy Town Special Primary School. The total target…

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.

A Rare Case Report of Neurodegenerative Disease: Duchenne Muscular Dystrophy in Two Male Siblings

PubMed Central

Suneja, B; Suneja, ES; Chandna, P

2015-01-01

ABSTRACT Duchenne muscular dystrophy (DMD) is an recessive X-linked mediated, musculoskeletal disorder that affects only males. It is the most common and severe form of muscular dystrophy where there is failure to manufacture dystrophin. Clinically, it is characterized by progressive muscle wasting eventually leading to premature death. This case report describes the genetic, oral and systemic findings in two cases of DMD in male siblings. How to cite this article: Suneja B, Suneja ES, Adlakha VK, Chandna P. A Rare Case Report of Neurodegenerative Disease: Duchenne Muscular Dystrophy in Two Male Siblings. Int J Clin Pediatr Dent 2015;8(2):163-165. PMID:26379389

Mechanisms and management of the heart in Myotonic Dystrophy

PubMed Central

McNally, Elizabeth M.; Sparano, Dina

2015-01-01

Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy and is caused by expansion of short nucleotide repeats that, in turn, produce toxic RNA aggregates within cells. DM is multisystemic, and the heart is primary site of pathology. DM patients exhibit cardiac conduction disorders including atrial fibrillation, atrio-ventricular heart block and ventricular arrhythmias. DM patients are also at risk for cardiomyopathy and congestive heart failure. Myotonic dystrophy is also characterized by myotonia, muscle weakness, and profound fatigue. The management of these symptoms requires input from the cardiologist and a team approach to minimize the debilitating aspects of the disorder and optimize cardiac function. PMID:21642660

Genetics and emerging treatments for Duchenne and Becker muscular dystrophy.

PubMed

Wein, Nicolas; Alfano, Lindsay; Flanigan, Kevin M

2015-06-01

Mutations in the DMD gene result in Duchenne or Becker muscular dystrophy due to absent or altered expression of the dystrophin protein. The more severe Duchenne muscular dystrophy typically presents around ages 2 to 5 with gait disturbance, and historically has led to the loss of ambulation by age 12. It is important for the practicing pediatrician, however, to be aware of other presenting signs, such as delayed motor or cognitive milestones, or elevated serum transaminases. Becker muscular dystrophy is milder, often presenting after age 5, with ambulation frequently preserved past 20 years and sometimes into late decades. Copyright © 2015 Elsevier Inc. All rights reserved.

Secondary reduction of alpha7B integrin in laminin alpha2 deficient congenital muscular dystrophy supports an additional transmembrane link in skeletal muscle.

PubMed

Cohn, R D; Mayer, U; Saher, G; Herrmann, R; van der Flier, A; Sonnenberg, A; Sorokin, L; Voit, T

1999-03-01

The integrins are a large family of heterodimeric transmembrane cellular receptors which mediate the association between the extracellular matrix (ECM) and cytoskeletal proteins. The alpha7beta1 integrin is a major laminin binding integrin in skeletal and cardiac muscle and is thought to be involved in myogenic differentiation and migration processes. The main binding partners of the alpha7 integrin are laminin-1 (alpha1-beta1-gamma1), laminin-2 (alpha2-beta1-gamma1) and laminin-4 (alpha2-beta2-gamma1). Targeted deletion of the gene for the alpha7 integrin subunit (ITGA7) in mice leads to a novel form of muscular dystrophy. In the present study we have investigated the expression of two alternative splice variants, the alpha7B and beta1D integrin subunits, in normal human skeletal muscle, as well as in various forms of muscular dystrophy. In normal human skeletal muscle the expression of the alpha7 integrin subunit appeared to be developmentally regulated: it was first detected at 2 years of age. In contrast, the beta1D integrin could be detected in immature and mature muscle in the sarcolemma of normal fetal skeletal muscle at 18 weeks gestation. The expression of alpha7B integrin was significantly reduced at the sarcolemma in six patients with laminin alpha2 chain deficient congenital muscular dystrophy (CMD) (age >2 years). However, this reduction was not correlated with the amount of laminin alpha2 chain expressed. In contrast, the expression of the laminin alpha2 chain was not altered in the skeletal muscle of the alpha7 knock-out mice. These data argue in favor that there is not a tight correlation between the expression of the alpha7 integrin subunit and that of the laminin alpha2 chain in either human or murine dystrophic muscle. Interestingly, in dystrophinopathies (Duchenne and Becker muscular dystrophy; DMD/BMD) expression of alpha7B was upregulated irrespective of the level of dystrophin expression as shown by a strong sarcolemmal staining pattern even in young boys (age <2 years). The expression of the beta1D integrin subunit was not altered in any of our patients with different types of muscular dystrophy. In contrast, sarcolemmal expression of beta1D integrin was significantly reduced in the alpha7 integrin knock-out mice, whereas the expression of the components of the DGC was not altered. The secondary loss of alpha7B in laminin alpha2 chain deficiency defines a biochemical change in the composition of the plasma membrane resulting from a primary protein deficiency in the basal lamina. These findings, in addition to the occurrence of a muscular dystrophy in alpha7 deficient mice, implies that the alpha7B integrin is an important laminin receptor within the plasma membrane which plays a significant role in skeletal muscle function and stability.

Autonomic dysfunction in muscular dystrophy: a theoretical framework for muscle reflex involvement

PubMed Central

Smith, Scott A.; Downey, Ryan M.; Williamson, Jon W.; Mizuno, Masaki

2014-01-01

Muscular dystrophies are a heterogeneous group of genetically inherited disorders whose most prominent clinical feature is progressive degeneration of skeletal muscle. In several forms of the disease, the function of cardiac muscle is likewise affected. The primary defect in this group of diseases is caused by mutations in myocyte proteins important to cellular structure and/or performance. That being stated, a growing body of evidence suggests that the development of autonomic dysfunction may secondarily contribute to the generation of skeletal and cardio-myopathy in muscular dystrophy. Indeed, abnormalities in the regulation of both sympathetic and parasympathetic nerve activity have been reported in a number of muscular dystrophy variants. However, the mechanisms mediating this autonomic dysfunction remain relatively unknown. An autonomic reflex originating in skeletal muscle, the exercise pressor reflex, is known to contribute significantly to the control of sympathetic and parasympathetic activity when stimulated. Given the skeletal myopathy that develops with muscular dystrophy, it is logical to suggest that the function of this reflex might also be abnormal with the pathogenesis of disease. As such, it may contribute to or exacerbate the autonomic dysfunction that manifests. This possibility along with a basic description of exercise pressor reflex function in health and disease are reviewed. A better understanding of the mechanisms that possibly underlie autonomic dysfunction in muscular dystrophy may not only facilitate further research but could also lead to the identification of new therapeutic targets for the treatment of muscular dystrophy. PMID:24600397

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.

Oxidative stress and pathology in muscular dystrophies: focus on protein thiol oxidation and dysferlinopathies.

PubMed

Terrill, Jessica R; Radley-Crabb, Hannah G; Iwasaki, Tomohito; Lemckert, Frances A; Arthur, Peter G; Grounds, Miranda D

2013-09-01

The muscular dystrophies comprise more than 30 clinical disorders that are characterized by progressive skeletal muscle wasting and degeneration. Although the genetic basis for many of these disorders has been identified, the exact mechanism for pathogenesis generally remains unknown. It is considered that disturbed levels of reactive oxygen species (ROS) contribute to the pathology of many muscular dystrophies. Reactive oxygen species and oxidative stress may cause cellular damage by directly and irreversibly damaging macromolecules such as proteins, membrane lipids and DNA; another major cellular consequence of reactive oxygen species is the reversible modification of protein thiol side chains that may affect many aspects of molecular function. Irreversible oxidative damage of protein and lipids has been widely studied in Duchenne muscular dystrophy, and we have recently identified increased protein thiol oxidation in dystrophic muscles of the mdx mouse model for Duchenne muscular dystrophy. This review evaluates the role of elevated oxidative stress in Duchenne muscular dystrophy and other forms of muscular dystrophies, and presents new data that show significantly increased protein thiol oxidation and high levels of lipofuscin (a measure of cumulative oxidative damage) in dysferlin-deficient muscles of A/J mice at various ages. The significance of this elevated oxidative stress and high levels of reversible thiol oxidation, but minimal myofibre necrosis, is discussed in the context of the disease mechanism for dysferlinopathies, and compared with the situation for dystrophin-deficient mdx mice. © 2013 The Authors Journal compilation © 2013 FEBS.

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.

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

PABPN1 gene therapy for oculopharyngeal muscular dystrophy

PubMed Central

Malerba, A.; Klein, P.; Bachtarzi, H.; Jarmin, S. A.; Cordova, G.; Ferry, A.; Strings, V.; Espinoza, M. Polay; Mamchaoui, K.; Blumen, S. C.; St Guily, J. Lacau; Mouly, V.; Graham, M.; Butler-Browne, G.; Suhy, D. A.; Trollet, C.; Dickson, G.

2017-01-01

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome. The efficacy of the combined treatment is further confirmed in cells derived from OPMD patients. These results pave the way towards a gene replacement approach for OPMD treatment. PMID:28361972

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family

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

Frydman, M.; Straussberg, R.; Shomrat, R.

1995-09-11

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. {open_quotes}Idiopathic{close_quotes} hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggestmore » that the unusually early and severe manifestations of DMD in this patient may be related to the coincidental inheritance of the maternal DMD gene and of a paternal gene, causing hyperCKemia. 13 refs., 3 figs., 1 tab.« less

Mapping of the serotonin 5-HT{sub 1D{beta}} autoreceptor gene on chromosome 6 and direct analysis for sequence variants

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

Lappalainen, J.; Dean, M.; Virkkunen, M.

1995-04-24

Abnormal brain serotonin function may be characteristic of several neuropsychiatric disorders. Thus, it is important to identify polymorphic genes and screen for functional variants at loci coding for genes that control normal serotonin functions. 5-HT{sub 1D{beta}} is a terminal serotonin autoreceptor which may play a role in regulating serotonin synthesis and release. Using an SSCP technique we screened for 5-HT{sub 1D{beta}} coding sequence variants in psychiatrically interviewed populations, which included controls, alcoholics, and alcoholic arsonists and alcoholic violent offenders with low CSF concentrations of the main serotonin metabolite 5-HIAA. A common polymorphism was identified in the 5-HT{sub 1D{beta}} gene withmore » allele frequencies of 0.72 and 0.28. The SSCP variant was caused by a silent G to C substitution at nucleotide 861 of the coding region. This polymorphism could also be detected as a HincII RFLP of amplified DNA. DNAs from informative CEPH families were typed for the HincII RFLP and analyzed with respect to 20 linked markers on chromosome 6. Multipoint analysis placed the 5-HT{sub 1D{beta}} receptor gene between markers D6S286 and D6S275. A maximum two-point lod score of 10.90 was obtained to D6S26, which had been previously localized on 6q14-15. Chromosomal aberrations involving this region have been previously shown to cause retinal anomalies, developmental delay, and abnormal brain development. This region also contains the gene for North Carolina-type macular dystrophy. 34 refs., 3 figs., 1 tab.« less

Targeted deletion of RIC8A in mouse neural precursor cells interferes with the development of the brain, eyes, and muscles.

PubMed

Kask, Keiu; Tikker, Laura; Ruisu, Katrin; Lulla, Sirje; Oja, Eva-Maria; Meier, Riho; Raid, Raivo; Velling, Teet; Tõnissoo, Tambet; Pooga, Margus

2018-04-01

Autosomal recessive disorders such as Fukuyama congenital muscular dystrophy, Walker-Warburg syndrome, and the muscle-eye-brain disease are characterized by defects in the development of patient's brain, eyes, and skeletal muscles. These syndromes are accompanied by brain malformations like type II lissencephaly in the cerebral cortex with characteristic overmigrations of neurons through the breaches of the pial basement membrane. The signaling pathways activated by laminin receptors, dystroglycan and integrins, control the integrity of the basement membrane, and their malfunctioning may underlie the pathologies found in the rise of defects reminiscent of these syndromes. Similar defects in corticogenesis and neuromuscular disorders were found in mice when RIC8A was specifically removed from neural precursor cells. RIC8A regulates a subset of G-protein α subunits and in several model organisms, it has been reported to participate in the control of cell division, signaling, and migration. Here, we studied the role of RIC8A in the development of the brain, muscles, and eyes of the neural precursor-specific conditional Ric8a knockout mice. The absence of RIC8A severely affected the attachment and positioning of radial glial processes, Cajal-Retzius' cells, and the arachnoid trabeculae, and these mice displayed additional defects in the lens, skeletal muscles, and heart development. All the discovered defects might be linked to aberrancies in cell adhesion and migration, suggesting that RIC8A has a crucial role in the regulation of cell-extracellular matrix interactions and that its removal leads to the phenotype characteristic to type II lissencephaly-associated diseases. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 374-390, 2018. © 2018 Wiley Periodicals, Inc.

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.

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

[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.

Crystalline Subtype of Pre-Descemetic Corneal Dystrophy

PubMed Central

Dolz-Marco, Rosa; Gallego-Pinazo, Roberto; Pinazo-Durán, María Dolores; Díaz-Llopis, Manuel

2014-01-01

Purpose To report corneal findings in a familial case of the crystalline subtype of pre-Descemetic corneal dystrophy. Case Report A 19-year-old girl and her 44-year-old mother were found to have asymptomatic, bilateral, punctiform and multi-colored crystalline opacities across the whole posterior layer of the corneas. Endothelial specular microscopy revealed the presence of white round flecks located at different levels anterior to the endothelium. No systemic abnormalities or medications could be related to account for these findings. Conclusion To the best of our knowledge, this is the third familial report of this rare corneal disorder. Differential diagnosis may include Schnyder corneal dystrophy, cystinosis, Bietti´s dystrophy and monoclonal gammopathy. PMID:25279130

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.

Mutations in CTNNA1 cause butterfly-shaped pigment dystrophy and perturbed retinal pigment epithelium integrity

PubMed Central

Saksens, Nicole T.M.; Krebs, Mark P.; Schoenmaker-Koller, Frederieke E.; Hicks, Wanda; Yu, Minzhong; Shi, Lanying; Rowe, Lucy; Collin, Gayle B.; Charette, Jeremy R.; Letteboer, Stef J.; Neveling, Kornelia; van Moorsel, Tamara W.; Abu-Ltaif, Sleiman; De Baere, Elfride; Walraedt, Sophie; Banfi, Sandro; Simonelli, Francesca; Cremers, Frans P.M.; Boon, Camiel J.F.; Roepman, Ronald; Leroy, Bart P.; Peachey, Neal S.; Hoyng, Carel B.; Nishina, Patsy M.; den Hollander, Anneke I.

