Science.gov

Sample records for emery-dreifuss muscular dystrophy

  1. [Emery-Dreifuss muscular dystrophy: case report].

    PubMed

    Carsten, Ana Lucila Moreira; Lorenzoni, Paulo Jos; Scola, Rosana Herminia; Werneck, Lineu Csar

    2006-06-01

    The Emery-Dreifuss muscular dystrophy is a form of muscular dystrophy that frequently presents early contractures and cardiac conduction defects, caused by emerin deficiency in the inner nuclear membrane of the muscular fibers. A 19-years-old man it presented muscle weakness and hypotrophy in the proximal upper and lower limbs, dysphagia and early contractures in elbows and ankles, with familiar history compatible with X-linked inheritance form. The investigation showed increased serum creatinekinase levels electrocardiogram had a first degree atrioventricular block and right bundle branch block normal electromyography and nerve conduction study muscle biopsy disclosed myopathic characteristics and nuclear protein immunohystochemical analysis showed deficiency of emerin. The clinical and genetics manifestations, laboratorial and electromyography changes, as well as, the study of the pattern of inheritance for genetic counseling are discussed. PMID:16791377

  2. Emery-Dreifuss muscular dystrophy with unusual features.

    PubMed

    Deymeer, F; Oge, A E; Bayindir, C; Kaymaz, C; Ni?anci, Y; Adalet, K; Yates, J R; Ozdemir, C

    1993-12-01

    Two families with Emery-Dreifuss muscular dystrophy (EMD) are described. Several unusual features for EMD are emphasized. One of the patients had severe neuromuscular disability with inability to walk during early childhood. This patient also had mild bifacial paresis. His brothers had the typical slow progression of EMD. In some of the patients, muscle weakness distribution was more widespread than has usually been reported, with prominent involvement of finger extensors. It is suggested that there is a wide phenotypic spectrum in EMD. In both families, the disease segregated with markers spanning the EMD locus in Xq28. PMID:8232393

  3. Cardiac transplantation in twins with autosomal dominant Emery-Dreifuss muscular dystrophy.

    PubMed

    Kichuk Chrisant, Maryanne R; Drummond-Webb, Jonathan; Hallowell, Sara; Friedman, Neil R

    2004-04-01

    Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder resulting in progressive muscle weakness, contractures, and cardiomyopathy. We report successful cardiac transplantation in identical twin brothers with autosomal dominant EDMD, complicated by ventricular arrhythmias and end-stage cardiomyopathy. Early recognition of progressive cardiac disease and subsequent cardiac transplantation are lifesaving in children with EDMD. PMID:15063412

  4. Increased resting energy expenditure in subjects with Emery-Dreifuss muscular dystrophy.

    PubMed

    Vaisman, N; Katzenellenbogen, S; Nevo, Y

    2004-02-01

    We have studied changes in energy expenditure and body composition in adult males with Emery-Dreifuss muscular dystrophy, age-matched males with hyperCKemia and age-matched healthy controls. All participants were studied twice, 2-3 years apart. Resting energy expenditure was studied by indirect calorimetry, lean body mass and body fat by dual X-ray absorptiometry, and muscle mass was estimated based on 24-h urinary creatinine excretion. At baseline and 2-3 years later, body fat was significantly higher (P < 0.011 and P < 0.003, respectively) and lean body mass significantly lower (P < 0.024 and P < 0.012, respectively) in patients with Emery-Dreifuss muscular dystrophy as compared to subjects with hyperCKemia and healthy controls. Resting energy expenditure, over the study period, increased significantly in patients with Emery-Dreifuss muscular dystrophy (P < 0.031), but not in patients with hyperCKemia nor in healthy controls. Our study suggests that patients with Emery-Dreifuss muscular dystrophy may have increased energy expenditure relative to healthy subjects. If not met by increased caloric intake, this greater energy expenditure may partially contribute to a further deterioration in their muscle performance. PMID:14733961

  5. Increased dispersion of ventricular repolarization in emery dreifuss muscular dystrophy patients

    PubMed Central

    Russo, Vincenzo; Rago, Anna; Politano, Luisa; Papa, Andrea Antonio; Di Meo, Federica; Russo, Maria Giovanna; Golino, Paolo; Calabrò, Raffaele; Nigro, Gerardo

    2012-01-01

    Summary Background Sudden cardiac death (SCD) is common in patients with Emery-Dreifuss muscular dystrophy (EDMD) and is attributed to the development of life-threatening arrhythmias that occur in the presence of normal left ventricular systolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D) and JTc dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with Emery-Dreifuss muscular dystrophy with preserved systolic and diastolic cardiac function Material/Methods The study involved 36 EDMD patients (age 20±12, 26 M) and 36 healthy subjects used as controls, matched for age and sex. Heart rate, QRS duration, maximum and minimum QT and JT interval, QTc-D and JTc-D measurements were performed. Results Compared to the healthy control group, the EDMD group presented increased values of QTc-D (82.7±44.2 vs. 53.1±13.7; P=0,003) and JTc-D (73.6±32.3 vs. 60.4±11.1 ms; P=0.001). No correlation between QTc dispersion and ejection fraction (R=0.2, P=0.3) was found. Conclusions Our study showed a significant increase of QTc-D and JTc-D in Emery-Dreifuss muscular dystrophy patients with preserved systolic and diastolic cardiac function. PMID:23111739

  6. In Vitro Contracture Test Results and Anaesthetic Management of a Patient with Emery-Dreifuss Muscular Dystrophy for Cardiac Transplantation

    PubMed Central

    Schuster, Frank; Wessig, Carsten; Schimmer, Christoph; Johannsen, Stephan; Lazarus, Marc; Aleksic, Ivan; Leyh, Rainer; Roewer, Norbert

    2012-01-01

    Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required. PMID:22973525

  7. Distribution of emerin and lamins in the heart and implications for Emery-Dreifuss muscular dystrophy.

    PubMed

    Manilal, S; Sewry, C A; Pereboev, A; Man, N; Gobbi, P; Hawkes, S; Love, D R; Morris, G E

    1999-02-01

    Emerin is a nuclear membrane protein which is missing or defective in Emery-Dreifuss muscular dystrophy (EDMD). It is one member of a family of lamina-associated proteins which includes LAP1, LAP2 and lamin B receptor (LBR). A panel of 16 monoclonal antibodies (mAbs) has been mapped to six specific sites throughout the emerin molecule using phage-displayed peptide libraries and has been used to localize emerin in human and rabbit heart. Several mAbs against different emerin epitopes did not recognize intercalated discs in the heart, though they recognized cardiomyocyte nuclei strongly, both at the rim and in intranuclear spots or channels. A polyclonal rabbit antiserum against emerin did recognize both nuclear membrane and intercalated discs but, after affinity purification against a pure-emerin band on a western blot, it stained only the nuclear membrane. These results would not be expected if immunostaining at intercalated discs were due to a product of the emerin gene and, therefore, cast some doubt upon the hypothesis that cardiac defects in EDMD are caused by absence of emerin from intercalated discs. Although emerin was abundant in the membranes of cardiomyocyte nuclei, it was absent from many non-myocyte cells in the heart. This distribution of emerin was similar to that of lamin A, a candidate gene for an autosomal form of EDMD. In contrast, lamin B1 was absent from cardiomyocyte nuclei, showing that lamin B1 is not essential for localization of emerin to the nuclear lamina. Lamin B1 is also almost completely absent from skeletal muscle nuclei. In EDMD, the additional absence of lamin B1 from heart and skeletal muscle nuclei which already lack emerin may offer an alternative explanation of why these tissues are particularly affected. PMID:9949197

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

    MedlinePLUS

    ... actually happening inside the muscles. Modern techniques can use the biopsy to distin- guish muscular dystrophies from infec- tions, inflammatory disorders and other problems. Other tests on the biopsy sample can provide information about ...

  9. Emery-Dreifuss muscular dystrophy type 2 associated (?) with mild peripheral polyneuropathy.

    PubMed

    Madej-Pilarczyk, Agnieszka; Kotruchow, Katarzyna; Kabzinska, Dagmara; Cegielska, Joanna; Kochanski, Andrzej; Hausmanowa-Petrusewicz, Irena

    2015-01-01

    In recent years numerous mutations in the LMNA gene encoding lamin A/C were shown to segregate with a wide spectrum of phenotypes. A recurrent p.R377H mutation in the LMNA gene was reported in patients with Emery-Dreifuss dystrophy (EDMD2) with various ethnic backgrounds. We present a patient with EDMD2 caused by a p.R377H mutation, associated with mild peripheral polyneuropathy. The analysis of peripheral myelin protein 22 (PMP22), ganglioside induced differentiation-associated protein 1 (GDAP1), gap junction ?-1 protein (GJB1), and myelin protein zero (MPZ) genes did not reveal mutations; however, we identified a new sequence intronic variant in the mitofusin 2 (MFN2) gene of unknown pathogenic significance. A complex phenotype in the presented patient might depend either on single mutation in the LMNA gene or on bigenic defect; therefore, a wide genetic investigation is needed to elucidate the molecular background of EDMD2/polyneuropathy in this case. PMID:26443318

  10. Emery-Dreifuss muscular dystrophy mutations impair TRC40-mediated targeting of emerin to the inner nuclear membrane.

    PubMed

    Pfaff, Janine; Rivera Monroy, Jhon; Jamieson, Cara; Rajanala, Kalpana; Vilardi, Fabio; Schwappach, Blanche; Kehlenbach, Ralph H

    2016-02-01

    Emerin is a tail-anchored protein that is found predominantly at the inner nuclear membrane (INM), where it associates with components of the nuclear lamina. Mutations in the emerin gene cause Emery-Dreifuss muscular dystrophy (EDMD), an X-linked recessive disease. Here, we report that the TRC40/GET pathway for post-translational insertion of tail-anchored proteins into membranes is involved in emerin-trafficking. Using proximity ligation assays, we show that emerin interacts with TRC40 in situ. Emerin expressed in bacteria or in a cell-free lysate was inserted into microsomal membranes in an ATP- and TRC40-dependent manner. Dominant-negative fragments of the TRC40-receptor proteins WRB and CAML (also known as CAMLG) inhibited membrane insertion. A rapamycin-based dimerization assay revealed correct transport of wild-type emerin to the INM, whereas TRC40-binding, membrane integration and INM-targeting of emerin mutant proteins that occur in EDMD was disturbed. Our results suggest that the mode of membrane integration contributes to correct targeting of emerin to the INM. PMID:26675233

  11. Cardiac effects of the c.1583 C?G LMNA mutation in two families with Emery-Dreifuss muscular dystrophy.

    PubMed

    Zhang, Li; Shen, Hongrui; Zhao, Zhe; Bing, Qi; Hu, Jing

    2015-10-01

    The present study aimed to examine and analyze cardiac involvement in two Emery?Dreifuss muscular dystrophy (EDMD) pedigrees caused by the c.1583 C?G mutation of the lamin A/C gene (LMNA). The clinical and genetic characteristics of members of two families with EDMD were evaluated by performing neurological examinations, skeletal muscle biopsies, cardiac evaluations, including electrocardiography, 24 h Holter, ultrasound cardiography and 99TcM?MIBI?gated myocardiac perfusion imaging, and genomic DNA sequencing. Family history investigations revealed an autosomal dominant transmission pattern of the disease in Family 1 and a sporadic case in Family 2. The three affected patients exhibited typical clinical features of EDMD, including joint contractures, muscle weakness and cardiac involvement. Muscle histopathological investigation revealed dystrophic features. In addition, each affected individual exhibited either cardiac arrhythmia, which was evident as sinus tachycardia, atrial flutter or complete atrioventricular inhibition. Cardiac imaging revealed dilated cardiomyopathy in two of the individuals, one of whom was presented with heart failure. The second patient presented with no significant abnormalities in cardiac structure or function. The three affected individuals exhibited a heterozygous missense mutation in the LMNA gene (c.1583 C?G), which caused a T528R amino acid change in the LMNA protein. In conclusion, the present study identified three patients with EDMD, exhibiting the same dominant LMNA mutation and presenting with a spectrum of severe cardiac abnormalities, including cardiac conduction system defects, cardiomyopathy and heart failure. As LMNA mutations have been associated with at least six clinical disorders, including EDMD, the results of the present study provide additional mutational and functional data, which may assist in further establishing LMNA mutational variation and disease pathogenesis. PMID:26165385

  12. Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked EmeryDreifuss muscular dystrophy

    PubMed Central

    Meinke, Peter; Schneiderat, Peter; Srsen, Vlastimil; Korfali, Nadia; L Thnh, Ph; Cowan, Graeme J.M.; Cavanagh, David R.; Wehnert, Manfred; Schirmer, Eric C.; Walter, Maggie C.

    2015-01-01

    EmeryDreifuss muscular dystrophy (EDMD) is a neuromuscular disease characterized by early contractures, slowly progressive muscular weakness and life-threatening cardiac arrhythmia that can develop into cardiomyopathy. In X-linked EDMD (EDMD1), female carriers are usually unaffected. Here we present a clinical description and in vitro characterization of a mildly affected EDMD1 female carrying the heterozygous EMD mutation c.174_175delTT; p.Y59* that yields loss of protein. Muscle tissue sections and cultured patient myoblasts exhibited a mixed population of emerin-positive and -negative cells; thus uneven X-inactivation was excluded as causative. Patient blood cells were predominantly emerin-positive, but considerable nuclear lobulation was observed in non-granulocyte cells a novel phenotype in EDMD. Both emerin-positive and emerin-negative myoblasts exhibited spontaneous differentiation in tissue culture, though emerin-negative myoblasts were more proliferative than emerin-positive cells. The preferential proliferation of emerin-negative myoblasts together with the high rate of spontaneous differentiation in both populations suggests that loss of functional satellite cells might be one underlying mechanism for disease pathology. This could also account for the slowly developing muscle phenotype. PMID:25454731

  13. Abnormal proliferation and spontaneous differentiation of myoblasts from a symptomatic female carrier of X-linked Emery-Dreifuss muscular dystrophy.

    PubMed

    Meinke, Peter; Schneiderat, Peter; Srsen, Vlastimil; Korfali, Nadia; L Thnh, Ph; Cowan, Graeme J M; Cavanagh, David R; Wehnert, Manfred; Schirmer, Eric C; Walter, Maggie C

    2015-02-01

    Emery-Dreifuss muscular dystrophy (EDMD) is a neuromuscular disease characterized by early contractures, slowly progressive muscular weakness and life-threatening cardiac arrhythmia that can develop into cardiomyopathy. In X-linked EDMD (EDMD1), female carriers are usually unaffected. Here we present a clinical description and in vitro characterization of a mildly affected EDMD1 female carrying the heterozygous EMD mutation c.174_175delTT; p.Y59* that yields loss of protein. Muscle tissue sections and cultured patient myoblasts exhibited a mixed population of emerin-positive and -negative cells; thus uneven X-inactivation was excluded as causative. Patient blood cells were predominantly emerin-positive, but considerable nuclear lobulation was observed in non-granulocyte cells - a novel phenotype in EDMD. Both emerin-positive and emerin-negative myoblasts exhibited spontaneous differentiation in tissue culture, though emerin-negative myoblasts were more proliferative than emerin-positive cells. The preferential proliferation of emerin-negative myoblasts together with the high rate of spontaneous differentiation in both populations suggests that loss of functional satellite cells might be one underlying mechanism for disease pathology. This could also account for the slowly developing muscle phenotype. PMID:25454731

  14. [Case with Emery-Dreifuss muscular dystrophy diagnosed forty-two years after onset and implanted with a cardiac resynchronization therapy defibrillator].

    PubMed

    Sakiyama, Yoshio; Watanabe, Eri; Otsuka, Mieko; Hirahara, Taishi; Momomura, Shinichi; Hayashi, Yukiko

    2014-01-01

    The patient was a 53-year-old male. He showed steppage gait at the age of 11 and equinus foot at 13. He walked unaided with shoe-insoles to support his heels. Atrial fibrillation and cardiac hypertrophy were found in his 30s, and ventricular tachycardia (VT) was observed at the age of 48. Electrophysiological studies were performed, but VT was not sustained, symptomatic, or showed signs of infra-Hisian block, and a pacemaker was not indicated. At 53, he was introduced to a neurologist because of tetraplegia after the first episode of syncope. A spinal MR showed ossification of posterior longitudinal ligament (OPLL) and central cervical cord injury. Furthermore, he presented not only contracture in his shoulder, elbow, and ankles but also atrophy in his scapulohumeral and gastrocnemius muscles. In accordance with a diagnosis of Emery-Dreifuss muscular dystrophy (EDMD), provocative testing of VT was carried out, and a cardiac resynchronization therapy defibrillator (CRT-D) was implanted. Later, a mutation analysis of the LMNA gene disclosed a known missense mutation of p.Arg377His, and we diagnosed him as EDMD2 (laminopathy). Contractures could be the clue to diagnose EDMD and indicate the need for pacemakers and defibrillators in patients with cardiac conduction disorders. PMID:24990833

  15. Distinct functional domains in nesprin-1{alpha} and nesprin-2{beta} bind directly to emerin and both interactions are disrupted in X-linked Emery-Dreifuss muscular dystrophy

    SciTech Connect

    Wheeler, Matthew A.; Davies, John D.; Zhang Qiuping; Emerson, Lindsay J.; Hunt, James; Shanahan, Catherine M.; Ellis, Juliet A. . E-mail: juliet.ellis@kcl.ac.uk

    2007-08-01

    Emerin and specific isoforms of nesprin-1 and -2 are nuclear membrane proteins which are binding partners in multi-protein complexes spanning the nuclear envelope. We report here the characterisation of the residues both in emerin and in nesprin-1{alpha} and -2{beta} which are involved in their interaction and show that emerin requires nesprin-1 or -2 to retain it at the nuclear membrane. Using several protein-protein interaction methods, we show that residues 368 to 627 of nesprin-1{alpha} and residues 126 to 219 of nesprin-2{beta}, which show high homology to one another, both mediate binding to emerin residues 140-176. This region has previously been implicated in binding to F-actin, {beta}-catenin and lamin A/C suggesting that it is critical for emerin function. Confirmation that these protein domains interact in vivo was shown using GFP-dominant negative assays. Exogenous expression of either of these nesprin fragments in mouse myoblast C2C12 cells displaced endogenous emerin from the nuclear envelope and reduced the targeting of newly synthesised emerin. Furthermore, we are the first to report that emerin mutations which give rise to X-linked Emery-Dreifuss muscular dystrophy, disrupt binding to both nesprin-1{alpha} and -2{beta} isoforms, further indicating a role of nesprins in the pathology of Emery-Dreifuss muscular dystrophy.

  16. 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

    SciTech Connect

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

    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 of 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.

  17. Genetics Home Reference: Emery-Dreifuss muscular dystrophy

    MedlinePLUS

    ... components of the nuclear envelope, which surrounds the nucleus in cells. The nuclear envelope regulates the movement of molecules into and out of the nucleus, and researchers believe it may play a role ...

  18. An Indian family with an Emery-Dreifuss myopathy and familial dilated cardiomyopathy due to a novel LMNA mutation

    PubMed Central

    Jadhav, Khushal B.; Karpe, Kedarnath K.; Maramattom, Boby V.

    2012-01-01

    Emery-Dreifuss myopathy can be associated with a cardiomyopathy and cardiac dysrhythmias. The inheritance pattern of Emery-Dreifuss muscular dystrophy (EDMD) is X linked, whereas EDMD2 is autosomal dominant. EDMD2 is caused by lamin A/C gene (LMNA) mutations that produce alterations in the lamin proteins that are integral to nuclear and cell integrity. A 53-year-old man was brought to us with a right internal carotid artery dissection. Detailed work-up of the patient and family members revealed some unusual features, and genetic sequencing of the LMNA gene was undertaken. A novel mutation was identified in two of the samples sent for analysis. We present the first Indian family of EDMD2 with familial dilated cardiomyopathy and cardiac dysrhythmias in whom LMNA gene sequencing was performed. A novel mutation was identified and additional unusual clinical features were described. PMID:23349612

  19. The nuclear muscular dystrophies.

    PubMed

    Wehnert, Manfred S; Bonne, Gisle

    2002-06-01

    Nuclear muscular dystrophies are referred to as inherited muscular dystrophies caused by mutations in genes--(STA) or lamina (LMNA)--encoding components of the nuclear envelope. Phenotypically, they present as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscle dystrophy 1B (LGMD1B), or dilated cardiomyopathy with conduction defects (DCM-CD). Genetically related are the Dunnigan-type of familial partial lipodystrophy (FPLD) and Charcot-Marie-Tooth neuropathy type 2 (CMT2B). Until now, approximately 70 unique STA mutations, leading to X-linked EDMD or DCM-CD, have resulted mostly in a complete lack of emerin. Further 50 mostly missense mutations in LMNA result in autosomal-dominant EDMD, autosomal-recessive EDMD, LGMD1B, DCM-CD, FPLD, or CMT2B. Independent of type or location of the mutations, emerinopathies and laminopathies show wide clinical intrafamilial and interfamilial variability. Although structural abnormalities of nuclei in animal and cell models have been observed, the molecular pathology of the nuclear muscular dystrophies needs still to be elucidated. PMID:12138994

  20. Muscular Dystrophy

    MedlinePLUS

    ... References: 1. Emery AEH. The muscular dystrophies. The Lancet. 2002 Feb 23 2002;359(9307):687-695. ... 3186. 2. Emery AEH. The muscular dystrophies. The Lancet. 2002 Feb 23 2002;359(9307):687-695. ...

  1. Muscular dystrophy

    MedlinePLUS

    Muscular dystrophy is a group of inherited disorders that cause muscle weakness and loss of muscle tissue, which ... Muscular dystrophies, or MD, are a group of inherited conditions. This means they are passed down through families. ...

  2. Muscular Dystrophy

    MedlinePLUS

    Muscular dystrophy (MD) is a group of more than 30 inherited diseases. They all cause muscle weakness and ... ability to walk. There is no cure for muscular dystrophy. Treatments can help with the symptoms and prevent ...

  3. Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Registry

    ClinicalTrials.gov

    2016-01-21

    Myotonic Dystrophy; Facioscapulohumeral Muscular Dystrophy; Muscular Dystrophy; Myotonic Dystrophy Type 1; Myotonic Dystrophy Type 2; Congenital Myotonic Dystrophy; PROMM (Proximal Myotonic Myopathy); Steinert's Disease; Myotonic Muscular Dystrophy

  4. Muscular Dystrophy

    MedlinePLUS

    ... affects about 1 out of every 3,500 boys. (Girls can carry the gene that causes the disease, ... and heart problems. Limb-girdle muscular dystrophy affects boys and girls equally. Symptoms usually start when kids are between ...

  5. 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 ...

  6. Meaning of Muscular Dystrophy

    MedlinePLUS

    ... Skating Crushes What's a Booger? The Meaning of Muscular Dystrophy KidsHealth > For Kids > The Meaning of Muscular Dystrophy ... you know someone who has MD. What Is Muscular Dystrophy? Muscular dystrophy (say: MUS-kyoo-lur DIS-troh- ...

  7. Muscular dystrophy - resources

    MedlinePLUS

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

  8. PhenotypeGenotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy

    PubMed Central

    Tan, Dandan; Yang, Haipo; Yuan, Yun; Bonnemann, Carsten; Chang, Xingzhi; Wang, Shuang; Wu, Yuchen; Wu, Xiru; Xiong, Hui

    2015-01-01

    This study aimed to analyze the correlation between the phenotype and genotype of Chinese patients with early-onset lamin A (LMNA)-related muscular dystrophy (MD). The clinical and myopathological data of 21 Chinese pediatric patients with early-onset LMNA-related MD were collected and analyzed. LMNA gene mutation analysis was performed by direct sequencing of genomic DNA. Sublocalization of wild-type and mutant proteins were observed by immunofluorescence using cultured fibroblasts and human embryonic kidney 293 (HEK 293) cell. Seven patients were diagnosed with Emery-Dreifuss muscular dystrophy (EDMD) and 14 were diagnosed with LMNA-associated congenital muscular dystrophy (L-CMD). Four biopsy specimens from the L-CMD cases exhibited inflammatory changes. Abnormal nuclear morphology was observed with both transmission electron microscopy and lamin A/C staining. We identified 10 novel and nine known LMNA gene mutations in the 21 patients. Some mutations (c.91G>A, c.94_96delAAG, c.116A>G, c.745C>T, c.746G>A, and c.1580G>C) were well correlated with EDMD or L-CMD. LMNA-related MD has a common symptom triad of muscle weakness, joint contractures, and cardiac involvement, but the severity of symptoms and disease progression differ greatly. Inflammatory change in biopsied muscle is a characteristic of early-stage L-CMD. Phenotypegenotype analysis determines that some mutations are well correlated with LMNA-related MD. PMID:26098624

  9. Motor unit reorganization in progressive muscular dystrophies and congenital myopathies.

    PubMed

    Szmidt-Sałkowska, Elżbieta; Gaweł, Małgorzata; Lipowska, Marta

    2015-01-01

    The aim of this study was to analyze motor unit reorganization in different types of progressive muscular dystrophies and congenital myopathies. The study population consisted of patients with genetically verified progressive muscular dystrophies: Duchenne (DMD) (n=54), Becker (BMD) (n=30), facio-scapulo-humeral (FSHD) (n=37), and Emery-Dreifuss (E-DD) (n=26). Patients with probable limb-girdle dystrophy (L-GD) (n=58) and congenital myopathies (n=35) were also included in the study. Quantitative EMG recordings were obtained from 469 muscles. Muscle activity at rest and during slight voluntary and maximal muscle contraction was analyzed. The motor unit activity potential (MUAP) duration, amplitude, area, size index (SI), polyphasicity, and the presence of "outliers" were evaluated. Diminished values of MUAP parameters and decreased maximal amplitude of maximal muscle contraction were recorded most frequently in DMD and mainly in the biceps brachii muscles. SI was the most frequently changed EMG parameter. "Outliers" with amplitude below the normal range were recorded more frequently then a decreased mean MUAP amplitude (what could indicate a very high sensitivity of this EMG parameter). Pathological interference pattern was recorded in 34.7% of biceps brachii and in 21.2% of rectus femoris muscles. In FSHD, decreased MUAP duration and SI and pathological interference pattern with low amplitude were recorded most frequently in the tibial anterior and deltoid muscles. The presence of potentials with reduced parameters is a result of decreasing motor unit area (reduced number and size of muscle fibers), while high amplitude potentials recorded in BMD and E-DD could indicate a slow and mild course of disease and muscle regeneration. PMID:26188938

  10. Muscular Dystrophy (MD)

    MedlinePLUS

    ... NINDS Funding Information Research Programs Training & Career Awards Enhancing Diversity Find People About NINDS NINDS Muscular Dystrophy ... Funding | News From NINDS | Find People | Training | Research | Enhancing Diversity Careers@NINDS | FOIA | Accessibility Policy | Contact Us | ...

  11. Facioscapulohumeral muscular dystrophy

    MedlinePLUS

    There is no known cure for facioscapulohumeral muscular dystrophy. Treatments are given to control symptoms and improve quality of life. Activity is encouraged. Inactivity such as bedrest can make the muscle disease worse. ...

  12. Evaluation of Limb-Girdle Muscular Dystrophy

    ClinicalTrials.gov

    2014-03-06

    Becker Muscular Dystrophy; Limb-Girdle Muscular Dystrophy, Type 2A (Calpain-3 Deficiency); Limb-Girdle Muscular Dystrophy, Type 2B (Miyoshi Myopathy, Dysferlin Deficiency); Limb-Girdle Muscular Dystrophy, Type 2I (FKRP-deficiency)

  13. Muscular Dystrophy Mutations Impair the Nuclear Envelope Emerin Self-assembly Properties.

    PubMed

    Herrada, Isaline; Samson, Camille; Velours, Christophe; Renault, Louis; stlund, Cecilia; Chervy, Pierre; Puchkov, Dmytro; Worman, Howard J; Buendia, Brigitte; Zinn-Justin, Sophie

    2015-12-18

    More than 100 genetic mutations causing X-linked Emery-Dreifuss muscular dystrophy have been identified in the gene encoding the integral inner nuclear membrane protein emerin. Most mutations are nonsense or frameshift mutations that lead to the absence of emerin in cells. Only very few cases are due to missense or short in-frame deletions. Molecular mechanisms explaining the corresponding emerin variants' loss of function are particularly difficult to identify because of the mostly intrinsically disordered state of the emerin nucleoplasmic region. We now demonstrate that this EmN region can be produced as a disordered monomer, as revealed by nuclear magnetic resonance, but rapidly self-assembles in vitro. Increases in concentration and temperature favor the formation of long curvilinear filaments with diameters of approximately 10 nm, as observed by electron microscopy. Assembly of these filaments can be followed by fluorescence through Thioflavin-T binding and by Fourier-transform Infrared spectrometry through formation of ?-structures. Analysis of the assembly properties of five EmN variants reveals that del95-99 and Q133H impact filament assembly capacities. In cells, these variants are located at the nuclear envelope, but the corresponding quantities of emerin-emerin and emerin-lamin proximities are decreased compared to wild-type protein. Furthermore, variant P183H favors EmN aggregation in vitro, and variant P183T provokes emerin accumulation in cytoplasmic foci in cells. Substitution of residue Pro183 might systematically favor oligomerization, leading to emerin aggregation and mislocalization in cells. Our results suggest that emerin self-assembly is necessary for its proper function and that a loss of either the protein itself or its ability to self-assemble causes muscular dystrophy. PMID:26415001

  14. Facioscapulohumeral muscular dystrophy.

    PubMed

    Fitzsimons, R B

    1999-10-01

    A decade's progress in facioscapulohumeral muscular dystrophy genetics has been marked by the discovery of novel genetic phenomena such as crossover of subtelomeric DNA between chromosomes 4 and 10 in normal individuals and by the recognition that the facioscapulohumeral muscular dystrophy deletion-mutation may cause a position variegation effect on more proximal DNA. The mutated DNA itself is probably not transcribed. Larger deletions tend to cause more severe disease. Antenatal diagnosis, based on detection of the short fragment of mutated DNA, is possible in between 95 and 100% of cases, depending on the precise nature of the parental facioscapulohumeral muscular dystrophy mutation. Yet remarkably, the nature of the gene product(s) of the affected proximal gene(s), as well as of the molecular pathogenesis of facioscapulohumeral muscular dystrophy muscle, retinal and cochlear disease, is completely unknown. Marked perivascular inflammation is often present in facioscapulohumeral muscular dystrophy muscle biopsies. The expression of facioscapulohumeral muscular dystrophy within reported monozygotic twinships differs greatly. This raises the question of whether variations in expression of the T-cell receptor gene repertoire or of other immune genes play an important modifying role in determining the severity of facioscapulohumeral muscular dystrophy. A focus on traditional scientific disciplines may now be appropriate. Symptomatic treatments, for instance of scapular winging and of lagophthalmos, are important, and timely photocoagulation of the retinal exudates which are a very rare, but real, complication of retinal telangiectasis can curtail visual loss. The results of collobarative trials of pharmacological agents such as albuterol which affect muscle mass and development are awaited. PMID:10590886

  15. How Is Muscular Dystrophy Diagnosed?

    MedlinePLUS

    ... Information Clinical Trials Resources and Publications How is muscular dystrophy diagnosed? Skip sharing on social media links Share this: Page Content The first step in diagnosing muscular dystrophy (MD) is a visit with a health care ...