2015-01-01

Butterfly-shaped pigment dystrophy is an eye disease characterized by lesions in the macula that can resemble the wings of a butterfly. Here, we report the identification of heterozygous missense mutations in the α-catenin 1 (CTNNA1) gene in three families with butterfly-shaped pigment dystrophy. In addition, we identified a Ctnna1 missense mutation in a chemically induced mouse mutant, tvrm5. Parallel clinical phenotypes were observed in the retinal pigment epithelium (RPE) of individuals with butterfly-shaped pigment dystrophy and in tvrm5 mice, including pigmentary abnormalities, focal thickening and elevated lesions, and decreased light-activated responses. Morphological studies in tvrm5 mice revealed increased cell shedding and large multinucleated RPE cells, suggesting defects in intercellular adhesion and cytokinesis. This study identifies CTNNA1 gene variants as a cause of macular dystrophy, suggests that CTNNA1 is involved in maintaining RPE integrity, and suggests that other components that participate in intercellular adhesion may be implicated in macular disease. PMID:26691986

Zebrafish models flex their muscles to shed light on muscular dystrophies.

PubMed

Berger, Joachim; Currie, Peter D

2012-11-01

Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix.

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

N-Acetylcysteine Increases Corneal Endothelial Cell Survival in a Mouse Model of Fuchs Endothelial Corneal Dystrophy

PubMed Central

Kim, Eun Chul; Meng, Huan; Jun, Albert S.

2014-01-01

The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo® luminescent reagent. Two-month-old homozygous knock-in Col8a2L450W/L450W mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (pitalic>0.01). Corneal endothelial cell density (CD) was higher (p=0.001) and percent polymegathism was lower (p=0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD. PMID:24952277

N-Acetylcysteine increases corneal endothelial cell survival in a mouse model of Fuchs endothelial corneal dystrophy.

PubMed

Kim, Eun Chul; Meng, Huan; Jun, Albert S

2014-10-01

The present study evaluated survival effects of N-acetylcysteine (NAC) on cultured corneal endothelial cells exposed to oxidative and endoplasmic reticulum (ER) stress and in a mouse model of early-onset Fuchs endothelial corneal dystrophy (FECD). Cultured bovine corneal endothelial cell viability against oxidative and ER stress was determined by CellTiter-Glo(®) luminescent reagent. Two-month-old homozygous knock-in Col8a2(L450W/L450W) mutant (L450W) and C57/Bl6 wild-type (WT) animals were divided into two groups of 15 mice. Group I received 7 mg/mL NAC in drinking water and Group II received control water for 7 months. Endothelial cell density and morphology were evaluated with confocal microscopy. Antioxidant gene (iNos) and ER stress/unfolded protein response gene (Grp78 and Chop) mRNA levels and protein expression were measured in corneal endothelium by real time PCR and Western blotting. Cell viability of H2O2 and thapsigargin exposed cells pre-treated with NAC was significantly increased compared to untreated controls (p < 0.01). Corneal endothelial cell density (CD) was higher (p = 0.001) and percent polymegathism was lower (p = 0.04) in NAC treated L450W mice than in untreated L450W mice. NAC treated L450W endothelium showed significant upregulation of iNos, whereas Grp78 and Chop were downregulated compared to untreated L450W endothelium by real time PCR and Western blotting. NAC increases survival in cultured corneal endothelial cells exposed against ER and oxidative stress. Systemic NAC ingestion increases corneal endothelial cell survival which is associated with increased antioxidant and decreased ER stress markers in a mouse model of early-onset FECD. Our study presents in vivo evidence of a novel potential medical treatment for FECD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impact of three genetic musculoskeletal diseases: a comparative synthesis of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

PubMed

Dogba, Maman Joyce; Rauch, Frank; Douglas, Erin; Bedos, Christophe

2014-10-25

Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta.

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.

[Central aleolar choroidal dystrophy in sibilings coexisting with alopecia].

PubMed

Brydak-Godowska, Joanna; Dróbecka-Brydak, Ewa; Paćkowska, Maria; Kecik, Dariusz

2007-01-01

Central areolar choroidal dystrophy is localized in macular region and is characterized by atrophy of pigment epithelium, photoreceptors and choriocapillaris. This paper presents the history of two sibilings at the age of 23 and 30, with central aleolar choroidal dystrophy coexisting with alopecia. The results of erg, eog and fluorescein angiography are presented. The results of therapy for glaucoma associated with the Sturge-Weber syndrome are often disappointing.

Delayed Diagnosis in Duchenne Muscular Dystrophy: Data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet)

PubMed Central

Ciafaloni, Emma; Fox, Deborah J.; Pandya, Shree; Westfield, Christina P.; Puzhankara, Soman; Romitti, Paul A.; Mathews, Katherine D.; Miller, Timothy M.; Matthews, Dennis J.; Miller, Lisa A.; Cunniff, Christopher; Druschel, Charlotte M.; Moxley, Richard T.

2018-01-01

Objective To identify key factors for the delay in diagnosis of Duchenne muscular dystrophy (DMD) without known family history. Study design The cohort comes from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet), a multistate, multiple-source, population-based surveillance system that identifies and gathers information on all cases of Duchenne and Becker muscular dystrophy born since 1982. We analyzed medical records of 453 Duchenne and Becker muscular dystrophy boys to document the time course and steps taken to reach a definitive diagnosis. Results Among 156 boys without known family history of DMD prior to birth, first signs or symptoms were noted at a mean age of 2.5 years. Concerns resulted in primary care provider evaluation of the child at a mean age of 3.6 years. Mean age at time of initial creatine kinase was 4.7 years. Mean age at definitive diagnosis of DMD was 4.9 years. Conclusions There is a delay of about 2.5 years between onset of DMD symptoms and the time of definitive diagnosis, unchanged over the previous 2 decades. This delay results in lost opportunities for timely genetic counseling and initiation of corticosteroid treatment. We recommend checking creatine kinase early in the evaluation of boys with unexplained developmental delay. PMID:19394035

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.

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.

Glucocorticoid Steroid and Alendronate Treatment Alleviates Dystrophic Phenotype with Enhanced Functional Glycosylation of α-Dystroglycan in Mouse Model of Limb-Girdle Muscular Dystrophy with FKRPP448L Mutation.

PubMed

Wu, Bo; Shah, Sapana N; Lu, Peijuan; Richardson, Stephanie M; Bollinger, Lauren E; Blaeser, Anthony; Madden, Kyle L; Sun, Yubo; Luckie, Taylor M; Cox, Michael D; Sparks, Susan; Harper, Amy D; Lu, Qi Long

2016-06-01

Fukutin-related protein-muscular dystrophy is characterized by defects in glycosylation of α-dystroglycan with variable clinical phenotypes, most commonly as limb-girdle muscular dystrophy 2I. There is no effective therapy available. Glucocorticoid steroids have become the standard treatment for Duchenne and other muscular dystrophies with serious adverse effects, including excessive weight gain, immune suppression, and bone loss. Bisphosphonates have been used to treat Duchenne muscular dystrophy for prevention of osteoporosis. Herein, we evaluated prednisolone and alendronate for their therapeutic potential in the FKRPP448L-mutant mouse representing moderate limb-girdle muscular dystrophy 2I. Mice were treated with prednisolone, alendronate, and both in combination for up to 6 months. Prednisolone improved muscle pathology with significant reduction in muscle degeneration, but had no effect on serum creatine kinase levels and muscle strength. Alendronate treatment did not ameliorate muscle degeneration, but demonstrated a limited enhancement on muscle function test. Combined treatment of prednisolone and alendronate provided best improvement in muscle pathology with normalized fiber size distribution and significantly reduced serum creatine kinase levels, but had limited effect on muscle force generation. The use of alendronate significantly mitigated the bone loss. Prednisolone alone and in combination with alendronate enhance functionally glycosylated α-dystroglycan. These results, for the first time, demonstrate the efficacy and feasibility of this alliance treatment of the two drugs for fukutin-related protein-muscular dystrophy. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ

PubMed Central

Gardner, Brandon B.; Gao, Quan Q.; Hadhazy, Michele; Vo, Andy H.; Wren, Lisa; Molkentin, Jeffery D.; McNally, Elizabeth M.

2016-01-01

Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression. PMID:27148972

Overexpression of Latent TGFβ Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGFβ.

PubMed

Lamar, Kay-Marie; Bogdanovich, Sasha; Gardner, Brandon B; Gao, Quan Q; Miller, Tamari; Earley, Judy U; Hadhazy, Michele; Vo, Andy H; Wren, Lisa; Molkentin, Jeffery D; McNally, Elizabeth M

2016-05-01

Latent TGFβ binding proteins (LTBPs) regulate the extracellular availability of latent TGFβ. LTBP4 was identified as a genetic modifier of muscular dystrophy in mice and humans. An in-frame insertion polymorphism in the murine Ltbp4 gene associates with partial protection against muscular dystrophy. In humans, nonsynonymous single nucleotide polymorphisms in LTBP4 associate with prolonged ambulation in Duchenne muscular dystrophy. To better understand LTBP4 and its role in modifying muscular dystrophy, we created transgenic mice overexpressing the protective murine allele of LTBP4 specifically in mature myofibers using the human skeletal actin promoter. Overexpression of LTBP4 protein was associated with increased muscle mass and proportionally increased strength compared to age-matched controls. In order to assess the effects of LTBP4 in muscular dystrophy, LTBP4 overexpressing mice were bred to mdx mice, a model of Duchenne muscular dystrophy. In this model, increased LTBP4 led to greater muscle mass with proportionally increased strength, and decreased fibrosis. The increase in muscle mass and reduction in fibrosis were similar to what occurs when myostatin, a related TGFβ family member and negative regulator of muscle mass, was deleted in mdx mice. Supporting this, we found that myostatin forms a complex with LTBP4 and that overexpression of LTBP4 led to a decrease in myostatin levels. LTBP4 also interacted with TGFβ and GDF11, a protein highly related to myostatin. These data identify LTBP4 as a multi-TGFβ family ligand binding protein with the capacity to modify muscle disease through overexpression.

Impact of three-phase bone scintigraphy on the diagnosis and treatment of complex regional pain syndrome type I or reflex sympathetic dystrophy.

PubMed

Shehab, Dia; Elgazzar, Abdelhamid; Collier, B David; Naddaf, Sleiman; Al-Jarallah, Khalid; Omar, Abdelmoneim; Al-Mutairy, Moudi

2006-01-01

To determine the impact of three-phase bone scintigraphy (TPBS) on the diagnosis and management of complex regional pain syndrome type I (CRPSI) or reflex sympathetic dystrophy (RSD). Twenty consecutive patients with a recent clinical evidence of CRPSI were referred for TPBS as part of their routine management plan. All patients underwent neurological examinations with special attention to the evaluation of clinical features of vasomotor, sudomotor, motor and sensory dysfunction. Patients were followed prospectively. When both the clinical and TPBS results supported the diagnosis of CRPSI, patients were started on treatment. Of the 20 patients, TPBS supported the diagnosis of RSD in 9 who were treated with steroids and physiotherapy. Complete follow-up was available for 7 of them and all had a satisfactory response to treatment. For the remaining 11 patients RSD was diagnosed clinically but not confirmed by TPBS. On follow-up there was no evidence that TPBS failed to identify RSD in these 11 patients. The results indicate that TPBS confirmed the clinical diagnosis of RSD, and, more importantly, had a significant impact on its management.

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.

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.

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

FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1.

PubMed

Park, Hyung Jun; Lee, Wookjae; Kim, Se Hoon; Lee, Jung Hwan; Shin, Ha Young; Kim, Seung Min; Park, Kee Duk; Lee, Ji Hyun; Choi, Young Chul

2018-03-01

Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is caused by contraction of the D4Z4 repeat array. Recent studies revealed that the FAT1 expression is associated with disease activity of FSHD, and the FAT1 alterations result in myopathy with a FSHD-like phenotype. We describe a 59-year-old woman with both contracted D4Z4 repeat units and a FAT1 mutation. Shoulder girdle muscle weakness developed at the age of 56 years, and was followed by proximal leg weakness. When we examined her at 59 years of age, she displayed asymmetric and predominant weakness of facial and proximal muscles. Muscle biopsy showed increased variation in fiber size and multifocal degenerating fibers with lymphocytic infiltration. Southern blot analysis revealed 8 D4Z4 repeat units, and targeted sequencing of modifier genes demonstrated the c.10331 A>G variant in the FAT1 gene. This FAT1 variant has previously been reported as pathogenic variant in a patient with FSHD-like phenotype. Our study is the first report of a FAT1 mutation in a FSHD1 patient, and suggests that FAT1 alterations might work as a genetic modifier. © Copyright: Yonsei University College of Medicine 2018.

LRRTM4-C538Y novel gene mutation is associated with hereditary macular degeneration with novel dysfunction of ON-type bipolar cells.

PubMed

Kawamura, Yuichi; Suga, Akiko; Fujimaki, Takuro; Yoshitake, Kazutoshi; Tsunoda, Kazushige; Murakami, Akira; Iwata, Takeshi

2018-05-14

The macula is a unique structure in higher primates, where cone and rod photoreceptors show highest density in the fovea and the surrounding area, respectively. The hereditary macular dystrophies represent a heterozygous group of rare disorders characterized by central visual loss and atrophy of the macula and surrounding retina. Here we report an atypical absence of ON-type bipolar cell response in a Japanese patient with autosomal dominant macular dystrophy (adMD). To identify a causal genetic mutation for the adMD, we performed whole-exome sequencing (WES) on four affected and four-non affected members of the family for three generations, and identified a novel p.C538Y mutation in a post-synaptic gene, LRRTM4. WES analysis revealed seven rare genetic variations in patients. We further referred to our in-house WES data from 1360 families with inherited retinal diseases, and found that only p.C538Y mutation in LRRTM4 was associated with adMD-affected patients. Combinatorial filtration using public database of single-nucleotide polymorphism frequency and genotype-phenotype annotated database identified novel mutation in atypical adMD.

Fukutin-related protein localizes to the Golgi apparatus and mutations lead to mislocalization in muscle in vivo.

PubMed

Keramaris-Vrantsis, Elizabeth; Lu, Pei J; Doran, Timothy; Zillmer, Allen; Ashar, Jignya; Esapa, Christopher T; Benson, Matthew A; Blake, Derek J; Rosenfeld, Jeffrey; Lu, Qi L

2007-10-01

Mutations in the fukutin-related protein gene (FKRP) are associated with a spectrum of diseases from mild limb-girdle muscular dystrophy type 2I to severe congenital muscular dystrophy type 1C, muscle-eye-brain disease (MEB), and Walker-Warburg syndrome (WWS). The effect of mutations on the transportation of the mutant proteins may constitute the underlying mechanisms for the pathogenesis of these diseases. Here we examined the subcellular localization of mouse and human normal and mutant FKRP proteins in cells and in muscle in vivo. Both normal human and mouse FKRPs localize in part of the Golgi apparatus in muscle fibers. Mutations in the FKRP gene invariably altered the localization of the protein, leading to endoplasmic reticulum retention within cells and diminished Golgi localization in muscle fibers. Our results therefore suggest that an individual missense point mutation can confer at least two independent effects on the protein, causing (1) reduction or loss of the presumed glycosyltransferase activity directly and (2) mislocalization that could further alter the function of the protein. The complexity of the effect of individual missense point mutations may partly explain the wide variation of the FKRP-related myopathies.

KMeyeDB: a graphical database of mutations in genes that cause eye diseases.

PubMed

Kawamura, Takashi; Ohtsubo, Masafumi; Mitsuyama, Susumu; Ohno-Nakamura, Saho; Shimizu, Nobuyoshi; Minoshima, Shinsei

2010-06-01

KMeyeDB (http://mutview.dmb.med.keio.ac.jp/) is a database of human gene mutations that cause eye diseases. We have substantially enriched the amount of data in the database, which now contains information about the mutations of 167 human genes causing eye-related diseases including retinitis pigmentosa, cone-rod dystrophy, night blindness, Oguchi disease, Stargardt disease, macular degeneration, Leber congenital amaurosis, corneal dystrophy, cataract, glaucoma, retinoblastoma, Bardet-Biedl syndrome, and Usher syndrome. KMeyeDB is operated using the database software MutationView, which deals with various characters of mutations, gene structure, protein functional domains, and polymerase chain reaction (PCR) primers, as well as clinical data for each case. Users can access the database using an ordinary Internet browser with smooth user-interface, without user registration. The results are displayed on the graphical windows together with statistical calculations. All mutations and associated data have been collected from published articles. Careful data analysis with KMeyeDB revealed many interesting features regarding the mutations in 167 genes that cause 326 different types of eye diseases. Some genes are involved in multiple types of eye diseases, whereas several eye diseases are caused by different mutations in one gene.

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.

Cross-sectional evaluation of electrical impedance myography and quantitative ultrasound for the assessment of Duchenne muscular dystrophy in a clinical trial setting.

PubMed

Rutkove, Seward B; Geisbush, Tom R; Mijailovic, Aleksandar; Shklyar, Irina; Pasternak, Amy; Visyak, Nicole; Wu, Jim S; Zaidman, Craig; Darras, Basil T

2014-07-01

Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = -0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = -0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = -0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = -0.40; P = 0.054 and rho = -0.32; P = 0.13, respectively). Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted. Copyright © 2014 Elsevier Inc. All rights reserved.

Stem cell transplantation for treating Duchenne muscular dystrophy: A Web of Science-based literature analysis.

PubMed

Yang, Xiaofeng

2012-08-05

To identify global research trends in stem cell transplantation for treating Duchenne muscular dystrophy using a bibliometric analysis of Web of Science. We performed a bibliometric analysis of studies on stem cell transplantation for treating Duchenne muscular dystrophy from 2002 to 2011 retrieved from Web of Science. (a) peer-reviewed published articles on stem cell transplantation for treating Duchenne muscular dystrophy indexed in Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and (c) publication between 2002 and 2011. (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) corrected papers. (1) Annual publication output; (2) distribution according to subject areas; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) distribution according to institution in China; (7) distribution according to institution that cooperated with Chinese institutions; (8) top-cited articles from 2002 to 2006; (9) top-cited articles from 2007 to 2011. A total of 318 publications on stem cell transplantation for treating Duchenne muscular dystrophy were retrieved from Web of Science from 2002 to 2011, of which almost half derived from American authors and institutes. The number of publications has gradually increased over the past 10 years. Most papers appeared in journals with a focus on gene and molecular research, such as Molecular Therapy, Neuromuscular Disorders, and PLoS One. The 10 most-cited papers from 2002 to 2006 were mostly about different kinds of stem cell transplantation for muscle regeneration, while the 10 most-cited papers from 2007 to 2011 were mostly about new techniques of stem cell transplantation for treating Duchenne muscular dystrophy. The publications on stem cell transplantation for treating Duchenne muscular dystrophy were relatively few. It also needs more research to confirm that stem cell therapy is a reliable treatment for Duchenne muscular dystrophy.

The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy

PubMed Central

Ohsawa, Yutaka; Takayama, Kentaro; Nishimatsu, Shin-ichiro; Okada, Tadashi; Fujino, Masahiro; Fukai, Yuta; Murakami, Tatsufumi; Hagiwara, Hiroki; Itoh, Fumiko; Tsuchida, Kunihiro; Hayashi, Yoshio; Sunada, Yoshihide

2015-01-01

Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings. PMID:26226340

The Inhibitory Core of the Myostatin Prodomain: Its Interaction with Both Type I and II Membrane Receptors, and Potential to Treat Muscle Atrophy.

PubMed

Ohsawa, Yutaka; Takayama, Kentaro; Nishimatsu, Shin-ichiro; Okada, Tadashi; Fujino, Masahiro; Fukai, Yuta; Murakami, Tatsufumi; Hagiwara, Hiroki; Itoh, Fumiko; Tsuchida, Kunihiro; Hayashi, Yoshio; Sunada, Yoshihide

2015-01-01

Myostatin, a muscle-specific transforming growth factor-β (TGF-β), negatively regulates skeletal muscle mass. The N-terminal prodomain of myostatin noncovalently binds to and suppresses the C-terminal mature domain (ligand) as an inactive circulating complex. However, which region of the myostatin prodomain is required to inhibit the biological activity of myostatin has remained unknown. We identified a 29-amino acid region that inhibited myostatin-induced transcriptional activity by 79% compared with the full-length prodomain. This inhibitory core resides near the N-terminus of the prodomain and includes an α-helix that is evolutionarily conserved among other TGF-β family members, but suppresses activation of myostatin and growth and differentiation factor 11 (GDF11) that share identical membrane receptors. Interestingly, the inhibitory core co-localized and co-immunoprecipitated with not only the ligand, but also its type I and type II membrane receptors. Deletion of the inhibitory core in the full-length prodomain removed all capacity for suppression of myostatin. A synthetic peptide corresponding to the inhibitory core (p29) ameliorates impaired myoblast differentiation induced by myostatin and GDF11, but not activin or TGF-β1. Moreover, intramuscular injection of p29 alleviated muscle atrophy and decreased the absolute force in caveolin 3-deficient limb-girdle muscular dystrophy 1C model mice. The injection suppressed activation of myostatin signaling and restored the decreased numbers of muscle precursor cells caused by caveolin 3 deficiency. Our findings indicate a novel concept for this newly identified inhibitory core of the prodomain of myostatin: that it not only suppresses the ligand, but also prevents two distinct membrane receptors from binding to the ligand. This study provides a strong rationale for the use of p29 in the amelioration of skeletal muscle atrophy in various clinical settings.

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.

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.

The Identification of Carriers in Duchenne Muscular Dystrophy

PubMed Central

Monckton, George; Ludvigsen, Bernhard

1963-01-01

Following recurrent reports in the literature that it is possible to detect carriers of the gene for progressive muscular dystrophy (Duchenne), a survey of nine families was performed. No unequivocal results could be obtained in comparison of clinical data with circulation-time measurements or serum enzyme studies. It is concluded that carrier-labelling with respect to progressive muscular dystrophy is not yet at a satisfactory stage, although progress is being made. PMID:13935998

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.

Raman spectroscopic study of acute oxidative stress induced changes in mice skeletal muscles

NASA Astrophysics Data System (ADS)

Sriramoju, Vidyasagar; Alimova, Alexandra; Chakraverty, Rahul; Katz, A.; Gayen, S. K.; Larsson, L.; Savage, H. E.; Alfano, R. R.

2008-02-01

The oxidative stress due to free radicals is implicated in the pathogenesis of tissue damage in diseases such as muscular dystrophy, Alzheimer dementia, diabetes mellitus, and mitochrondrial myopathies. In this study, the acute oxidative stress induced changes in nicotinamide adenine dinucleotides in mouse skeletal muscles are studied in vitro using Raman spectroscopy. Mammalian skeletal muscles are rich in nicotinamide adenine dinucleotides in both reduced (NADH) and oxidized (NAD) states, as they are sites of aerobic and anaerobic respiration. The relative levels of NAD and NADH are altered in certain physiological and pathological conditions of skeletal muscles. In this study, near infrared Raman spectroscopy is used to identify the molecular fingerprints of NAD and NADH in five-week-old mice biceps femoris muscles. A Raman vibrational mode of NADH is identified in fresh skeletal muscle samples suspended in buffered normal saline. In the same samples, when treated with 1% H IIO II for 5 minutes and 15 minutes, the Raman spectrum shows molecular fingerprints specific to NAD and the disappearance of NADH vibrational bands. The NAD bands after 15 minutes were more intense than after 5 minutes. Since NADH fluoresces and NAD does not, fluorescence spectroscopy is used to confirm the results of the Raman measurements. Fluorescence spectra exhibit an emission peak at 460 nm, corresponding to NADH emission wavelength in fresh muscle samples; while the H IIO II treated muscle samples do not exhibit NADH fluorescence. Raman spectroscopy may be used to develop a minimally invasive, in vivo optical biopsy method to measure the relative NAD and NADH levels in muscle tissues. This may help to detect diseases of muscle, including mitochondrial myopathies and muscular dystrophies.

Muscular dystrophy

MedlinePlus

... are no known cures for the various muscular dystrophies. The goal of treatment is to control symptoms. Physical therapy may help maintain muscle strength and function. Leg braces and a wheelchair ...

Inhibition of muscle fibrosis results in increases in both utrophin levels and the number of revertant myofibers in Duchenne muscular dystrophy.

PubMed

Levi, Oshrat; Genin, Olga; Angelini, Corrado; Halevy, Orna; Pines, Mark

2015-09-15

Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3-9 years) an inverse correlation was observed between the levels of collagen type I - representing fibrosis - and the levels of utrophin. This correlation was independent of the patient's age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius. In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis.

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.

[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.

Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

PubMed Central

2014-01-01

Background Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies. Methods We developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice. Results These strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma. Conclusions We have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration. PMID:25157321

Asynchronous Inflammation and Myogenic Cell Migration Limit Muscle Tissue Regeneration Mediated by a Cellular Scaffolds

DTIC Science & Technology

2015-02-11

such as duchenne muscular dystrophy ) results in impaired regeneration, increased atrophy and fibrosis of skeletal muscle [24-27]. It has also been...2005; 122:289-301. 24. Cohn RDCampbell KP. Molecular basis of muscular dystrophies . Muscle Nerve 2000; 23:1456-1471. 25. Morgan JEZammit PS. Direct...et al. Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy . Neurology 2005; 65:826-834. 28. Lepper C

Automatic Fibrosis Quantification By Using a k-NN Classificator

DTIC Science & Technology

2001-10-25

Fluthrope, “Stages in fiber breakdown in duchenne muscular dystrophy ,” J. Neurol. Sci., vol. 24, pp. 179– 186, 1975. [6] F. Cornelio and I. Dones, “ Muscle ...an automatic algorithm to measure fibrosis in muscle sections of mdx mice, a mutant species used as a model of the Duchenne dystrophy . The al- gorithm...fiber degeneration and necro- sis in muscular dystrophy and other muscle diseases: cytochem- ical and immunocytochemical data,” Ann. Neurol., vol. 16

Translational Studies of GALGT2 Gene Therapy for Duchenne Muscular Dystrophy

DTIC Science & Technology

2013-10-01

muscles once the experimental problems related to expression are solved. Figure 2. Percentage change in specific force after GALGT2 treatment of wild...cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice. Proc Natl Acad Sci U S A 99, 5616-5621 (2002). 3. Xu, R...Camboni, M. & Martin, P.T. Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth

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.

Disparities in the diagnostic process of Duchenne and Becker muscular dystrophy.

PubMed

Holtzer, Caleb; Meaney, F John; Andrews, Jennifer; Ciafaloni, Emma; Fox, Deborah J; James, Katherine A; Lu, Zhenqiang; Miller, Lisa; Pandya, Shree; Ouyang, Lijing; Cunniff, Christopher

2011-11-01

To determine whether sociodemographic factors are associated with delays at specific steps in the diagnostic process of Duchenne and Becker muscular dystrophy. We examined abstracted medical records for 540 males from population-based surveillance sites in Arizona, Colorado, Georgia, Iowa, and western New York. We used linear regressions to model the association of three sociodemographic characteristics with age at initial medical evaluation, first creatine kinase measurement, and earliest DNA analysis while controlling for changes in the diagnostic process over time. The analytical dataset included 375 males with information on family history of Duchenne and Becker muscular dystrophy, neighborhood poverty levels, and race/ethnicity. Black and Hispanic race/ethnicity predicted older ages at initial evaluation, creatine kinase measurement, and DNA testing (P < 0.05). A positive family history of Duchenne and Becker muscular dystrophy predicted younger ages at initial evaluation, creatine kinase measurement and DNA testing (P < 0.001). Higher neighborhood poverty was associated with earlier ages of evaluation (P < 0.05). Racial and ethnic disparities in the diagnostic process for Duchenne and Becker muscular dystrophy are evident even after adjustment for family history of Duchenne and Becker muscular dystrophy and changes in the diagnostic process over time. Black and Hispanic children are initially evaluated at older ages than white children, and the gap widens at later steps in the diagnostic process.

Scoliosis

MedlinePlus

... problem that affects the muscles. Problems can include cerebral palsy , muscular dystrophy , spina bifida, and polio . ... They may have another serious disorder, such as cerebral palsy or muscular dystrophy, so their goals are much ...

Muscular Dystrophy

MedlinePlus

... Gardner-Medwin D. Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy . Neuromuscul. Disord. Jan 1993;3(1):57-64. 3. Bushby KM, Appleton R, Anderson ...