  16. Duchenne muscular dystrophy.

    PubMed

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. PMID:25752877

  17. Progressive muscular dystrophies.

    PubMed

    Chelly, Jamel; Desguerre, Isabelle

    2013-01-01

    Infancy- or childhood-onset muscular dystrophies may be associated with profound loss of muscle function, affecting ambulation, posture, cardiac and respiratory functions, while those of late onset may be mild and associated with slight weakness or fatigability induced by effort. In addition to the distribution of muscle weakness, symptoms, and course of the disease, the diagnosis of muscular dystrophy is usually ascertained by histological findings. There is connective tissue proliferation in the perimysium and endomysium, variation in muscle fiber size, cytoarchitectural alterations of myofibers such as internal nuclei, myofibrillar whorls, and fiber splitting and lobulation, but, most of all, degeneration and regeneration of myofibers. Causes of muscular dystrophies characterized by muscle weakness and wasting are heterogeneous and include dysfunction of diverse genetic pathways and genes encoding proteins of the plasma membrane, extracellular matrix, sarcomere, and nuclear membrane components. Duchenne and Becker muscular dystrophies are prototypes illustrating advances in the field of myology. Limb-girdle muscular dystrophies (LGMDs) are clinically and genetically heterogeneous, some with autosomal dominant (LGMD1) and others with autosomal recessive (LGMD2) inheritance. Neither clinical and genetic grounds nor biopsy patterns are specific enough to distinguish them, but two common denominators are: (1) weakness and wasting predominating in pelvic and shoulder girdle muscles, with occasional involvement of the myocardium; and (2) necrosis and regeneration of myofibers. While identification of genetic causes and molecular diagnosis are increasingly improved, especially with the advent of new generation sequencing technologies, optimized care, information for the family, and prevention, including genetic counseling and prenatal diagnosis, require multidisciplinary follow-up with genetic, pediatric, and psychological involvement. PMID:23622359

  18. Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey M.; Tawil, Rabi

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHSD) is one of the most common adult muscular dystrophies and is divided into types 1 and 2 based on genetic mutation. Clinically both FSHD types 1 and 2 demonstrate often asymmetric and progressive muscle weakness affecting initially the face, shoulder, and arms, followed by the distal and then proximal lower extremities later in the disease course. Approximately 95% of patients, termed FSHD1, have a deletion of a key number of repetitive elements on chromosome 4q35. The remaining 5%, termed FSHD2, have no deletion on chromosome 4q35. Nevertheless, both FSHD types 1 and 2 share a common downstream mechanism making it possible that future disease-directed therapies will be effective for both FSHD types 1 and 2. PMID:25037087

  19. Genetics Home Reference: Tibial muscular dystrophy

    MedlinePLUS

    ... Recent literature OMIM Genetic disorder catalog Conditions > Tibial muscular dystrophy On this page: Description Genetic changes Inheritance Diagnosis ... Glossary definitions Reviewed February 2012 What is tibial muscular dystrophy? Tibial muscular dystrophy is a condition that affects ...

  20. Therapeutic advances in muscular dystrophy

    PubMed Central

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. PMID:23939629

  1. Genetics Home Reference: Tibial muscular dystrophy

    MedlinePLUS

    ... Where can I find information about diagnosis or management of tibial muscular dystrophy? These resources address the diagnosis or management of tibial muscular dystrophy and may include treatment ...

  2. 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

  3. 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 ...

  4. Muscular Dystrophy: Hope Through Research

    MedlinePLUS

    ... the most common of the muscular dystrophies overall, accounting for approximately 50 percent of all cases. Because ... relax muscles following a sudden contraction. neuropathy – nervous ... Page See a list of all NINDS Disorders ...

  5. 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 ?-sarcoglycan, ?-sarcoglycan and ?-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. PMID:24529507

  6. What Are the Treatments for Muscular Dystrophy?

    MedlinePLUS

    ... Resources and Publications What are the treatments for muscular dystrophy? Skip sharing on social media links Share this: ... available to stop or reverse any form of muscular dystrophy (MD). Instead, certain therapies and medications aim to ...

  7. How Do People Cope with Muscular Dystrophy?

    MedlinePLUS

    ... NICHD Research Information Clinical Trials Resources and Publications Muscular Dystrophy: Other FAQs Skip sharing on social media links ... in this section. How do people cope with muscular dystrophy (MD)? Although MD presents many challenges in many ...

  8. Facioscapulohumeral muscular dystrophy.

    PubMed

    Sacconi, Sabrina; Salviati, Leonardo; Desnuelle, Claude

    2015-04-01

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis. Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because the DUX4 transcript is polyadenylated and translated into stable protein. FSHD2 is instead a digenic disease. Chromatin relaxation of the D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:24882751

  9. Diagnosing and managing muscular dystrophy.

    PubMed

    Orrell, Richard W

    2012-09-01

    Muscular dystrophy refers to a range of muscle diseases caused by defects in muscle proteins, leading to death of the muscle cells, with loss of muscle tissue, and weakness. The development of clinical symptoms is usually gradual, and the earliest features may be difficult to identify and determine. With established disease the presence of muscle weakness and wasting is clear. In children, the presentation may be delayed walking, or poor performance in sporting activity. In children and adults presenting symptoms may include: difficulty raising from a squat; difficulty raising from a chair; difficulty lifting the arms above the head; poor balance; drooping eyelids; and joint contractures. In the presence of slowly progressive muscle weakness and wasting, an elevated serum creatine kinase would be a strong pointer to a muscle disease. Retention of limb reflexes would favour a myopathy over a neuropathy. The major differential diagnosis is an inflammatory myopathy, such as polymyositis. The muscular dystrophies have a genetic basis. There may be important genetic issues to discuss with the family, including the possibility of prenatal diagnosis. In Duchenne muscular dystrophy the inheritance is X-linked, with typically only boys affected. Many limb girdle muscular dystrophies are autosomal recessive, affecting only one generation of a family and facioscapulohumeral dystrophy is autosomal dominant. PMID:23252132

  10. The Cardiomyopathy of Muscular Dystrophy

    PubMed Central

    Hooey, M. A.; Jerry, L. M.

    1964-01-01

    About 50% of patients with progressive muscular dystrophy have a cardiomyopathy, manifested commonly by tachycardia, but also by arrythmias, refractory congestive heart failure and sudden death. Studies from the literature report manifold but nonspecific electrocardiographic changes in 41% to 85% of patients with progressive muscular dystrophy. The principal lesion is a diffuse myocardial fibrosis with minor degenerative changes in myocardial fibres unaccompanied by significant inflammation. The heart is enlarged and has a prominent deposit of epicardial fat. The myocardium is pale, coarse, flabby and friable, often showing gross evidence of scarring. The dilated chambers often contain mural thrombus. ImagesFig. 1Fig. 2 PMID:14133625

  11. Duchenne and Becker Muscular Dystrophies

    MedlinePLUS

    ... a muscular dystrophy or inflam- mation. Therefore, a high CK level suggests that the muscles themselves are the likely cause of the weakness, but it doesnt tell exactly what the muscle dis- order might be. The availability of DNA diagnos- tic tests, using either blood ...

  12. Porcine models of muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  13. Dysregulation of calcium homeostasis in muscular dystrophies.

    PubMed

    Vallejo-Illarramendi, Ainara; Toral-Ojeda, Ivan; Aldanondo, Garazi; Lpez de Munain, Adolfo

    2014-01-01

    Muscular dystrophies are a group of diseases characterised by the primary wasting of skeletal muscle, which compromises patient mobility and in the most severe cases originate a complete paralysis and premature death. Existing evidence implicates calcium dysregulation as an underlying crucial event in the pathophysiology of several muscular dystrophies, such as dystrophinopathies, calpainopathies or myotonic dystrophy among others. Duchenne muscular dystrophy is the most frequent myopathy in childhood, and calpainopathy or LGMD2A is the most common form of limb-girdle muscular dystrophy, whereas myotonic dystrophy is the most frequent inherited muscle disease worldwide. In this review, we summarise recent advances in our understanding of calcium ion cycling through the sarcolemma, the sarcoplasmic reticulum and mitochondria, and its involvement in the pathogenesis of these dystrophies. We also discuss some of the clinical implications of recent findings regarding Ca2+ handling as well as novel approaches to treat muscular dystrophies targeting Ca2+ regulatory proteins. PMID:25293420

  14. Genetics Home Reference: Limb-girdle muscular dystrophy

    MedlinePLUS

    ... literature OMIM Genetic disorder catalog Conditions > Limb-girdle muscular dystrophy On this page: Description Genetic changes Inheritance Diagnosis ... definitions Reviewed April 2011 What is limb-girdle muscular dystrophy? Limb-girdle muscular dystrophy is a term for ...

  15. Genetics Home Reference: Facioscapulohumeral muscular dystrophy

    MedlinePLUS

    ... remaining 5 percent are FSHD2. What are the genetic changes related to facioscapulohumeral muscular dystrophy? Facioscapulohumeral muscular ... Center . Where can I find general information about genetic conditions? The Handbook provides basic information about genetics ...

  16. Arrhythmias in the muscular dystrophies.

    PubMed

    Rajdev, Archana; Groh, William J

    2015-06-01

    In patients with muscular dystrophies, cardiac involvement leading to cardiomyopathy and arrhythmias occurs with variable prevalence, mirroring the phenotypic variability seen among and within the various hereditary myopathies. Knowledge of the incidence of arrhythmias and predictors of sudden death in the various hereditary myopathies can help guide screening and appropriate management of these patients, thereby improving survival. The noncardiac manifestations can lead to delayed recognition of symptoms, affect the decision to implant a prophylactic device, and once a decision is made to proceed with device implant, increase peri-procedural respiratory and anesthesia-related complications. PMID:26002394

  17. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bożena; Paszko-Patej, Grażyna; Kawnik, Katarzyna

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cell therapy and the use of granulocyte colony-stimulating factor (G-CSF) in muscular dystrophy was performed. PMID:26136844

  18. Porcine models of muscular dystrophy.

    PubMed

    Selsby, Joshua T; Ross, Jason W; Nonneman, Dan; Hollinger, Katrin

    2015-01-01

    Duchenne muscular dystrophy is a progressive, fatal, X-linked disease caused by a failure to accumulate the cytoskeletal protein dystrophin. This disease has been studied using a variety of animal models including fish, mice, rats, and dogs. While these models have contributed substantially to our mechanistic understanding of the disease and disease progression, limitations inherent to each model have slowed the clinical advancement of therapies, which necessitates the development of novel large-animal models. Several porcine dystrophin-deficient models have been identified, although disease severity may be so severe as to limit their potential contributions to the field. We have recently identified and completed the initial characterization of a natural porcine model of dystrophin insufficiency. Muscles from these animals display characteristic focal necrosis concomitant with decreased abundance and localization of dystrophin-glycoprotein complex components. These pigs recapitulate many of the cardinal features of muscular dystrophy, have elevated serum creatine kinase activity, and preliminarily appear to display altered locomotion. They also suffer from sudden death preceded by EKG abnormalities. Pig dystrophinopathy models could allow refinement of dosing strategies in human-sized animals in preparation for clinical trials. From an animal handling perspective, these pigs can generally be treated normally, with the understanding that acute stress can lead to sudden death. In summary, the ability to create genetically modified pig models and the serendipitous discovery of genetic disease in the swine industry has resulted in the emergence of new animal tools to facilitate the critical objective of improving the quality and length of life for boys afflicted with such a devastating disease. PMID:25991703

  19. Physical Therapy and Facioscapulohumeral Muscular Dystrophy (FSHD)

    MedlinePLUS

    ... facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2005 Mar; 76(3):375‐86. Review. PMID: 15674778. 14. ... for tax purposes. ‐18‐ Contact Information FSH Society, Inc. 64 Grove Street Watertown, MA 02472 (617) 658‐ ...

  20. Genetics Home Reference: Oculopharyngeal muscular dystrophy

    MedlinePLUS

    ... contains an area where the protein building block (amino acid) alanine is repeated 10 times. This stretch of ... definitions help with understanding oculopharyngeal muscular dystrophy? alanine ; amino acid ; atrophy ; autosomal ; autosomal dominant ; autosomal recessive ; cell ; difficulty ...

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

    ClinicalTrials.gov

    2014-10-15

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

  2. [Muscular Dystrophies Involving the Retinal Function].

    PubMed

    Jägle, H

    2016-03-01

    Muscular dystrophies are rare disorders, with an incidence of approx. 20 in 100 000. Some dystrophies also affect retinal or optic nerve function. In such cases, the ophthalmological findings may be critical for differential diagnosis or patient counseling. For example in Duchenne muscular dystrophy, where the alteration in retinal function seems to reflect cerebral involvement. Other important forms are mitochondrial and metabolic disorders, such as the Kearns-Sayre syndrome and the Refsum syndrome. Molecular genetic analysis has become a major tool for differential diagnosis, but may be complex and demanding. This article gives an overview of major muscular dystrophies involving retinal function and their genetic origin, in order to guide differential diagnosis. PMID:27011029

  3. Genetics Home Reference: Limb-girdle muscular dystrophy

    MedlinePLUS

    ... most common form of limb-girdle muscular dystrophy, accounting for about 30 percent of cases. Dysferlinopathy, also ... Where can I find information about diagnosis or management of limb-girdle muscular dystrophy? These resources address ...

  4. Cellular and molecular mechanisms underlying muscular dystrophy

    PubMed Central

    2013-01-01

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  5. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to…

  6. Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    De Moura, Maria Clara Drummond Soares; do Valle, Luiz Eduardo Ribeiro; Resende, Maria Bernadete Dutra; Pinto, Katia Osternack

    2010-01-01

    Aim: The cognitive deficits present in the Duchenne muscular dystrophy (DMD) are not yet well characterized. Attention, considered to be the brain mechanism responsible for the selection of sensory stimuli, could be disturbed in DMD, contributing, at least partially, to the observed global cognitive deficit. The aim of this study was to

  7. Prevalence of congenital muscular dystrophy in Italy

    PubMed Central

    Graziano, Alessandra; Bianco, Flaviana; D'Amico, Adele; Moroni, Isabella; Messina, Sonia; Bruno, Claudio; Pegoraro, Elena; Mora, Marina; Astrea, Guja; Magri, Francesca; Comi, Giacomo P.; Berardinelli, Angela; Moggio, Maurizio; Morandi, Lucia; Pini, Antonella; Petillo, Roberta; Tasca, Giorgio; Monforte, Mauro; Minetti, Carlo; Mongini, Tiziana; Ricci, Enzo; Gorni, Ksenija; Battini, Roberta; Villanova, Marcello; Politano, Luisa; Gualandi, Francesca; Ferlini, Alessandra; Muntoni, Francesco; Santorelli, Filippo Maria; Bertini, Enrico; Pane, Marika

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with ?-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin ?2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  8. Exon Snipping in Duchenne Muscular Dystrophy.

    PubMed

    Kemaladewi, Dwi U; Cohn, Ronald D

    2016-03-01

    Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. We discuss very recent studies that used CRISPR/Cas9 technology to 'snip out' mutated exons in DMD, restoring the reading frame of the gene. We also present cautionary aspects of translating this exciting technology into clinical practice. PMID:26856237

  9. Echinocytes in families with Duchenne muscular dystrophy.

    PubMed Central

    Soltan, H C

    1977-01-01

    The results of the present investigation have failed to confirm the suggestion that there is a significant increase in the proportion of echinocytes in preparation of fresh erythrocytes in patients with Duchenne muscular dystrophy and heterozygous carriers of this disorder. PMID:926140

  10. Obstructive apnoeas in Duchenne muscular dystrophy.

    PubMed Central

    Khan, Y.; Heckmatt, J. Z.

    1994-01-01

    BACKGROUND--In order to clarify the treatment of sleep hypoxaemias in Duchenne muscular dystrophy polysomnographic studies were performed on patients at home with the purpose of recruiting them into two clinical therapeutic trials. Observations concerning the nature of sleep hypoxaemia in these patients are presented. METHODS--Twenty one non-ambulant patients with Duchenne muscular dystrophy aged 13-23 years with no symptoms of sleep hypoventilation or apnoea were studied for two consecutive nights with eight channel polysomnography. A comparative study was performed in 12 age matched normal male subjects. The evolution of sleep hypoxaemia with age was studied in 14 patients with Duchenne muscular dystrophy. RESULTS--Thirteen of the 21 patients had hypoxaemia below 90% during sleep, and 12 of the 13 had discrete hypoxaemic dips in association with apnoeas; 60% of all apnoeas were obstructive in nature. The hypoxaemic periods became more frequent with increasing age and, in two patients at three year follow up, were more frequently associated with central or possibly "pseudocentral" apnoeas. Although the normal subjects had a few apnoeic episodes, none had sleep hypoxaemia below 90% saturation. CONCLUSION--The sleep related breathing abnormality in Duchenne muscular dystrophy is initially obstructive and this has implications for management. PMID:8128406

  11. Limb Girdle Muscular Dystrophy (LGMD): Case Report

    PubMed Central

    Kalyan, Meenakshi; Gaikwad, Anu N.; Makadia, Ankit; Shah, Harshad

    2015-01-01

    We report a young male of autosomal recessive limb girdle muscular dystrophy (LGMD) with positive family history presented with gradual onset proximal muscle weakness in all four limbs since eight years and thinning of shoulders, arms and thighs. Neurological examination revealed atrophy of both shoulders with wasting of both deltoids thinning of thighs and pseudo hypertrophy of both calves, hypotonia in all four limbs. Gowers sign was positive. Winging of scapula was present. Power was 3/5 at both shoulders, 4/5 at both elbows, 5/5 at both wrists, 3/5 at both hip joints, 3/5 at both knees, 5/5 at both ankles. All deep tendon reflexes and superficial reflexes were present with plantars bilateral flexors. Electromyography (EMG) showed myopathic pattern. He had elevated creatinine phosphokinase levels and muscle biopsy findings consistent with muscular dystrophy. PMID:25738022

  12. Osteoprotegerin protects against muscular dystrophy.

    PubMed

    Dufresne, Sbastien S; Dumont, Nicolas A; Bouchard, Patrice; Lavergne, liane; Penninger, Josef M; Frenette, Jrme

    2015-04-01

    Receptor-activator of NF-?B, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis. PMID:25708645

  13. Ullrich's congenital atonic sclerotic muscular dystrophy. A case report.

    PubMed

    De Paillette, L; Aicardi, J; Goutires, F

    1989-02-01

    A 5-year old girl with Ullrich's atonic-sclerotic muscular dystrophy is reported and 16 previously reported cases are reviewed. The clinical features, in particular proximal contractures, distal hyperextensibility, mild dysmorphism and hyperhidrosis, allow recognition of this subtype of congenital muscular dystrophy, which has no specific pathological characteristics. There is evidence in favour of an autosomal recessive mode of inheritance. PMID:2651568

  14. Purloined mechanisms of bacterial immunity can cure muscular dystrophy.

    PubMed

    Tidball, James G; Bertoni, Carmen

    2014-12-01

    Myriad strategies have been explored to compensate for the lack of dystrophin or to skip mutations that cause the lethal disease Duchenne muscular dystrophy (DMD). A new study shows that gene editing strategies used by bacteria can be applied in zygotes of a mouse model of DMD to correct the genetic defect that causes muscular dystrophy (Long etal., 2014). PMID:25470540

  15. Exon skipping therapy for Duchenne muscular dystrophy.

    PubMed

    Kole, Ryszard; Krieg, Arthur M

    2015-06-29

    Duchenne muscular dystrophy (DMD) is caused mostly by internal deletions in the gene for dystrophin, a protein essential for maintaining muscle cell membrane integrity. These deletions abrogate the reading frame and the lack of dystrophin results in progressive muscle deterioration. DMD patients experience progressive loss of ambulation, followed by a need for assisted ventilation, and eventual death in mid-twenties. By the method of exon skipping in dystrophin pre-mRNA the reading frame is restored and the internally deleted but functional dystrophin is produced. Two oligonucleotide drugs that induce desired exon skipping are currently in advanced clinical trials. PMID:25980936

  16. Upper Girdle Imaging in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Tasca, Giorgio; Monforte, Mauro; Iannaccone, Elisabetta; Laschena, Francesco; Ottaviani, Pierfrancesco; Leoncini, Emanuele; Boccia, Stefania; Galluzzi, Giuliana; Pelliccioni, Marco; Masciullo, Marcella; Frusciante, Roberto; Mercuri, Eugenio; Ricci, Enzo

    2014-01-01

    Background In Facioscapulohumeral muscular dystrophy (FSHD), the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment. Methods We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed. Results The trapezius (100% of the patients) and serratus anterior (85% of the patients) were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients) were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR) sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies. Conclusions The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease. PMID:24932477

  17. The Pathogenesis and Therapy of Muscular Dystrophies.

    PubMed

    Guiraud, Simon; Aartsma-Rus, Annemieke; Vieira, Natassia M; Davies, Kay E; van Ommen, Gert-Jan B; Kunkel, Louis M

    2015-01-01

    Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics. PMID:26048046

  18. Birdshot chorioretinopathy in a male patient with facioscapulohumeral muscular dystrophy.

    PubMed

    Papavasileiou, Evangelia; Lobo, Ann-Marie

    2015-01-01

    We report a case of birdshot chorioretinopathy (BSCR) in a patient with facioscapulohumeral muscular dystrophy (FSHD). A 40-year-old male with history of facioscapulohumeral muscular dystrophy with significant facial diplegia and lagophthalmos presents for an evaluation of bilateral choroiditis with vasculitis and optic disc edema. Clinical examination included fundus and autofluorescence photographs, fluorescein angiography, and optical coherence tomography. To our knowledge, this patient represents the first reported case of birdshot chorioretinopathy with facioscapulohumeral muscular dystrophy. Patients with FSHD can present with ocular findings and should be screened with dilated fundus examinations for retinal vascular changes and posterior uveitis. PMID:25861398

  19. Membrane Injury and Repair in the Muscular Dystrophies.

    PubMed

    Cooper, Sandra T; Head, Stewart I

    2015-12-01

    Muscle cells have an elaborate plasma membrane and t-tubule system that has been evolutionarily refined to maximize electrical conductivity for synchronous muscle contraction. However, this elaborate plasma membrane network has intrinsic vulnerabilities to stretch-induced membrane injury, and thus requires ongoing maintenance and repair. Herein we discuss the types of membrane injuries encountered by myofibers in healthy muscle and in muscular dystrophy. We review the different mechanisms by which muscle fibers in patients with muscular dystrophy are rendered more susceptible to injury, and we summarize the latest developments in our understanding of how the muscular dystrophy protein dysferlin mediates satellite-cell independent membrane repair. PMID:25406223

  20. 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. PMID:26022172

  1. Congenital Muscular Dystrophies: A Brief Review

    PubMed Central

    Bertini, Enrico; D'Amico, Adele; Gualandi, Francesca; Petrini, Stefania

    2011-01-01

    Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments. PMID:22172424

  2. Current treatment of adult Duchenne muscular dystrophy.

    PubMed

    Wagner, Kathryn R; Lechtzin, Noah; Judge, Daniel P

    2007-02-01

    Patients with Duchenne muscular dystrophy (DMD) are living longer into adulthood due to a variety of improvements in health care practices. This growing patient population presents new therapeutic challenges. In this article, we review the literature on current treatment of adult DMD as well as our own experience as a multidisciplinary team actively caring for 23 men ages 19-38 years of age. Approximately one quarter of our adult DMD patients have remained on moderate dose corticosteroids. Daily stretching exercises are recommended, particularly of the distal upper extremities. Cardiomyopathy is anticipated, detected, and treated early with afterload reduction. Oxygen saturation monitoring, noninvasive positive pressure ventilation and cough assist devices are routinely used. Other medical issues such as osteoporosis, gastrointestinal and urinary symptoms are addressed. Current and future therapies directed at prolonging the lifespan of those with DMD will result in further increases in this adult population with special needs and concerns. These needs are best addressed in a multidisciplinary clinic. PMID:16887341

  3. uPA deficiency exacerbates muscular dystrophy in MDX mice

    PubMed Central

    Suelves, Mnica; Vidal, Berta; Serrano, Antonio L.; Tjwa, Marc; Roma, Josep; Lpez-Alemany, Roser; Luttun, Aernout; de Lagrn, Mara Martnez; Daz, Maria ngels; Jard, Merc; Roig, Manuel; Dierssen, Mara; Dewerchin, Mieke; Carmeliet, Peter; Muoz-Cnoves, Pura

    2007-01-01

    Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy. PMID:17785520

  4. 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

  5. Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

    ERIC Educational Resources Information Center

    Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-01-01

    Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of

  6. Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire

    ERIC Educational Resources Information Center

    Archer, Sally K.; Garrod, Rachel; Hart, Nicholas; Miller, Simon

    2013-01-01

    Background: Duchenne muscular dystrophy (DMD) leads to progressive muscular weakness and death, most typically from respiratory complications. Dysphagia is common in DMD; however, the most appropriate swallowing assessments have not been universally agreed and the symptoms of dysphagia remain under-reported. Aims: To investigate symptoms of…

  7. Left ventricular noncompaction in Duchenne muscular dystrophy

    PubMed Central

    2013-01-01

    Background Left ventricular noncompaction (LVNC) describes deep trabeculations in the left ventricular (LV) endocardium and a thinned epicardium. LVNC is seen both as a primary cardiomyopathy and as a secondary finding in other syndromes affecting the myocardium such as neuromuscular disorders. The objective of this study is to define the prevalence of LVNC in the Duchenne Muscular Dystrophy (DMD) population and characterize its relationship to global LV function. Methods Cardiac magnetic resonance (CMR) was used to assess ventricular morphology and function in 151 subjects: DMD with ejection fraction (EF)?>?55% (n?=?66), DMD with EF??2.3 for any segment. Results LVNC criteria were met by 27/96 DMD patients (prevalence of 28%): 11 had an EF?>?55% (prevalence of 16.7%), and 16 had an EF??55%, 2.46 for DMD with EF?muscular degeneration versus compensatory remodeling. PMID:23914774

  8. Satellite Cells: Regenerative Mechanisms and Applicability in Muscular Dystrophy

    PubMed Central

    Zanette, Rafaella de Souza Salomão; do Amaral, Danielle Luciana Aurora Soares; da Guia, Francisco Carlos; Maranduba, Claudinéia Pereira; de Souza, Camila Maurmann; Guimarães, Ernesto da Silveira Goulart; Rettore, João Vitor Paes; Rabelo, Natana Chaves; do Carmo, Antônio Márcio Resende; Silva, Fernando de Sá; Maranduba, Carlos Magno da Costa

    2015-01-01

    The satellite cells are long regarded as heterogeneous cell population, which is intimately linked to the processes of muscular recovery. The heterogeneous cell population may be classified by specific markers. In spite of the significant amount of variation amongst the satellite cell populations, it seems that their activity is tightly bound to the paired box 7 transcription factor expression, which is, therefore, used as a canonical marker for these cells. Muscular dystrophic diseases, such as Duchenne muscular dystrophy, elicit severe tissue injuries leading those patients to display a very specific pattern of muscular recovery abnormalities. There have been works on the application of precursors cells as a therapeutic alternative for Duchenne muscular dystrophy and initial attempts have proven the cells inefficient; however later endeavours have proposed solutions for the experiments improving significantly the results. The presence of a range of satellite cells populations indicates the existence of specific cells with enhanced capability of muscular recovery in afflicted muscles. PMID:25763072

  9. Limb-girdle muscular dystrophy 2A.

    PubMed

    Gallardo, Eduard; Saenz, Amets; Illa, Isabel

    2011-01-01

    Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the gene CAPN3 located in the chromosome region 15q15.1-q21.1. To date more than 300 mutations have been described. This gene encodes for a 94-kDa nonlysosomal calcium-dependent cysteine protease and its function in skeletal muscle is not fully understood. It seems that calpain-3 has an unusual zymogenic activation that involves, among other substrates, cytoskeletal proteins. Calpain-3 is thought to interact with titin and dysferlin. Calpain-3 deficiency produces abnormal sarcomeres that lead eventually to muscle fiber death. Hip adductors and gluteus maximus are the earliest clinically affected muscles. No clinical differences have been reported depending on the type of mutation in the CAPN3 gene. The muscle biopsy shows variability of fiber size, interstitial fibrosis, internal nuclei, lobulated fibers, and, in some cases, presence of eosinophils. Recent gene expression profiling studies have shown upregulation of interleukin-32 and immunoglobulin genes, which may explain the eosinophilic infiltration. Two mouse knockout models of CAPN3 have been characterized. There are no curative treatments for this disease. However, experimental therapeutics using mouse models conclude that adeno-associated virus (AAV) vectors seem to be one of the best approaches because of their efficiency and persistency of gene transfer. PMID:21496626

  10. Restrictive Lung Involvement in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Scully, Michele A; Eichinger, Katy J; Donlin-Smith, Colleen M; Tawil, Rabi; Statland, Jeffery M

    2014-01-01

    Introduction Few studies have evaluated the frequency or predisposing factors for respiratory involvement in facioscapulohumeral muscular dystrophy type 1 (FSHD1) and type 2 (FSHD2). Methods We performed a prospective cross-sectional observational study of 61 genetically confirmed FSHD participants (53 FSHD1 and 8 FSHD2). Participants underwent bedside pulmonary function testing in sitting and supine positions, a standard clinical history and physical assessment, and manual muscle testing. Results Restrictive respiratory involvement was suggested in 9.8% (95% confidence interval 2.4 17.3): 7.5% FSHD1 and 25.0% FSHD2 (P=0.17). Participants with testing suggestive of restrictive lung involvement (n=6) were more severely affected (P=0.005), had weaker hip flexion (P=0.0007), and were more likely to use a wheelchair (P=0.01). Conclusion Restrictive respiratory involvement should be considered in all moderate to severely affected FSHD patients with proximal lower extremity weakness. The higher frequency of restrictive lung disease in FSHD2 seen here requires confirmation in a larger cohort of FSHD2 patients. PMID:24639337

  11. Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Upadhyaya, M.; Maynard, J.; Osborn, M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. The disease locus maps to 4q35 and is associated with a de novo DNA rearrangement, detected by a probe p13E-11 (D4F104S1) which maps proximal to the disease locus. An informative distal flanking marker for this condition is still required. Using p13E-11, we have analyzed 35 FSHD families in which the disease is apparently associated with a new mutation. Twenty three of these cases were found to have a smaller rearranged DNA fragment which was not present in either of the parents. Pulsed-field gel analysis of 5 of these families also revealed evidence of DNA deletion. During the course of this study, we identified one case with a DNA rearrangement which was also present in the unaffected mother, but at very low intensity. This finding has been confirmed by pulsed-field gel analysis, and indicates that the mother is probably a gonosomal mosaic. In order to saturate the FSHD region with new DNA markers, a laser microdissection and microcloning technique was used to construct a genomic library from the distal end of chromosome 4. Of the 72 microclones analyzed, 42 mapped into the relevant 4q35 region. 4 sequences were conserved and may be considered potential candidate genes for FSHD. The microclones mapping to 4q35 are under study to identify additional polymorphic markers for the FSHD region.