Nonmechanical Roles of Dystrophin and Associated Proteins in Exercise, Neuromuscular Junctions, and Brains

PubMed Central

Nichols, Bailey; Takeda, Shin’ichi; Yokota, Toshifumi

2015-01-01

Dystrophin-glycoprotein complex (DGC) is an important structural unit in skeletal muscle that connects the cytoskeleton (f-actin) of a muscle fiber to the extracellular matrix (ECM). Several muscular dystrophies, such as Duchenne muscular dystrophy, Becker muscular dystrophy, congenital muscular dystrophies (dystroglycanopathies), and limb-girdle muscular dystrophies (sarcoglycanopathies), are caused by mutations in the different DGC components. Although many early studies indicated DGC plays a crucial mechanical role in maintaining the structural integrity of skeletal muscle, recent studies identified novel roles of DGC. Beyond a mechanical role, these DGC members play important signaling roles and act as a scaffold for various signaling pathways. For example, neuronal nitric oxide synthase (nNOS), which is localized at the muscle membrane by DGC members (dystrophin and syntrophins), plays an important role in the regulation of the blood flow during exercise. DGC also plays important roles at the neuromuscular junction (NMJ) and in the brain. In this review, we will focus on recently identified roles of DGC particularly in exercise and the brain. PMID:26230713

Choroidal dystrophies

MedlinePlus

... dystrophies. In: Tasman W, Jaeger EA, eds. Duane's Foundations of Clinical Ophthalmology . 2013 ed. Philadelphia, PA: Lippincott ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

Total intravenous anesthesia in a 10-month-old patient with congenital myotonic dystrophy undergoing endoscopic third ventriculostomy -A case report-

PubMed Central

Joh, Jung Hwa; Kim, Ji Yeon; Baek, Seung-Hye; Song, Jun-Gol; Lee, Yu Mi

2012-01-01

Myotonic dystrophy is a rare genetic disorder characterized by muscle atrophy and weakness. Surgical treatment of this condition poses various problems for the anesthesiologist. We describe the anesthetic management of a 10-month-old infant with congenital myotonic dystrophy, who was scheduled for endoscopic third ventriculostomy under general anesthesia. Anesthesia was induced with thiopental sodium, fentanyl, and vecuronium, and thereafter maintained via continuous infusion of propofol and remifentanil. The train-of-four ratio was monitored throughout the operation, and muscle relaxation was reversed with pyridostigmine and glycopyrrolate at the end of the procedure. We show that total intravenous anesthesia using propofol and remifentanil is a satisfactory anesthetic technique in very young patients with congenital myotonic dystrophy. PMID:22949987

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.

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.

The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy

PubMed Central

Marshall, Jamie L.; Kwok, Yukwah; McMorran, Brian; Baum, Linda G.; Crosbie-Watson, Rachelle H.

2013-01-01

Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

Skeletal muscle contractile properties in a novel murine model for limb girdle muscular dystrophy 2i.

PubMed

Rehwaldt, Jordan D; Rodgers, Buel D; Lin, David C

2017-12-01

Limb-girdle muscular dystrophy (LGMD) 2i results from mutations in fukutin-related protein and aberrant α-dystroglycan glycosylation. Although this significantly compromises muscle function and ambulation, the comprehensive characteristics of contractile dysfunction are unknown. Therefore, we quantified the in situ contractile properties of the medial gastrocnemius in young adult P448L mice, an affected muscle of a novel model of LGMD2i. Normalized maximal twitch force, tetanic force, and power were significantly smaller in P448L mice, compared with sex-matched, wild-type mice. These differences were consistent with the replacement of contractile fibers by passive tissue. The shape of the active force-length relationships were similar in both groups, regardless of sex, consistent with an intact sarcomeric structure in P448L mice. Passive force-length curves normalized to maximal isometric force were steeper in P448L mice, and passive elements contribute disproportionately more to total contractile force in P448L mice. Sex differences were mostly noted in the force-velocity curves, as normalized values for maximal and optimal velocities were significantly slower in P448L males, compared with wild-type, but not in P448L females. This suggests that the dystrophic phenotype, which may include possible changes in cross-bridge kinetics and fiber-type proportions, progresses more quickly in P448L males. These results together indicate that active force and power generation are compromised in both sexes of P448L mice, while passive forces increase. More importantly, the results identified several functional markers of disease pathophysiology that could aid in developing and assessment of novel therapeutics for LGMD2i and possibly other dystroglycanopathies as well. NEW & NOTEWORTHY Comprehensive assessments of muscle contractile function have, until now, never been performed in an animal model for any dystroglycanopathy. This study suggests that skeletal muscle contractile properties are significantly compromised in a recently developed model for limb-girdle muscular dystrophy 2i, the P448L mouse. It further identifies novel pathological markers of muscle function that are suitable for developing therapeutics and for better understanding of disease pathogenesis.

Novel Intriguing Strategies Attenuating to Sarcopenia

PubMed Central

Sakuma, Kunihiro; Yamaguchi, Akihiko

2012-01-01

Sarcopenia, the age-related loss of skeletal muscle mass, is characterized by a deterioration of muscle quantity and quality leading to a gradual slowing of movement, a decline in strength and power, increased risk of fall-related injury, and, often, frailty. Since sarcopenia is largely attributed to various molecular mediators affecting fiber size, mitochondrial homeostasis, and apoptosis, the mechanisms responsible for these deleterious changes present numerous therapeutic targets for drug discovery. Resistance training combined with amino acid-containing supplements is often utilized to prevent age-related muscle wasting and weakness. In this review, we summarize more recent therapeutic strategies (myostatin or proteasome inhibition, supplementation with eicosapentaenoic acid (EPA) or ursolic acid, etc.) for counteracting sarcopenia. Myostatin inhibitor is the most advanced research with a Phase I/II trial in muscular dystrophy but does not try the possibility for attenuating sarcopenia. EPA and ursolic acid seem to be effective as therapeutic agents, because they attenuate the degenerative symptoms of muscular dystrophy and cachexic muscle. The activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle by exercise and/or unknown supplementation would be an intriguing approach to attenuating sarcopenia. In contrast, muscle loss with age may not be influenced positively by treatment with a proteasome inhibitor or antioxidant. PMID:22500226

Standard Operating Procedures (SOPs) for Evaluating the Heart in Preclinical Studies of Duchenne Muscular Dystrophy.

PubMed

Duan, Dongsheng; Rafael-Fortney, Jill A; Blain, Alison; Kass, David A; McNally, Elizabeth M; Metzger, Joseph M; Spurney, Christopher F; Kinnett, Kathi

2016-02-01

A recent working group meeting focused on contemporary cardiac issues in Duchenne muscular dystrophy (DMD) was hosted by the National Heart, Lung, and Blood Institute in collaboration with the Parent Project Muscular Dystrophy. An outcome of this meeting was to provide freely available detailed protocols for preclinical animal studies. The goal of these protocols is to improve the quality and reproducibility of cardiac preclinical studies aimed at developing new therapeutics for the prevention and treatment of DMD cardiomyopathy.

Limb-girdle muscular dystrophies

MedlinePlus

... diseases in which there is muscle weakness and wasting (muscular dystrophy). In most cases, both parents must ... which are not actually strong Loss of muscle mass, thinning of certain body parts Low back pain ...

Polymyositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Dermatomyositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

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

Muscular Dystrophy

MedlinePlus

... forms of MD grow worse as the person's muscles get weaker. Most people with MD eventually lose the ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent complications. ...

Signs and Symptoms

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Expression of Pannexin 1 and Pannexin 3 during skeletal muscle development, regeneration, and Duchenne muscular dystrophy.

PubMed

Pham, Tammy L; St-Pierre, Marie-Eve; Ravel-Chapuis, Aymeric; Parks, Tara E C; Langlois, Stéphanie; Penuela, Silvia; Jasmin, Bernard J; Cowan, Kyle N

2018-05-10

Pannexin 1 (Panx1) and Pannexin 3 (Panx3) are single membrane channels recently implicated in myogenic commitment, as well as myoblast proliferation and differentiation in vitro. However, their expression patterns during skeletal muscle development and regeneration had yet to be investigated. Here, we show that Panx1 levels increase during skeletal muscle development becoming highly expressed together with Panx3 in adult skeletal muscle. In adult mice, Panx1 and Panx3 were differentially expressed in fast- and slow-twitch muscles. We also report that Panx1/PANX1 and Panx3/PANX3 are co-expressed in mouse and human satellite cells, which play crucial roles in skeletal muscle regeneration. Interestingly, Panx1 and Panx3 levels were modulated in muscle degeneration/regeneration, similar to the pattern seen during skeletal muscle development. As Duchenne muscular dystrophy is characterized by skeletal muscle degeneration and impaired regeneration, we next used mild and severe mouse models of this disease and found a significant dysregulation of Panx1 and Panx3 levels in dystrophic skeletal muscles. Together, our results are the first demonstration that Panx1 and Panx3 are differentially expressed amongst skeletal muscle types with their levels being highly modulated during skeletal muscle development, regeneration, and dystrophy. These findings suggest that Panx1 and Panx3 channels may play important and distinct roles in healthy and diseased skeletal muscles. © 2018 Wiley Periodicals, Inc.

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

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.

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.

Genome-wide association study to identify potential genetic modifiers in a canine model for Duchenne muscular dystrophy.

PubMed

Brinkmeyer-Langford, Candice; Balog-Alvarez, Cynthia; Cai, James J; Davis, Brian W; Kornegay, Joe N

2016-08-22

Duchenne muscular dystrophy (DMD) causes progressive muscle degeneration, cardiomyopathy and respiratory failure in approximately 1/5,000 boys. Golden Retriever muscular dystrophy (GRMD) resembles DMD both clinically and pathologically. Like DMD, GRMD exhibits remarkable phenotypic variation among affected dogs, suggesting the influence of modifiers. Understanding the role(s) of genetic modifiers of GRMD may identify genes and pathways that also modify phenotypes in DMD and reveal novel therapies. Therefore, our objective in this study was to identify genetic modifiers that affect discrete GRMD phenotypes. We performed a linear mixed-model (LMM) analysis using 16 variably-affected dogs from our GRMD colony (8 dystrophic, 8 non-dystrophic). All of these dogs were either full or half-siblings, and phenotyped for 19 objective, quantitative biomarkers at ages 6 and 12 months. Each biomarker was individually assessed. Gene expression profiles of 59 possible candidate genes were generated for two muscle types: the cranial tibialis and medial head of the gastrocnemius. SNPs significantly associated with GRMD biomarkers were identified on multiple chromosomes (including the X chromosome). Gene expression levels for candidate genes located near these SNPs correlated with biomarker values, suggesting possible roles as GRMD modifiers. The results of this study enhance our understanding of GRMD pathology and represent a first step toward the characterization of GRMD modifiers that may be relevant to DMD pathology. Such modifiers are likely to be useful for DMD treatment development based on their relationships to GRMD phenotypes.

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.

[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.

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

[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.

Optical coherence tomography can assess skeletal muscle tissue from mouse models of muscular dystrophy by parametric imaging of the attenuation coefficient

PubMed Central

Klyen, Blake R.; Scolaro, Loretta; Shavlakadze, Tea; Grounds, Miranda D.; Sampson, David D.

2014-01-01

We present the assessment of ex vivo mouse muscle tissue by quantitative parametric imaging of the near-infrared attenuation coefficient µt using optical coherence tomography. The resulting values of the local total attenuation coefficient µt (mean ± standard error) from necrotic lesions in the dystrophic skeletal muscle tissue of mdx mice are higher (9.6 ± 0.3 mm−1) than regions from the same tissue containing only necrotic myofibers (7.0 ± 0.6 mm−1), and significantly higher than values from intact myofibers, whether from an adjacent region of the same sample (4.8 ± 0.3 mm−1) or from healthy tissue of the wild-type C57 mouse (3.9 ± 0.2 mm−1) used as a control. Our results suggest that the attenuation coefficient could be used as a quantitative means to identify necrotic lesions and assess skeletal muscle tissue in mouse models of human Duchenne muscular dystrophy. PMID:24761302

Evaluation of the behavioral characteristics of the mdx mouse model of duchenne muscular dystrophy through operant conditioning procedures.

PubMed

Lewon, Matthew; Peters, Christina M; Van Ry, Pam M; Burkin, Dean J; Hunter, Kenneth W; Hayes, Linda J

2017-09-01

The mdx mouse is an important nonhuman model for Duchenne muscular dystrophy (DMD) research. Characterizing the behavioral traits of the strain relative to congenic wild-type (WT) mice may enhance our understanding of the cognitive deficits observed in some humans with DMD and contribute to treatment development and evaluation. In this paper we report the results of a number of experiments comparing the behavior of mdx to WT mice in operant conditioning procedures designed to assess learning and memory. We found that mdx outperformed WT in all learning and memory tasks involving food reinforcement, and this appeared to be related to the differential effects of the food deprivation motivating operation on mdx mice. Conversely, WT outperformed mdx in an escape/avoidance learning task. These results suggest motivational differences between the strains and demonstrate the potential utility of operant conditioning procedures in the assessment of the behavioral characteristics of the mdx mouse. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial.

PubMed

Coleman, D Jackson; Lee, Winston; Chang, Stanley; Silverman, Ronald H; Lloyd, Harriet O; Daly, Suzanne; Tsang, Stephen H

2018-04-25

To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery. © 2018 S. Karger AG, Basel.

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

Deficiency in Cardiac Dystrophin Affects the Abundance of the α-/β-Dystroglycan Complex

PubMed Central

2005-01-01

Although Duchenne muscular dystrophy is primarily categorised as a skeletal muscle disease, deficiency in the membrane cytoskeletal protein dystrophin also affects the heart. The central transsarcolemmal linker between the actin membrane cytoskeleton and the extracellular matrix is represented by the dystrophin-associated dystroglycans. Chemical cross-linking analysis revealed no significant differences in the dimeric status of the α-/β-dystroglycan subcomplex in the dystrophic mdx heart as compared to normal cardiac tissue. In analogy to skeletal muscle fibres, heart muscle also exhibited a greatly reduced abundance of both dystroglycans in dystrophin-deficient cells. Immunoblotting demonstrated that the degree of reduction in α-dystroglycan is more pronounced in matured mdx skeletal muscle as contrasted to the mdx heart. The fact that the deficiency in dystrophin triggers a similar pathobiochemical response in both types of muscle suggests that the cardiomyopathic complications observed in x-linked muscular dystrophy might be initiated by the loss of the dystrophin-associated surface glycoprotein complex. PMID:15689636

How Is Muscular Dystrophy Diagnosed?

MedlinePlus

... dystrophy advanced by new genetic test. Medical News Today. Retrieved June 21, 2012, from http://www.medicalnewstoday. ... Here’s How NICHD Research Is Improving Patients’ Lives Today’s Research on Medicines for Children Offers Hope for ...

Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

MedlinePlus

... 43. 2. The FSH‐DY Group. A prospective, quantitative study of the natural history of facioscapulohumeral muscular ... regarding facioscapulohumeral muscular dystrophy (FSHD). It actively promotes research toward the prevention, cause and treatment of FSHD. ...

Muscular Dystrophy

MedlinePlus

... be affected. Limb-girdle muscular dystrophy (LGMD) affects boys and girls equally, weakening muscles in the shoulders and upper ... weakness and poor muscle tone. Occurring in both girls and boys, it can have different symptoms. It varies in ...