  12. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

    PubMed Central

    van der Maarel, Silvre M.; Miller, Daniel G.; Tawil, Rabi; Filippova, Galina N.; Tapscott, Stephen J.

    2013-01-01

    Purpose of review In recent years we have seen remarkable progress in our understanding of the disease mechanism underlying facioscapulohumeral muscular dystrophy (FSHD). The purpose of this review is to provide a comprehensive overview of our current understanding of the disease mechanism and to discuss the observations supporting the possibility of a developmental defect in this disorder. Recent findings In the majority of cases FSHD is caused by contraction of the D4Z4 repeat array (FSHD1). This results in local chromatin relaxation and stable expression of the DUX4 retrogene in skeletal muscle, but only when a polymorphic DUX4 polyadenylation signal is present. In some cases (FSHD2), D4Z4 chromatin relaxation and stable DUX4 expression occurs in the absence of D4Z4 array contraction. DUX4 is a germline transcription factor and its expression in skeletal muscle leads to activation of early stem cell and germline programs and transcriptional activation of retroelements. Summary Recent studies have provided a plausible disease mechanism for FSHD where FSHD results from inappropriate expression of the germline transcription factor DUX4. The genes regulated by DUX4 suggest several mechanisms of muscle damage, and provide potential biomarkers and therapeutic targets that should be investigated in future studies. PMID:22892954

  13. Gene Therapy for Duchenne muscular dystrophy

    PubMed Central

    Ramos, Julian; Chamberlain, Jeffrey S

    2015-01-01

    Introduction Duchenne muscular dystrophy (DMD) is a relatively common inherited disorder caused by defective expression of the protein dystrophin. The most direct approach to treating this disease would be to restore dystrophin production in muscle. Recent progress has greatly increased the prospects for successful gene therapy of DMD, and here we summarize the most promising developments. Areas Covered Gene transfer using vectors derived from adeno-associated virus (AAV) has emerged as a promising method to restore dystrophin production in muscles bodywide, and represents a treatment option applicable to all DMD patients. Using information gleaned from PubMed searches of the literature, attendance at scientific conferences and results from our own lab, we provide an overview of the potential for gene therapy of DMD using AAV vectors including a summary of promising developments and issues that need to be resolved prior to large-scale therapeutic implementation. Expert Opinion Of the many approaches being pursued to treat DMD and BMD, gene therapy based on AAV-mediated delivery of microdystrophin is the most direct and promising method to treat the cause of the disorder. The major challenges to this approach are ensuring that microdystrophin can be delivered safely and efficiently without eliciting an immune response. PMID:26594599

  14. Optimizing Bone Health in Duchenne Muscular Dystrophy

    PubMed Central

    Buckner, Jason L.; Bowden, Sasigarn A.; Mahan, John D.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder characterized by progressive muscle weakness, with eventual loss of ambulation and premature death. The approved therapy with corticosteroids improves muscle strength, prolongs ambulation, and maintains pulmonary function. However, the osteoporotic impact of chronic corticosteroid use further impairs the underlying reduced bone mass seen in DMD, leading to increased fragility fractures of long bones and vertebrae. These serious sequelae adversely affect quality of life and can impact survival. The current clinical issues relating to bone health and bone health screening methods in DMD are presented in this review. Diagnostic studies, including biochemical markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry (DXA), as well as spinal imaging using densitometric lateral spinal imaging, and treatment to optimize bone health in patients with DMD are discussed. Treatment with bisphosphonates offers a method to increase bone mass in these children; oral and intravenous bisphosphonates have been used successfully although treatment is typically reserved for children with fractures and/or bone pain with low bone mass by DXA. PMID:26124831

  15. Lipomatous muscular 'dystrophy' of Piedmontese cattle.

    PubMed

    Biasibetti, E; Amedeo, S; Brugiapaglia, A; Destefanis, G; Di Stasio, L; Valenza, F; Capucchio, M T

    2012-11-01

    Lipomatous myopathy is a degenerative muscle pathology characterized by the substitution of muscle cells with adipose tissue, sporadically reported in cattle, pigs, and rarely in sheep, horses and dogs. This study investigated the pathology of this myopathy in 40 muscle samples collected from regularly slaughtered Piedmontese cattle living in Piedmont region (Italy). None of the animals showed clinical signs of muscular disease. Muscle specimens were submitted to histological and enzymatic investigations. Gross pathology revealed a different grade of infiltration of adipose tissue, involving multiple or single muscles. The most affected regions were the ventral abdomen and the shoulders, especially the cutaneous muscles and the muscles of the thoracic group. Morphological staining revealed an infiltration of adipose tissue varying in distribution and severity, changes in muscle fibre size and increased number of fibres with centrally located nuclei, suggesting muscle degeneration-regeneration. Necrosis and non-suppurative inflammatory cells were also seen. Furthermore, proliferation of connective tissue and non-specific myopathic changes were present. Chemical and physical characteristics of the affected tissue were also evaluated. The authors discuss about the aetiopathogenesis and classification of this muscle disorder whose histological lesions were similar to those reported in human dystrophies. PMID:22717052

  16. [Specific features of Becker Muscular Dystrophy patients and female carriers of Duchenne Muscular Dystrophy].

    PubMed

    Magot, A; Mercier, S; Pron, Y

    2015-12-01

    Becker muscular dystrophy (BMD) was first described in 1955 and linked to the DMD gene in 1987. Compared to Duchenne muscular dystrophy (DMD), clinical onset of BMD usually occurs after the age of 12 and wheelchair is required after the age of 16. BMD is characterized by generalized weakness first affecting limb girdle muscles, hypertrophy of the calves and cardiomyopathy in males. Some patients have only mild symptoms such as cramps or elevated serum creatine kinases (SCK) throughout all their lives. SCK levels are usually elevated. Muscle biopsy (immunohistochemistry or immunoblotting) shows a dystrophic pattern with abnormal dystrophin staining. Diagnosis is confirmed by DMD gene sequencing. Deletions or duplications of one or several exons are identified in the majority of cases. A multidisciplinary approach is recommended for the care management of these patients with a particular attention to the cardiomyopathy, which is typically responsible for death but can be prevented by specific treatment. X-linked dilated cardiomyopathies linked to DMD gene are a phenotypic continuum of BMD. Some female carriers of DMD mutations exhibit clinical symptoms of variable severity, often milder and beginning later than in males. The cardiomyopathy is the most frequent feature that should be especially monitored in these patients. Genetic counselling should be systematically proposed. PMID:26773584

  17. Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication

    MedlinePLUS

    ... 2013 March 2013 (historical) Experimental Treatment for Duchenne Muscular Dystrophy Gets Boost from Existing Medication A readily available ... effects of a promising experimental treatment for Duchenne muscular dystrophy (DMD), according to research partially funded by the ...

  18. NIH study shows increased risk for two types of myotonic muscular dystrophy

    Cancer.gov

    Adults with a form of muscular dystrophy called myotonic muscular dystrophy (MMD) may be at increased risk of developing cancer, according to a study by investigators at the National Cancer Institute (NCI), part of the National Institutes of Health.

  19. Neurocognitive Profiles in Duchenne Muscular Dystrophy and Gene Mutation Site

    PubMed Central

    D’Angelo, Maria Grazia; Lorusso, Maria Luisa; Civati, Federica; Comi, Giacomo Pietro; Magri, Francesca; Del Bo, Roberto; Guglieri, Michela; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo

    2011-01-01

    The presence of nonprogressive cognitive impairment is recognized as a common feature in a substantial proportion of patients with Duchenne muscular dystrophy. To investigate the possible role of mutations along the dystrophin gene affecting different brain dystrophin isoforms and specific cognitive profiles, 42 school-age children affected with Duchenne muscular dystrophy, subdivided according to sites of mutations along the dystrophin gene, underwent a battery of tests tapping a wide range of intellectual, linguistic, and neuropsychologic functions. Full-scale intelligence quotient was approximately 1 S.D. below the population average in the whole group of dystrophic children. Patients with Duchenne muscular dystrophy and mutations located in the distal portion of the dystrophin gene (involving the 140-kDa brain protein isoform, called Dp140) were generally more severely affected and expressed different patterns of strengths and impairments, compared with patients with Duchenne muscular dystrophy and mutations located in the proximal portion of the dystrophin gene (not involving Dp140). Patients with Duchenne muscular dystrophy and distal mutations demonstrated specific impairments in visuospatial functions and visual memory (which seemed intact in proximally mutated patients) and greater impairment in syntactic processing. PMID:22000308

  20. The burden of Duchenne muscular dystrophy

    PubMed Central

    Landfeldt, Erik; Lindgren, Peter; Bell, Christopher F.; Schmitt, Claude; Guglieri, Michela; Straub, Volker; Lochmller, Hanns

    2014-01-01

    Objective: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Methods: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in EuropeAssessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. Results: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and $54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and $120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and $71,900. Conclusions: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies. PMID:24991029

  1. Gastrointestinal manifestations in myotonic muscular dystrophy

    PubMed Central

    Bellini, Massimo; Biagi, Sonia; Stasi, Cristina; Costa, Francesco; Mumolo, Maria Gloria; Ricchiuti, Angelo; Marchi, Santino

    2006-01-01

    Myotonic dystrophy (MD) is characterized by myotonic phenomena and progressive muscular weakness. Involvement of the gastrointestinal tract is frequent and may occur at any level. The clinical manifestations have previously been attributed to motility disorders caused by smooth muscle damage, but histologic evidence of alterations has been scarce and conflicting. A neural factor has also been hypothesized. In the upper digestive tract, dysphagia, heartburn, regurgitation and dyspepsia are the most common complaints, while in the lower tract, abdominal pain, bloating and changes in bowel habits are often reported. Digestive symptoms may be the first sign of dystrophic disease and may precede the musculo-skeletal features. The impairment of gastrointestinal function may be sometimes so gradual that the patients adapt to it with little awareness of symptoms. In such cases routine endoscopic and ultrasonographic evaluations are not sufficient and targeted techniques (electrogastrography, manometry, electromyography, functional ultrasonography, scintigraphy, etc.) are needed. There is a low correlation between the degree of skeletal muscle involvement and the presence and severity of gastrointestinal disturbances whereas a positive correlation with the duration of the skeletal muscle disease has been reported. The drugs recommended for treating the gastrointestinal complaints such as prokinetic, anti-dyspeptic drugs and laxatives, are mainly aimed at correcting the motility disorders. Gastrointestinal involvement in MD remains a complex and intriguing condition since many important problems are still unsolved. Further studies concentrating on genetic aspects, early diagnostic techniques and the development of new therapeutic strategies are needed to improve our management of the gastrointestinal manifestations of MD. PMID:16609987

  2. Duchenne Muscular Dystrophy: From Diagnosis to Therapy.

    PubMed

    Falzarano, Maria Sofia; Scotton, Chiara; Passarelli, Chiara; Ferlini, Alessandra

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options. PMID:26457695

  3. Neuropsychological profile of duchenne muscular dystrophy.

    PubMed

    Perumal, Anna Roshini; Rajeswaran, Jamuna; Nalini, Atchayaram

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder characterized by progressive muscle wasting. DMD is a fatal X-linked recessive disorder with an estimated prevalence of 1 in 3,500 male live births. This disease has long been associated with intellectual impairment. Research has shown that boys with DMD have variable intellectual performance, indicating the presence of specific cognitive deficits. The aim of the study was to use a battery of intelligence, learning, and memory tests to identify a neuropsychological profile in boys with DMD. A total of 22 boys diagnosed with DMD in the age range of 6 to 10 years old were evaluated using the Wechsler Intelligence Scale for Children-Third Edition, Rey's Auditory Verbal Learning Test, and the Memory for Designs Test. The data were interpreted using means, standard deviations, percentages, and percentiles. Normative data were also used for further interpretation. The results showed that boys with DMD had a significantly lower IQ (88.5). Verbal IQ (86.59) was found to be lower than Performance IQ (92.64). There was evidence of impaired performance on the Processing Speed, Freedom From Distractibility, and Verbal Comprehension Indexes. Specific deficits in information processing, complex attention, immediate verbal memory span, verbal working memory, verbal comprehension, vocabulary, visuoconstruction ability, and verbal learning and encoding were observed. However, perceptional organization, general fund of information, abstract reasoning, visual discrimination and acuity, visual learning and memory, and verbal memory were adequate. The neuropsychological findings support the hypothesis that these children have specific cognitive deficits as opposed to a global intellectual deficit. PMID:24279481

  4. Treatment options for Duchenne muscular dystrophy.

    PubMed

    Ciafaloni, Emma; Moxley, Richard T

    2008-03-01

    The main goal in the treatment of Duchenne muscular dystrophy (DMD) is to maintain ambulation for as long as possible and to anticipate and manage the associated complications, such as joint contractures, scoliosis, cardiomyopathy, respiratory insufficiency, and weight gain. Cognitive and behavioral symptoms occur in about one third of patients, and it is important to recognize and manage them promptly, developing an individualized plan at school and at home to maximize the patient's cognitive abilities. In the late phase of the disease, palliative care is of paramount importance. Corticosteroid therapy (prednisone and deflazacort) is the only effective pharmacologic treatment for DMD. Daily prednisone treatment increases muscle strength and function, improves pulmonary function, and significantly slows the progression of weakness. Deflazacort has a similar effect on muscle strength, but it is not available in the United States. Treatment with corticosteroid should be offered to all patients with DMD, but the beneficial effects and potential adverse effects should be fully discussed before treatment begins. The optimal dose of prednisone is 0.75 mg/kg per day, up to a maximum of 40 mg/d. If adverse effects occur, a decrease in dosage is appropriate. Monitoring of muscle function and adverse effects by a neurologist or neuromuscular specialist is strongly recommended. Physical and occupational therapists should be involved early in the treatment of patients with DMD to develop a program that includes heel cord stretching and exercise. In the later phases, these therapists can recommend adaptive equipment and maximize independence. Orthopedic consultation is important in monitoring and managing scoliosis and joint contractures in the nonambulatory phase of the disease. Pulmonary evaluation for ventilatory care is important; pulmonary consultation is essential when vital capacity declines. The use of assistive cough devices, nasal bilevel positive airway pressure, and tracheostomy must be discussed with patients and their families. For all patients with DMD, particularly those receiving prednisone, consultation with a dietitian is very helpful to control weight and maintain a healthy diet. PMID:18334131

  5. Duchenne muscular dystrophy: current knowledge, treatment, and future prospects.

    PubMed

    Biggar, W Douglas; Klamut, Henry J; Demacio, Paula C; Stevens, Daniel J; Ray, Peter N

    2002-08-01

    The cloning of the dystrophin gene has led to major advances in the understanding of the molecular genetic basis of Duchenne, Becker, and other muscular dystrophies associated with mutations in genes encoding members of the dystrophin-associated glycoprotein complex. The recent introduction of pharmaceutical agents such as prednisone has shown great promise in delaying the progression of Duchenne muscular dystrophy but there remains a need to develop more long-term therapeutic interventions. Knowledge of the nature of the dystrophin gene and the glycoprotein complex has led many researchers to think that somatic gene replacement represents the most promising approach to treatment. The potential use of this strategy has been shown in the mdx mouse model of Duchenne muscular dystrophy, where germ line gene transfer of either a full-length or a smaller Becker-type dystrophin minigene prevents necrosis and restores normal muscle function. PMID:12151886

  6. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

    PubMed

    Vieira, Natassia M; Elvers, Ingegerd; Alexander, Matthew S; Moreira, Yuri B; Eran, Alal; Gomes, Juliana P; Marshall, Jamie L; Karlsson, Elinor K; Verjovski-Almeida, Sergio; Lindblad-Toh, Kerstin; Kunkel, Louis M; Zatz, Mayana

    2015-11-19

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP. PMID:26582133

  7. Determinants of the incidence of Duchenne muscular dystrophy

    PubMed Central

    2015-01-01

    Duchenne muscular dystrophy (DMD), an X-linked disorder, is the most common muscular dystrophy with an incidence in boys of about 200 per million births. It presents in early childhood leading to death in early teens. Its relatively high incidence and severity have stimulated many studies from epidemiological to curative. Recent advances in molecular biology have opened up the possibility of carrier identification and potential reduction of the incidence of cases. This paper gives a population genetics model which can be used to predict the reduction in incidence. PMID:26697447

  8. Dystrophin-deficient muscular dystrophy in two lurcher siblings.

    PubMed

    Giannasi, C; Tappin, S W; Guo, L T; Shelton, G D; Palus, V

    2015-09-01

    Two cases of dystrophin-deficient muscular dystrophy in 16-week-old male lurcher siblings are reported. The myopathies were characterised by regurgitation, progressive weakness and muscle wastage. The dogs had generalised weakness in all four limbs, with more pronounced weakness in the pelvic limbs. Reduced withdrawal in all limbs, muscle contracture and lingual hypertrophy were noted. Serum creatine kinase activities were markedly elevated. Electromyographic abnormalities included fibrillation potentials. Histopathological and immunohistochemical staining were consistent with dystrophin-deficient muscular dystrophy. Clinical improvement was noted in one of the cases with L-carnitine supplementation and supportive therapy. Genetic transmission of the disease was postulated as the dogs were siblings. PMID:25622540

  9. Cardiac involvement in Duchenne and Becker muscular dystrophy

    PubMed Central

    Mavrogeni, Sophie; Markousis-Mavrogenis, George; Papavasiliou, Antigoni; Kolovou, Genovefa

    2015-01-01

    Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscular diseases responsible for over 80% of all muscular dystrophies. Cardiac disease is a common manifestation, not necessarily related to the degree of skeletal myopathy; it may be the predominant manifestation with or without any other evidence of muscular disease. Death is usually due to ventricular dysfunction, heart block or malignant arrhythmias. Not only DMD/BMD patients, but also female carriers may present cardiac involvement. Clinically overt heart failure in dystrophinopathies may be delayed or absent, due to relative physical inactivity. The commonest electrocardiographic findings include conduction defects, arrhythmias (supraventricular or ventricular), hypertrophy and evidence of myocardial necrosis. Echocardiography can assess a marked variability of left ventricular dysfunction, independently of age of onset or mutation groups. Cardiovascular magnetic resonance (CMR) has documented a pattern of epicardial fibrosis in both dystrophinopathies patients and carriers that can be observed even if overt muscular disease is absent. Recently, new CMR techniques, such as postcontrast myocardial T1 mapping, have been used in Duchenne muscular dystrophy to detect diffuse myocardial fibrosis. A combined approach using clinical assessment and CMR evaluation may motivate early cardioprotective treatment in both patients and asymptomatic carriers and delay the development of serious cardiac complications. PMID:26225202

  10. Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  11. The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1979-01-01

    Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).…

  12. Phosphorylation of intact erythrocytes in human muscular dystrophy

    SciTech Connect

    Johnson, R.M.; Nigro, M.

    1986-04-01

    The uptake of exogenous /sup 32/Pi into the membrane proteins of intact erythrocytes was measured in 8 patients with Duchenne muscular dystrophy. No abnormalities were noted after autoradiographic analysis. This contrasts with earlier results obtained when isolated membranes were phosphorylated with gamma-(/sup 32/P)ATP, and suggests a possible reinterpretation of those experiments.

  13. Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Waring, Phoebe; Woodyatt, Gail

    2011-01-01

    Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results…

  14. 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;…

  15. Occupational Potential in a Population with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Schkade, Janette K.; And Others

    1987-01-01

    Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skill…

  16. Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; Fee, R. J.; De Vivo, D. C.; Goldstein, E.

    2007-01-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a…

  17. Muscle Weakness and Speech in Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

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

    2015-01-01

    Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals

  18. The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1979-01-01

    Challenges assumptions and research procedures leading to the position that below-average intellectual potential is an integral part of Duchenne muscular dystrophy. A study of 58 boys (ages 5 to 18) from urban, suburban, and rural settings indicated IQ range of 59 to 131 and no evidence of significant verbal deficit (reported in earlier studies).

  19. Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Waring, Phoebe; Woodyatt, Gail

    2011-01-01

    Substantial research has detailed the reading deficits experienced by children with Duchenne muscular dystrophy (DMD). Although phonological awareness (PA) is vital in reading development, little is known about PA in the DMD population. This pilot study describes the PA abilities of a group of five young children with DMD, comparing the results

  20. Dasatinib as a treatment for Duchenne muscular dystrophy

    PubMed Central

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

    2016-01-01

    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. PMID:26604135

  1. Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; Fee, R. J.; De Vivo, D. C.; Goldstein, E.

    2007-01-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a

  2. Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

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

    2010-01-01

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

  3. 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 ?-dystroglycan as a key event in the aetiology of Duchenne muscular dystrophy. Thus, preventing tyrosine phosphorylation and degradation of ?-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 ?-dystroglycan phosphorylation on tyrosine and to increase the relative levels of non-phosphorylated ?-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 ?-dystroglycan on tyrosine and subsequent steps in the degradation pathway as therapeutic targets for the treatment of Duchenne muscular dystrophy. PMID:26604135

  4. Muscle Weakness and Speech in Oculopharyngeal Muscular Dystrophy

    ERIC Educational Resources Information Center

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

    2015-01-01

    Purpose: We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Methods: Twelve individuals…

  5. Occupational Potential in a Population with Duchenne Muscular Dystrophy.

    ERIC Educational Resources Information Center

    Schkade, Janette K.; And Others

    1987-01-01

    Twenty-five males with Duchenne muscular dystrophy were tested to assess their potential for occupational activity. Tests measured possible sensory deficits, strength, endurance, and fatigue in response to sustained fine motor activity. Results indicate that, within limitations, persons with this diagnosis can engage in activity leading to skill

  6. [Diagnosis and natural history of Duchenne muscular dystrophy].

    PubMed

    Desguerre, I; Laugel, V

    2015-12-01

    Duchenne myopathy is today the most frequently encountered progressive muscular dystrophy in children, with an inexorable, progressive development to death in the third decade. Improvement in survival is related to improvement in orthopaedic management, early screening of cardiac and respiratory complications, but no curative therapy can be applied today beyond recent pharmacogenetic advances. This diagnosis is raised with evidence of proximal muscular deficit beginning after an interval free of symptoms lasting from 1 to several years. Muscular dystrophy's mechanism is suggested by a significant increase in CK (creatine kinase) and confirmed by muscle biopsy. The clinical motor and cognitive heterogeneity of this disease and its natural history need to be well known because it conditions future therapeutic trials. Identification of outcome measures such as the 6-minute walk test, the MFM score, manual muscle testing musculaire, or biomarkers is indispensable for patient follow-up and collaborative studies. PMID:26773582

  7. The role of fibrosis in Duchenne muscular dystrophy.

    PubMed

    Klingler, Werner; Jurkat-Rott, Karin; Lehmann-Horn, Frank; Schleip, Robert

    2012-12-01

    Muscular dystrophies such as Duchenne muscular dystrophy (DMD) are usually approached as dysfunctions of the affected skeletal myofibres and their force transmission. Comparatively little attention has been given to the increase in connective tissue (fibrosis) which accompanies these muscular changes. Interestingly, an increase in endomysial tissue is apparent long before any muscular degeneration can be observed. Fibrosis is the result of a reactive or reparative process involving mechanical, humoral and cellular factors. Originating from vulnerable myofibres, muscle cell necrosis and inflammatory processes are present in DMD. Muscular recovery is limited due to the limited number and capacity of satellite cells. Hence, a proactive and multimodal approach is necessary in order to activate protective mechanisms and to hinder catabolic and tissue degrading pathways. Several avenues are discussed in terms of potential antifibrotic therapy approaches. These include pharmaceutical, nutritional, exercise-based and other mechanostimulatory modalities (such as massage or yoga-like stretching) with the intention of exerting an anti-inflammatory and antifibrotic effect on the affected muscular tissues. A preventive intervention at an early age is crucial, based on the early and seemingly non-reversible nature of the fibrotic tissue changes. Since consistent assessment is essential, different measurement technologies are discussed. PMID:23620650

  8. The importance of genetic diagnosis for Duchenne muscular dystrophy

    PubMed Central

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-01-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  9. The importance of genetic diagnosis for Duchenne muscular dystrophy.

    PubMed

    Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate

    2016-03-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy are caused by mutations in the dystrophin-encoding DMD gene. Large deletions and duplications are most common, but small mutations have been found as well. Having a correct diagnosis is important for family planning and providing proper care to patients according to published guidelines. With mutation-specific therapies under development for DMD, a correct diagnosis is now also important for assessing whether patients are eligible for treatments. This review discusses different mutations causing DMD, diagnostic techniques available for making a genetic diagnosis for children suspected of DMD and the importance of having a specific genetic diagnosis in the context of emerging genetic therapies for DMD. PMID:26754139

  10. A unifying genetic model for facioscapulohumeral muscular dystrophy.

    PubMed

    Lemmers, Richard J L F; van der Vliet, Patrick J; Klooster, Rinse; Sacconi, Sabrina; Camao, Pilar; Dauwerse, Johannes G; Snider, Lauren; Straasheijm, Kirsten R; van Ommen, Gert Jan; Padberg, George W; Miller, Daniel G; Tapscott, Stephen J; Tawil, Rabi; Frants, Rune R; van der Maarel, Silvre M

    2010-09-24

    Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript. PMID:20724583

  11. Cell therapy in Duchenne muscular dystrophy treatment: clinical trials overview.

    PubMed

    Bajek, Anna; Porowinska, Dorota; Kloskowski, Tomasz; Brzoska, Edyta; Ciemerych, Maria A; Drewa, Tomasz

    2015-01-01

    Duchenne muscular dystrophy (DMD), the most common and most severe form of all muscular dystrophies, leads to progressive muscle fiber necrosis, fibroblast proliferation, and growth of fibrous tissue and fat. The most common cause of death in DMD patients is cardiac and respiratory failure. Current pharmacological and other treatment methods do not lead to full recovery. For this reason, new alternatives for skeletal muscle regeneration are being investigated. Transplantation of myoblasts from healthy donors is one studied approach to muscle treatment in DMD patients. However, the results of intramuscular injection of in vitro cultured myoblasts are still not satisfactory. The use of autologous stem cells is also proposed. Despite many ongoing studies, this therapy is still in preliminary testing and requires more experiments. PMID:25955813

  12. Evolution of molecular diagnosis of Duchenne muscular dystrophy.

    PubMed

    Itto, Afaf Ben; Hamzi, Khalil; Bellayou, Hanane; Itri, Mohammed; Slassi, Ilham; Nadifi, Sellama

    2013-06-01

    Duchenne muscular dystrophy (DMD) is the commonest of the muscular dystrophies. The DMD gene (DMD) is the biggest human gene and the most common molecular defect in the DMD gene, accounting for approximately 65 % of cases of DMD, is the deletion of one or more exons. The most basic method still in regular use involves multiplex PCR of the exons, known to be most commonly deleted. The multiplex is relatively simple. Quantitative analysis of all exons of the gene and multiplex ligation-dependent probe amplification have brought about an improvement in mutation detection rate, as they will detect all exon scale deletions as well as duplications, widely used to detect exonic and intronic mutations. As a sensitive and discriminative tool, MLPA can be used for prenatal testing. A more recent development in quantitative analysis is the use of oligonucleotide-based array comparative genomic hybridization. PMID:23381834

  13. [DIAGNOSTIC VARIATIONS OF X-LINKED MUSCULAR DYSTROPHY WITH CONTRACTURES].