Inclusion-Body Myositis: Diagnosis

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Learn About Neuromuscular Disease

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

Dermatomyositis: Signs and Symptoms

MedlinePlus

... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ... Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2018, Muscular Dystrophy Association Inc. All ...

The potential of sarcospan in adhesion complex replacement therapeutics for the treatment of muscular dystrophy.

PubMed

Marshall, Jamie L; Kwok, Yukwah; McMorran, Brian J; Baum, Linda G; Crosbie-Watson, Rachelle H

2013-09-01

Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and α7β1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein-replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important potential therapeutic target. Here, we review current protein-replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. © 2013 FEBS.

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.

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.

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.

Dog as a model in studies on human hereditary diseases and their gene therapy.

PubMed

Switonski, Marek

2014-03-01

During the last 15 years spectacular progress has been achieved in knowledge on the dog genome organization and the molecular background of hereditary diseases in this species. A majority of canine genetic diseases have their counterparts in humans and thus dogs are considered as a very important large animal model in human biomedicine. Among canine monogenic diseases with known causative gene mutations there are two large groups classified as retinal dystrophies and lysosomal storage diseases. Specific types of these diseases are usually diagnosed in a single or several breeds. A well known disorder, restricted to a single breed, is congenital stationary night blindness described in Briards. This disease is a counterpart of Leber amaurosis in children. On the other hand, one of the most common monogenic human diseases (Duchenne muscular dystrophy), has its canine counterparts in several breeds (e.g., the Golden retriever, Beagle and German short-haired pointer). For some of the canine diseases gene therapy strategy was successfully applied, e.g., for congenital stationary night blindness, rod-cone dystrophy and muccopolysaccharydoses type I, IIIB and VII. Since phenotypic variability between the breeds is exceptionally high, the dog is an interesting model to study the molecular background of congenital malformations (e.g., dwarfism and osteoporosis imperfecta). Also disorders of sexual development (DSD), especially testicular or ovotesticular DSD (78,XX; SRY-negative), which is widely distributed across dozens of breeds, are of particular interest. Studies on the genetic background of canine cancers, a major health problem in this species, are also quite advanced. On the other hand, genetic studies on canine counterparts of major human complex diseases (e.g., obesity, the metabolic syndrome and diabetes mellitus) are still in their infancy. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

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.

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.

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

Becker muscular dystrophy severity is linked to the structure of dystrophin.

PubMed

Nicolas, Aurélie; Raguénès-Nicol, Céline; Ben Yaou, Rabah; Ameziane-Le Hir, Sarah; Chéron, Angélique; Vié, Véronique; Claustres, Mireille; Leturcq, France; Delalande, Olivier; Hubert, Jean-François; Tuffery-Giraud, Sylvie; Giudice, Emmanuel; Le Rumeur, Elisabeth

2015-03-01

In-frame exon deletions of the Duchenne muscular dystrophy (DMD) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e. Δ45-47, Δ45-48, Δ45-49 and Δ45-51. Molecular homology modelling revealed that the proteins corresponding to deletions Δ45-48 and Δ45-51 displayed a similar structure (hybrid repeat) than the wild-type dystrophin, whereas deletions Δ45-47 and Δ45-49 lead to proteins with an unrelated structure (fractional repeat). All four proteins in vitro expressed in a fragment encoding repeats 16-21 were folded in α-helices and remained highly stable. Refolding dynamics were slowed and molecular surface hydrophobicity were higher in fractional repeat containing Δ45-47 and Δ45-49 deletions compared with hybrid repeat containing Δ45-48 and Δ45-51 deletions. By retrospectively collecting data for a series of French BMD patients, we showed that the age of dilated cardiomyopathy (DCM) onset was delayed by 11 and 14 years in Δ45-48 and Δ45-49 compared with Δ45-47 patients, respectively. A clear trend toward earlier wheelchair dependency (minimum of 11 years) was also observed in Δ45-47 and Δ45-49 patients compared with Δ45-48 patients. Muscle dystrophin levels were moderately reduced in most patients without clear correlation with the deletion type. Disease progression in BMD patients appears to be dependent on the deletion itself and associated with a specific structure of dystrophin at the deletion site. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Sensorimotor control of breathing in the mdx mouse model of Duchenne muscular dystrophy.

PubMed

Burns, David P; Roy, Arijit; Lucking, Eric F; McDonald, Fiona B; Gray, Sam; Wilson, Richard J; Edge, Deirdre; O'Halloran, Ken D

2017-11-01

Respiratory failure is a leading cause of mortality in Duchenne muscular dystrophy (DMD), but little is known about the control of breathing in DMD and animal models. We show that young (8 weeks of age) mdx mice hypoventilate during basal breathing due to reduced tidal volume. Basal CO 2 production is equivalent in wild-type and mdx mice. We show that carotid bodies from mdx mice have blunted responses to hyperoxia, revealing hypoactivity in normoxia. However, carotid body, ventilatory and metabolic responses to hypoxia are equivalent in wild-type and mdx mice. Our study revealed profound muscle weakness and muscle fibre remodelling in young mdx diaphragm, suggesting severe mechanical disadvantage in mdx mice at an early age. Our novel finding of potentiated neural motor drive to breathe in mdx mice during maximal chemoactivation suggests compensatory neuroplasticity enhancing respiratory motor output to the diaphragm and probably other accessory muscles. Patients with Duchenne muscular dystrophy (DMD) hypoventilate with consequential arterial blood gas derangement relevant to disease progression. Whereas deficits in DMD diaphragm are recognized, there is a paucity of knowledge in respect of the neural control of breathing in dystrophinopathies. We sought to perform an analysis of respiratory control in a model of DMD, the mdx mouse. In 8-week-old male wild-type and mdx mice, ventilation and metabolism, carotid body afferent activity, diaphragm muscle force-generating capacity, and muscle fibre size, distribution and centronucleation were determined. Diaphragm EMG activity and responsiveness to chemostimulation was determined. During normoxia, mdx mice hypoventilated, owing to a reduction in tidal volume. Basal CO 2 production was not different between wild-type and mdx mice. Carotid sinus nerve responses to hyperoxia were blunted in mdx, suggesting hypoactivity. However, carotid body, ventilatory and metabolic responses to hypoxia were equivalent in wild-type and mdx mice. Diaphragm force was severely depressed in mdx mice, with evidence of fibre remodelling and damage. Diaphragm EMG responses to chemoactivation were enhanced in mdx mice. We conclude that there is evidence of chronic hypoventilation in young mdx mice. Diaphragm dysfunction confers mechanical deficiency in mdx resulting in impaired capacity to generate normal tidal volume at rest and decreased absolute ventilation during chemoactivation. Enhanced mdx diaphragm EMG responsiveness suggests compensatory neuroplasticity facilitating respiratory motor output, which may extend to accessory muscles of breathing. Our results may have relevance to emerging treatments for human DMD aiming to preserve ventilatory capacity. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Occurrence of Emery-Dreifuss muscular dystrophy in a rural setting of Cameroon: a case report and review of the literature.

PubMed

Ekabe, Cyril Jabea; Kehbila, Jules; Sama, Carlson-Babila; Kadia, Benjamin Momo; Abanda, Martin Hongieh; Monekosso, Gottlieb Lobe

2017-01-09

Emery-Dreifuss muscular dystrophy is a rare genetic muscular disease, presenting mainly with contractures, weakness and cardiac conduction abnormalities. Its clinical and laboratory similarities to other muscular dystrophies, and rarity poses diagnostic challenges, requiring a high index of suspicion in resource limited settings. An 8 year old sub-Saharan male presented with rigidity and deformity of both elbows and ankles, and weakness of the upper limbs and lower limbs for duration of 4 months. This progressed to inability to stand and walk. There was no mental impairment. Physical examination was remarkable for contractures of the elbows and ankles, and wasting of muscles of the limbs and trunk, with a scapulohumeroperoneal pattern, and tachycardia. After laboratory investigations, a diagnosis of Emery-Dreifuss muscular dystrophy was suspected. Physiotherapy was started, wheel chair was prescribed, and referral to a specialist center was done for appropriate management. Emery-Dreifuss muscular dystrophy is a rare disabling muscular disease which poses a diagnostic challenge. High index of suspicion is paramount for its early diagnoses to prevent orthopedic and cardiac complications. Prompt diagnosis and management is essential to improve on the prognosis of this disease.

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.

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.

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.

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.

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.

A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature.

PubMed

Brusa, Roberta; Magri, Francesca; Papadimitriou, Dimitra; Govoni, Alessandra; Del Bo, Roberto; Ciscato, Patrizia; Savarese, Marco; Cinnante, Claudia; Walter, Maggie C; Abicht, Angela; Bulst, Stefanie; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Nigro, Vincenzo; Comi, Giacomo Pietro

2018-04-13

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. Copyright © 2018 Elsevier B.V. All rights reserved.

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

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.

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.

Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Muscle Cells

PubMed Central

Fontes-Oliveira, Cibely C.; Steinz, Maarten; Schneiderat, Peter; Mulder, Hindrik; Durbeej, Madeleine

2017-01-01

Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. PMID:28367954

Targeted Deletion of the Muscular Dystrophy Gene myotilin Does Not Perturb Muscle Structure or Function in Mice▿

PubMed Central

Moza, Monica; Mologni, Luca; Trokovic, Ras; Faulkner, Georgine; Partanen, Juha; Carpén, Olli

2007-01-01

Myotilin, palladin, and myopalladin form a novel small subfamily of cytoskeletal proteins that contain immunoglobulin-like domains. Myotilin is a thin filament-associated protein localized at the Z-disk of skeletal and cardiac muscle cells. The direct binding to F-actin, efficient cross-linking of actin filaments, and prevention of induced disassembly of filaments are key roles of myotilin that are thought to be involved in structural maintenance and function of the sarcomere. Missense mutations in the myotilin-encoding gene cause dominant limb girdle muscular dystrophy type 1A and spheroid body myopathy and are the molecular defect that can cause myofibrillar myopathy. Here we describe the generation and analysis of mice that lack myotilin, myo−/− mice. Surprisingly, myo−/− mice maintain normal muscle sarcomeric and sarcolemmal integrity. Also, loss of myotilin does not cause alterations in the heart or other organs of newborn or adult myo−/− mice. The mice develop normally and have a normal life span, and their muscle capacity does not significantly differ from wild-type mice even after prolonged physical stress. The results suggest that either myotilin does not participate in muscle development and basal function maintenance or other proteins serve as structural and functional compensatory molecules when myotilin is absent. PMID:17074808

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.

[Emerging novel therapeutic strategy for α-dystroglycanopathy by Large].

PubMed

Saito, Fumiaki

2011-11-01

The past decade of researches have revealed mutations of known or putative glycosyltransferases in several types of muscular dystrophy, including Fukuyama-type congenital muscular dystrophy. In these disorders, the function of α-dystroglycan is severely decreased, therefore they are called α-dystroglycanopathy. Recently, putative glycosyltransferase Large was shown to restore the defective function of α-dystroglycan, thus, it is an intriguing idea to apply this effect to the therapy of α-dystroglycanopathy. In the present study, we sought to test this possibility. Using several cultured cell lines, we confirmed that the overexpression of Large results in hyperglycosylation and marked enhancement of the function of α-dystroglycan. For this effect, the whole luminal domain of Large was shown to be necessary using several deletion constructs. We further generated transgenic mice overexpressing Large ubiquitously. In each tissue of the mice, the glycosylation of α-dystroglycan and its laminin binding activity was remarkably increased. Moreover, the morphological analyses on each tissue stained by H-E revealed no significant abnormality in the transgenic mice, suggesting no serious side effects by the overexpression of Large. Taken together, these results indicate that the restoration of the function of α-dystroglycan by Large should be an important molecular target to develop therapeutic strategies for α-dystroglycanopathy.

[The specific features of Doppler ultrasound study of ophthalmic vessels in young persons with peripheral vitreochorioretinal dystrophies].

PubMed

Pozdeeva, O G

2005-01-01

Hemodynamic parameters were studied in the ophthalmic artery, short posterior ciliary arteries (SPCA), long posterior ciliary arteries (LPCA), and central artery of the retina (CAR). Doppler ultrasound study (DUSS) was performed on an Acuson Aspen multipurpose diagnostic system using a linear transducer at a frequency of 7.5 MHz in the pulse mode. Chelyabinsk students aged 17-25 years were examined. A number of specific features of retinal blood supply were detected in young persons with dystrophic diseases of the periphery of the fundus oculi. These included decreased blood flow velocities and less systolic flow acceleration time in SPCA, LPCA, and CAR in peripheral vitreochorioretinal dystrophies (PVCRD). The higher pulsatile index (PI) in the LPCA system characterized a possible mechanism responsible for compensation of impaired blood supply in the retinal periphery in the development of PVCRD. The high values of the pulsatile index and the vascular wall resistivity index in CAR reflected the changes determining the absence of complications as retinal ruptures and detachment. There were neither changes in ophthalmic arterial blood flow depending on the type of PVCRD and the nature of its course nor significant differences in blood supply to the eye in different types of refraction.

Motor Physical Therapy Affects Muscle Collagen Type I and Decreases Gait Speed in Dystrophin-Deficient Dogs

PubMed Central

Gaiad, Thaís P.; Araujo, Karla P. C.; Serrão, Júlio C.; Miglino, Maria A.; Ambrósio, Carlos Eduardo

2014-01-01

Golden Retriever Muscular Dystrophy (GRMD) is a dystrophin-deficient canine model genetically homologous to Duchenne Muscular Dystrophy (DMD) in humans. Muscular fibrosis secondary to cycles of degeneration/regeneration of dystrophic muscle tissue and muscular weakness leads to biomechanical adaptation that impairs the quality of gait. Physical therapy (PT) is one of the supportive therapies available for DMD, however, motor PT approaches have controversial recommendations and there is no consensus regarding the type and intensity of physical therapy. In this study we investigated the effect of physical therapy on gait biomechanics and muscular collagen deposition types I and III in dystrophin-deficient dogs. Two dystrophic dogs (treated dogs-TD) underwent a PT protocol of active walking exercise, 3×/week, 40 minutes/day, 12 weeks. Two dystrophic control dogs (CD) maintained their routine of activities of daily living. At t0 (pre) and t1 (post-physical therapy), collagen type I and III were assessed by immunohistochemistry and gait biomechanics were analyzed. Angular displacement of shoulder, elbow, carpal, hip, stifle and tarsal joint and vertical (Fy), mediolateral (Fz) and craniocaudal (Fx) ground reaction forces (GRF) were assessed. Wilcoxon test was used to verify the difference of biomechanical variables between t0 and t1, considering p<.05. Type I collagen of endomysium suffered the influence of PT, as well as gait speed that had decreased from t0 to t1 (p<.000). The PT protocol employed accelerates morphological alterations on dystrophic muscle and promotes a slower velocity of gait. Control dogs which maintained their routine of activities of daily living seem to have found a better balance between movement and preservation of motor function. PMID:24713872

Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy

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

Othmane, K.B.; Speer, M.C.; Stauffer, J.