    PubMed

    Kvirkvelia, N; Shakarishvili, R; Gugutsidze, D; Khizanishvili, N

    2015-01-01

    Case report with review describes X-linked muscular dystrophy with contractures in 28 years old man and his cousin. The disease revealed itself in an early stage (age 5-10), the process was progressing with apparent tendons retraction and contraction, limited movement in the areas of the neck and back of spine, atrophy of shoulder and pelvic yard and back muscles. Intellect was intact. Cardyomyopathy was exhibited. CK was normal. EMG showed classic myopathic features. Muscle biopsy showed different caliber groups of muscle fibers, growth of endo-perimesial connective tissue. Clinical manifestations together with electrophysiological and histological data suggest consistency with Rotthauwe-Mortier-Bayer X-linked muscular dystrophy. PMID:26177134

  14. The link between stress disorders and autonomic dysfunction in muscular dystrophy

    PubMed Central

    Sabharwal, Rasna

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time—(i) outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii) propose therapies that would improve behavioral and autonomic functions in muscular dystrophy. PMID:24523698

  15. Halofuginone promotes satellite cell activation and survival in muscular dystrophies.

    PubMed

    Barzilai-Tutsch, Hila; Bodanovsky, Anna; Maimon, Hadar; Pines, Mark; Halevy, Orna

    2016-01-01

    Halofuginone is a leading agent in preventing fibrosis and inflammation in various muscular dystrophies. We hypothesized that in addition to these actions, halofuginone directly promotes the cell-cycle events of satellite cells in the mdx and dysf(-/-) mouse models of early-onset Duchenne muscular dystrophy and late-onset dysferlinopathy, respectively. In both models, addition of halofuginone to freshly prepared single gastrocnemius myofibers derived from 6-week-old mice increased BrdU incorporation at as early as 18h of incubation, as well as phospho-histone H3 (PHH3) and MyoD protein expression in the attached satellite cells, while having no apparent effect on myofibers derived from wild-type mice. BrdU incorporation was abolished by an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, suggesting involvement of this pathway in mediating halofuginone's effects on cell-cycle events. In cultures of myofibers and myoblasts isolated from dysf(-/-) mice, halofuginone reduced Bax and induced Bcl2 expression levels and induced Akt phosphorylation in a time-dependent manner. Addition of an inhibitor of the phosphinositide-3-kinase/Akt pathway reversed the halofuginone-induced cell survival, suggesting this pathway's involvement in mediating halofuginone's effects on survival. Thus, in addition to its known role in inhibiting fibrosis and inflammation, halofuginone plays a direct role in satellite cell activity and survival in muscular dystrophies, regardless of the mutation. These actions are of the utmost importance for improving muscle pathology and function in muscular dystrophies. PMID:26454207

  16. Immune-mediated pathology in Duchenne muscular dystrophy.

    PubMed

    Rosenberg, Amy S; Puig, Montserrat; Nagaraju, Kanneboyina; Hoffman, Eric P; Villalta, S Armando; Rao, V Ashutosh; Wakefield, Lalage M; Woodcock, Janet

    2015-08-01

    Immunological and inflammatory processes downstream of dystrophin deficiency as well as metabolic abnormalities, defective autophagy, and loss of regenerative capacity all contribute to muscle pathology in Duchenne muscular dystrophy (DMD). These downstream cascades offer potential avenues for pharmacological intervention. Modulating the inflammatory response and inducing immunological tolerance to de novo dystrophin expression will be critical to the success of dystrophin-replacement therapies. This Review focuses on the role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention. PMID:26246170

  17. [Advance in therapy for Duchenne/Becker muscular dystrophy].

    PubMed

    Xu, Tian-Tian; Lan, Dan

    2015-03-01

    Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common X-linked recessive inherited neuromuscular disease, characterized by progressive muscle weakness. Mutations in the dystrophin gene are responsible for this disease. Treatment for this disease has always been a topic of interest. With the development of diagnosis and treatment technology of molecular biology, promising therapies have been developed. This review article summarizes the advance in traditional therapy, cell transplantation and gene therapy for this disease. PMID:25815505

  18. Neurotrophins, cytokines, oxidative parameters and funcionality in Progressive Muscular Dystrophies.

    PubMed

    Comim, Clarissa M; Mathia, Gisiane B; Hoepers, Andreza; Tuon, Lisiane; Kapczinski, Flvio; Dal-Pizzol, Felipe; Quevedo, Joo; Rosa, Maria I

    2015-09-01

    We investigated the levels of brain derived-neurotrophic factor (BDNF), cytokines and oxidative parameters in serum and tried to correlate them with the age and functionality of patients with Progressive Muscle Dystrophies (PMD). The patients were separated into six groups (case and controls pared by age and gender), as follows: Duchenne Muscular Dystrophy (DMD); Steinert Myotonic Dystrophy (SMD); and Limb-girdle Muscular Dystrophy type-2A (LGMD2A). DMD patients ( 17.9 years old) had a decrease of functionality, an increase in the IL-1? and TNF-? levels and a decrease of IL-10 levels and superoxide dismutase activity in serum. SMD patients ( 25.8 years old) had a decrease of BDNF and IL-10 levels and superoxide dismutase activity and an increase of IL-1? levels in serum. LGMD2A patients ( 27.7 years old) had an decrease only in serum levels of IL-10. This research showed the first evidence of BDNF involvement in the SMD patients and a possible unbalance between pro-inflammatory and anti-inflammatory cytokine levels, along with decreased superoxide dismutase activity in serum of DMD and SMD patients. PMID:25910175

  19. Gene therapy in large animal models of muscular dystrophy.

    PubMed

    Wang, Zejing; Chamberlain, Jeffrey S; Tapscott, Stephen J; Storb, Rainer

    2009-01-01

    The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases characterized by progressive muscle wasting, which can lead to premature death in severe forms such as Duchenne muscular dystrophy (DMD). In many cases they are caused by the absence of proteins that are critical components of the dystrophin-glycoprotein complex, which links the cytoskeleton and the basal lamina. There is no effective treatment for these disorders at present, but several novel strategies for replacing or repairing the defective gene are in development, with early encouraging results from animal models. We review these strategies, which include the use of stem cells of different tissue origins, gene replacement therapies mediated by various viral vectors, and transcript repair treatments using exon skipping strategies. We comment on their advantages and on limitations that must be overcome before successful application to human patients. Our focus is on studies in a clinically relevant large canine model of DMD. Recent advances in the field suggest that effective therapies for muscular dystrophies are on the horizon. Because of the complex nature of these diseases, it may be necessary to combine multiple approaches to achieve a successful treatment. PMID:19293461

  20. 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. PMID:25660133

  1. RESPIRATORY DYSFUNCTION IN UNSEDATED DOGS WITH GOLDEN RETRIEVER MUSCULAR DYSTROPHY

    PubMed Central

    DeVanna, Justin C.; Kornegay, Joe N.; Bogan, Daniel J.; Bogan, Janet R.; Dow, Jennifer L.; Hawkins, Eleanor C.

    2013-01-01

    Golden retriever muscular dystrophy (GRMD) is a well-established model of Duchenne muscular dystrophy. The value of this model would be greatly enhanced with practical tools to monitor progression of respiratory dysfunction during treatment trials. Arterial blood gas analysis, tidal breathing spirometry, and respiratory inductance plethysmography (RIP) were performed to determine if quantifiable abnormalities could be identified in unsedated, untrained, GRMD dogs. Results from 11 dogs with a mild phenotype of GRMD and 11 age-matched carriers were compared. Arterial blood gas analysis was successfully performed in all dogs, spirometry in 21 of 22 (95%) dogs, and RIP in 18 of 20 (90%) dogs. Partial pressure of carbon dioxide and bicarbonate concentration were higher in GRMD dogs. Tidal breathing peak expiratory flows were markedly higher in GRMD dogs. Abnormal abdominal motion was present in 7 of 10 (70%) GRMD dogs. Each technique provided objective, quantifiable measures that will be useful for monitoring respiratory function in GRMD dogs during clinical trials while avoiding the influence of sedation on results. Increased expiratory flows and the pattern of abdominal breathing are novel findings, not reported in people with Duchenne muscular dystrophy, and might be a consequence of hyperinflation. PMID:24295812

  2. Genetic Engineering of Dystroglycan in Animal Models of Muscular Dystrophy

    PubMed Central

    Sciandra, Francesca; Bigotti, Maria Giulia; Giardina, Bruno; Bozzi, Manuela; Brancaccio, Andrea

    2015-01-01

    In skeletal muscle, dystroglycan (DG) is the central component of the dystrophin-glycoprotein complex (DGC), a multimeric protein complex that ensures a strong mechanical link between the extracellular matrix and the cytoskeleton. Several muscular dystrophies arise from mutations hitting most of the components of the DGC. Mutations within the DG gene (DAG1) have been recently associated with two forms of muscular dystrophy, one displaying a milder and one a more severe phenotype. This review focuses specifically on the animal (murine and others) model systems that have been developed with the aim of directly engineering DAG1 in order to study the DG function in skeletal muscle as well as in other tissues. In the last years, conditional animal models overcoming the embryonic lethality of the DG knock-out in mouse have been generated and helped clarifying the crucial role of DG in skeletal muscle, while an increasing number of studies on knock-in mice are aimed at understanding the contribution of single amino acids to the stability of DG and to the possible development of muscular dystrophy. PMID:26380289

  3. Lipogenesis mitigates dysregulated sarcoplasmic reticulum calcium uptake in muscular dystrophy.

    PubMed

    Paran, Christopher W; Zou, Kai; Ferrara, Patrick J; Song, Haowei; Turk, John; Funai, Katsuhiko

    2015-12-01

    Muscular dystrophy is accompanied by a reduction in activity of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) that contributes to abnormal Ca(2+) homeostasis in sarco/endoplasmic reticulum (SR/ER). Recent findings suggest that skeletal muscle fatty acid synthase (FAS) modulates SERCA activity and muscle function via its effects on SR membrane phospholipids. In this study, we examined muscle's lipid metabolism in mdx mice, a mouse model for Duchenne muscular dystrophy (DMD). De novo lipogenesis was ~50% reduced in mdx muscles compared to wildtype (WT) muscles. Gene expressions of lipogenic and other ER lipid-modifying enzymes were found to be differentially expressed between wildtype (WT) and mdx muscles. A comprehensive examination of muscles' SR phospholipidome revealed elevated phosphatidylcholine (PC) and PC/phosphatidylethanolamine (PE) ratio in mdx compared to WT mice. Studies in primary myocytes suggested that defects in key lipogenic enzymes including FAS, stearoyl-CoA desaturase-1 (SCD1), and Lipin1 are likely contributing to reduced SERCA activity in mdx mice. Triple transgenic expression of FAS, SCD1, and Lipin1 (3TG) in mdx myocytes partly rescued SERCA activity, which coincided with an increase in SR PE that normalized PC/PE ratio. These findings implicate a defect in lipogenesis to be a contributing factor for SERCA dysfunction in muscular dystrophy. Restoration of muscle's lipogenic pathway appears to mitigate SERCA function through its effects on SR membrane composition. PMID:26361872

  4. Noncoding RNAs: Emerging Players in Muscular Dystrophies

    PubMed Central

    2014-01-01

    The fascinating world of noncoding RNAs has recently come to light, thanks to the development of powerful sequencing technologies, revealing a variety of RNA molecules playing important regulatory functions in most, if not all, cellular processes. Many noncoding RNAs have been implicated in regulatory networks that are determinant for skeletal muscle differentiation and disease. In this review, we outline the noncoding RNAs involved in physiological mechanisms of myogenesis and those that appear dysregulated in muscle dystrophies, also discussing their potential use as disease biomarkers and therapeutic targets. PMID:24729974

  5. Ehlers-Danlos syndrome, clotting disorders and muscular dystrophy.

    PubMed Central

    Bertin, P; Treves, R; Julia, A; Gaillard, S; Desproges-Gotteron, R

    1989-01-01

    Ehlers-Danlos syndrome includes 11 distinct entities. The diversity of this collagen dysplasia and its combination with other abnormalities make it difficult to understand physiopathologically. A case of Ehlers-Danlos syndrome is reported, which is novel owing to its combination with clotting abnormalities and especially with muscular dystrophy. To our knowledge this has not previously been reported. The patient was a young man aged 16 years who presented with Ehlers-Danlos syndrome satisfying Perelman's diagnostic criteria. His father and two brothers had comparable clinical symptoms, but his mother and sister were healthy. The four male subjects had an increased cephalin-kaolin time, reduced levels of factor VIII and Willebrand's factor (but without haemophilia A or Willebrand's disease), and, especially, an abnormal platelet ATP secretion. The proband alone had muscular disease with bilateral quadriceps fatigability and amyotrophy. The muscle enzyme levels were greatly increased, the electromyographic trace was myogenic, and the biopsy showed severe muscular dystrophy. This new observation poses the problem of the relation between clotting abnormalities and collagen abnormalities in the Ehlers-Danlos syndrome. It is difficult to classify this case within any of the 11 known types because of its muscular manifestations. It may perhaps be a fortuitous combination or an extension of the nosological framework of this syndrome. Images PMID:2512864

  6. Scalpel or Straitjacket: CRISPR/Cas9 Approaches for Muscular Dystrophies.

    PubMed

    Himeda, Charis L; Jones, Takako I; Jones, Peter L

    2016-04-01

    Versatility of CRISPR/Cas9-based platforms makes them promising tools for the correction of diverse genetic/epigenetic disorders. Here we contrast the use of these genome editing tools in two myopathies with very different molecular origins: Duchenne muscular dystrophy, a monogenetic disease, and facioscapulohumeral muscular dystrophy, an epigenetic disorder with unique therapeutic challenges. PMID:26917062

  7. 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…

  8. 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

  9. [A case of symptomatic sinus dysfunction described in oculopharyngeal muscular dystrophy. Fortuitous association or syndrome?].

    PubMed

    Belmihoub-Salmi, S

    2016-02-01

    Oculopharyngeal muscular dystrophy is a rare genetic disease manifesting after 45years old, affecting the levator muscles of eyelids and muscles of swallowing. We report the first case of a patient of 73years old suffering from an oculopharyngeal muscular dystrophy hospitalized for syncope, a complication of severe sinus dysfunction, requiring the implantation of a pacemaker. PMID:23177757

  10. New type of X-linked progressive muscular dystrophy involving shoulder girdle and back.

    PubMed

    Ji, X W; Tan, J; Chen, X Y; Yi, S X; Liang, H

    1990-10-01

    A new type of X-linked muscular dystrophy is described in a family in which 7 men had boyhood onset of progressive dystrophy involving muscles of the shoulder and back but not the calves or face. The scapula-back muscles are affected, but the calf muscles are normal. All patients are still able to walk. The oldest patient is now 37 years old. The muscular dystrophy has been specified by electromyography, pathologic tissue microscopic examination, electron microscopic study, and elevated CK. This type of muscular dystrophy has not been reported previously. PMID:2248287

  11. NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy.

    PubMed

    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

  12. 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

  13. Similarity of IQs of siblings with Duchenne progressive muscular dystrophy.

    PubMed

    Ogasawara, A

    1989-03-01

    The similarity of IQs of siblings with Duchenne progressive muscular dystrophy (DMD) was examined to determine whether the view that downward shift in IQ of patients with DMD is a genetically determined primary manifestation of the disease. The mean IQ difference was smaller and the IQ correlation was higher for siblings with DMD than for siblings without the disease. Moreover, these two indices were closer to those for healthy monozygotic twins reared together. These results suggest that the lowered IQ in patients with DMD has a genetic background. PMID:2706123

  14. RNAseq analysis for the diagnosis of muscular dystrophy.

    PubMed

    Gonorazky, Hernan; Liang, Minggao; Cummings, Beryl; Lek, Monkol; Micallef, Johann; Hawkins, Cynthia; Basran, Raveen; Cohn, Ronald; Wilson, Michael D; MacArthur, Daniel; Marshall, Christian R; Ray, Peter N; Dowling, James J

    2016-01-01

    The precise genetic cause remains elusive in nearly 50% of patients with presumed neurogenetic disease, representing a significant barrier for clinical care. This is despite significant advances in clinical genetic diagnostics, including the application of whole-exome sequencing and next-generation sequencing-based gene panels. In this study, we identify a deep intronic mutation in the DMD gene in a patient with muscular dystrophy using both conventional and RNAseq-based transcriptome analyses. The implications of our data are that noncoding mutations likely comprise an important source of unresolved genetic disease and that RNAseq is a powerful platform for detecting such mutations. PMID:26783550

  15. 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. PMID:24113355

  16. Cardiac MRI in muscular dystrophy: an overview and future directions.

    PubMed

    Otto, Randolph K; Ferguson, Mark R; Friedman, Seth D

    2012-02-01

    Cardiac complications are a common feature of many muscular dystrophies. Although many modalities (eg, ultrasound) provide exceptional efficacy for early diagnosis, repeated monitoring, and therapeutic management, MRI has become the gold standard for anatomic and functional characterization. An increasing number of studies, especially in the dystrophinopathies, use strain imaging to evaluate function. This article summarizes these studies and attempts to integrate an understanding of other relevant cardiac features (eg, fibrosis) into interpreting this work. Finally, a general roadmap forward is provided as these tools are increasingly used for treatment assessment and tactical patient management in the future. PMID:22239879

  17. Short stature and pubertal delay in Duchenne muscular dystrophy.

    PubMed

    Wood, Claire L; Straub, Volker; Guglieri, Michela; Bushby, Kate; Cheetham, Tim

    2016-01-01

    Children with Duchenne muscular dystrophy (DMD) are shorter than their healthy peers. The introduction of corticosteroid (CS) has beneficial effects on muscle function but slows growth further and is associated with pubertal delay. In contrast to CS usage in most children and adolescents, weaning glucocorticoid is not a key objective of management in DMD. As the outlook for these young people improves, one of the main challenges is to reduce or offset the detrimental effects of CS on growth and development. This is a review of the aetiology and prevalence of short stature and delayed puberty in DMD, a summary of the treatments available and suggestions for areas of further research. PMID:26141541

  18. Recent developments in the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

    PubMed Central

    Liew, Wendy K. M.

    2013-01-01

    Pediatric neuromuscular disorders comprise a large variety of disorders that can be classified based on their neuroanatomical localization, patterns of weakness, and laboratory test results. Over the last decade, the field of translational research has been active with many ongoing clinical trials. This is particularly so in two common pediatric neuromuscular disorders: Duchenne muscular dystrophy and spinal muscular atrophy. Although no definitive therapy has yet been found, numerous active areas of research raise the potential for novel therapies in these two disorders, offering hope for improved quality of life and life expectancy for affected individuals. PMID:23634188

  19. Immunohistochemical Characterization of Facioscapulohumeral Muscular Dystrophy Muscle Biopsies

    PubMed Central

    Statland, Jeffrey M; Odrzywolski, Karen J; Shah, Bharati; Henderson, Don; Fricke, Alex F.; van der Maarel, Silvère M; Tapscott, Stephen J; Tawil, Rabi

    2015-01-01

    Background Posited pathological mechanisms in Facioscapulohumeral Muscular Dystrophy (FSHD) include activation in somatic tissue of normally silenced genes, increased susceptibility to oxidative stress, and induction of apoptosis. Objective To determine the histopathological changes in FSHD muscle biopsies and compare to possible pathological mechanisms of disease. Methods We performed a cross-sectional study on quadriceps muscle biopsies from 32 genetically confirmed FSHD participants, compared to healthy volunteers and myotonic dystrophy type 1 as disease controls. Biopsies were divided into groups to evaluate apoptosis rates, capillary density, myonuclear and satellite cell counts. Results Apoptosis rates were increased in FSHD (n=10, 0.74%) compared to myotonic dystrophy type 1 (n=10, 0.14%, P=0.003) and healthy volunteers (n=14, 0.13%, P=0.002). Apoptosis was higher in FSHD patients with the smallest residual D4Z4 fragments. Capillary density was decreased in FSHD1 (n=10, 316 capillaries/mm2) compared to healthy volunteers (n=15, 448 capillaries/mm2, P=0.001). No differences were seen in myonuclear or satellite cell counts. Conclusions Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD. The molecular-pathological correlates to these changes warrants further investigation. PMID:26345300

  20. Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy

    SciTech Connect

    Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. ); Shokeir, M. )

    1992-09-01

    In a previous study the authors identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. They have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases they detected slightly lower-molecular-weight dystrophin in 12%-15% abundance relative to the normal. By sequencing amplified mRNA they have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternate splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame. 34 refs., 5 figs. 1 tab.

  1. Congenital Muscular Dystrophy and Generalized Epilepsy Caused by GMPPB Mutations

    PubMed Central

    Raphael, Alya R.; Couthouis, Julien; Sakamuri, Sarada; Siskind, Carly; Vogel, Hannes; Day, John W.; Gitler, Aaron D.

    2014-01-01

    The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (?-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutation were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. PMID:24780531

  2. Congenital muscular dystrophy and generalized epilepsy caused by GMPPB mutations.

    PubMed

    Raphael, Alya R; Couthouis, Julien; Sakamuri, Sarada; Siskind, Carly; Vogel, Hannes; Day, John W; Gitler, Aaron D

    2014-08-01

    The alpha-dystroglycanopathies are genetically heterogeneous muscular dystrophies that result from hypoglycosylation of alpha-dystroglycan (?-DG). Alpha-dystroglycan is an essential link between the extracellular matrix and the muscle fiber sarcolemma, and proper glycosylation is critical for its ability to bind to ligands in the extracellular matrix. We sought to identify the genetic basis of alpha-dystroglycanopathy in a family wherein the affected individuals presented with congenital muscular dystrophy, brain abnormalities and generalized epilepsy. We performed whole exome sequencing and identified compound heterozygous GMPPB mutations in the affected children. GMPPB is an enzyme in the glycosylation pathway, and GMPPB mutations were recently linked to eight cases of alpha-dystroglycanopathy with a range of symptoms. We identified a novel mutation in GMPPB (p.I219T) as well as a previously published mutation (p.R287Q). Thus, our work further confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. This article is part of a Special Issue entitled RNA Metabolism 2013. PMID:24780531

  3. Duchenne muscular dystrophy in one of monozygotic twin girls.

    PubMed

    Burn, J; Povey, S; Boyd, Y; Munro, E A; West, L; Harper, K; Thomas, D

    1986-12-01

    Monozygotic twin girls are reported, one of whom has the typical clinical features of Duchenne muscular dystrophy despite a normal female karyotype. Although certain features of the biopsy were atypical, the clinical diagnosis was supported by persistent markedly raised blood creatine kinase levels and findings typical of DMD on electromyography and magnetic resonance spectroscopy. Analysis of an X linked DNA polymorphism in 16 independent somatic cell hybrids made between cells derived from each girl and a mouse line suggest that in one twin only the maternal X chromosome is active, whereas in the other the active X was paternally derived. More data are needed to exclude sampling error. These preliminary experimental results support the hypothesis that both girls are heterozygous for Duchenne muscular dystrophy. X inactivation, by chance, resulted in two contrasting cell masses with different active X chromosomes. This segregation was followed by, and may even have resulted in, twinning into a female pair, one normal and one with the full clinical features of the disease. PMID:2879922

  4. [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 ?-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 T2-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. PMID:26873231

  5. Restoring Dystrophin Expression in Duchenne Muscular Dystrophy Muscle

    PubMed Central

    Hoffman, Eric P.; Bronson, Abby; Levin, Arthur A.; Takeda, Shin'ichi; Yokota, Toshifumi; Baudy, Andreas R.; Connor, Edward M.

    2011-01-01

    The identification of the Duchenne muscular dystrophy gene and protein in the late 1980s led to high hopes of rapid translation to molecular therapeutics. These hopes were fueled by early reports of delivering new functional genes to dystrophic muscle in mouse models using gene therapy and stem cell transplantation. However, significant barriers have thwarted translation of these approaches to true therapies, including insufficient therapeutic material (eg, cells and viral vectors), challenges in systemic delivery, and immunological hurdles. An alternative approach is to repair the patient's own gene. Two innovative small-molecule approaches have emerged as front-line molecular therapeutics: exon skipping and stop codon read through. Both approaches are in human clinical trials and aim to coax dystrophin protein production from otherwise inactive mutant genes. In the clinically severe dog model of Duchenne muscular dystrophy, the exon-skipping approach recently improved multiple functional outcomes. We discuss the status of these two methods aimed at inducing de novo dystrophin production from mutant genes and review implications for other disorders. PMID:21703390

  6. Primary Murine Myotubes as a Model for Investigating Muscular Dystrophy

    PubMed Central

    Smolina, Natalia; Kostareva, Anna; Bruton, Joseph; Karpushev, Alexey; Sjoberg, Gunnar; Sejersen, Thomas

    2015-01-01

    Muscular dystrophies caused by defects in various genes are often associated with impairment of calcium homeostasis. Studies of calcium currents are hampered because of the lack of a robust cellular model. Primary murine myotubes, formed upon satellite cell fusion, were examined for their utilization as a model of adult skeletal muscle. We enzymatically isolated satellite cells and induced them to differentiation to myotubes. Myotubes displayed morphological and physiological properties resembling adult muscle fibers. Desmin and myosin heavy chain immunoreactivity in the differentiated myotubes were similar to the mature muscle cross-striated pattern. The myotubes responded to electrical and chemical stimulations with sarcoplasmic reticulum calcium release. Presence of L-type calcium channels in the myotubes sarcolemma was confirmed via whole-cell patch-clamp technique. To assess the use of myotubes for studying functional mutation effects lentiviral transduction was applied. Satellite cells easily underwent transduction and were able to retain a positive expression of lentivirally encoded GFP up to and after the formation of myotubes, without changes in their physiological and morphological properties. Thus, we conclude that murine myotubes may serve as a fruitful cell model for investigating calcium homeostasis in muscular dystrophy and the effects of gene modifications can be assessed due to lentiviral transduction. PMID:26380282

  7. Drug screening in a zebrafish model of Duchenne muscular dystrophy

    PubMed Central

    Kawahara, Genri; Karpf, Jeremy A.; Myers, Jennifer A.; Alexander, Matthew S.; Guyon, Jeffrey R.; Kunkel, Louis M.