1995-09-01

Duchenne-like muscular dystrophy (DLMD) is an autosomal recessive Limb Girdle muscular dystrophy (LGMD2C) characterized by late age of onset, proximal muscle weakness leading to disability, high creatine kinase values, normal intelligence and normal dystrophin in muscle biopsy. We have shown previously that three DLMD families from Tunisia are linked to chromosome 13q12. To further localize the LGMD2C gene, we have investigated seven additional families (119 individuals). Both genotyping and two-point linkage analysis were performed as described elsewhere. 7 refs., 1 fig., 1 tab.

Gelatinous drop-like corneal dystrophy: a review.

PubMed

Kaza, Hrishikesh; Barik, Manas R; Reddy, Mamatha M; Mittal, Ruchi; Das, Sujata

2017-01-01

Gelatinous drop-like corneal dystrophy (GDLD) is a rare autosomal recessive form of corneal dystrophy characterised by subepithelial and stromal amyloid deposits. It is relatively common in Japan. It usually presents in the first two decades of life with subepithelial nodular lesions that later coalesce to form mulberry-like opacities. Although various surgical modalities have been attempted, recurrence remains a major challenge. 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/.

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.

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.

Genetics Home Reference: Meesmann corneal dystrophy

MedlinePlus

... Smith FJ, Rochels R, Uitto J, McLEAN WH. Molecular genetics of Meesmann's corneal dystrophy: ancestral and novel mutations ... Free article on PubMed Central Smith F. The molecular genetics of keratin disorders. Am J Clin Dermatol. 2003; ...

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.

Sparks, signals and shock absorbers: how dystrophin loss causes muscular dystrophy.

PubMed

Batchelor, Clare L; Winder, Steve J

2006-04-01

The dystrophin-glycoprotein complex (DGC) can be considered as a specialized adhesion complex, linking the extracellular matrix to the actin cytoskeleton, primarily in muscle cells. Mutations in several components of the DGC lead to its partial or total loss, resulting in various forms of muscular dystrophy. These typically manifest as progressive wasting diseases with loss of muscle integrity. Debate is ongoing about the precise function of the DGC: initially a strictly mechanical role was proposed but it has been suggested that there is aberrant calcium handling in muscular dystrophy and, more recently, changes in MAP kinase and GTPase signalling have been implicated in the aetiology of the disease. Here, we discuss new and interesting developments in these aspects of DGC function and attempt to rationalize the mechanical, calcium and signalling hypotheses to provide a unifying hypothesis of the underlying process of muscular dystrophy.

Is There a Delay in Diagnosis of Duchenne Muscular Dystrophy Among Preterm-Born Males?

PubMed

Soim, Aida; Smith, Michael G; Kwon, Jennifer M; Mann, Joshua R; Thomas, Shiny; Ciafaloni, Emma

2018-07-01

The objective of this study was to investigate whether males who were born preterm took longer to receive a Duchenne muscular dystrophy diagnosis than term males. Data for males with Duchenne muscular dystrophy identified through a population-based surveillance system were analyzed using a Kaplan-Meier estimator. The first signs and symptoms were noted at a median age of 2 years in both groups. Median age when first signs and symptoms prompted medical evaluation was 2.59 years among preterm and 4.01 years among term males. Median age at definitive diagnosis was 4.25 years and 4.92 years for preterm and term males, respectively. Neither difference was statistically significant. Preterm males tended to be seen for their initial medical evaluation earlier than term males, though they were not diagnosed significantly earlier. It may take clinicians longer after the initial evaluation of preterm males to arrive at a Duchenne muscular dystrophy diagnosis.

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.

Detection of ultrastructural changes in genetically altered and exercised skeletal muscle using PS-OCT

NASA Astrophysics Data System (ADS)

Pasquesi, James J.; Schlachter, Simon C.; Boppart, Marni D.; Chaney, Eric; Kaufman, Stephen J.; Boppart, Stephen A.

2006-02-01

Birefringence of skeletal muscle has been associated with the ultrastructure of individual sarcomeres, specifically the arrangement of A-bands corresponding to the thick myosin filaments. Murine skeletal muscle (gastrocnemius) was imaged with a fiber-based PS-OCT imaging system to determine the level of birefringence present in the tissue under various conditions. In addition to muscle controls from wild-type mice, muscle from abnormal mice included: genetically-modified (mdx) mice which model human muscular dystrophy, transgenic mice exhibiting an overexpression of integrin (α7β1), and transgenic integrin (α7β1)knockout mice. Comparisons were also made between rested and exercised muscles to determine the effects of exercise on muscle birefringence for each of these normal and abnormal conditions. The PS-OCT images revealed that the presence of birefringence was similar in the rested muscle with dystrophy-like features (i.e., lacking the structural protein dystrophin - mdx) and in the integrin (α7β1)knockout muscle when compared to the normal (wild-type) control. However, exercising these abnormal muscle tissues drastically reduced the presence of birefringence detected by the PS-OCT system. The muscle exhibiting an overexpression of integrin (α7β1) remained heavily birefringent before and after exercise, similar to the normal (wild-type) muscle. These results suggest that there is a distinct relationship between the degree of birefringence detected using PS-OCT and the sarcomeric ultrastructure present within skeletal muscle.

[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.

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.

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.

Macular pattern dystrophy and homonymous hemianopia in MELAS syndrome.

PubMed

Kamal-Salah, Radua; Baquero-Aranda, Isabel; Grana-Pérez, María Del Mar; García-Campos, Jose Manuel

2015-03-12

We report an unusual association of a pattern dystrophy of the retinal pigment epithelium and homonymous hemianopia in a woman diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes syndrome. 2015 BMJ Publishing Group Ltd.

Prevalence and histopathological characteristics of corneal stromal dystrophies in Saudi Arabia.

PubMed

Alzuhairy, Sultan; Alkatan, Hind M; Al-Rajhi, Ali A

2015-01-01

The aim was to determine the frequency and describe the main histopathologic features of corneal stromal dystrophy in Saudi Arabia. A single-center, retrospective analysis of 193 corneal specimens diagnosed with stromal dystrophy. All samples were retrieved from the Histopathology Department at King Khaled Eye Specialist Hospital over a 10-year period (2002 to December 31, 2011). Cases of stromal dystrophy undergoing keratoplasty were included in the study. Routine histopathologic stains and specific stains were used to determine a diagnosis. The corresponding demographic data and basic clinical/surgical information were collected via chart review. The study sample was comprised of 193 eyes. The final diagnoses were macular corneal dystrophy (MCD) in 180 (93.26%) eyes, granular corneal dystrophy (GCD) in 9 (4.66%) and lattice corneal dystrophy (LCD) in 4 (2.07%) eyes. The mean age at presentation was 27.03 years for MCD, 26.33 years for GCD and 53.75 years for LCD. The interval between diagnosis and surgical intervention was not statistically different between the macular and granular groups (P = 0.141). There was a positive family history for the MCD (37.22%) and GCD (44.44%) groups. All eyes underwent penetrating keratoplasty (PKP) except 10 MCD cases that underwent lamellar keratoplasty. Diffuse stromal deposits were present in 87.2% of MCD corneas and 66.67% of GCD corneas. Seventeen eyes with MCD were misdiagnosed as GCD. None of the LCD cases were clinically identified since all of these cases were diagnosed as corneal scarring. In eyes with MCD that underwent PKP, there was diffuse stromal involvement (in 87.22% eyes) and changes in Descemet's membrane (in 53.5% eyes). This pathological study suggested that MCD was the most common corneal stromal dystrophy that required keratoplasty in Saudi Arabia. Patient with MCD and GCD presented at a significantly younger age than LCD. The clinical diagnosis of MCD is not achieved in all cases likely due to a more severe phenotype in the Saudi population or the presence of corneal scarring that is associated with previous trachoma, which obscures the classical appearance of LCD. We believe that PKP is first-line surgical treatment, especially for MCD because it involves all corneal layers. However, deep stromal involvement and changes in Descemet's membrane in MCD should be considered when selecting the surgical procedure.

Prevalence and Histopathological Characteristics of Corneal Stromal Dystrophies in Saudi Arabia

PubMed Central

Alzuhairy, Sultan; Alkatan, Hind M.; Al-Rajhi, Ali A.

2015-01-01

Purpose: The aim was to determine the frequency and describe the main histopathologic features of corneal stromal dystrophy in Saudi Arabia. Methods: A single-center, retrospective analysis of 193 corneal specimens diagnosed with stromal dystrophy. All samples were retrieved from the Histopathology Department at King Khaled Eye Specialist Hospital over a 10-year period (2002 to December 31, 2011). Cases of stromal dystrophy undergoing keratoplasty were included in the study. Routine histopathologic stains and specific stains were used to determine a diagnosis. The corresponding demographic data and basic clinical/surgical information were collected via chart review. Results: The study sample was comprised of 193 eyes. The final diagnoses were macular corneal dystrophy (MCD) in 180 (93.26%) eyes, granular corneal dystrophy (GCD) in 9 (4.66%) and lattice corneal dystrophy (LCD) in 4 (2.07%) eyes. The mean age at presentation was 27.03 years for MCD, 26.33 years for GCD and 53.75 years for LCD. The interval between diagnosis and surgical intervention was not statistically different between the macular and granular groups (P = 0.141). There was a positive family history for the MCD (37.22%) and GCD (44.44%) groups. All eyes underwent penetrating keratoplasty (PKP) except 10 MCD cases that underwent lamellar keratoplasty. Diffuse stromal deposits were present in 87.2% of MCD corneas and 66.67% of GCD corneas. Seventeen eyes with MCD were misdiagnosed as GCD. None of the LCD cases were clinically identified since all of these cases were diagnosed as corneal scarring. In eyes with MCD that underwent PKP, there was diffuse stromal involvement (in 87.22% eyes) and changes in Descemet's membrane (in 53.5% eyes). Conclusion: This pathological study suggested that MCD was the most common corneal stromal dystrophy that required keratoplasty in Saudi Arabia. Patient with MCD and GCD presented at a significantly younger age than LCD. The clinical diagnosis of MCD is not achieved in all cases likely due to a more severe phenotype in the Saudi population or the presence of corneal scarring that is associated with previous trachoma, which obscures the classical appearance of LCD. We believe that PKP is first-line surgical treatment, especially for MCD because it involves all corneal layers. However, deep stromal involvement and changes in Descemet's membrane in MCD should be considered when selecting the surgical procedure. PMID:25949075

Restoration of pharyngeal dilator muscle force in dystrophin-deficient (mdx) mice following co-treatment with neutralizing interleukin-6 receptor antibodies and urocortin 2.

PubMed

Burns, David P; Rowland, Jane; Canavan, Leonie; Murphy, Kevin H; Brannock, Molly; O'Malley, Dervla; O'Halloran, Ken D; Edge, Deirdre

2017-09-01

What is the central question of this study? We previously reported impaired upper airway dilator muscle function in the mdx mouse model of Duchenne muscular dystrophy (DMD). Our aim was to assess the effect of blocking interleukin-6 receptor signalling and stimulating corticotrophin-releasing factor receptor 2 signalling on mdx sternohyoid muscle structure and function. What is the main finding and its importance? The interventional treatment had a positive inotropic effect on sternohyoid muscle force, restoring mechanical work and power to wild-type values, reduced myofibre central nucleation and preserved the myosin heavy chain type IIb fibre complement of mdx sternohyoid muscle. These data might have implications for development of pharmacotherapies for DMD with relevance to respiratory muscle performance. The mdx mouse model of Duchenne muscular dystrophy shows evidence of impaired pharyngeal dilator muscle function. We hypothesized that inflammatory and stress-related factors are implicated in airway dilator muscle dysfunction. Six-week-old mdx (n = 26) and wild-type (WT; n = 26) mice received either saline (0.9% w/v) or a co-administration of neutralizing interleukin-6 receptor antibodies (0.2 mg kg -1 ) and corticotrophin-releasing factor receptor 2 agonist (urocortin 2; 30 μg kg -1 ) over 2 weeks. Sternohyoid muscle isometric and isotonic contractile function was examined ex vivo. Muscle fibre centronucleation and muscle cellular infiltration, collagen content, fibre-type distribution and fibre cross-sectional area were determined by histology and immunofluorescence. Muscle chemokine content was examined by use of a multiplex assay. Sternohyoid peak specific force at 100 Hz was significantly reduced in mdx compared with WT. Drug treatment completely restored force in mdx sternohyoid to WT levels. The percentage of centrally nucleated muscle fibres was significantly increased in mdx, and this was partly ameliorated after drug treatment. The areal density of infiltrates and collagen content were significantly increased in mdx sternohyoid; both indices were unaffected by drug treatment. The abundance of myosin heavy chain type IIb fibres was significantly decreased in mdx sternohyoid; drug treatment preserved myosin heavy chain type IIb complement in mdx muscle. The chemokines macrophage inflammatory protein 2, interferon-γ-induced protein 10 and macrophage inflammatory protein 3α were significantly increased in mdx sternohyoid compared with WT. Drug treatment significantly increased chemokine expression in mdx but not WT sternohyoid. Recovery of contractile function was impressive in our study, with implications for Duchenne muscular dystrophy. The precise molecular mechanisms by which the drug treatment exerts an inotropic effect on mdx sternohyoid muscle remain to be elucidated. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Genetics Home Reference: Bietti crystalline dystrophy

MedlinePlus

... broken down and converted into energy, but the enzyme's specific function is not well understood. CYP4V2 gene mutations that cause Bietti crystalline dystrophy impair or eliminate the function of this enzyme and are believed to affect lipid breakdown. However, ...

Compulsory DNA Sampling of Service Members for Inclusion in the DOD DNA Registry: Remains Identification With a Risk

DTIC Science & Technology

1996-04-01

for Tay-Sachs disease, cystic fibrosis, Huntingtons disease, Duchenne muscular dystrophy , 26alcoholism, and susceptibility to certain types of cancer...and an increased risk of infection and injury to muscle , nerves, and blood vessels was sufficiently compelling to outweigh the state’s interest in...them into electrical impulses. These surgically implanted devices could produce electronic impulses to induce paralyzed muscles to contract and

[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.

Implicit learning deficit in children with Duchenne muscular dystrophy: Evidence for a cerebellar cognitive impairment?

PubMed

Vicari, Stefano; Piccini, Giorgia; Mercuri, Eugenio; Battini, Roberta; Chieffo, Daniela; Bulgheroni, Sara; Pecini, Chiara; Lucibello, Simona; Lenzi, Sara; Moriconi, Federica; Pane, Marika; D'Amico, Adele; Astrea, Guja; Baranello, Giovanni; Riva, Daria; Cioni, Giovanni; Alfieri, Paolo

2018-01-01

This study aimed at comparing implicit sequence learning in individuals affected by Duchenne Muscular Dystrophy without intellectual disability and age-matched typically developing children. A modified version of the Serial Reaction Time task was administered to 32 Duchenne children and 37 controls of comparable chronological age. The Duchenne group showed a reduced rate of implicit learning even if in the absence of global intellectual disability. This finding provides further evidence of the involvement of specific aspects of cognitive function in Duchenne muscular dystrophy and on its possible neurobiological substrate.

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

Dasatinib as a treatment for Duchenne muscular dystrophy.

PubMed

Lipscomb, Leanne; Piggott, Robert W; Emmerson, Tracy; Winder, Steve J

2016-01-15

Identification of a systemically acting and universal small molecule therapy for Duchenne muscular dystrophy would be an enormous advance for this condition. Based on evidence gained from studies on mouse genetic models, we have identified tyrosine phosphorylation and degradation of β-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of β-dystroglycan presents itself as a potential therapeutic strategy. Using the dystrophic sapje zebrafish, we have investigated the use of tyrosine kinase and other inhibitors to treat the dystrophic symptoms in this model of Duchenne muscular dystrophy. Dasatinib, a potent and specific Src tyrosine kinase inhibitor, was found to decrease the levels of β-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated β-dystroglycan in sapje zebrafish. Furthermore, dasatinib treatment resulted in the improved physical appearance of the sapje zebrafish musculature and increased swimming ability as measured by both duration and distance of swimming of dasatinib-treated fish compared with control animals. These data suggest great promise for pharmacological agents that prevent the phosphorylation of β-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy. © The Author 2015. Published by Oxford University Press.

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury

PubMed Central

Quattrocelli, Mattia; Capote, Joanna; Ohiri, Joyce C.; Warner, James L.; Vo, Andy H.; Hadhazy, Michele; Demonbreun, Alexis R.; Spencer, Melissa J.; McNally, Elizabeth M.

2017-01-01

Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor β (TGFβ) pathway, osteopontin encoded by the SPP1 gene and latent TGFβ binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFβ and TGFβ-associated pathways. We identified that increased TGFβ resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFβ and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy. PMID:29065150

Genetic modifiers of muscular dystrophy act on sarcolemmal resealing and recovery from injury.

PubMed

Quattrocelli, Mattia; Capote, Joanna; Ohiri, Joyce C; Warner, James L; Vo, Andy H; Earley, Judy U; Hadhazy, Michele; Demonbreun, Alexis R; Spencer, Melissa J; McNally, Elizabeth M

2017-10-01

Genetic disruption of the dystrophin complex produces muscular dystrophy characterized by a fragile muscle plasma membrane leading to excessive muscle degeneration. Two genetic modifiers of Duchenne Muscular Dystrophy implicate the transforming growth factor β (TGFβ) pathway, osteopontin encoded by the SPP1 gene and latent TGFβ binding protein 4 (LTBP4). We now evaluated the functional effect of these modifiers in the context of muscle injury and repair to elucidate their mechanisms of action. We found that excess osteopontin exacerbated sarcolemmal injury, and correspondingly, that loss of osteopontin reduced injury extent both in isolated myofibers and in muscle in vivo. We found that ablation of osteopontin was associated with reduced expression of TGFβ and TGFβ-associated pathways. We identified that increased TGFβ resulted in reduced expression of Anxa1 and Anxa6, genes encoding key components of the muscle sarcolemma resealing process. Genetic manipulation of Ltbp4 in dystrophic muscle also directly modulated sarcolemmal resealing, and Ltbp4 alleles acted in concert with Anxa6, a distinct modifier of muscular dystrophy. These data provide a model in which a feed forward loop of TGFβ and osteopontin directly impacts the capacity of muscle to recover from injury, and identifies an intersection of genetic modifiers on muscular dystrophy.

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

Unilateral retinitis pigmentosa and cone-rod dystrophy

PubMed Central

Farrell, Donald F

2009-01-01

Purpose: The purpose of this paper is to report 14 new cases of unilateral retinitis pigmentosa and three new cases of cone-rod dystrophy and to compare the similarities and dissimilarities to those found in the bilateral forms of these disorders. Methods: A total of 272 cases of retinitis pigmentosa and 167 cases of cone-rod dystrophy were studied by corneal full field electroretinograms and electrooculograms. The student t-test was used to compare categories. Results: The percentage of familial and nonfamilial cases was the same for the bilateral and unilateral forms of the disease. In our series, unilateral retinitis pigmentosa makes up approximately 5% of the total population of retinitis pigmentosa, while unilateral cone-rod dystrophy makes up only about 2% of the total. In the familial forms of unilateral retinitis pigmentosa the most common inheritance pattern was autosomal dominant and all affected relatives had bilateral disease. Conclusion: Unilateral retinitis pigmentosa and cone-rod dystrophy appear to be directly related to the more common bilateral forms of these disorders. The genetic mechanisms which account for asymmetric disorders are not currently understood. It may be a different unidentified mutation at a single loci or it is possible that nonlinked mutations in multiple loci account for this unusual disorder. PMID:19668577

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.

Up-regulation of Paxillin and Focal Adhesion Signaling follows Dystroglycan Complex deletions and promotes a Hypertensive State of Differentiation

PubMed Central

Sen, Shamik; Tewari, Manorama; Zajac, Allison; Barton, Elisabeth; Sweeney, H. Lee; Discher, Dennis E.

2010-01-01

Anchorage to matrix is mediated for many cells not only by integrin-based focal adhesions but also by a parallel assembly of integral and peripheral membrane proteins known as the Dystroglycan Complex. Deficiencies in either dystrophin (mdx mice) or γ-sarcoglycan (γSG−/− mice) components of the Dystroglycan Complex lead to upregulation of numerous focal adhesion proteins, and the phosphoprotein paxillin proves to be among the most prominent. In mdx muscle, paxillin-Y31 and Y118 are both hyper-phosphorylated as are key sites in focal adhesion kinase (FAK) and the stretch-stimulatable pro-survival MAPK pathway, whereas γSG−/− muscle exhibits more erratic hyper-phosphorylation. In cultured myotubes, cell tension generated by myosin-II appears required for localization of paxillin to adhesions while vinculin appears more stably integrated. Over-expression of wild-type (WT) paxillin has no obvious effect on focal adhesion density or the physical strength of adhesion, but WT and a Y118F mutant promote contractile sarcomere formation whereas a Y31F mutant shows no effect, implicating Y31 in striation. Self-peeling of cells as well as Atomic Force Microscopy (AFM) probing of cells with or without myosin II inhibition indicate an increase in cell tension within paxillin-overexpressing cells. However, prednisolone, a first-line glucocorticoid for muscular dystrophies, decreases cell tension without affecting paxillin at adhesions, suggesting a non-linear relationship between paxillin and cell tension. Hypertension that results from upregulation of integrin adhesions is thus a natural and treatable outcome of dystroglycan complex down-regulation. PMID:20663583

Use of the six-minute walk test to characterize golden retriever muscular dystrophy.

PubMed

Acosta, Austin R; Van Wie, Emiko; Stoughton, William B; Bettis, Amanda K; Barnett, Heather H; LaBrie, Nicholas R; Balog-Alvarez, Cynthia J; Nghiem, Peter P; Cummings, Kevin J; Kornegay, Joe N

2016-12-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which loss of the dystrophin protein causes progressive skeletal/cardiac muscle degeneration and death within the third decade. For clinical trials and supportive animal studies, DMD disease progression and response to treatment must be established using outcome parameters (biomarkers). The 6-minute walk test (6MWT), defined as the distance an individual can walk in 6 minutes, is commonly used in DMD clinical trials and has been employed in dogs to characterize cardiac and respiratory disease severity. Building on methods established in DMD and canine clinical studies, we assessed the 6MWT in dogs with the DMD genetic homolog, golden retriever muscular dystrophy (GRMD). Twenty-one cross-bred golden retrievers were categorized as affected (DMD mutation and GRMD phenotype), carrier (female heterozygous for DMD mutation and no phenotype), and normal (wild type DMD gene and normal phenotype). When compared to grouped normal/carrier dogs, GRMD dogs walked shorter height-adjusted distances at 6 and 12 months of age and their distances walked declined with age. Percent change in creatine kinase after 6MWT was greater in GRMD versus normal/carrier dogs at 6 months, providing another potential biomarker. While these data generally support use of the 6MWT as a biomarker for preclinical GRMD treatment trials, there were certain limitations. Results of the 6MWT did not correlate with other outcome parameters for GRMD dogs when considered alone and an 80% increase in mean distance walked would be necessary to achieve satisfactory power. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparison of Short-Wavelength Reduced-Illuminance and Conventional Autofluorescence Imaging in Stargardt Macular Dystrophy.

PubMed

Strauss, Rupert W; Muñoz, Beatriz; Jha, Anamika; Ho, Alexander; Cideciyan, Artur V; Kasilian, Melissa L; Wolfson, Yulia; Sadda, SriniVas; West, Sheila; Scholl, Hendrik P N; Michaelides, Michel

2016-08-01

To compare grading results between short-wavelength reduced-illuminance and conventional autofluorescence imaging in Stargardt macular dystrophy. Reliability study. setting: Moorfields Eye Hospital, London (United Kingdom). Eighteen patients (18 eyes) with Stargardt macular dystrophy. A series of 3 fundus autofluorescence images using 3 different acquisition parameters on a custom-patched device were obtained: (1) 25% laser power and total sensitivity 87; (2) 25% laser power and freely adjusted sensitivity; and (3) 100% laser power and freely adjusted total sensitivity (conventional). The total area of 2 hypoautofluorescent lesion types (definitely decreased autofluorescence and poorly demarcated questionably decreased autofluorescence) was measured. Agreement in grading between the 3 imaging methods was assessed by kappa coefficients (κ) and intraclass correlation coefficients. The mean ± standard deviation area for images acquired with 25% laser power and freely adjusted total sensitivity was 2.04 ± 1.87 mm(2) for definitely decreased autofluorescence (n = 15) and 1.86 ± 2.14 mm(2) for poorly demarcated questionably decreased autofluorescence (n = 12). The intraclass correlation coefficient (95% confidence interval) was 0.964 (0.929, 0.999) for definitely decreased autofluorescence and 0.268 (0.000, 0.730) for poorly demarcated questionably decreased autofluorescence. Short-wavelength reduced-illuminance and conventional fundus autofluorescence imaging showed good concordance in assessing areas of definitely decreased autofluorescence. However, there was significantly higher variability between imaging modalities for assessing areas of poorly demarcated questionably decreased autofluorescence. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Dystrophin Expressing Chimeric (DEC) Human Cells Provide a Potential Therapy for Duchenne Muscular Dystrophy.

PubMed

Siemionow, Maria; Cwykiel, Joanna; Heydemann, Ahlke; Garcia, Jesus; Marchese, Enza; Siemionow, Krzysztof; Szilagyi, Erzsebet

2018-06-01

Duchenne Muscular Dystrophy (DMD) is a progressive and lethal disease caused by mutations of the dystrophin gene. Currently no cure exists. Stem cell therapies targeting DMD are challenged by limited engraftment and rejection despite the use of immunosuppression. There is an urgent need to introduce new stem cell-based therapies that exhibit low allogenic profiles and improved cell engraftment. In this proof-of-concept study, we develop and test a new human stem cell-based approach to increase engraftment, limit rejection, and restore dystrophin expression in the mdx/scid mouse model of DMD. We introduce two Dystrophin Expressing Chimeric (DEC) cell lines created by ex vivo fusion of human myoblasts (MB) derived from two normal donors (MB N1 /MB N2 ), and normal and DMD donors (MB N /MB DMD ). The efficacy of fusion was confirmed by flow cytometry and confocal microscopy based on donor cell fluorescent labeling (PKH26/PKH67). In vitro, DEC displayed phenotype and genotype of donor parent cells, expressed dystrophin, and maintained proliferation and myogenic differentiation. In vivo, local delivery of both DEC lines (0.5 × 10 6 ) restored dystrophin expression (17.27%±8.05-MB N1 /MB N2 and 23.79%±3.82-MB N /MB DMD ) which correlated with significant improvement of muscle force, contraction and tolerance to fatigue at 90 days after DEC transplant to the gastrocnemius muscles (GM) of dystrophin-deficient mdx/scid mice. This study establishes DEC as a potential therapy for DMD and other types of muscular dystrophies.

Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

PubMed

Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

2016-01-01

Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis.

PubMed

Cabrera, Daniel; Gutiérrez, Jaime; Cabello-Verrugio, Claudio; Morales, Maria Gabriela; Mezzano, Sergio; Fadic, Ricardo; Casar, Juan Carlos; Hancke, Juan L; Brandan, Enrique

2014-01-01

Duchenne muscular dystrophy (DMD) is characterized by the absence of the cytoskeletal protein dystrophin, muscle wasting, increased transforming growth factor type beta (TGF-β) signaling, and fibrosis. At the present time, the only clinically validated treatments for DMD are glucocorticoids. These drugs prolong muscle strength and ambulation of patients for a short term only and have severe adverse effects. Andrographolide, a bicyclic diterpenoid lactone, has traditionally been used for the treatment of colds, fever, laryngitis, and other infections with no or minimal side effects. We determined whether andrographolide treatment of mdx mice, an animal model for DMD, affects muscle damage, physiology, fibrosis, and efficiency of cell therapy. mdx mice were treated with andrographolide for three months and skeletal muscle histology, creatine kinase activity, and permeability of muscle fibers were evaluated. Fibrosis and TGF-β signaling were evaluated by indirect immunofluorescence and Western blot analyses. Muscle strength was determined in isolated skeletal muscles and by a running test. Efficiency of cell therapy was determined by grafting isolated skeletal muscle satellite cells onto the tibialis anterior of mdx mice. mdx mice treated with andrographolide exhibited less severe muscular dystrophy than untreated dystrophic mice. They performed better in an exercise endurance test and had improved muscle strength in isolated muscles, reduced skeletal muscle impairment, diminished fibrosis and a significant reduction in TGF-β signaling. Moreover, andrographolide treatment of mdx mice improved grafting efficiency upon intramuscular injection of dystrophin-positive satellite cells. These results suggest that andrographolide could be used to improve quality of life in individuals with DMD.

A Novel Lamin A Mutant Responsible for Congenital Muscular Dystrophy Causes Distinct Abnormalities of the Cell Nucleus.