    2011-01-01

    Two known zebrafish dystrophin mutants, sapje and sapje-like (sapc/100), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy. PMID:21402949

  8. Nitric oxide synthase deficiency and the pathophysiology of muscular dystrophy

    PubMed Central

    Tidball, James G; Wehling-Henricks, Michelle

    2014-01-01

    The secondary loss of neuronal nitric oxide synthase (nNOS) that occurs in dystrophic muscle is the basis of numerous, complex and interacting features of the dystrophic pathology that affect not only muscle itself, but also influence the interaction of muscle with other tissues. Many mechanisms through which nNOS deficiency contributes to misregulation of muscle development, blood flow, fatigue, inflammation and fibrosis in dystrophic muscle have been identified, suggesting that normalization in NO production could greatly attenuate diverse aspects of the pathology of muscular dystrophy through multiple regulatory pathways. However, the relative importance of the loss of nNOS from the sarcolemma versus the importance of loss of total nNOS from dystrophic muscle remains unknown. Although most current evidence indicates that nNOS localization at the sarcolemma is not required to achieve NO-mediated reductions of pathology in muscular dystrophy, the question remains open concerning whether membrane localization would provide a more efficient rescue from features of the dystrophic phenotype. PMID:25194047

  9. Muscle exercise in limb girdle muscular dystrophies: pitfall and advantages.

    PubMed

    Siciliano, Gabriele; Simoncini, Costanza; Giannotti, Stefano; Zampa, Virna; Angelini, Corrado; Ricci, Giulia

    2015-05-01

    Different genetic mutations underlying distinct pathogenic mechanisms have been identified as cause of muscle fibers degeneration and strength loss in limb girdle muscular dystrophies (LGMD). As a consequence, exercise tolerance is affected in patients with LGMD, either as a direct consequence of the loss of muscle fibers or secondary to the sedentary lifestyle due to the motor impairment. It has been debated for many years whether or not muscle exercise is beneficial or harmful for patients with myopathic disorders. In fact, muscular exercise would be considered in helping to hinder the loss of muscle tissue and strength. On the other hand, muscle structural defects in LGMD can result in instability of the sarcolemma, making it more likely to induce muscle damage as a consequence of intense muscle contraction, such as that performed during eccentric training. Several reports have suggested that supervised aerobic exercise training is safe and may be considered effective in improving oxidative capacity and muscle function in patients with LGMD, such as LGMD2I, LGMD2L, LGMD2A. More or less comfortable investigation methods applied to assess muscle function and structure can be useful to detect the beneficial effects of supervised training in LGMD. However, it is important to note that the available trials assessing muscle exercise in patients with LGMD have often involved a small number of patients, with a wide clinical heterogeneity and a different experimental design. Based on these considerations, resistance training can be considered part of the rehabilitation program for patients with a limb-girdle type of muscular dystrophy, but it should be strictly supervised to assess its effects and prevent possible development of muscle damage. PMID:26155063

  10. FHL1 Reduces Dystrophy in Transgenic Mice Overexpressing FSHD Muscular Dystrophy Region Gene 1 (FRG1)

    PubMed Central

    Feeney, Sandra J.; McGrath, Meagan J.; Sriratana, Absorn; Gehrig, Stefan M.; Lynch, Gordon S.; D’Arcy, Colleen E.; Price, John T.; McLean, Catriona A.; Tupler, Rossella; Mitchell, Christina A.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

  11. FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1).

    PubMed

    Feeney, Sandra J; McGrath, Meagan J; Sriratana, Absorn; Gehrig, Stefan M; Lynch, Gordon S; D'Arcy, Colleen E; Price, John T; McLean, Catriona A; Tupler, Rossella; Mitchell, Christina A

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1. PMID:25695429

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

    PubMed

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

    2013-07-15

    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 ?-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

  13. 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 ?-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

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

    PubMed

    Suneja, B; Suneja, E S; Adlakha, V K; Chandna, P

    2015-01-01

    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

  15. The Intriguing Regulators of Muscle Mass in Sarcopenia and Muscular Dystrophy

    PubMed Central

    Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

    2014-01-01

    Recent advances in our understanding of the biology of muscle have led to new interest in the pharmacological treatment of muscle wasting. Loss of muscle mass and increased intramuscular fibrosis occur in both sarcopenia and muscular dystrophy. Several regulators (mammalian target of rapamycin, serum response factor, atrogin-1, myostatin, etc.) seem to modulate protein synthesis and degradation or transcription of muscle-specific genes during both sarcopenia and muscular dystrophy. This review provides an overview of the adaptive changes in several regulators of muscle mass in both sarcopenia and muscular dystrophy. PMID:25221510

  16. 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

  17. 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 19821987) to 94% in the cohort born 20042009. PMID:20817884

  18. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence.

    PubMed

    van der Maarel, Silvre M; Tawil, Rabi; Tapscott, Stephen J

    2011-05-01

    Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array. PMID:21288772

  19. Carrier Woman of Duchenne Muscular Dystrophy Mimicking Inflammatory Myositis

    PubMed Central

    Yoon, Jiyeol; Kim, Se Hoon; Ki, Chang-Seok; Kwon, Min-Jung; Lim, Mie-Jin; Kwon, Seong-Ryul; Joo, Kowoon; Moon, Chang-Gi

    2011-01-01

    Carrier woman of Duchenne muscular dystrophy (DMD) can mimic the inflammatory myositis in presenting symptoms. Two diseases should be differentiated by the clinical history, muscle biopsy and genetic study. There are few reports in which both histochemical and genetic study showed the possible link of overlapping inflammatory pathophysiology with dystrophinopathy. We report a 40-yr-old woman who presented with subacute proximal muscle weakness and high serum level of creatine kinase. She had a history of Graves' disease and fluctuation of serum liver aminotransferase without definite cause. MRI, EMG and NCV were compatible with proximal muscle myopathy. Muscle biopsy on vastus lateralis showed suspicious perifascicular atrophy and infiltration of mono-macrophage lineage cells complicating the diagnosis. Dystrophin staining showed heterogeneous diverse findings from normal to interrupted mosaic pattern. Multiple ligation probe amplification and X chromosome inactivation test confirmed DMD gene deletion mutation in exon 44 and highly skewed X inactivation. PMID:21468271

  20. Facioscapulohumeral muscular dystrophy and respiratory failure; what about the diaphragm?

    PubMed Central

    Hazenberg, A.; van Alfen, N.; Voet, N.B.M.; Kerstjens, H.A.M.; Wijkstra, P.J.

    2014-01-01

    Introduction We present a case of facioscapulohumeral muscular dystrophy (FSHD) with a diaphragm paralysis as the primary cause of ventilatory failure. FSHD is an autosomal dominant inherited disorder with a restricted pattern of weakness. Although respiratory weakness is a relatively unknown in FSHD, it is not uncommon. Methods We report on the clinical findings of a 68-year old male who presented with severe dyspnea while supine. Results Supplementing our clinical findings with laboratory, electrophysiological and radiological performances led to the diagnosis of diaphragm paralysis. Arterial blood gas in sitting position without supplemental oxygen showed a mild hypercapnia. His sleep improved after starting non-invasive ventilation and his daytime sleepiness disappeared. Discussion We conclude that in patients with FSHD who have symptoms of nocturnal hypoventilation, an adequate assessment of the diaphragm is recommended. This is of great importance as we know that nocturnal hypoventilation can be treated effectively by non-invasive ventilation. PMID:26029575

  1. Becker muscular dystrophy recombinant DNA studies in identical twins.

    PubMed

    Ionasescu, V; Ionasescu, R; Searby, C; Burns, T

    1988-04-01

    Two identical twins with Becker Muscular Dystrophy are reported. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing detected the same antigens in both twins: A1, A26, B8, B17, DR3, DR7. Family history was negative. The twin patients showed identical haplotypes that were different from the haplotypes of the normal male members of the family. The sister of the twins showed a recombinant X chromosome. The informative haplotype with respect to the gene of BMD, present in the twins, was ascertained in their mother as well. Our findings strongly suggest that a mutation has occurred either in the mother or in the twins. PMID:3398874

  2. Recent advances in the management of Duchenne muscular dystrophy.

    PubMed

    Strehle, Eugen-Matthias; Straub, Volker

    2015-12-01

    Duchenne muscular dystrophy (DMD) is the commonest inherited neuromuscular disorder of childhood and mainly affects males. Over the course of the last century, the average life expectancy of these patients has doubled and now stands at ?25?years. This progress has been made possible through advances in the diagnosis, treatment and long-term care of patients with DMD. Basic and clinical research, national and international scientific networks, and parent and patient support groups have all contributed to achieving this goal. The advent of molecular genetic therapies and personalised medicine has opened up new avenues and raised hopes that one day a cure for this debilitating orphan disease will be found. The main purpose of this short review is to enable paediatricians to have informed discussions with parents of boys with DMD about recent scientific advances affecting their child's clinical care. PMID:26153505

  3. [Respiratory and intensive care aspects of muscular dystrophies].

    PubMed

    Ambrosi, X; Lamothe, L; Heming, N; Orlikowski, D

    2015-12-01

    Among the various myopathies, Duchenne muscular dystrophy represents the myopathy with the most stereotypical respiratory evolution. This progressive respiratory failure is going to develop in a parallel way of motor deficit, conducting patients to mechanical ventilation at the end of their second decade. In the absence of curative therapeutics, respiratory cares like home ventilation and prevention of respiratory complications, in a systematic and organized way, allowed to decrease the morbidity and the mortality of these patients. It is not exceptional to meet patients with life expectancy of which overtakes about forty. Besides axial stabilization, cough assistance techniques and swallowing disorders management need to be associated to mechanical ventilation. Invasive techniques of ventilation as tracheostomy keep their place in this pathology even if alternative techniques allowing full day non-invasive ventilation were generalized these last years. PMID:26773587

  4. Merosin-negative congenital muscular dystrophy: Report of five cases

    PubMed Central

    Incecik, Faruk; Herguner, Ozlem M.; Ceylaner, Serdar; Altunbasak, Sakir

    2015-01-01

    Context: Congenital muscular dystrophy type 1A (MDC1A) is caused by mutations in the laminin α-2 gene encoding laminin-a2. Aims: The purpose of this study is to determine clinical and genetic results in five Turkish patients with MDC1A. Setting and Designs: Five children with MDC1A were retrospectively analyzed. Results: Three (60%) were boys, and 2 (40%) were girls. Parental consanguinity was found in all the families. In all the patients, hypotonia, weakness, delayed motor milestones, markedly elevated creatine phosphokinase (CPK) concentration, and brain white matter abnormalities on magnetic resonance imaging were detected. Mutation analysis was performed in all the patients, and 3 different mutations were detected. However, a mutation in patient 1 and 2 has not been previously described in the literature. Conclusions: When a patient presents with severe congenital hypotonia, muscle weakness, high serum CPK levels, and white matter abnormalities, should be suspected as MDC1A. PMID:26962340

  5. Acetoacetate Accelerates Muscle Regeneration and Ameliorates Muscular Dystrophy in Mice.

    PubMed

    Zou, Xiaoting; Meng, Jiao; Li, Li; Han, Wanhong; Li, Changyin; Zhong, Ran; Miao, Xuexia; Cai, Jun; Zhang, Yong; Zhu, Dahai

    2016-01-29

    Acetoacetate (AA) is a ketone body and acts as a fuel to supply energy for cellular activity of various tissues. Here, we uncovered a novel function of AA in promoting muscle cell proliferation. Notably, the functional role of AA in regulating muscle cell function is further evidenced by its capability to accelerate muscle regeneration in normal mice, and it ameliorates muscular dystrophy in mdx mice. Mechanistically, our data from multiparameter analyses consistently support the notion that AA plays a non-metabolic role in regulating muscle cell function. Finally, we show that AA exerts its function through activation of the MEK1-ERK1/2-cyclin D1 pathway, revealing a novel mechanism in which AA serves as a signaling metabolite in mediating muscle cell function. Our findings highlight the profound functions of a small metabolite as signaling molecule in mammalian cells. PMID:26645687

  6. Poor facial affect recognition among boys with duchenne muscular dystrophy.

    PubMed

    Hinton, V J; Fee, R J; De Vivo, D C; Goldstein, E

    2007-11-01

    Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine whether comprehension of facial affect is compromised in boys with MD, children were given a matching-to-sample test with four types of visual recognition (Object, Face, Affect, and Situation matching) developed by Lucci and Fein. Within-group analyses on 50 boys with MD found decreased Affect matching relative to the other matching conditions. Between-group comparisons on 20 sibling pairs found the boys with Duchenne performed more poorly only on the Affect-matching condition. Thus, mildly impaired facial affect recognition may be part of the phenotype associated with Duchenne or Becker MD. PMID:17177118

  7. Pathogenesis of Duchenne muscular dystrophy: the calcium hypothesis revisited.

    PubMed

    Tay, J S; Lai, P S; Low, P S; Lee, W L; Gan, G C

    1992-08-01

    Rapid advances in the molecular genetics of Duchenne muscular dystrophy (DMD) and the discovery and localization of the gene product dystrophin has brought new hope that successful treatment for this disease may not be too far away. Dystrophin has been postulated to have a mechanical function, helping to resist stress associated with muscle contraction. The presence of dystrophin in low concentrations in muscle cells, its expression in nervous tissue and the observation that hypercontraction of the sarcomeres precedes membrane rupture make the hypothesis unlikely. On the basis of an analogy with a cytoskeletal protein ankyrin, which is associated with the sodium/potassium adenosine triphosphatase (ATPase) in the kidney, it is possible that dystrophin deficiency leads initially to an increased but inefficient calcium-ATPase activity, which pumps calcium out of the cell. Partial failure of the pump would result in intracellular accumulation of calcium, hypercontractions of the sarcomeres, rupture of the cell membrane, massive influx of calcium and cell necrosis. PMID:1497954

  8. Drug Discovery of Therapies for Duchenne Muscular Dystrophy.

    PubMed

    Blat, Yuval; Blat, Shachar

    2015-12-01

    Duchenne muscular dystrophy (DMD) is a genetic, lethal, muscle disorder caused by the loss of the muscle protein, dystrophin, leading to progressive loss of muscle fibers and muscle weakness. Drug discovery efforts targeting DMD have used two main approaches: (1) the restoration of dystrophin expression or the expression of a compensatory protein, and (2) the mitigation of downstream pathological mechanisms, including dysregulated calcium homeostasis, oxidative stress, inflammation, fibrosis, and muscle ischemia. The aim of this review is to introduce the disease, its pathophysiology, and the available research tools to a drug discovery audience. This review will also detail the most promising therapies that are currently being tested in clinical trials or in advanced preclinical models. PMID:25975656

  9. FSHD: copy number variations on the theme of muscular dystrophy

    PubMed Central

    Cabianca, Daphne Selvaggia

    2010-01-01

    In humans, copy number variations (CNVs) are a common source of phenotypic diversity and disease susceptibility. Facioscapulohumeral muscular dystrophy (FSHD) is an important genetic disease caused by CNVs. It is an autosomal-dominant myopathy caused by a reduction in the copy number of the D4Z4 macrosatellite repeat located at chromosome 4q35. Interestingly, the reduction of D4Z4 copy number is not sufficient by itself to cause FSHD. A number of epigenetic events appear to affect the severity of the disease, its rate of progression, and the distribution of muscle weakness. Indeed, recent findings suggest that virtually all levels of epigenetic regulation, from DNA methylation to higher order chromosomal architecture, are altered at the disease locus, causing the de-regulation of 4q35 gene expression and ultimately FSHD. PMID:21149563

  10. Progression of equinus deformity in Duchenne muscular dystrophy.

    PubMed

    Seeger, B R; Caudrey, D J; Little, J D

    1985-05-01

    This study investigated the influence of orthoses, regular passive stretching, and surgery on progression of equinus deformity in Duchenne muscular dystrophy. The extent of passive dorsiflexion on the right foot of ambulant and wheelchair-ambulatory patients was measured monthly with an electronic ankle goniometer calibrated to an accuracy of 1 degree. The mean rate of equinus progression was 0.4 degree per month during the 12-month study. Progression was less in those boys who had prior surgery and were older. Progression was slowest during the first five months of the study (when night splints were used more frequently) and greatest during a long vacation when regular passive stretching by physiotherapists and supervision of splinting were unavailable. These results, although based on a limited patient sample size, indicate that gains from use of orthoses and passive stretching can be lost in the absence of professional supervision. PMID:4004517

  11. Clinical features of facioscapulohumeral muscular dystrophy 2(CME)

    PubMed Central

    de Greef, J.C.; Lemmers, R.J.L.F.; Camao, P.; Day, J.W.; Sacconi, S.; Dunand, M.; van Engelen, B.G.M.; Kiuru-Enari, S.; Padberg, G.W.; Rosa, A.L.; Desnuelle, C.; Spuler, S.; Tarnopolsky, M.; Venance, S.L.; Frants, R.R.; van der Maarel, S.M.; Tawil, R.

    2010-01-01

    Objective: In some 5% of patients with facioscapulohumeral muscular dystrophy (FSHD), no D4Z4 repeat contraction on chromosome 4q35 is observed. Such patients, termed patients with FSHD2, show loss of DNA methylation and heterochromatin markers at the D4Z4 repeat that are similar to patients with D4Z4 contractions (FSHD1). This commonality suggests that a change in D4Z4 chromatin structure unifies FSHD1 and FSHD2. The aim of our study was to critically evaluate the clinical features in patients with FSHD2 in order to establish whether these patients are phenotypically identical to FSHD1 and to establish the effects of the (epi-) genotype on the phenotype. Methods: This cross-sectional study studied 33 patients with FSHD2 from 27 families, the largest cohort described to date. All patients were clinically assessed using a standardized clinical evaluation form. Genotype analysis was performed by pulsed field gel electrophoresis and PCR; D4Z4 methylation was studied by methylation-sensitive Southern blot analysis. Results: FSHD2 is identical to FSHD1 in its clinical presentation. Notable differences include a higher incidence (67%) of sporadic cases and the absence of gender differences in disease severity in FSHD2. Overall, average disease severity in FSHD2 was similar to that reported in FSHD1 and was not influenced by D4Z4 repeat size. In FSHD2, a small effect of the degree of hypomethylation on disease severity was observed. Conclusions: Clinically, patients with FSHD2 are indistinguishable from patients with FSHD1. The present data suggest that FSHD1 and FSHD2 are the result of the same pathophysiologic process. GLOSSARY CSS = clinical severity score; FSHD = facioscapulohumeral muscular dystrophy; PBL = peripheral blood lymphocyte; SSLP = simple sequence length polymorphism. PMID:20975055

  12. A review of nutrition in Duchenne muscular dystrophy.

    PubMed

    Davidson, Z E; Truby, H

    2009-10-01

    Duchenne muscular dystrophy (DMD) is a recessive X linked genetic disorder characterised by progressive muscle weakness and reduced muscle tone. Affecting only boys, it limits life expectancy to approximately 20 years. A literature review was conducted using MEDLINE and the Cochrane Library, employing the term 'Duchenne muscular dystrophy'. A total of 1491 articles in English were recovered. These papers were searched thematically under the headings: body composition (n = 10), energy expenditure (n = 10), nutrition (n = 6), corticosteroid therapy (n = 55) and gene therapy (n = 199). Key dietetic practice points were identified relevant to nutritional management. Papers supporting these key themes were assigned a level of evidence and grade of recommendation. There is limited high-quality evidence to guide the nutritional management of boys with DMD. Currently, the majority of evidence is based on expert opinion and clinical expertise. Delayed growth, short stature, muscle wasting and increased fat mass are characteristics of DMD and impact on nutritional status and energy requirements. The early introduction of steroids has altered the natural history of the disease, but can exacerbate weight gain in a population already susceptible to obesity. Prior to commencing steroids, anticipatory guidance for weight management should be provided. Malnutrition is a feature of end stage disease requiring a multidisciplinary approach, such as texture modification and supplemental feeding. Micronutrient requirements are yet to be determined but, as a result of corticosteroid treatment, vitamin D and calcium should be supplemented. Some evidence exists supporting supplementation with creatine monohydrate to improve muscle strength. More research is needed to provide a higher quality of evidence for dietitians working within this area. PMID:19743977

  13. Symptom Burden in Persons with Myotonic and Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Smith, Amanda E.; McMullen, Kara; Jensen, Mark P.; Carter, Gregory T.; Molton, Ivan R.

    2013-01-01

    Objective This study examines the prevalence of pain, fatigue, imbalance, memory impairment and vision loss in persons with myotonic and facioscapulohumeral dystrophy, and their association with functioning. Design A survey (n=170) included measures of severity (0–10 scales) and course of these symptoms, as well as measures of social integration, home competency, mental health and productive activity. Descriptive and regression analyses examined the associations between symptoms and functioning. Results Fatigue (91%), imbalance (82%) and pain (77%) were most commonly reported. The most severe symptom was fatigue (mean severity 5.14 ± 2.81), followed by imbalance (4.95 ± 3.25). Symptoms were most likely to stay the same or worsen since onset. Controlling for potential medical and demographic confounds, symptoms were associated with 17% of the mental health variance, 10% of home competency, 10% of social integration, 16% of productive activity for DM1 and 12% of productive activity for FSHD. Conclusions Pain, fatigue and imbalance are common in persons with muscular dystrophy. Interventions may be useful to mitigate their impact on functioning. Further research should examine these relationships to guide clinical practices. PMID:24247759

  14. Pathways Implicated in Tadalafil Amelioration of Duchenne Muscular Dystrophy.

    PubMed

    De Arcangelis, Valeria; Strimpakos, Georgios; Gabanella, Francesca; Corbi, Nicoletta; Luvisetto, Siro; Magrelli, Armando; Onori, Annalisa; Passananti, Claudio; Pisani, Cinzia; Rome, Sophie; Severini, Cinzia; Naro, Fabio; Mattei, Elisabetta; Di Certo, Maria Grazia; Monaco, Lucia

    2016-01-01

    Numerous therapeutic approaches for Duchenne and Becker Muscular Dystrophy (DMD and BMD), the most common X-linked muscle degenerative disease, have been proposed. So far, the only one showing a clear beneficial effect is the use of corticosteroids. Recent evidence indicates an improvement of dystrophic cardiac and skeletal muscles in the presence of sustained cGMP levels secondary to a blocking of their degradation by phosphodiesterase five (PDE5). Due to these data, we performed a study to investigate the effect of the specific PDE5 inhibitor, tadalafil, on dystrophic skeletal muscle function. Chronic pharmacological treatment with tadalafil has been carried out in mdx mice. Behavioral and physiological tests, as well as histological and biochemical analyses, confirmed the efficacy of the therapy. We then performed a microarray-based genomic analysis to assess the pattern of gene expression in muscle samples obtained from the different cohorts of animals treated with tadalafil. This scrutiny allowed us to identify several classes of modulated genes. Our results show that PDE5 inhibition can ameliorate dystrophy by acting at different levels. Tadalafil can lead to (1) increased lipid metabolism; (2) a switch towards slow oxidative fibers driven by the up-regulation of PGC-1?; (3) an increased protein synthesis efficiency; (4) a better actin network organization at Z-disk. PMID:26097015

  15. Imperatives for DUCHENNE MD: a Simplified Guide to Comprehensive Care for Duchenne Muscular Dystrophy

    PubMed Central

    Kinnett, Kathi; Rodger, Sunil; Vroom, Elizabeth; Furlong, Pat; Aartsma-Rus, Annemieke; Bushby, Kate

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive, life-limiting muscle-wasting disease. Although no curative treatment is yet available, comprehensive multidisciplinary care has increased life expectancy significantly in recent decades. An international consensus care publication in 2010 outlined best-practice care, which includes corticosteroid treatment, respiratory, cardiac, orthopedic and rehabilitative interventions to address disease manifestations. While disease specialists are largely aware of these care standards, local physicians responsible for the day-to-day care of patients and families may be less familiar. To facilitate optimal care, a one-page document has been generated from published care recommendations, summarizing the key elements of comprehensive care for people living with DMD (“Imperatives for Duchenne muscular dystrophy). This document was developed through an international collaboration between Parent Project Muscular Dystrophy (PPMD), United Parent Projects Muscular Dystrophy (UPPMD) and TREAT-NMD.  PMID:26331093

  16. Management of scoliosis in patients with Duchenne muscular dystrophy and spinal muscular atrophy: A literature review.

    PubMed

    Garg, Sumeet

    2016-02-27

    Scoliosis occurs in nearly all non-ambulatory children with spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). Non-operative treatments have not been shown to be effective at preventing progression of scoliosis. Progressive scoliosis can impact the ability of patients to sit comfortably, be cosmetically unappealing, and in severe cases exacerbate pulmonary disease. The main goal of operative treatment is to improve sitting balance and prevent progression of scoliosis. Complication rates are high and there is little data on effect of operative treatment on quality of life in children with SMA and DMD. Comprehensive multi-disciplinary pre-operative evaluations are vital to reduce the risks of operative treatment. PMID:26966797

  17. 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.

  18. Back pain in Duchenne muscular dystrophy: steroids are not always the culprit.

    PubMed

    Segal, Lee S; Odgers, Ryan; Carpentieri, David; Shrader, M Wade

    2016-01-01

    We report on a child with Duchenne muscular dystrophy on prolonged corticosteroid treatment who presented with back pain and was subsequently found to have a monostotic fibrous dysplasia lesion of the spine. It is the intent of this case report to emphasize the need to maintain a high index of suspicion for other potential causes of back pain in Duchenne muscular dystrophy besides vertebral compression fractures. PMID:25714938

  19. [A family of scapula-back type of x-linked recessive muscular dystrophy].

    PubMed

    Ji, X W

    1989-06-01

    In this paper are described seven men with a scapula-back type of x-linked recessive muscular dystrophy in a family. Onset began in boyhood. The scapula-back muscles were affected, but the calf muscles were normal. All of the patients were able to walk. The oldest patient was thirty-seven years old. Muscular dystrophy was confirmed by electro-myography (EMG), pathologic and CPK examinations. Pedigree analysis indicated x-linked recessive inheritance. PMID:2591265

  20. 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…

  1. Nuclear envelope dystrophies show a transcriptional fingerprint suggesting disruption of Rb-MyoD pathways in muscle regeneration.

    PubMed

    Bakay, Marina; Wang, Zuyi; Melcon, Gisela; Schiltz, Louis; Xuan, Jianhua; Zhao, Po; Sartorelli, Vittorio; Seo, Jinwook; Pegoraro, Elena; Angelini, Corrado; Shneiderman, Ben; Escolar, Diana; Chen, Yi-Wen; Winokur, Sara T; Pachman, Lauren M; Fan, Chenguang; Mandler, Raul; Nevo, Yoram; Gordon, Erynn; Zhu, Yitan; Dong, Yibin; Wang, Yue; Hoffman, Eric P

    2006-04-01

    Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell-specific perturbations of the mRNA transcriptome in terminally differentiated cells. To test this model, we studied 125 human muscle biopsies from 13 diagnostic groups (125 U133A, 125 U133B microarrays), including EDMD patients with LMNA and emerin mutations. A Visual and Statistical Data Analyzer (VISDA) algorithm was used to statistically model cluster hierarchy, resulting in a tree of phenotypic classifications. Validations of the diagnostic tree included permutations of U133A and U133B arrays, and use of two probe set algorithms (MAS5.0 and MBEI). This showed that the two nuclear envelope defects (EDMD LMNA, EDMD emerin) were highly related disorders and were also related to fascioscapulohumeral muscular dystrophy (FSHD). FSHD has recently been hypothesized to involve abnormal interactions of chromatin with the nuclear envelope. To identify disease-specific transcripts for EDMD, we applied a leave-one-out (LOO) cross-validation approach using LMNA patient muscle as a test data set, with reverse transcription-polymerase chain reaction (RT-PCR) validations in both LMNA and emerin patient muscle. A high proportion of top-ranked and validated transcripts were components of the same transcriptional regulatory pathway involving Rb1 and MyoD during muscle regeneration (CRI-1, CREBBP, Nap1L1, ECREBBP/p300), where each was specifically upregulated in EDMD. Using a muscle regeneration time series (27 time points) we develop a transcriptional model for downstream consequences of LMNA and emerin mutations. We propose that key interactions between the nuclear envelope and Rb and MyoD fail in EDMD at the point of myoblast exit from the cell cycle, leading to poorly coordinated phosphorylation and acetylation steps. Our data is consistent with mutations of nuclear lamina components leading to destabilization of the transcriptome in differentiated cells. PMID:16478798

  2. 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

  3. Some Dynamics of Personality Development in Boys Suffering from Muscular Dystrophy

    ERIC Educational Resources Information Center

    Mearig, Judith S.

    1973-01-01

    Discussed are personality aspects of Duchenne or pseudohypertrophic muscular dystrophy, a progressive wasting of muscular tissue, which afflicts only boys, and usually has its noticeable onset before the age of 6 years; and described is the development of three male dystrophic siblings. (DB)

  4. Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

    2004-01-01

    Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the…

  5. Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Hinton, V. J.; De Vivo, D. C.; Fee, R.; Goldstein, E.; Stern, Y.