PubMed

Barateau, Alice; Vadrot, Nathalie; Vicart, Patrick; Ferreiro, Ana; Mayer, Michèle; Héron, Delphine; Vigouroux, Corinne; Buendia, Brigitte

2017-01-01

A-type lamins, the intermediate filament proteins participating in nuclear structure and function, are encoded by LMNA. LMNA mutations can lead to laminopathies such as lipodystrophies, premature aging syndromes (progeria) and muscular dystrophies. Here, we identified a novel heterozygous LMNA p.R388P de novo mutation in a patient with a non-previously described severe phenotype comprising congenital muscular dystrophy (L-CMD) and lipodystrophy. In culture, the patient's skin fibroblasts entered prematurely into senescence, and some nuclei showed a lamina honeycomb pattern. C2C12 myoblasts were transfected with a construct carrying the patient's mutation; R388P-lamin A (LA) predominantly accumulated within the nucleoplasm and was depleted at the nuclear periphery, altering the anchorage of the inner nuclear membrane protein emerin and the nucleoplasmic protein LAP2-alpha. The mutant LA triggered a frequent and severe nuclear dysmorphy that occurred independently of prelamin A processing, as well as increased histone H3K9 acetylation. Nuclear dysmorphy was not significantly improved when transfected cells were treated with drugs disrupting microtubules or actin filaments or modifying the global histone acetylation pattern. Therefore, releasing any force exerted at the nuclear envelope by the cytoskeleton or chromatin did not rescue nuclear shape, in contrast to what was previously shown in Hutchinson-Gilford progeria due to other LMNA mutations. Our results point to the specific cytotoxic effect of the R388P-lamin A mutant, which is clinically related to a rare and severe multisystemic laminopathy phenotype.

Cost-Effectiveness Analysis of Diagnosis of Duchenne/Becker Muscular Dystrophy in Colombia.

PubMed

Atehortúa, Sara C; Lugo, Luz H; Ceballos, Mateo; Orozco, Esteban; Castro, Paula A; Arango, Juan C; Mateus, Heidi E

2018-03-09

To determine the cost-effectiveness ratio of different courses of action for the diagnosis of Duchenne or Becker muscular dystrophy in Colombia. The cost-effectiveness analysis was performed from the Colombian health system perspective. Decision trees were constructed, and different courses of action were compared considering the following tests: immunohistochemistry (IHC), Western blot (WB), multiplex polymerase chain reaction, multiplex ligation-dependent probe amplification (MLPA), and the complete sequencing of the dystrophin gene. The time horizon matched the duration of sample extraction and analysis. Transition probabilities were obtained from a systematic review. Costs were constructed with a type-case methodology using the consensus of experts and the valuation of resources from consulting laboratories and the 2001 Social Security Institute cost manual. Deterministic sensitivity and scenario analyses were performed with one or more unavailable alternatives. Costs were converted from Colombian pesos to US dollars using the 2014 exchange rate. In the base case, WB was the dominant strategy, with a cost of US $419.07 and a sensitivity of 100%. This approach remains the dominant strategy down to a 98.2% sensitivity and while costs do not exceed US $837.38. If WB was not available, IHC had the best cost-effectiveness ratio, followed by MLPA and sequencing. WB is a cost-effective alternative for the diagnosis of patients suspected of having Duchenne or Becker muscular dystrophy in the Colombian health system. The IHC test is rated as the second-best detection method. If these tests are not available, MLPA followed by sequencing would be the most cost-effective alternative. Copyright © 2018. Published by Elsevier Inc.

Porcine models of muscular dystrophy

USDA-ARS?s Scientific Manuscript database

Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein, dystrophin. This disease is modeled by a variety of animal models including several fish models, mice, rats, and dogs. While these models have contributed substantially t...

The Child with Muscular Dystrophy in School. Revised.

ERIC Educational Resources Information Center

Schock, Nancy C.

Practical information on children with muscular dystrophy is intended to help parents and teachers facilitate their inclusion in mainstreamed classrooms. Major topics addressed include the following: transportation arrangements; providing full information to the teacher regarding the child's specific abilities and physical limitations;…

Effects of functional level on balance in children with Duchenne Muscular Dystrophy.

PubMed

Alkan, Halil; Mutlu, Akmer; Fırat, Tüzün; Bulut, Numan; Karaduman, Aynur Ayşe; Yılmaz, Öznur Tunca

2017-07-01

This study was planned to compare the static and dynamic balance in children with Duchenne Muscular Dystrophy (DMD) at different functional levels with each other and with healthy peers. Sixty nine children between the ages of 6 and 11 were included in this study where 52 of them were diagnosed with DMD in Level I (18 patients), Level II (17 patients), and Level III (17 patients) according to Brooke Functional Classification Scale and 17 of them healthy peers were included. In order to assess static and dynamic balance pediatric functional reach test (PFRT) and timed up and go test (TUGT) were used. When compared in terms of the TUGT, differences were found between all groups, i.e. Level 1 and 2, Level 2 and 3, Level 1 and 3, Healthy peers and Level 1, Healthy peers and Level 2, and Healthy peers and Level 3 (p < 0.0083). When compared in terms of the PFRT in the standing positions, there was difference between level 3 and healthy peers (p < 0.0083), but not between the other groups. We found poor functional level in DMD to affect the dynamic and static balance parameters in this study. The dynamic balance of a child with DMD at Level 3 is decreased to a third of a healthy peer. Copyright © 2017 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Exome sequencing identifies a novel SMCHD1 mutation in facioscapulohumeral muscular dystrophy 2.

PubMed

Mitsuhashi, Satomi; Boyden, Steven E; Estrella, Elicia A; Jones, Takako I; Rahimov, Fedik; Yu, Timothy W; Darras, Basil T; Amato, Anthony A; Folkerth, Rebecca D; Jones, Peter L; Kunkel, Louis M; Kang, Peter B

2013-12-01

FSHD2 is a rare form of facioscapulohumeral muscular dystrophy (FSHD) characterized by the absence of a contraction in the D4Z4 macrosatellite repeat region on chromosome 4q35 that is the hallmark of FSHD1. However, hypomethylation of this region is common to both subtypes. Recently, mutations in SMCHD1 combined with a permissive 4q35 allele were reported to cause FSHD2. We identified a novel p.Lys275del SMCHD1 mutation in a family affected with FSHD2 using whole-exome sequencing and linkage analysis. This mutation alters a highly conserved amino acid in the ATPase domain of SMCHD1. Subject III-11 is a male who developed asymmetrical muscle weakness characteristic of FSHD at 13 years. Physical examination revealed marked bilateral atrophy at biceps brachii, bilateral scapular winging, some asymmetrical weakness at tibialis anterior and peroneal muscles, and mild lower facial weakness. Biopsy of biceps brachii in subject II-5, the father of III-11, demonstrated lobulated fibers and dystrophic changes. Endomysial and perivascular inflammation was found, which has been reported in FSHD1 but not FSHD2. Given the previous report of SMCHD1 mutations in FSHD2 and the clinical presentations consistent with the FSHD phenotype, we conclude that the SMCHD1 mutation is the likely cause of the disease in this family. Copyright © 2013 Elsevier B.V. All rights reserved.

Changes in calsequestrin, TNF-α, TGF-β and MyoD levels during the progression of skeletal muscle dystrophy in mdx mice: a comparative analysis of the quadriceps, diaphragm and intrinsic laryngeal muscles.

PubMed

Barros Maranhão, Juliana; de Oliveira Moreira, Drielen; Maurício, Adriana Fogagnolo; de Carvalho, Samara Camaçari; Ferretti, Renato; Pereira, Juliano Alves; Santo Neto, Humberto; Marques, Maria Julia

2015-10-01

In Duchenne muscular dystrophy (DMD), the search for new biomarkers to follow the evolution of the disease is of fundamental importance in the light of the evolving gene and pharmacological therapies. In addition to the lack of dystrophin, secondary events including changes in calcium levels, inflammation and fibrosis greatly contribute to DMD progression and the molecules involved in these events may represent potential biomarkers. In this study, we performed a comparative evaluation of the progression of dystrophy within muscles that are differently affected by dystrophy (diaphragm; DIA and quadriceps; QDR) or spared (intrinsic laryngeal muscles) using the mdx mice model of DMD. We assessed muscle levels of calsequestrin (calcium-related protein), tumour necrosis factor (TNF-α; pro-inflammatory cytokine), tumour growth factor (TGF-β; pro-fibrotic factor) and MyoD (muscle proliferation) vs. histopathology at early (1 and 4 months of age) and late (9 months of age) stages of dystrophy. Fibrosis was the primary feature in the DIA of mdx mice (9 months: 32% fibrosis), which was greater than in the QDR (9 months: 0.6% fibrosis). Muscle regeneration was the primary feature in the QDR (9 months: 90% of centrally nucleated fibres areas vs. 33% in the DIA). The QDR expressed higher levels of calsequestrin than the DIA. Laryngeal muscles showed normal levels of TNF-α, TGF-β and MyoD. A positive correlation between histopathology and cytokine levels was observed only in the diaphragm, suggesting that TNF-α and TGF-β serve as markers of dystrophy primarily for the diaphragm. © 2015 The Authors. International Journal of Experimental Pathology © 2015 International Journal of Experimental Pathology.

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.

Multiple organ histopathological changes in broiler chickens fed on genetically modified organism.

PubMed

Cîrnatu, Daniela; Jompan, A; Sin, Anca Ileana; Zugravu, Cornelia Aurelia

2011-01-01

Diet can influence the structural characteristics of internal organs. An experiment involving 130 meat broilers was conducted during 42 days (life term for a meat broiler) to study the effect of feed with protein from genetically modified soy. The 1-day-old birds were randomly allocated to five study groups, fed with soy, sunflower, wheat, fish flour, PC starter. In the diet of each group, an amount of protein from soy was replaced with genetically modified soy (I - 0%, II - 25%, III - 50%, IV - 75%, V - 100% protein from genetically modified soy). The level of protein in soy, either modified, or non-modified, was the same. Organs and carcass weights were measured at about 42 days of age of the birds and histopathology exams were performed during May-June 2009. No statistically significant differences were observed in mortality, growth performance variables or carcass and organ yields between broilers consuming diets produced with genetically modified soybean fractions and those consuming diets produced with near-isoline control soybean fractions. Inflammatory and degenerative liver lesions, muscle hypertrophy, hemorrhagic necrosis of bursa, kidney focal tubular necrosis, necrosis and superficial ulceration of bowel and pancreatic dystrophies were found in tissues from broilers fed on protein from genetically modified soy. Different types of lesions found in our study might be due to other causes (parasites, viral) superimposed but their presence exclusively in groups fed with modified soy raises some serious questions about the consequences of use of this type of feed.

Meaning of Muscular Dystrophy

MedlinePlus

... is very similar to Duchenne, except kids with Becker MD may not have problems until much later, when they're teenagers or adults. It takes a long time for their muscles to become weak. How Does a Kid Get Muscular Dystrophy? MD is not contagious (say: con-TAY-juss), ...

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

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.

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.

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.

Histopathological Evaluation of Skeletal Muscle with Specific Reference to Mouse Models of Muscular Dystrophy.

PubMed

Terry, Rebecca L; Wells, Dominic J

2016-12-01

The muscular dystrophies are a diverse group of degenerative diseases for which many mouse models are available. These models are frequently used to assess potential therapeutic interventions and histological evaluation of multiple muscles is an important part of this assessment. Histological evaluation is especially useful when combined with tests of muscle function. This unit describes a protocol for necropsy, processing, cryosectioning, and histopathological evaluation of murine skeletal muscles, which is applicable to both models of muscular dystrophy and other neuromuscular conditions. Key histopathological features of dystrophic muscle are discussed using the mdx mouse (a model of Duchenne muscular dystrophy) as an example. Optimal handling during dissection, processing and sectioning is vital to avoid artifacts that can confound or prevent future analyses. Muscles carefully processed using this protocol are suitable for further evaluation using immunohistochemistry, immunofluorescence, special histochemical stains, and immuoblotting. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy.

PubMed

Yamamoto, Guilherme L; Baratela, Wagner A R; Almeida, Tatiana F; Lazar, Monize; Afonso, Clara L; Oyamada, Maria K; Suzuki, Lisa; Oliveira, Luiz A N; Ramos, Ester S; Kim, Chong A; Passos-Bueno, Maria Rita; Bertola, Débora R

2014-01-02

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive disorder characterized by severe short stature, progressive lower-limb bowing, flattened vertebral bodies, metaphyseal involvement, and visual impairment caused by cone-rod dystrophy. Whole-exome sequencing of four individuals affected by this disorder from two Brazilian families identified two previously unreported homozygous mutations in PCYT1A. This gene encodes the alpha isoform of the phosphate cytidylyltransferase 1 choline enzyme, which is responsible for converting phosphocholine into cytidine diphosphate-choline, a key intermediate step in the phosphatidylcholine biosynthesis pathway. A different enzymatic defect in this pathway has been previously associated with a muscular dystrophy with mitochondrial structural abnormalities that does not have cartilage and/or bone or retinal involvement. Thus, the deregulation of the phosphatidylcholine pathway may play a role in multiple genetic diseases in humans, and further studies are necessary to uncover its precise pathogenic mechanisms and the entirety of its phenotypic spectrum. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

High resolution magic angle spinning NMR spectroscopy reveals that pectoralis muscle dystrophy in chicken is associated with reduced muscle content of anserine and carnosine.

PubMed

Sundekilde, Ulrik K; Rasmussen, Martin K; Young, Jette F; Bertram, Hanne Christine

2017-02-15

Increased incidences of pectoralis muscle dystrophy are observed in commercial chicken products, but the muscle physiological causes for the condition remain to be identified. In the present study a high-resolution magic angle spinning (HR-MAS) proton ((1)H) NMR spectroscopic examination of intact pectoralis muscle samples (n=77) were conducted to explore metabolite perturbations associated with the muscle dystrophy condition for the very first time. Both in chicken with an age of 21 and 31days, respectively, pectoralis muscle dystrophy was associated with a significantly lower content of anserine (p=0.034), carnosine (p=0.019) and creatine (p=0.049). These findings must be considered intriguing as they corroborate that characteristic muscle di-peptides composed of β-alanine and histidine derivatives such as anserine are extremely important in homeostasis of contractile muscles as a results of their role as buffering, anti-oxidative, and anti-glycation capacities. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cognitive and Neurobehavioral Profile in Boys With Duchenne Muscular Dystrophy.

PubMed

Banihani, Rudaina; Smile, Sharon; Yoon, Grace; Dupuis, Annie; Mosleh, Maureen; Snider, Andrea; McAdam, Laura

2015-10-01

Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy. © The Author(s) 2015.

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

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

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.