    2004-01-01

    Duchenne Muscular Dystrophy (DMD) is a neurogenetic developmental disorder that presents with progressive muscular weakness. It is caused by a mutation in a gene that results in the absence of specific products that normally localize to muscle cells and the central nervous system (CNS). The majority of affected individuals have IQs within the

  6. Spectrum of muscular dystrophies associated with sarcolemmal-protein genetic defects.

    PubMed

    Nigro, Vincenzo; Piluso, Giulio

    2015-04-01

    Muscular dystrophies are heterogeneous genetic disorders that share progressive muscle wasting. This may generate partial impairment of motility as well as a dramatic and fatal course. Less than 30 years ago, the identification of the genetic basis of Duchenne muscular dystrophy opened a new era. An explosion of new information on the mechanisms of disease was witnessed, with many thousands of publications and the characterization of dozens of other genetic forms. Genes mutated in muscular dystrophies encode proteins of the plasma membrane and extracellular matrix, several of which are part of the dystrophin-associated complex. Other gene products localize at the sarcomere and Z band, or are nuclear membrane components. In the present review, we focus on muscular dystrophies caused by defects that affect the sarcolemmal and sub-sarcolemmal proteins. We summarize the nature of each disease, the genetic cause, and the pathogenic pathways that may suggest future treatment options. We examine X-linked Duchenne and Becker muscular dystrophies and the autosomal recessive limb-girdle muscular dystrophies caused by mutations in genes encoding sarcolemmal proteins. The mechanism of muscle damage is reviewed starting from disarray of the shock-absorbing dystrophin-associated complex at the sarcolemma and activation of inflammatory response up to the final stages of fibrosis. We trace only a part of the biochemical, physiopathological and clinical aspects of muscular dystrophy to avoid a lengthy list of different and conflicting observations. We attempt to provide a critical synthesis of what we consider important aspects to better understand the disease. In our opinion, it is becoming ever more important to go back to the bedside to validate and then translate each proposed mechanism. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis. PMID:25086336

  7. Sarcopenia and Sarcopenic Obesity in Patients with Muscular Dystrophy

    PubMed Central

    Merlini, Luciano; Vagheggini, Alessandro; Cocchi, Daniela

    2014-01-01

    Aging sarcopenia and muscular dystrophy (MD) are two conditions characterized by lower skeletal muscle quantity, lower muscle strength, and lower physical performance. Aging is associated with a peculiar alteration in body composition called sarcopenic obesity characterized by a decrease in lean body mass and increase in fat mass. To evaluate the presence of sarcopenia and obesity in a cohort of adult patients with MD, we have used the measurement techniques considered golden standard for sarcopenia that is for muscle mass dual-energy X-ray absorptiometry (DXA), for muscle strength hand-held dynamometry (HHD), and for physical performance gait speed. The study involved 14 adult patients with different types of MD. We were able to demonstrate that all patients were sarcopenic obese. We showed, in fact, that all were sarcopenic based on appendicular lean, fat and bone free, mass index (ALMI). In addition, all resulted obese according to the percentage of body fat determined by DXA in contrast to their body mass index ranging from underweight to obese. Skeletal muscle mass determined by DXA was markedly reduced in all patients and correlated with residual muscle strength determined by HHD, and physical performances determined by gait speed and respiratory function. Finally, we showed that ALMI was the best linear explicator of muscle strength and physical function. Altogether, our study suggests the relevance of a proper evaluation of body composition in MD and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia. PMID:25339901

  8. Adult care for Duchenne muscular dystrophy in the UK.

    PubMed

    Rodger, Sunil; Woods, Katherine L; Bladen, Catherine L; Stringer, Angela; Vry, Julia; Gramsch, Kathrin; Kirschner, Janbernd; Thompson, Rachel; Bushby, Katharine; Lochmüller, Hanns

    2015-03-01

    Survival in Duchenne muscular dystrophy (DMD) has increased in recent years due to iterative improvements in care. We describe the results of the CARE-NMD survey of care practices for adults with DMD in the UK in light of international consensus care guidelines. We also compare the UK experience of adult care with the care available to pediatric patients and adults in other European countries (Germany, Denmark, Bulgaria, Czech Republic, Hungary, and Poland). UK adults experience less comprehensive care compared to children in their access to specialized clinics, frequency of cardiac and respiratory assessments, and access to professional physiotherapy. Access to the latter is especially poor when compared to other European adult cohorts. Although the total number of nights in hospital (planned and unplanned admissions) is lower among UK adults than elsewhere in Western Europe, social inclusion lags behind other Western European countries. We observe that attendance at specialized clinic is associated with more frequent cardiac and respiratory assessments among adults, in line with international best practice. Attendance at such clinics in the UK, though comparable to other countries, is still far from universal. With an increasing adult population living with DMD, and cardiac and respiratory failure the leading causes of death in this population, we suggest the need for an urgent improvement in adult access to specialized clinics and to consistent, comprehensive best practice care. PMID:25536903

  9. The immune system in Duchenne muscular dystrophy: Friend or foe

    PubMed Central

    Villalta, S Armando; Rosenberg, Amy S; Bluestone, Jeffrey A

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the X-linked dystrophin gene, resulting in reduced or absent protein production, subsequently leading to the structural instability of the dystroglycan complex (DGC), muscle degeneration, and early death in males. Thus, current treatments have been targeting the genetic defect either by bypassing the mutation through exon skipping or replacing the defective gene through gene therapy and stem cell approaches. However, what has been an underappreciated mediator of muscle pathology and, ultimately, of muscle degeneration and fibrotic replacement, is the prominent inflammatory response. Of potentially critical importance, however, is the fact that the elements mediating the inflammatory response also play an essential role in tissue repair. In this opinion piece, we highlight the detrimental and supportive immune parameters that occur as a consequence of the genetic disorder and discuss how changes to immunity can potentially ameliorate the disease intensity and be employed in conjunction with efforts to correct the genetic disorder. PMID:26481612

  10. Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy

    PubMed Central

    Zhu, Yuling; Zhang, Huili; Sun, Yiming; Li, Yaqin; Deng, Langhui; Wen, Xingxuan; Wang, Huaqiao; Zhang, Cheng

    2015-01-01

    Background. Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. Methods. The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. Results. The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 ± 59 U/L versus 45 ± 9 U/L, resp., p < 0.05). Conclusions. Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed. PMID:26063958

  11. Treatment of Duchenne muscular dystrophy with growth hormone inhibitors.

    PubMed

    Zatz, M; Betti, R T; Frota-Pessoa, O

    1986-07-01

    A controlled, double-blind therapeutic trial with the drug mazindol, a growth hormone inhibitor, was performed in a pair of 7 1/2 year-old monozygotic twins, with Duchenne muscular dystrophy (DMD). The rationale for this trial was based on a patient (reported previously) affected simultaneously with DMD and growth hormone (GH) deficiency, who is showing a benign course of the dystrophic process and is still walking at 18 years. One of the twins received 2 mg of mazindol daily, while the other received a placebo. The assessment, repeated every 2 months, included weight and height measurements, functional and motor ability tests, ergometry and determinations of serum enzymes and GH levels. After one year of trial the code was broken and it was seen that the twin under placebo treatment was strikingly worse than his brother, the progression of whose condition was practically arrested. These results strongly suggest that treatment with a GH inhibitor is beneficial for DMD patients. PMID:3524231

  12. [Principles of multidisciplinary management of Duchenne muscular dystrophy].

    PubMed

    Chabrol, B; Mayer, M

    2015-12-01

    Given the gradual progression observed in Duchenne muscular dystrophy, organization of care in multidisciplinary consultations is essential for optimal management of the different aspects of the disease. Drawing up a care plan is always preceded by a specific consultation for the announcement of the diagnosis with both the parents and the child. Explaining to the child the origin of his problems with simple words, telling him that why he experienced a particular symptom has been understood, is a fundamental step. The child needs to receive the information at different times of the disease following the rhythms of the disease stages, with an appropriate lead time. With the progress achieved in managing this disease, more than 90% of these children now live into adulthood. The switch from pediatric consultations to adult consultations, marking the transition from childhood management at adulthood, is a major challenge in the organization of care. Although today death occurs most often in adulthood, some children die in childhood. For the majority of teams who care for children, whatever the initial pathology may be, the notion of care continuity and accompaniment from the announcement of the disease to the terminal phase is essential. Increasing numbers of therapeutic trials have been developed over the past few years aiming to investigate children with DMD. However, they must not neglect the overall management of these patients and provide the best accompaniment possible. PMID:26773590

  13. Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011.

    PubMed

    Attarian, S; Salort-Campana, E; Nguyen, K; Behin, A; Andoni Urtizberea, J

    2012-12-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a neuromuscular disease, characterized by an autosomal dominant mode of inheritance, facial involvement, and selectivity and asymmetry of muscle involvement. In general, FSHD typically presents before age 20 years. Usually, FSHD muscle involvement starts in the face and then progresses to the shoulder girdle, the humeral muscles and the abdominal muscles, and then the anterolateral compartment of the leg. Disease severity is highly variable and progression is very slow. About 20% of FSHD patients become wheelchair-bound. Lifespan is not shortened. The diagnosis of FSHD is based on a genetic test by which a deletion of 3.3kb DNA repeats (named D4Z4 and mapping to the subtelomeric region of chromosome 4q35) is identified. The progressive pattern of FSHD requires that the severity of symptoms as well as their physical, social and psychological impact be evaluated on a regular basis. A yearly assessment is recommended. Multidisciplinary management of FSHD--consisting of a combination of genetic counselling, functional assessment, an assessment by a physical therapist, prescription of symptomatic therapies and prevention of known complications of this disease--is required. Prescription of physical therapy sessions and orthopedic appliances are to be adapted to the patient's deficiencies and contractures. PMID:22551571

  14. The Congenital Muscular Dystrophies: Recent Advances and Molecular Insights

    PubMed Central

    Mendell, Jerry R.; Bou, Daniel R.; Martin, Paul T.

    2010-01-01

    Over the past decade, molecular understanding of the congenital muscular dystrophies (CMDs) has greatly expanded. The diseases can be classified into 3 major groups based on the affected genes and the location of their expressed protein: abnormalities of extracellular matrix proteins (LAMA2, COL6A1, COL6A2, COL6A3), abnormalities of membrane receptors for the extracellular matrix (fukutin, POMGnT1, POMT1, POMT2, FKRP, LARGE, and ITGA7), and abnormal endoplasmic reticulum protein (SEPN1). The diseases begin in the perinatal period or shortly thereafter. A specific diagnosis can be challenging because the muscle pathology is usually not distinctive. Immunostaining of muscle using a battery of antibodies can help define a disorder that will need confirmation by gene testing. In muscle diseases with overlapping pathological features, such as CMD, careful attention to the clinical clues (e.g., family history, central nervous system features) can help guide the battery of immunostains necessary to target an unequivocal diagnosis. PMID:17163796

  15. Duchenne Muscular Dystrophy Gene Therapy in the Canine Model

    PubMed Central

    2015-01-01

    Abstract Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

  16. Predictive factors for masticatory performance in Duchenne muscular dystrophy.

    PubMed

    van Bruggen, H W; van de Engel-Hoek, L; Steenks, M H; Bronkhorst, E M; Creugers, N H J; de Groot, I J M; Kalaykova, S I

    2014-08-01

    Patients with Duchenne muscular dystrophy (DMD) report masticatory and swallowing problems. Such problems may cause complications such as choking, and feeling of food sticking in the throat. We investigated whether masticatory performance in DMD is objectively impaired, and explored predictive factors for compromised mastication. Twenty-three patients and 23 controls filled out two questionnaires about mandibular function, and underwent a clinical examination of the masticatory system and measurements of anterior bite force and masticatory performance. In the patients, moreover, quantitative ultrasound of the tongue and motor function measurement was performed. The patients were categorized into ambulatory stage (early or late), early non-ambulatory stage, or late non-ambulatory stage. Masticatory performance, anterior bite force and occlusal contacts were all reduced in the patient group compared to the controls (all p < 0.001). Mastication abnormalities were present early in the disease process prior to a reduction of motor function measurement. The early non-ambulatory and late non-ambulatory stage groups showed less masticatory performance compared to the ambulatory stage group (p < 0.028 and p < 0.010, respectively). Multiple linear regression analysis revealed that stage of the disease was the strongest independent risk factor for the masticatory performance (R(2) = 0.52). Anterior bite force, occlusal contacts and masticatory performance in DMD are severely reduced. PMID:24969130

  17. The immune system in Duchenne muscular dystrophy: Friend or foe.

    PubMed

    Villalta, S Armando; Rosenberg, Amy S; Bluestone, Jeffrey A

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the X-linked dystrophin gene, resulting in reduced or absent protein production, subsequently leading to the structural instability of the dystroglycan complex (DGC), muscle degeneration, and early death in males. Thus, current treatments have been targeting the genetic defect either by bypassing the mutation through exon skipping or replacing the defective gene through gene therapy and stem cell approaches. However, what has been an underappreciated mediator of muscle pathology and, ultimately, of muscle degeneration and fibrotic replacement, is the prominent inflammatory response. Of potentially critical importance, however, is the fact that the elements mediating the inflammatory response also play an essential role in tissue repair. In this opinion piece, we highlight the detrimental and supportive immune parameters that occur as a consequence of the genetic disorder and discuss how changes to immunity can potentially ameliorate the disease intensity and be employed in conjunction with efforts to correct the genetic disorder. PMID:26481612

  18. Duchenne muscular dystrophy gene therapy in the canine model.

    PubMed

    Duan, Dongsheng

    2015-03-01

    Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disease caused by dystrophin deficiency. Gene therapy has significantly improved the outcome of dystrophin-deficient mice. Yet, clinical translation has not resulted in the expected benefits in human patients. This translational gap is largely because of the insufficient modeling of DMD in mice. Specifically, mice lacking dystrophin show minimum dystrophic symptoms, and they do not respond to the gene therapy vector in the same way as human patients do. Further, the size of a mouse is hundredfolds smaller than a boy, making it impossible to scale-up gene therapy in a mouse model. None of these limitations exist in the canine DMD (cDMD) model. For this reason, cDMD dogs have been considered a highly valuable platform to test experimental DMD gene therapy. Over the last three decades, a variety of gene therapy approaches have been evaluated in cDMD dogs using a number of nonviral and viral vectors. These studies have provided critical insight for the development of an effective gene therapy protocol in human patients. This review discusses the history, current status, and future directions of the DMD gene therapy in the canine model. PMID:25710459

  19. Testosterone Treatment of Pubertal Delay in Duchenne Muscular Dystrophy.

    PubMed

    Wood, Claire L; Cheetham, Tim D; Guglieri, Michela; Bushby, Kate; Owen, Catherine; Johnstone, Helen; Straub, Volker

    2015-12-01

    Background?The outlook for adolescents with Duchenne muscular dystrophy (DMD) has improved greatly as a result of corticosteroid use, but treatment will compromise growth and delay puberty. Whether exogenous testosterone can promote growth, development, and skeletal health is unclear. Methods?We collected data retrospectively on growth and pubertal response in 14 adolescents with DMD who were treated with testosterone between 2008 and 2014. Results?A total of 14 boys were treated at a median age of 14.5 years. Eight have finished treatment after a mean age of 3.1 years and the feedback from families was generally positive. The mean testicular volume pretreatment was 2.4 and 3.9 mL posttreatment. The mean baseline testosterone concentrations were?

  20. Composite biomarkers for assessing Duchenne muscular dystrophy: an initial assessment

    PubMed Central

    Shklyar, Irina; Pasternak, Amy; Kapur, Kush; Darras, Basil T.; Rutkove, Seward B.

    2014-01-01

    BACKGROUND Compared to individual parameters, composite biomarkers may provide a more effective means for monitoring disease progression and the effects of therapy in clinical trials than single measures. In this study, we built composite biomarkers for use in Duchenne muscular dystrophy (DMD) by combining values from two objective measures of disease severity: electrical impedance myography (EIM) and quantitative ultrasound (QUS) and evaluating how well they correlated to standard functional measures. METHODS Utilizing data from an ongoing study of EIM and QUS in 31 DMD and 26 healthy boys aged 214 years, we combined data sets by first creating z-scores based on the normal subject data and then using simple mathematical operations (addition and multiplication) to create composite measures. These composite scores were then correlated to age and standard measures of function including the six-minute walk test, the North Star Ambulatory Assessment (NSAA), and handheld dynamometry. RESULTS Combining data sets resulted in stronger correlations with all four outcomes than for either EIM or QUS alone in six of eight instances. These improvements reached statistical significance (p < 0.05) in several cases. For example, the correlation coefficient for the composite measure with the NSAA was 0.79 but was only 0.66 and 0.67 (respectively) for GSL and EIM separately. CONCLUSIONS Arithmetically derived composite scores can provide stronger correlations to functional measures than isolated biomarkers. Longitudinal study of such composite markers in DMD clinical trials is warranted. PMID:25447928

  1. Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.

    PubMed

    Paim, Julia F; Cotta, Ana; Vargas, Antonio P; Navarro, Monica M; Valicek, Jaquelin; Carvalho, Elmano; da-Cunha, Antonio L; Plentz, Estevo; Braz, Shelida V; Takata, Reinaldo I; Almeida, Camila F; Vainzof, Mariz

    2013-06-01

    Limb girdle muscular dystrophy type 2G (LGMD2G) is caused by mutations in the telethonin gene. Only few families were described presenting this disease, and they are mainly Brazilians. Here, we identified one additional case carrying the same common c.157C > T mutation in the telethonin gene but with an atypical histopathological muscle pattern. In a female patient with a long duration of symptoms (46years), muscle biopsy showed, in addition to telethonin deficiency, the presence of nemaline rods, type 1 fiber predominance, nuclear internalization, lobulated fibers, and mitochondrial paracrystalline inclusions. Her first clinical signs were identified at 8years old, which include tiptoe walking, left lower limb deformity, and frequent falls. Ambulation loss occurred at 41years old, and now, at 54years old, she presented pelvic girdle atrophy, winging scapula, foot deformity with incapacity to perform ankle dorsiflexion, and absent tendon reflexes. The presence of nemaline bodies could be a secondary phenomenon, possibly associated with focal Z-line abnormalities of a long-standing disease. However, these new histopathological findings, characteristic of congenital myopathies, expand muscle phenotypic variability of telethoninopathy. PMID:23479141

  2. Rationale for treating oedema in Duchenne muscular dystrophy with eplerenone.

    PubMed

    Lehmann-Horn, Frank; Weber, Marc-Andr; Nagel, Armin M; Meinck, Hans-Michael; Breitenbach, Simon; Scharrer, Johannes; Jurkat-Rott, Karin

    2012-05-01

    Recently we reported a cytoplasmic sodium overload to cause a severe osmotic oedema in Duchenne muscular dystrophy (DMD). Our results suggested that this dual overload of sodium ions and water precedes the dystrophic process and persists until fatty muscle degeneration is complete. The present paper addresses the questions as to whether these overloads are important for the pathogenesis of the disease, and if so, whether they can be treated. As a first step, we investigated the effects of various diuretic drugs on a cell model of DMD, i.e. rat diaphragm strips previously exposed to amphotericin B. We found that both carbonic anhydrase inhibitors and aldosterone antagonists were able to repolarise depolarised muscle fibres. Since carbonic anhydrase inhibitors are known to have acidifying effects and this might be detrimental to the ventilation of DMD patients, we mainly concentrated on the modern spironolactone derivative, eplerenone. This drug had a very high repolarizing power, the parameter considered by us as being most relevant for a beneficial effect. In a pilot study we administered this drug to a 22-yr-old female DMD patient who was bound to an electric wheelchair and has had no corticosteroid therapy before. Eplerenone decreased both cytoplasmic sodium and water overload and increased muscle strength and mobility. We conclude that eplerenone has beneficial effects on DMD muscle. In our opinion the cytoplasmic oedema is cytotoxic and should be treated before fatty degeneration takes place. PMID:22655515

  3. Confocal analysis of the dystrophin protein complex in muscular dystrophy.

    PubMed

    Draviam, R; Billington, L; Senchak, A; Hoffman, E P; Watkins, S C

    2001-02-01

    The dystrophin protein complex (DPC), composed of at least 10 proteins that associate with dystrophin, is critical for the maintenance of normal muscle fiber structure and physiology. In this study, we used immunohistochemistry and confocal microscopy to examine the relative abundance and distribution of several of these proteins in muscle biopsies taken from patients with various muscular dystrophies. The optical sectioning capability of confocal microscopy allowed us to comprehensively analyze the semiquantitative expression of components of the DPC. Alpha-sarcoglycan-deficient patients displayed a marked reduction in membrane immunostaining of the sarcoglycan complex. Gamma-sarcoglycan-deficient patients showed variable decreased immunostaining of the sarcoglycan complex proteins. When beta-sarcoglycan was expressed appropriately at the sarcolemma of gamma-sarcoglycan-deficient patients, intracellular labeling of beta-sarcoglycan was also present. Beta-sarcoglycan-deficient patients showed poor localization of extracellular matrix proteins in addition to a complete absence of the sarcoglycans. Merosin-deficient patients showed relatively normal immunostaining levels of all other members of the DPC. Finally, dystrophin-deficient patients showed little or no change in the expression of extracellular matrix proteins; however, some sarcoglycans were significantly decreased. These data allowed us to suggest unique fundamental interactions between the members of the DPC. PMID:11180210

  4. Experimental Models of Duchenne Muscular Dystrophy: Relationship with Cardiovascular Disease

    PubMed Central

    Ameen, Venus; Robson, Lesley G

    2010-01-01

    Almost every boy that has Duchenne Muscular Dystrophy (DMD) will develop cardiac problems. Whereas, it used to be respiratory problems that was the main cause of death in these DMD boys; with the advent of better respiratory care it is now the cardiac involvement that is becoming the most common cause of their death. Once the heart is affected, there is progressive deterioration in the function of the heart over time. The main problem is the death of the cardiomyocytes. The cause of the cardiomyocyte death is due to the loss of dystrophin, this makes the sarcolemma more susceptible to damage, and leads to a cascade of calcium influx, calcium activated proteases and ultimately the death of the cardiomyocyte. The dead cardiomyocytes are replaced by fibrotic tissue, which results in a dilated cardiomyopathy (DCM) developing, which begins in the base of the left ventricle and progresses to involve the entire left ventricle. The treatments used for the DMD cardiomyopathy are based on ones designed for other forms of cardiac weakness and include ACE-inhibitors and ?-blockers. New therapies based around the pathophysiology in DMD are now being introduced. This review will look at the pathophysiology of the cardiac problems in DMD and how the various animal models that are available can be used to design new treatment options for DMD boys. PMID:21258567

  5. The Dutch patients' perspective on oculopharyngeal muscular dystrophy: A questionnaire study on fatigue, pain and impairments.

    PubMed

    van der Sluijs, Barbara M; Knoop, Hans; Bleijenberg, Gijs; van Engelen, Baziel G M; Voermans, Nicol C

    2016-03-01

    Research on oculopharyngeal muscular dystrophy focuses mainly on genetic and pathophysiological aspects. Clinically, oculopharyngeal muscular dystrophy is often considered as a disease with a relatively mild initial disease course with no or only mild functional disabilities. However the occurrence of fatigue, pain and functional impairments other than dysphagia has never been studied systematically. The aim of this study is therefore to assess the prevalence of fatigue, pain, and functional limitations, and the social participation and psychological well-being of oculopharyngeal muscular dystrophy patients. We performed a questionnaire study on fatigue, pain, functional impairments, social participation and psychological distress in 35 genetically confirmed oculopharyngeal muscular dystrophy patients with an average disease duration of 11.6 years. We showed that 19 (54%) of the patients experienced severe fatigue and also 19 (54%) experienced pain. Limitations in daily life activities and social participation were detected in 33 (94%) of the patients. Many patients reported pelvic girdle weakness and limitations in ambulation. Fatigue severity was related to functional impairments, while pain and disease duration were not. Psychological distress was not different from healthy adults. In conclusion, fatigue and pain are present among approximately half of the patients, and almost all patients are impaired in daily life activities, social participation and ambulation. These data should be taken into account in symptomatic management of oculopharyngeal muscular dystrophy. PMID:26948710

  6. Peripheral nerve blocks as the sole anesthetic technique in a patient with severe Duchenne muscular dystrophy.

    PubMed

    Bang, Seung Uk; Kim, Yee Suk; Kwon, Woo Jin; Lee, Sang Mook; Kim, Soo Hyang

    2016-04-01

    General anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are associated with high risks of complications, including rhabdomyolysis, malignant hyperthermia, hemodynamic instability, and postoperative mechanical ventilation. Here, we describe peripheral nerve blocks as a safe approach to anesthesia in a patient with severe Duchenne muscular dystrophy who was scheduled to undergo surgery. A 22-year-old male patient was scheduled to undergo reduction and internal fixation of a left distal femur fracture. He had been diagnosed with Duchenne muscular dystrophy at 5 years of age, and had no locomotive capability except for that of the finger flexors and toe extensors. He had developed symptoms associated with dyspnea 5 years before and required intermittent ventilation. We blocked the femoral nerve, lateral femoral cutaneous nerve, and parasacral plexus under ultrasound on the left leg. The patient underwent a successful operation using peripheral nerve blocks with no complications. In conclusion general anesthesia and central neuraxial blockades in patients with severe Duchenne muscular dystrophy are unsafe approaches to anesthesia because of hemodynamic instability and respiratory depression. Peripheral nerve blocks are the best way to reduce the risks of critical complications, and are a safe and feasible approach to anesthesia in patients with severe Duchenne muscular dystrophy. PMID:26721827

  7. Genetic and pharmacologic inhibition of mitochondrial-dependent necrosis attenuates muscular dystrophy

    PubMed Central

    Millay, Douglas P; Sargent, Michelle A; Osinska, Hanna; Baines, Christopher P; Barton, Elisabeth R; Vuagniaux, Grgoire; Sweeney, H Lee; Robbins, Jeffrey; Molkentin, Jeffery D

    2009-01-01

    Muscular dystrophies comprise a diverse group of genetic disorders that lead to muscle wasting and, in many instances, premature death1. Many mutations that cause muscular dystrophy compromise the support network that connects myofilament proteins within the cell to the basal lamina outside the cell, rendering the sarcolemma more permeable or leaky. Here we show that deletion of the gene encoding cyclophilin D (Ppif) rendered mitochondria largely insensitive to the calcium overloadinduced swelling associated with a defective sarcolemma, thus reducing myofiber necrosis in two distinct models of muscular dystrophy. Mice lacking ?-sarcoglycan (Scgd?/? mice) showed markedly less dystrophic disease in both skeletal muscle and heart in the absence of Ppif. Moreover, the premature lethality associated with deletion of Lama2, encoding the ?-2 chain of laminin-2, was rescued, as were other indices of dystrophic disease. Treatment with the cyclophilin inhibitor Debio-025 similarly reduced mitochondrial swelling and necrotic disease manifestations in mdx mice, a model of Duchenne muscular dystrophy, and in Scgd?/? mice. Thus, mitochondrial-dependent necrosis represents a prominent disease mechanism in muscular dystrophy, suggesting that inhibition of cyclophilin D could provide a new pharmacologic treatment strategy for these diseases. PMID:18345011

  8. Histone Deacetylase Inhibitors in the Treatment of Muscular Dystrophies: Epigenetic Drugs for Genetic Diseases

    PubMed Central

    Consalvi, Silvia; Saccone, Valentina; Giordani, Lorenzo; Minetti, Giulia; Mozzetta, Chiara; Puri, Pier Lorenzo

    2011-01-01

    Histone deacetylases inhibitors (HDACi) include a growing number of drugs that share the ability to inhibit the enzymatic activity of some or all the HDACs. Experimental and preclinical evidence indicates that these epigenetic drugs not only can be effective in the treatment of malignancies, inflammatory diseases and degenerative disorders, but also in the treatment of genetic diseases, such as muscular dystrophies. The ability of HDACi to counter the progression of muscular dystrophies points to HDACs as a crucial link between specific genetic mutations and downstream determinants of disease progression. It also suggests the contribution of epigenetic events to the pathogenesis of muscular dystrophies. Here we describe the experimental evidence supporting the key role of HDACs in the control of the transcriptional networks underlying the potential of dystrophic muscles either to activate compensatory regeneration or to undergo fibroadipogenic degeneration. Studies performed in mouse models of Duchenne muscular dystrophy (DMD) indicate that dystrophin deficiency leads to deregulated HDAC activity, which perturbs downstream networks and can be restored directly, by HDAC blockade, or indirectly, by reexpression of dystrophin. This evidence supports the current view that HDACi are emerging candidate drugs for pharmacological interventions in muscular dystrophies, and reveals unexpected common beneficial outcomes of pharmacological treatment or gene therapy. PMID:21308150

  9. [Pseudohypertrophic forms of progressive muscular dystrophy with the onset at puberty and a malignant course of the myodystrophic process].

    PubMed

    Badalian, L O; Arkhipov, B A; Temin, P A; Zavadenko, N N; Voloshina, T G

    1988-01-01

    The article describes two familial cases of pseudohypertrophic progressive muscular dystrophy with an onset in the pubertal age and a malignant course of the myodystrophic process. The cases presented are the first ever reported in the world literature. The questions of inter- and intrafamilial polymorphism of recessive X-linked forms of progressive muscular dystrophies are discussed. PMID:3381616

  10. Becker muscular dystrophy-like myopathy regarded as so-called "fatty muscular dystrophy" in a pig: a case report and its diagnostic method.

    PubMed

    Horiuchi, Noriyuki; Aihara, Naoyuki; Mizutani, Hiroshi; Kousaka, Shinichi; Nagafuchi, Tsuneyuki; Ochiai, Mariko; Ochiai, Kazuhiko; Kobayashi, Yoshiyasu; Furuoka, Hidefumi; Asai, Tetsuo; Oishi, Koji

    2014-03-01

    We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin-embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called "fatty muscular dystrophy". Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig. PMID:24162004

  11. Becker Muscular Dystrophy-Like Myopathy Regarded as So-Called Fatty Muscular Dystrophy in a Pig: A Case Report and Its Diagnostic Method

    PubMed Central

    HORIUCHI, Noriyuki; AIHARA, Naoyuki; MIZUTANI, Hiroshi; KOUSAKA, Shinichi; NAGAFUCHI, Tsuneyuki; OCHIAI, Mariko; OCHIAI, Kazuhiko; KOBAYASHI, Yoshiyasu; FURUOKA, Hidefumi; ASAI, Tetsuo; OISHI, Koji

    2013-01-01

    ABSTRACT We describe a case of human Becker muscular dystrophy (BMD)-like myopathy that was characterized by the declined stainability of dystrophin at sarcolemma in a pig and the immunostaining for dystrophin on the formalin-fixed, paraffin-embedded (FFPE) tissue. The present case was found in a meat inspection center. The pig looked appeared healthy at the ante-mortem inspection. Muscular abnormalities were detected after carcass dressing as pale, discolored skeletal muscles with prominent fat infiltrations and considered so-called fatty muscular dystrophy. Microscopic examination revealed following characteristics: diffused fat infiltration into the skeletal muscle and degeneration and regeneration of the remaining skeletal muscle fibers. Any lesions that were suspected of neurogenic atrophy, traumatic muscular degeneration, glycogen storage disease or other porcine muscular disorders were not observed. The immunostaining for dystrophin was conducted and confirmed to be applicable on FFPE porcine muscular tissues and revealed diminished stainability of dystrophin at the sarcolemma in the present case. Based on the histological observations and immunostaining results, the present case was diagnosed with BMD-like myopathy associated with dystrophin abnormality in a pig. Although the genetic properties were not clear, the present BMD-like myopathy implied the occurrence of dystrophinopathy in pigs. To the best of our knowledge, this is the first report of a natural case of myopathy associated with dystrophin abnormalities in a pig. PMID:24162004

  12. Growth and psychomotor development of patients with Duchenne muscular dystrophy.

    PubMed

    Sarrazin, Elisabeth; von der Hagen, Maja; Schara, Ulrike; von Au, Katja; Kaindl, Angela M

    2014-01-01

    Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment. PMID:24100172

  13. Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)

    SciTech Connect

    Gilbert, J.R.; Stajich, J.M.; Wall, S.; Carter, S.C.; Qiu, H.; Vance, J.M.; Stewart, C.S.; Speer, M.C.; Pufky, J.; Yamaoka, L.H.; Rozear, M.; Roses, A.D.; Pericak-Vance, M.A. ); Samson, F.; Fardeau, M. )

    1993-08-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study the authors have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this region of 4q (P<.01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD. 19 refs., 3 figs., 2 tabs.

  14. Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Statland, Jeffrey; Donlin-Smith, Colleen M; Tapscott, Stephen J; van der Maarel, Silvere; Tawil, Rabi

    2015-01-01

    Background Recent studies have proposed a unified genetic model for Facioscapulohumeral muscular dystrophy (FSHD), identifying potential therapeutic targets for future clinical trials. Serum biomarkers related to disease activity will be important for proof of concept or early phase clinical studies. Objective To identify potential serum biomarkers in FSHD for possible use in future clinical trials. Methods We performed a prospective cross-sectional study of serum biomarkers in 22 FSHD patients (19 FSHD1, 3 FSHD2) compared to 23 age and gender-matched healthy controls using a commercial multiplex, microsphere-based immune-fluorescent assay of 243 markers (Myriad, Human Discovery MAP 250, v2.0). Results 169 markers had values sufficient for analysis. Correction for multiple testing identified 7 biomarkers below a 5% false discovery rate: creatine kinase MB fraction (CKMB, 6.52 fold change, P<0.0001), tissue-type plasminogen activator (PLAT, 1.64 fold change, P<0.0001), myoglobin (2.23 fold change, P=0.0001), epidermal growth factor (EGF, 2.33 fold change, P=0.0004), chemokine (C-C motif) ligand 2 (1.48 fold change, P=0.0004), CD 40 ligand (1.89 fold change, P=0.001), and vitronectin (VTN, 1.28 fold change, P=0.001). Moderate correlations to measures of FSHD disease were seen for CKMB, PLAT, and EGF. Markers in the plasminogen pathway (PLAT, serpin peptidase inhibitor, and VTN) were correlated with each other in FSHD but not healthy controls. Conclusions Commercial multiplex immune-fluorescent screening is a potentially powerful tool for identifying biomarkers for future FSHD therapeutic trials. Biomarkers identified in this study warrant further study in a larger prospective validation study. PMID:25705588

  15. [A case of Becker muscular dystrophy with schizophrenic symptoms].

    PubMed

    Abe, M; Arai, M; Maehara, K; Arikawa, E; Arahata, K

    1990-11-01

    A 23-year-old male patient with Becker muscular dystrophy (BMD) who showed schizophrenic symptoms was reported. He tumbled easily and was poor at running since age at 8 years. He had difficulty in climbing stairs and was idle away all day long since age at 21 years. Although his premorbid personality was not schizoid, he showed auditory hallucinations and delusions without any psychogenetic moment at the age of 23. At first, he seemed to be schizophrenic, but after the treatment with antipsychotics, he always had an insight into his disease and exhibited natural emotional communication. He showed no autism and character changes. According to the Wechsler Adult Intelligence Scale (WAIS), intellectual impairment was notified (total IQ58). Neurological examinations revealed weakness and atrophy of muscles in the proximal part of his lower extremities, and pseudohypertrophy of calves. In the serum enzyme, serum creatine kinase (CK) level was elevated (700 U/L). Abnormal Q waves appeared in the leads, II, III, aVF, V5, V6 on the electrocardiogram (ECG), and the finding of the echocardiography suggested dilated cardiomyopathy. The electroencephalogram (EEG) revealed the basic rhythm of 9-10 Hz with 0 activities of 6-7 Hz which were predominant in frontparietal and central leads. The electromyogram (EMG) revealed a myopathic pattern with low voltage and short duration. A muscle biopsy from right biceps brachii disclosed the abnormal immunofluorescent staining pattern of dystrophin which is consistent with BMD patient, i.e., "patchy," discontinuous and faint immunoreaction at surface membrane of the fiber. Both molecular weight (380 kd: n = 400) and amount (30%; n = 100) of dystrophin were reduced.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2076351

  16. Direct interplay between two candidate genes in FSHD muscular dystrophy.

    PubMed

    Ferri, Giulia; Huichalaf, Claudia H; Caccia, Roberta; Gabellini, Davide

    2015-03-01

    Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are double homeobox 4 (DUX4), encoded by the most telomeric D4Z4 unit, and FSHD region gene 1 (FRG1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD. PMID:25326393

  17. Facioscapulohumeral muscular dystrophy: more complex than it appears.

    PubMed

    Ricci, G; Zatz, M; Tupler, R

    2014-10-10

    Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (≤8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as "permissive" specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD. PMID:25323867

  18. Compliance to Care Guidelines for Duchenne Muscular Dystrophy

    PubMed Central

    Landfeldt, Erik; Lindgren, Peter; Bell, Christopher F.; Schmitt, Claude; Guglieri, Michela; Straub, Volker

    2016-01-01

    Background International care guidelines for Duchenne muscular dystrophy (DMD) were published in 2010, but compliance in clinical practice is unknown. Objective The objective of our study was to compare real-world DMD care in Germany, Italy, the UK, and the US with the clinical recommendations. Methods DMD patients from Germany, Italy, the UK, and the US were identified through Translational Research in Europe Assessment & Treatment of Neuromuscular Diseases (TREAT-NMD) registries and invited with a caregiver to complete a questionnaire with questions regarding DMD-related healthcare. Estimates of care were stratified by disease stage (early/late ambulatory/non-ambulatory) and compared against the care guidelines. Results A total of 770 patients (173 German, 122 Italian, 191 UK, and 284 US) completed the questionnaire. Poor compliance to guidelines of routine follow-up by neuromuscular, cardiac, and respiratory specialists, physiotherapy, and access to medical devices and aids were observed in all countries. Less than 27% (209 of 770) of patients met all absolute recommendations, ranging from 9% (11 of 122) in Italy to 37% (70 of 191) in the UK, and from 49% (76 of 155) in the early ambulatory class to 16% (33 of 205) in the late non-ambulatory class. Conclusions We show that the medical management of DMD varies substantially between Germany, Italy, the UK, and the US. Experience of real-world DMD care appears to be in poor agreement with the DMD clinical guidelines and increased compliance is urgently needed to improve treatment outcomes and enable patients to lead fulfilling, independent lives into adulthood.

  19. Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears

    PubMed Central

    G, Ricci; M, Zatz; R, Tupler

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) has been classified as an autosomal dominant myopathy, linked to rearrangements in an array of 3.3 kb tandemly repeated DNA elements (D4Z4) located at the 4q subtelomere (4q35). For the last 20 years, the diagnosis of FSHD has been confirmed in clinical practice by the detection of one D4Z4 allele with a reduced number (?8) of repeats at 4q35. Although wide inter- and intra-familial clinical variability was found in subjects carrying D4Z4 alleles of reduced size, this DNA testing has been considered highly sensitive and specific. However, several exceptions to this general rule have been reported. Specifically, FSHD families with asymptomatic relatives carrying D4Z4 reduced alleles, FSHD genealogies with subjects affected with other neuromuscular disorders and FSHD affected patients carrying D4Z4 alleles of normal size have been described. In order to explain these findings, it has been proposed that the reduction of D4Z4 repeats at 4q35 could be pathogenic only in certain chromosomal backgrounds, defined as permissive specific haplotypes. However, our most recent studies show that the current DNA signature of FSHD is a common polymorphism and that in FSHD families the risk of developing FSHD for carriers of D4Z4 reduced alleles (DRA) depends on additional factors besides the 4q35 locus. These findings highlight the necessity to re-evaluate the significance and the predictive value of DRA, not only for research but also in clinical practice. Further clinical and genetic analysis of FSHD families will be extremely important for studies aiming at dissecting the complexity of FSHD.

  20. Red-Green Color Vision Impairment in Duchenne Muscular Dystrophy

    PubMed Central

    Costa, Marcelo Fernandes ; Oliveira, Andre Gustavo Fernandes ; Feitosa-Santana, Claudia ; Zatz, Mayana ; Ventura, Dora Fix 

    2007-01-01

    The present study evaluated the color vision of 44 patients with Duchenne muscular dystrophy (DMD) (mean age 14.8 years; SD 4.9) who were submitted to a battery of four different color tests: Cambridge Colour Test (CCT), Neitz Anomaloscope, Ishihara, and American Optical Hardy-Rand-Rittler (AO H-R-R). Patients were divided into two groups according to the region of deletion in the dystrophin gene: upstream of exon 30 (n=12) and downstream of exon 30 (n=32). The control group was composed of 70 age-matched healthy male subjects with no ophthalmological complaints. Of the patients with DMD, 47% (21/44) had a red-green color vision defect in the CCT, confirmed by the Neitz Anomaloscope with statistical agreement (P<.001). The Ishihara and the AO H-R-R had a lower capacity to detect color defects—5% and 7%, respectively, with no statistical similarity between the results of these two tests nor between CCT and Anomaloscope results (P>.05). Of the patients with deletion downstream of exon 30, 66% had a red-green color defect. No color defect was found in the patients with deletion upstream of exon 30. A negative correlation between the color thresholds and age was found for the controls and patients with DMD, suggesting a nonprogressive color defect. The percentage (66%) of patients with a red-green defect was significantly higher than the expected <10% for the normal male population (P<.001). In contrast, patients with DMD with deletion upstream of exon 30 had normal color vision. This color defect might be partially explained by a retina impairment related to dystrophin isoform Dp260. PMID:17503325

  1. Computer task performance by subjects with Duchenne muscular dystrophy

    PubMed Central

    Malheiros, Silvia Regina Pinheiro; da Silva, Talita Dias; Favero, Francis Meire; de Abreu, Luiz Carlos; Fregni, Felipe; Ribeiro, Denise Cardoso; de Mello Monteiro, Carlos Bandeira

    2016-01-01

    Aims Two specific objectives were established to quantify computer task performance among people with Duchenne muscular dystrophy (DMD). First, we compared simple computational task performance between subjects with DMD and age-matched typically developing (TD) subjects. Second, we examined correlations between the ability of subjects with DMD to learn the computational task and their motor functionality, age, and initial task performance. Method The study included 84 individuals (42 with DMD, mean age of 18±5.5 years, and 42 age-matched controls). They executed a computer maze task; all participants performed the acquisition (20 attempts) and retention (five attempts) phases, repeating the same maze. A different maze was used to verify transfer performance (five attempts). The Motor Function Measure Scale was applied, and the results were compared with maze task performance. Results In the acquisition phase, a significant decrease was found in movement time (MT) between the first and last acquisition block, but only for the DMD group. For the DMD group, MT during transfer was shorter than during the first acquisition block, indicating improvement from the first acquisition block to transfer. In addition, the TD group showed shorter MT than the DMD group across the study. Conclusion DMD participants improved their performance after practicing a computational task; however, the difference in MT was present in all attempts among DMD and control subjects. Computational task improvement was positively influenced by the initial performance of individuals with DMD. In turn, the initial performance was influenced by their distal functionality but not their age or overall functionality. PMID:26766911

  2. Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy

    PubMed Central

    Politano, Luisa; Melacini, Paola; Calore, Chiara; Polo, Angela; Vianello, Sara; Sorarù, Gianni; Semplicini, Claudio; Pantic, Boris; Taglia, Antonella; Picillo, Ester; Magri, Francesca; Gorni, Ksenija; Messina, Sonia; Vita, Gian Luca; Vita, Giuseppe; Comi, Giacomo P.; Ermani, Mario; Calvo, Vincenzo; Angelini, Corrado; Hoffman, Eric P.; Pegoraro, Elena

    2015-01-01

    Objective Dilated cardiomyopathy (DCM) is a major complication and leading cause of death in Duchenne muscular dystrophy (DMD). DCM onset is variable, suggesting modifier effects of genetic or environmental factors. We aimed to determine if polymorphisms previously associated with age at loss of independent ambulation (LoA) in DMD (rs28357094 in the SPP1 promoter, rs10880 and the VTTT/IAAM haplotype in LTBP4) also modify DCM onset. Methods A multicentric cohort of 178 DMD patients was genotyped by TaqMan assays. We performed a time-to-event analysis of DCM onset, with age as time variable, and finding of left ventricular ejection fraction < 50% and/or end diastolic volume > 70 mL/m2 as event (confirmed by a previous normal exam < 12 months prior); DCM-free patients were censored at the age of last echocardiographic follow-up. Results Patients were followed up to an average age of 15.9 ± 6.7 years. Seventy-one/178 patients developed DCM, and median age at onset was 20.0 years. Glucocorticoid corticosteroid treatment (n = 88 untreated; n = 75 treated; n = 15 unknown) did not have a significant independent effect on DCM onset. Cardiological medications were not administered before DCM onset in this population. We observed trends towards a protective effect of the dominant G allele at SPP1 rs28357094 and recessive T allele at LTBP4 rs10880, which was statistically significant in steroid-treated patients for LTBP4 rs10880 (< 50% T/T patients developing DCM during follow-up [n = 13]; median DCM onset 17.6 years for C/C-C/T, log-rank p = 0.027). Conclusions We report a putative protective effect of DMD genetic modifiers on the development of cardiac complications, that might aid in risk stratification if confirmed in independent cohorts. PMID:26513582

  3. Duchenne and Becker muscular dystrophies: an Indian update on genetics and rehabilitation.

    PubMed

    Nadkarni, Jayshree J; Dastur, Rashna S; Viswanathan, V; Gaitonde, Pradnya S; Khadilkar, Satish V

    2008-01-01

    The application of molecular diagnostic techniques has greatly improved the diagnosis, carrier detection, prenatal testing and genetic counseling for families with Duchenne and Becker muscular dystrophy (D/BMD) in India. The prediction of Duchenne muscular dystrophy (DMD) patients to have out-framed deletions and Becker's muscular dystrophy (BMD) patients to have in-frame deletions of dystrophin gene holds well in the vast majority of cases. Mutation detection is obviously critical for diagnosis but it may also be important for future therapeutic purposes. These factors underscore the need for earlier referral, genetic counseling and provision of support and rehabilitation services which are the main priorities for psychosocial assessment and intervention at medical and social levels. PMID:18974550

  4. Bethlem myopathy is not allelic to limb-girdle muscular dystrophy type 1A

    SciTech Connect

    Speer, M.C.; Yamaoka, L.H.; Stajich, J.; Lewis, K.

    1995-08-28

    The Bethlem myopathy, an autosomal-dominant myopathy, shows a distribution of proximal muscle weakness similar to that observed in dominant limb-girdle muscular dystrophy (LGMD). Yet the Bethlem myopathy differs from most limb-girdle dystrophies in two important regards. First, the Bethlem myopathy presents with joint contractures most commonly observed at the elbows, ankles, and neck. Secondly, disease onset in the Bethlem myopathy is in early childhood, while most dominant LGMDs present with adult onset. 6 refs., 1 fig.

  5. Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy.

    PubMed

    Illarioshkin, S N; Ivanova-Smolenskaya, I A; Tanaka, H; Vereshchagin, N V; Markova, E D; Poleshchuk, V V; Lozhnikova, S M; Sukhorukov, V S; Limborska, S A; Slominsky, P A; Bulayeva, K B; Tsuji, S

    1996-12-01

    We describe a unique six-generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb-girdle variant of muscular dystrophy (LGMD), with disease onset at 15-30 years and loss of ambulation within a 25-year course. The second group included three patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregated independently as an autosomal recessive trait, and muscle biopsies showed non-specific myopathic changes. Lastly, two male siblings exhibited an atypical variant of Duchenne muscular dystrophy confirmed by detection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrophy in this kindred, we performed molecular genetic studies on 67 family members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achieved at the zero recombination fraction (i.e. at theta = 0.00) for locus D2S291; multipoint linkage analysis confirmed the most likely location of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homozygous haplotype associated with the same founder chromosome; key recombinants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal recessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy, were recently mapped to the same locus. We suggest that all three chromosome 2p-linked conditions may represent allelic disorders, i.e. different phenotypic expressions of a single gene. PMID:9009996

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

    SciTech Connect

    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.

  7. Muscular dystrophy in a patient with multiple sclerosis. Another "double-trouble"?

    PubMed

    Parissis, Dimitrios; Ioannidis, Panagiotis; Bakirtzis, Christos; Grigoriadis, Nikolaos; Karacostas, Dimitrios

    2015-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is considered a relatively common muscular dystrophy affecting approximately 1:15,000 individuals in the general population. Single case reports have described the rare co-occurrence of FSHD with other hereditary neuromuscular disorders, leading to atypical phenotypes. We report herein the case of a 26-year-old woman with genetically proven FSHD, who additionally developed otherwise typical multiple sclerosis (MS). Although there is no direct relationship between FSHD and MS, they might, nevertheless, share some common pathophysiological mechanisms, as recent research suggests. In particular, we comment on the potential, but not yet proven, role of immunological factors in the pathogenesis of FSHD. PMID:26195054

  8. Usefulness of sugammadex in a patient with Becker muscular dystrophy and dilated cardiomyopathy.

    PubMed

    Shimauchi, Tsukasa; Yamaura, Ken; Sugibe, Sayaka; Hoka, Sumio

    2014-09-01

    A 54-year-old patient with Becker muscular dystrophy and dilated cardiomyopathy underwent laparoscopic cholecystectomy under total intravenous anesthesia. Muscle relaxation was induced by rocuronium (0.4mg/kg body weight) under train-of-four (TOF) ratio monitoring. The TOF ratio was 0 at intubation, and 0.2 at the end of surgery. Residual muscle relaxant activity was successfully reversed by sugammadex (2mg/kg body weight) without any hemodynamic adverse effects (TOF ratio 1.0 at extubation). The clinical and hemodynamic findings suggest that sugammadex can be safely used in patients with Becker muscular dystrophy and dilated cardiomyopathy. PMID:25199695

  9. Dysferlin-Deficient Muscular Dystrophy Identified Through Laboratory Testing for Elevated Aminotransferases

    PubMed Central

    Achdjian, Houry; Usta, Yousef; Nanda, Rakesh

    2016-01-01

    We present a 24-year-old combat veteran who underwent extensive work-up for elevated aminotransferases, including liver biopsy, with no underlying pathology identified. Subsequent investigations showed elevated creatinine kinase and aldolase. The patient was later diagnosed with biopsy-proven dysferlin-deficient muscular dystrophy. Persistent transaminase elevation despite negative liver work-up should prompt clinicians to consider extrahepatic sources of enzyme elevation. Promptly correlating aminotransferase elevation with musculoskeletal pathology may present an opportunity for clinicians to detect myopathies such as muscular dystrophy in their preclinical stages. PMID:26958568

  10. The cell biology of disease: cellular and molecular mechanisms underlying muscular dystrophy.

    PubMed

    Rahimov, Fedik; Kunkel, Louis M

    2013-05-13

    The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes. PMID:23671309

  11. Cytokines and Chemokines as Regulators of Skeletal Muscle Inflammation: Presenting the Case of Duchenne Muscular Dystrophy

    PubMed Central

    De Bleecker, Jan L.

    2013-01-01

    Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary effects on muscle fiber damage control and tissue regeneration. In this review, current knowledge of cytokine and chemokine expression in Duchenne muscular dystrophy and its relevant animal disease models is listed, and implications for future therapeutic avenues are discussed. PMID:24302815

  12. Selenoprotein N muscular dystrophy: differential diagnosis for early-onset limited mobility of the spine.

    PubMed

    Sponholz, Stefanie; von der Hagen, Maja; Hahn, Gabriele; Seifert, Jens; Richard, Pascale; Stoltenburg-Didinger, Gisela; Ferreiro, Ana; Kaindl, Angela M

    2006-04-01

    Early spinal rigidity is a nonspecific feature reported in diseases such as neuromuscular and central movement disorders. We present a male patient with rigid spine muscular dystrophy caused by newly identified compound heterozygote mutations of the selenoprotein N gene and discuss this disease as a possible differential diagnosis for early-onset reduced spine mobility. Rigid spine muscular dystrophy is a rare myopathy presenting in childhood with a typical combination of stable or slowly progressive mild to moderate muscle weakness, limitation in flexion of the spine, and progressive restrictive ventilatory disorder. The clinical features of our patient include early-onset rigidity of his spine, scoliosis, mild muscular weakness predominantly of neck and trunk flexors, and restrictive ventilatory disorder. Biopsy of the biceps muscle revealed nonspecific myopathic changes, and molecular analysis confirmed the diagnosis of rigid spine muscular dystrophy. Thus, neuromuscular diseases such as muscular dystrophy must be considered in all patients presenting with early spinal rigidity, and genetic determination is a possible way to determine the diagnosis. PMID:16900928

  13. 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. PMID:26323256

  14. Nutritional muscular dystrophy in a four-day-old Connemara foal

    PubMed Central

    2009-01-01

    This report describes a four-day-old, full-term Connemara colt, presented for the evaluation of a progressive inability to rise unassisted. A diagnosis of nutritional muscular dystrophy was made based on muscular weakness, elevated muscle enzymes and low vitamin E, selenium and glutathione peroxidase activity. The foal was treated with intramuscular vitamin E-selenium and made a full recovery. PMID:21851729

  15. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    MedlinePLUS

    ... dystrophy are two related conditions that primarily affect skeletal muscles, which are used for movement, and heart (cardiac) ... called dystrophin. This protein is located primarily in skeletal and cardiac muscle, where it helps stabilize and protect muscle fibers. ...

  16. Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.

    2007-01-01

    The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly

  17. Pregnancy and delivery in Leyden-Mbius muscular dystrophy. Case Report.

    PubMed

    Vavrinkova, Blanka; Binder, Tomas

    2015-01-01

    Leyden-Mbius muscular dystrophy is an autosomal recessive hereditary disease of unknown aetiology; it is a congenital disorder of protein metabolism primarily affecting proximal muscle groups leading to progressive muscular dystrophy. It later spreads to the muscles of the pelvic floor and lower extremities. The estimated incidence is 1:200,000. This paper describe a case of pregnancy and delivery in woman with progressive Leyden-Moebius muscular dystrophy. Cesarean section was performed due to progression of the underlying disease. First postoperative day DIC occure and surgical revision of abdominal cavity was performed. Although the uterine suture was strong, diffuse bleeding was present. Blood was not coagulating. Supravaginal amputation of the uterus was performed including left-sided adnexectomy due to bleeding from the left ovarium. Due to the severity of the condition and assumed necessity of long-term controlled ventilation, the patient was transferred to the intensive medicine department. She was dismissed home after 91 days of hospitalisation. Gravidity in advanced muscular dystrophy is rare and associated with a high risk. Due to muscle weakness, diaphragm weakness, atrophy of individual muscle groups, spine deformities and often dislocation of thoracic organs, these patients cannot avoid the caesarean section to end their pregnancy, followed by prolonged intubation and controlled ventilation. During pregnancy, the growing uterus elevates the diaphragm and impairs breathing. Therefore, pregnancies in such patients will probably always have to be ended prematurely. PMID:26313391

  18. Muscular dystrophy in a family of Labrador Retrievers with no muscle dystrophin and a mild phenotype.

    PubMed

    Vieira, Natassia M; Guo, Ling T; Estrela, Elicia; Kunkel, Louis M; Zatz, Mayana; Shelton, G Diane

    2015-05-01

    Animal models of dystrophin deficient muscular dystrophy, most notably canine X-linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies. PMID:25813339

  19. Parents' Perspectives on Coping with Duchenne Muscular Dystrophy and Concomitant Specific Learning Disabilities

    ERIC Educational Resources Information Center

    Webb, Carol L.

    2005-01-01

    This study addresses parental perspectives and coping strategies related to Duchenne muscular dystrophy and specific learning disabilities. Data were collected through individual semi-structured in-depth interviews with fifteen sets of parents. Participants were selected based on variables such as age of children, number of children with both…

  20. Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy

    ERIC Educational Resources Information Center

    Marini, A.; Lorusso, M. L.; D'Angelo, M. G.; Civati, F.; Turconi, A. C.; Fabbro, F.; Bresolin, N.

    2007-01-01

    The present work investigated cognitive, linguistic and narrative abilities in a group of children suffering from Duchenne Muscular Dystrophy, an allelic X-linked recessive disorder caused by mutations in the gene encoding dystrophin. The patients showed mildly reduced IQ with lower Verbal than Performance Intelligence Quotient and were mildly…

  1. Improving the Reading Skills of Young People with Duchenne Muscular Dystrophy in Preparation for Adulthood

    ERIC Educational Resources Information Center

    Hoskin, Janet; Fawcett, Angela

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34…

  2. Activities of antioxidant enzymes in muscle, liver and lung of chickens with inherited muscular dystrophy.

    PubMed

    Murphy, M E; Kehrer, J P

    1986-01-29

    An inherited form of muscular dystrophy in chickens has been used as a model of Duchenne muscular dystrophy. The pectoralis major muscle of chickens with this disease showed a significantly elevated activity of catalase (CAT) one day after hatching, and by 7 days showed elevated superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione-S-transferase (GST) activities. Increases were also found in tissues of the dystrophic birds that, unlike the pectoralis muscle, are considered to be unaffected by the pathology of muscular dystrophy. The soleus muscle contained significantly increased levels of SOD and GPX in 1 and 7 day old chickens, and increased GST in 1, 14, and 28 day old birds. CAT was significantly increased in liver from 1 and 7 day old chickens, while GPX was increased in lung from 1, 7 and 14 day old birds. These results support the possibility that excess oxygen free-radicals or altered cellular antioxidant defenses play some role in the pathogenesis of muscular dystrophy. PMID:3947339

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

    SciTech Connect

    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. These 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.

  4. Parents' Perspectives on Coping with Duchenne Muscular Dystrophy and Concomitant Specific Learning Disabilities

    ERIC Educational Resources Information Center

    Webb, Carol L.

    2005-01-01

    This study addresses parental perspectives and coping strategies related to Duchenne muscular dystrophy and specific learning disabilities. Data were collected through individual semi-structured in-depth interviews with fifteen sets of parents. Participants were selected based on variables such as age of children, number of children with both

  5. Na+ dysregulation coupled with Ca2+ entry through NCX1 promotes muscular dystrophy in mice.

    PubMed

    Burr, Adam R; Millay, Douglas P; Goonasekera, Sanjeewa A; Park, Ki Ho; Sargent, Michelle A; Collins, James; Altamirano, Francisco; Philipson, Kenneth D; Allen, Paul D; Ma, Jianjie; Lpez, Jos Rafael; Molkentin, Jeffery D

    2014-06-01

    Unregulated Ca(2+) entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na(+)-Ca(2+) exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in ?-sarcoglycan (Sgcd(-/-)), Dysf(-/-), and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd(-/-) mice. Measured increases in baseline Na(+) and Ca(2+) in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca(2+) influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca(2+) levels. Indeed, Atp1a2(+/-) (encoding Na(+)-K(+) ATPase ?2) mice, which have reduced Na(+) clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na(+)-K(+) ATPase inhibitor digoxin. Treatment of Sgcd(-/-) mice with ranolazine, a broadly acting Na(+) channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology. PMID:24662047

  6. Improving the Reading Skills of Young People with Duchenne Muscular Dystrophy in Preparation for Adulthood

    ERIC Educational Resources Information Center

    Hoskin, Janet; Fawcett, Angela

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a progressive genetic condition that affects both muscle and brain. Children with DMD are at risk of psycho-social difficulties such as poor academic achievement and behavioural and socio-emotional problems. This article by Janet Hoskin and Angela Fawcett, both from the University of Swansea, describes how 34

  7. LimbGirdle and Congenital Muscular Dystrophies: Current Diagnostics, Management, and Emerging Technologies

    PubMed Central

    Rocha, Carolina Tesi; Hoffman, Eric P.

    2014-01-01

    The muscular dystrophies show muscle degeneration and regeneration (necrotizing myopathy) on muscle biopsy, typically associated with elevated serum creatine kinase, and muscle weakness. In 1986, the first causative gene was identified for the most prevalent and best-characterized form of muscular dystrophy, Duchenne muscular dystrophy. Over the past 25 years, the number of other genes determined to cause different subtypes has grown rapidly. This review gives a synopsis of the 45 genetically defined types of muscular dystrophies and describes the clinical, pathologic, and molecular aspects of each disease. DNA diagnosis remains the most sensitive and specific method for differential diagnosis, but molecular diagnostics can be expensive and complex (because of multiple genes at multiple testing facilities) and reimbursement may be challenging to obtain. However, emerging DNA sequencing technologies (eg, single-molecule thirdgeneration sequencing units) promise to dramatically reduce the complexity and costs of DNA diagnostics. Treatment for nearly all forms remains supportive and is aimed at preventing complications. However, several promising approaches have entered clinical trials, providing tangible hope that quality of life will improve for many patients in the near future. PMID:20467841

  8. Dystropathology increases energy expenditure and protein turnover in the Mdx mouse model of Duchenne muscular dystrophy

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The skeletal muscles in Duchenne muscular dystrophy and the mdx mouse model lack functional dystrophin and undergo repeated bouts of necrosis, regeneration, and growth. These processes have a high metabolic cost. However, the consequences for whole body energy and protein metabolism, and on the diet...

  9. Excess SMAD signaling contributes to heart and muscle dysfunction in muscular dystrophy

    PubMed Central

    Goldstein, Jeffery A.; Bogdanovich, Sasha; Beiriger, Anastasia; Wren, Lisa M.; Rossi, Ann E.; Gao, Quan Q.; Gardner, Brandon B.; Earley, Judy U.; Molkentin, Jeffery D.; McNally, Elizabeth M.

    2014-01-01

    Disruption of the dystrophin complex causes muscle injury, dysfunction, cell death and fibrosis. Excess transforming growth factor (TGF) ? signaling has been described in human muscular dystrophy and animal models, where it is thought to relate to the progressive fibrosis that characterizes dystrophic muscle. We now found that canonical TGF? signaling acutely increases when dystrophic muscle is stimulated to contract. Muscle lacking the dystrophin-associated protein ?-sarcoglycan (Sgcg null) was subjected to a lengthening protocol to produce maximal muscle injury, which produced rapid accumulation of nuclear phosphorylated SMAD2/3. To test whether reducing SMAD signaling improves muscular dystrophy in mice, we introduced a heterozygous mutation of SMAD4 (S4) into Sgcg mice to reduce but not ablate SMAD4. Sgcg/S4 mice had improved body mass compared with Sgcg mice, which normally show a wasting phenotype similar to human muscular dystrophy patients. Sgcg/S4 mice had improved cardiac function as well as improved twitch and tetanic force in skeletal muscle. Functional enhancement in Sgcg/S4 muscle occurred without a reduction in fibrosis, suggesting that intracellular SMAD4 targets may be important. An assessment of genes differentially expressed in Sgcg muscle focused on those encoding calcium-handling proteins and responsive to TGF? since this pathway is a target for mediating improvement in muscular dystrophy. These data demonstrate that excessive TGF? signaling alters cardiac and muscle performance through the intracellular SMAD pathway. PMID:25070948

  10. Na+ Dysregulation Coupled with Ca2+ Entry through NCX1 Promotes Muscular Dystrophy in Mice

    PubMed Central

    Burr, Adam R.; Millay, Douglas P.; Goonasekera, Sanjeewa A.; Park, Ki Ho; Sargent, Michelle A.; Collins, James; Altamirano, Francisco; Philipson, Kenneth D.; Allen, Paul D.; Ma, Jianjie; López, José Rafael

    2014-01-01

    Unregulated Ca2+ entry is thought to underlie muscular dystrophy. Here, we generated skeletal-muscle-specific transgenic (TG) mice expressing the Na+-Ca2+ exchanger 1 (NCX1) to model its identified augmentation during muscular dystrophy. The NCX1 transgene induced dystrophy-like disease in all hind-limb musculature, as well as exacerbated the muscle disease phenotypes in δ-sarcoglycan (Sgcd−/−), Dysf−/−, and mdx mouse models of muscular dystrophy. Antithetically, muscle-specific deletion of the Slc8a1 (NCX1) gene diminished hind-limb pathology in Sgcd−/− mice. Measured increases in baseline Na+ and Ca2+ in dystrophic muscle fibers of the hind-limb musculature predicts a net Ca2+ influx state due to reverse-mode operation of NCX1, which mediates disease. However, the opposite effect is observed in the diaphragm, where NCX1 overexpression mildly protects from dystrophic disease through a predicted enhancement in forward-mode NCX1 operation that reduces Ca2+ levels. Indeed, Atp1a2+/− (encoding Na+-K+ ATPase α2) mice, which have reduced Na+ clearance rates that would favor NCX1 reverse-mode operation, showed exacerbated disease in the hind limbs of NCX1 TG mice, similar to treatment with the Na+-K+ ATPase inhibitor digoxin. Treatment of Sgcd−/− mice with ranolazine, a broadly acting Na+ channel inhibitor that should increase NCX1 forward-mode operation, reduced muscular pathology. PMID:24662047

  11. Model organisms in the fight against muscular dystrophy: lessons from drosophila and Zebrafish.

    PubMed

    Planti, Emilie; Migocka-Patrza?ek, Marta; Daczewska, Ma?gorzata; Jagla, Krzysztof

    2015-01-01

    Muscular dystrophies (MD) are a heterogeneous group of genetic disorders that cause muscle weakness, abnormal contractions and muscle wasting, often leading to premature death. More than 30 types of MD have been described so far; those most thoroughly studied are Duchenne muscular dystrophy (DMD), myotonic dystrophy type 1 (DM1) and congenital MDs. Structurally, physiologically and biochemically, MDs affect different types of muscles and cause individual symptoms such that genetic and molecular pathways underlying their pathogenesis thus remain poorly understood. To improve our knowledge of how MD-caused muscle defects arise and to find efficacious therapeutic treatments, different animal models have been generated and applied. Among these, simple non-mammalian Drosophila and zebrafish models have proved most useful. This review discusses how zebrafish and Drosophila MD have helped to identify genetic determinants of MDs and design innovative therapeutic strategies with a special focus on DMD, DM1 and congenital MDs. PMID:25859781

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

    PubMed Central

    Goldstein, Richard; Bennett, Donald; Guglieri, Michela; Straub, Volker; Bushby, Kate; Lochmller, Hanns; Morris, Carl

    2016-01-01

    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.

  13. A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy.

    PubMed

    Steffen, Frank; Bilzer, Thomas; Brands, Jan; Golini, Lorenzo; Jagannathan, Vidhya; Wiedmer, Michaela; Drgemller, Michaela; Drgemller, Cord; Leeb, Tosso

    2015-01-01

    A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy. PMID:26438297

  14. A Nonsense Variant in COL6A1 in Landseer Dogs with Muscular Dystrophy

    PubMed Central

    Steffen, Frank; Bilzer, Thomas; Brands, Jan; Golini, Lorenzo; Jagannathan, Vidhya; Wiedmer, Michaela; Drögemüller, Michaela; Drögemüller, Cord; Leeb, Tosso

    2015-01-01

    A novel canine muscular dystrophy in Landseer dogs was observed. We had access to five affected dogs from two litters. The clinical signs started at a few weeks of age, and the severe progressive muscle weakness led to euthanasia between 5 and 15 months of age. The pedigrees of the affected dogs suggested a monogenic autosomal-recessive inheritance of the trait. Linkage and homozygosity mapping indicated two potential genome segments for the causative variant on chromosomes 10 and 31 harboring a total of 4.8 Mb of DNA or 0.2% of the canine genome. Using the Illumina sequencing technology, we obtained a whole-genome sequence from one affected Landseer. Variants were called with respect to the dog reference genome and compared with the genetic variants of 170 control dogs from other breeds. The affected Landseer dog was homozygous for a single, private nonsynonymous variant in the critical intervals, a nonsense variant in the COL6A1 gene (Chr31:39,303,964G>T; COL6A1:c.289G>T; p.E97*). Genotypes at this variant showed perfect concordance with the muscular dystrophy phenotype in all five cases and more than 1000 control dogs. Variants in the human COL6A1 gene cause Bethlem myopathy or Ullrich congenital muscular dystrophy. We therefore conclude that the identified canine COL6A1 variant is most likely causative for the observed muscular dystrophy in Landseer dogs. On the basis of the nature of the genetic variant in Landseer dogs and their severe clinical phenotype these dogs represent a model for human Ullrich congenital muscular dystrophy. PMID:26438297

  15. [Duchenne-type muscular dystrophy: problems, early diagnosis, early treatment (author's transl)].

    PubMed

    Beckmann, R

    1978-11-01

    The aetiology and pathogenesis of the Duchenne-type muscular dystrophy (pseudohypertrophic muscular dystrophy) are still largely unknown. The possibilities of treating the disease are rather limited. Treatment is the more successful, the earlier diagnosis was possible, and the earlier treatment is initiated. The CK-Screening Test is an important aid for early diagnosis. The CK-Screening Test is also valuable for genetic consultation and advice, because it helps to identify women who are conductors or carriers of the disease. Current hypotheses on aetiology and pathogenesis are mentioned. Progress made in the fields of biochemistry, including enzyme histochemistry, and electron microscopy, raise hopes of finding more efficient therapeutic possibilities in the future. The many interests of patients with muscular diseases are being looked after by the European Alliance of Muscular Dystrophy Associations (EAMDA). Thirteen European associations are members of this organisation, including the German association "Bekmpfung der Muskelkrankheiten e.V." The number of sponsoring members of the EAMDA is at present about 300,000. 3 international congresses have already been held on the problems of muscular diseases. The fourth congress is scheduled to take place in Montreal in 1978. PMID:362050

  16. Immunological identification of a high molecular weight protein as a condidate for the product of the Duchenne muscular dystrophy gene

    SciTech Connect

    Kao, L.; Krstenansky, J.; Mendell, J.; Rammohan, K.W.; Gruenstein, E. )

    1988-06-01

    An oligopeptide was synthesized based on translation of the nucleotide sequence of the putative exon region of clone pERT87-25 from the gene for Duchenne muscular dystrophy. Immunization of rabbits with this oligopeptide induced the formation of antibodies directed against a protein present in human, rat, and rabbit skeletal muscle. This protein, which is missing in the skeletal muscle of two patients with Duchenne muscular dystrophy, has a molecular mass of {approx}320-420 kDa and is clearly different from the putative Duchenne muscular dystrophy-related protein nebulin. The data suggest that this 320-420-kDa protein is produced by the Duchenne muscular dystrophy gene.

  17. Estimate of severe autosomal recessive limb-girdle muscular dystrophy (LGMD2C, LGMD2D) among sporadic muscular dystrophy males: a study of 415 familes.

    PubMed Central

    Stec, I; Kress, W; Meng, G; Mller, B; Mller, C R; Grimm, T

    1995-01-01

    Ninety-five percent of cases of severe muscular dystrophy with early childhood onset result from mutations in the dystrophin region of the human X chromosome (DMD, McKusick 310200), whereas 5% are thought to result from mutations in autosomal genes. We examined a total of 415 families with at least one living patient whose clinical features suggested DMD. Based on formal genetics, haplotype analysis, and dystrophin determinations, we estimate that one in eight (11.8%) sporadic male patients carries autosomal rather than X chromosomal mutations. PMID:8825917

  18. Cardiac structure and function in female carriers of a canine model of Duchenne muscular dystrophy.

    PubMed

    Kane, A M; DeFrancesco, T C; Boyle, M C; Malarkey, D E; Ritchey, J W; Atkins, C E; Cullen, J M; Kornegay, J N; Keene, B W

    2013-06-01

    This investigation tested the hypothesis that carriers of golden retriever muscular dystrophy (GRMD), a genetically homologous condition of Duchenne muscular dystrophy (DMD), have quantifiable abnormalities in myocardial function, structure, or cardiac rhythm. Eleven GRMD carriers and four matched controls had cardiac evaluations and postmortem examinations. 24-h ECG Holter monitoring disclosed ventricular ectopy in 10 of 11 carriers and 2 of 4 controls. Conventional echocardiography failed to demonstrate significant differences between carriers and controls in systolic function. All carriers had multifocal, minimal to marked myofiber necrosis, fibrosis, mineralization, inflammation, and/or fatty change in their hearts. Immunohistochemistry revealed a mosaic dystrophin deficiency in scattered cardiac myofibers in all carriers. No controls had cardiac histologic lesions; all had uniform dystrophin staining. Despite cardiac mosaic dystrophin expression and degenerative cardiac lesions, GRMD carriers at up to 3 years of age could not be distinguished statistically from normal controls by echocardiography or 24-h Holter monitoring. PMID:23231955

  19. What do mouse models of muscular dystrophy tell us about the DAPC and its components?

    PubMed Central

    Whitmore, Charlotte; Morgan, Jennifer

    2014-01-01

    There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated. PMID:25270874

  20. Diffusion and ideal MRI techniques to characterize limb-girdle muscular dystrophy

    NASA Astrophysics Data System (ADS)

    Hernández-Salazar, G.; Hidalgo-Tobon, S.; Vargas-Cañas, S.; Marrufo-Melendez, O.; Solis-Najera, S.; Taboada-Barajas, J.; Rodríguez, A. O.; Delgado-Hernández, 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. In the thigh, muscles at the back are affected, with a tendency to preserve the tibialis anterior and gastrocnemius. The aim of this study was to compare quantitative MRI measurements from IDEAL-based imaging and DW imaging in the thigh muscles of adults with LGMDs and healthy volunteers(HC). Six women (three patients and three healthy volunteers) were examined. Imaging experiments were conducted on a 1.5T GE scanner (General Electric Medical Systems. Milwaukee). T1 IDEAL 2D images and diffusion images were acquired. Results demonstrated that the use of noninvasive MRI techniques may provide the means to characterize the muscle through quantitative methods to determine the percentage of fat and ADC values.

  1. Dystrophin Gene Replacement and Gene Repair Therapy for Duchenne Muscular Dystrophy in 2016: An Interview.

    PubMed

    Duan, Dongsheng

    2016-03-01

    After years of relentless efforts, gene therapy has now begun to deliver its therapeutic promise in several diseases. A number of gene therapy products have received regulatory approval in Europe and Asia. Duchenne muscular dystrophy (DMD) is an X-linked inherited lethal muscle disease. It is caused by mutations in the dystrophin gene. Replacing and/or repairing the mutated dystrophin gene holds great promises to treated DMD at the genetic level. Last several years have evidenced significant developments in preclinical experimentations in murine and canine models of DMD. There has been a strong interest in moving these promising findings to clinical trials. In light of rapid progress in this field, the Parent Project Muscular Dystrophy (PPMD) recently interviewed me on the current status of DMD gene therapy and readiness for clinical trials. Here I summarized the interview with PPMD. PMID:27003751

  2. Relatively low proportion of dystrophin gene deletions in Israeili Duchenne and Becker muscular dystrophy patients

    SciTech Connect

    Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y.

    1994-02-15

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic disorders caused by mutations in the X-linked dystrophin gene. The most common mutations in western populations are deletions that are spread non-randomly throughout the gene. Molecular analysis of the dystrophin gene structure by hybridization of the full length cDNA to Southern blots and by PCR in 62 unrelated Israeli male DMD/BMD patients showed deletions in 23 (37%). This proportion is significantly lower than that found in European and North American populations (55-65%). Seventy-eight percent of the deletions were confined to exons 44-52, half of these exons 44-45, and the remaining 22% to exons 1 and 19. There was no correlation between the size of the deletion and the severity of the disease. All the deletions causing frameshift resulted in the DMD phenotypes. 43 refs., 1 fig., 1 tab.

  3. Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain

    NASA Astrophysics Data System (ADS)

    Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas

    1988-03-01

    Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

  4. Evidence for mutation by unequal sister chromatid exchange in the Duchenne muscular dystrophy gene.

    PubMed Central

    Hu, X Y; Burghes, A H; Bulman, D E; Ray, P N; Worton, R G

    1989-01-01

    We have studied three families each containing a male with Duchenne or Becker muscular dystrophy. Southern blot analysis using both genomic and cDNA probes revealed that an exon-containing segment of DNA within the gene is duplicated in the probands, their mothers, and, in two cases, their sisters. The grandpaternal origin of the duplication has been demonstrated in these families by RFLP and duplication analysis. The results suggest that unequal sister-chromatid exchange, which most likely occurred in the germ cell lineage of the proband's grandfather, is responsible for generating these duplications and that this type of intrachromosomal rearrangement, although rarely reported in humans, is not uncommon in the muscular dystrophy gene. Images Figure 1 Figure 2 Figure 3 Figure 5 Figure 7 Figure 8 PMID:2567117

  5. Antisense Oligo-Mediated Multiple Exon Skipping in a Dog Model of Duchenne Muscular Dystrophy

    PubMed Central

    Yokota, Toshifumi; Hoffman, Eric; Takeda, Shin’ichi

    2015-01-01

    Exon skipping is currently one of the most promising molecular therapies for Duchenne muscular dystrophy (DMD). We have recently developed multiple exon skipping targeting exons 6 and 8 in dystrophin mRNA of canine X-linked muscular dystrophy (CXMD), an animal model of DMD, which exhibits severe dystrophic phenotype in skeletal muscles and cardiac muscle. We have induced efficient exon skipping both in vitro and in vivo by using cocktail antisense 2’ O-methyl oligonucleotides (2’OMePS) and cocktail phosphorodiamidate morpholino oligomers (morpholinos, or PMOs) and ameliorated phenotype of dystrophic dogs by systemic injections. The multiple exon skipping (double exon skipping) shown here provides the prospect of choosing deletions that optimize the functionality of the truncated dystrophin protein for DMD patients by using a common cocktail that could be validated as a single drug and also potentially applicable for more than 90% of DMD patients. PMID:21194037

  6. Experience and strategy for the molecular testing of Duchenne muscular dystrophy.

    PubMed

    Prior, Thomas W; Bridgeman, Scott J

    2005-08-01

    Mutations in the dystrophin gene result in both Duchenne and Becker muscular dystrophies (DMD and BMD). Approximately two-thirds of the affected patients have large deletions or duplications. Using the multiplex polymerase chain reaction and Southern blotting techniques, the detection of these larger mutations is relatively straightforward. Detection of the point mutations in the remaining one-third of the patients has been challenging, mainly due to the large gene size and lack of hotspots or prevalent mutations. However, with the addition of some of the newer molecular screening methods, it is becoming more feasible for clinical laboratories to test for point mutations in the larger genes like dystrophin. Here we review the clinical features, describe the mutation distributions, evaluate current molecular strategies, and illustrate how the genetic findings have impacted the current clinical diagnostics of Duchenne and Becker muscular dystrophies. PMID:16049303

  7. The clinical and molecular genetic approach to Duchenne and Becker muscular dystrophy: an updated protocol.

    PubMed Central

    van Essen, A J; Kneppers, A L; van der Hout, A H; Scheffer, H; Ginjaar, I B; ten Kate, L P; van Ommen, G J; Buys, C H; Bakker, E

    1997-01-01

    Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% of patients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a non-quantitative test method. Detection of microlesions in Duchenne and Becker muscular dystrophy is currently under way. Single strand conformational analysis, heteroduplex analysis, and the protein truncation test are mostly used for this purpose. In this paper we review the available methods for detection of large and small mutations in patients and in carriers and propose a systematic approach for genetic analysis and genetic counselling of DMD and BMD families, including prenatal and preimplantation diagnosis. Images PMID:9350811

  8. Peter Becker and his Nazi past: the man behind Becker muscular dystrophy and Becker myotonia.

    PubMed

    Zeidman, Lawrence A; Kondziella, Daniel

    2014-04-01

    Peter Becker was a German neurologist who helped classify the muscular dystrophies, and described Becker muscular dystrophy and Becker myotonia. His involvement in National Socialism began in 1933, when he was compelled by his peers to join the SA (brown shirts). He later joined the Nazi party, the Nazi Doctors Association, and the Nazi Lecturers' Association. He renewed his SA membership to maintain his position at a genetics institute. Colleagues stated postwar that he was not an active Nazi, and he was de-Nazified in 1947, able to continue his career. Later, Becker admitted to most, but not all, of his Nazi memberships in his autobiography, and wrote 2 books exploring the origins of Nazism and racial hygiene. The "neurologic court of opinion" must weigh in on how we should best remember Becker, and at the very least, we as neurologists must learn the dangers of career opportunism at any cost. PMID:23576413

  9. What do mouse models of muscular dystrophy tell us about the DAPC and its components?

    PubMed

    Whitmore, Charlotte; Morgan, Jennifer

    2014-12-01

    There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated. PMID:25270874

  10. Stages in fibre breakdown in Duchenne muscular dystrophy. An electron-microscopic study.

    PubMed

    Cullen, M J; Fulthorpe, J J

    1975-02-01

    A scheme is presented which divides the process of fibre breakdown in Duchenne muscular dystrophy into 5 sequential stages. In Stage 1 the fibre appears superficially normal although there are subtle changes in the relative volumes of the fibre components. In Stage 2 localised overcontraction of the myofibrils results in excessive stretching of the sarcomeres in other regions of the fibre. This continuing process results in the formation of contraction clumps in which the contractile filaments form an increasingly homogeneous mass. By the final stage the normal structural features of the fibre have completely disappeared and it is invaded by macrophages. It is suggested that the central process of myofibril clumping results from a localised inability of the sarcomeres to relax which implies a defect in the mitochondria, Z-line or sarcoplasmic reticulum. This is discussed in relation to other workers' findings of a decrease in the calcium-accumulating capacity of the sarcoplasmic reticulum in Duchenne muscular dystrophy. PMID:163299

  11. Update on neuromuscular disorders in pediatric orthopaedics: Duchenne muscular dystrophy, myelomeningocele, and cerebral palsy.

    PubMed

    Chambers, Henry G

    2014-01-01

    The purpose of this seminar was to review a large range of lower extremity and neuromuscular disorders. Because of the diversity of the topics covered, including clubfoot and vertical talus treatment, management of Legg-Calve-Perthes disease, and limb lengthening in dwarfism, this review will focus on the neuromuscular subsection reviewing the current management of the muscular dystrophies, myelomeningocele, and cerebral palsy. PMID:25207736

  12. Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle

    NASA Astrophysics Data System (ADS)

    Oronzi Scott, M.; Sylvester, J. E.; Heiman-Patterson, T.; Shi, Y.-J.; Fieles, W.; Stedman, H.; Burghes, A.; Ray, P.; Worton, R.; Fischbeck, K. H.

    1988-03-01

    A probe for the 5' end of the Duchenne muscular dystrophy (DMD) gene was used to study expression of the gene in normal human muscle, myogenic cell cultures, and muscle from patients with DMD. Expression was found in RNA from normal fetal muscle, adult cardiac and skeletal muscle, and cultured muscle after myoblast fusion. In DMD muscle, expression of this portion of the gene was also revealed by in situ RNA hybridization, particularly in regenerating muscle fibers.

  13. Acute heart failure during spinal surgery in a boy with Duchenne muscular dystrophy.

    PubMed

    Schmidt, G N; Burmeister, M-A; Lilje, C; Wappler, F; Bischoff, P

    2003-06-01

    Patients with Duchenne muscular dystrophy (DMD) are at high risk of perioperative complications. DMD may be accompanied by heart failure resulting from dystrophic involvement of the myocardium, which can be subclinical in the early stages of the disease. This case demonstrates that a normal preoperative ECG and echocardiograph cannot exclude the development of heart failure during anaesthesia in DMD patients undergoing major surgery. PMID:12765898

  14. Influence of Immune Responses in Gene/Stem Cell Therapies for Muscular Dystrophies

    PubMed Central

    Sitzia, Clementina; Erratico, Silvia; Torrente, Yvan

    2014-01-01

    Muscular dystrophies (MDs) are a heterogeneous group of diseases, caused by mutations in different components of sarcolemma, extracellular matrix, or enzymes. Inflammation and innate or adaptive immune response activation are prominent features of MDs. Various therapies under development are directed toward rescuing the dystrophic muscle damage using gene transfer or cell therapy. Here we discussed current knowledge about involvement of immune system responses to experimental therapies in MDs. PMID:24959590

  15. ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

    PubMed Central

    Cirak, Sebahattin; Foley, Aileen Reghan; Herrmann, Ralf; Willer, Tobias; Yau, Shu; Stevens, Elizabeth; Torelli, Silvia; Brodd, Lina; Kamynina, Alisa; Vondracek, Petr; Roper, Helen; Longman, Cheryl; Korinthenberg, Rudolf; Marrosu, Gianni; Nrnberg, Peter; Michele, Daniel E.; Plagnol, Vincent; Hurles, Matt; Moore, Steven A.; Sewry, Caroline A.; Campbell, Kevin P.; Voit, Thomas

    2013-01-01

    Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, WalkerWarburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of ?-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of ?-dystroglycan with extracellular matrix proteins such as laminin-?2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ?50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of WalkerWarburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of ?-dystroglycan, which not only causes the severe WalkerWarburg syndrome but is also a common cause of the milder forms of dystroglycanopathy. PMID:23288328

  16. Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis

    PubMed Central

    2013-01-01

    Background The diagnosis of neuromuscular diseases is strongly based on the histological characterization of muscle biopsies. However, this morphological analysis is mostly a subjective process and difficult to quantify. We have tested if network science can provide a novel framework to extract useful information from muscle biopsies, developing a novel method that analyzes muscle samples in an objective, automated, fast and precise manner. Methods Our database consisted of 102 muscle biopsy images from 70 individuals (including controls, patients with neurogenic atrophies and patients with muscular dystrophies). We used this to develop a new method, Neuromuscular DIseases Computerized Image Analysis (NDICIA), that uses network science analysis to capture the defining signature of muscle biopsy images. NDICIA characterizes muscle tissues by representing each image as a network, with fibers serving as nodes and fiber contacts as links. Results After a training phase with control and pathological biopsies, NDICIA was able to quantify the degree of pathology of each sample. We validated our method by comparing NDICIA quantification of the severity of muscular dystrophies with a pathologists evaluation of the degree of pathology, resulting in a strong correlation (R?=?0.900, P <0.00001). Importantly, our approach can be used to quantify new images without the need for prior training. Therefore, we show that network science analysis captures the useful information contained in muscle biopsies, helping the diagnosis of muscular dystrophies and neurogenic atrophies. Conclusions Our novel network analysis approach will serve as a valuable tool for assessing the etiology of muscular dystrophies or neurogenic atrophies, and has the potential to quantify treatment outcomes in preclinical and clinical trials. PMID:23514382

  17. Ahnak1 abnormally localizes in muscular dystrophies and contributes to muscle vesicle release.

    PubMed

    Zacharias, Ute; Purfrst, Bettina; Schwel, Verena; Morano, Ingo; Spuler, Simone; Haase, Hannelore

    2011-12-01

    Ahnak1 is a giant, ubiquitously expressed, plasma membrane support protein whose function in skeletal muscle is largely unknown. Therefore, we investigated whether ahnak would be influenced by alterations of the sarcolemma exemplified by dysferlin mutations known to render the sarcolemma vulnerable or by mutations in calpain3, a protease known to cleave ahnak. Human muscle biopsy specimens obtained from patients with limb girdle muscular dystrophy (LGMD) caused by mutations in dysferlin (LGMD2B) and calpain3 (LGMD2A) were investigated for ahnak expression and localization. We found that ahnak1 has lost its sarcolemmal localization in LGMD2B but not in LGMD2A. Instead ahnak1 appeared in muscle connective tissue surrounding the extracellular site of the muscle fiber in both muscular dystrophies. The entire giant ahnak1 molecule was present outside the muscle fiber and did only partially colocalize with CD45-positive immune cell infiltration and the extracelluar matrix proteins fibronectin and collagenVI. Further, vesicles shedded in response to Ca(2+) by primary human myotubes were purified and their protein content was analysed. Ahnak1 was prominently present in these vesicles. Electron microscopy revealed a homogenous population of vesicles with a diameter of about 150nm. This is the first study demonstrating vesicle release from human myotubes that may be one mechanism underlying abnormally localized ahnak1. Taken together, our results define ahnak1 in muscle connective tissue as a novel feature of two genetically distinct muscular dystrophies that might contribute to disease pathology. PMID:22057634

  18. Anti-gravity training improves walking capacity and postural balance in patients with muscular dystrophy.

    PubMed

    Berthelsen, Martin Peter; Husu, Edith; Christensen, Sofie Bouschinger; Prahm, Kira Philipsen; Vissing, John; Jensen, Bente Rona

    2014-06-01

    Recent studies in patients with muscular dystrophies suggest positive effects of aerobic and strength training. These studies focused training on using bicycle ergometers and conventional strength training, which precludes more severely affected patients from participating, because of their weakness. We investigated the functional effects of combined aerobic and strength training in patients with Becker and limb-girdle muscular dystrophies with knee muscle strength levels as low as 3% of normal strength. Eight patients performed 10 weeks of aerobic and strength training on an anti-gravity treadmill, which offered weight support up to 80% of their body weight. Six minute walking distance, dynamic postural balance, and plasma creatine kinase were assessed 10 weeks prior to training, immediately before training and after 10 weeks of training. Training elicited an improvement of walking distance by 82% and dynamic postural balance by 134%, indicating an improved physical function. Plasma creatine kinase remained unchanged. These results provide evidence that a combination of aerobic and strength training during anti-gravity has the potential to safely improve functional ability in severely affected patients with Becker and limb-girdle muscular dystrophies. PMID:24684860

  19. Affinity proteomics within rare diseases: a BIO-NMD study for blood biomarkers of muscular dystrophies

    PubMed Central

    Ayoglu, Burcu; Chaouch, Amina; Lochmüller, Hanns; Politano, Luisa; Bertini, Enrico; Spitali, Pietro; Hiller, Monika; Niks, Eric H; Gualandi, Francesca; Pontén, Fredrik; Bushby, Kate; Aartsma-Rus, Annemieke; Schwartz, Elena; Le Priol, Yannick; Straub, Volker; Uhlén, Mathias; Cirak, Sebahattin; ‘t Hoen, Peter A C; Muntoni, Francesco; Ferlini, Alessandra; Schwenk, Jochen M; Nilsson, Peter; Al-Khalili Szigyarto, Cristina

    2014-01-01

    Despite the recent progress in the broad-scaled analysis of proteins in body fluids, there is still a lack in protein profiling approaches for biomarkers of rare diseases. Scarcity of samples is the main obstacle hindering attempts to apply discovery driven protein profiling in rare diseases. We addressed this challenge by combining samples collected within the BIO-NMD consortium from four geographically dispersed clinical sites to identify protein markers associated with muscular dystrophy using an antibody bead array platform with 384 antibodies. Based on concordance in statistical significance and confirmatory results obtained from analysis of both serum and plasma, we identified eleven proteins associated with muscular dystrophy, among which four proteins were elevated in blood from muscular dystrophy patients: carbonic anhydrase III (CA3) and myosin light chain 3 (MYL3), both specifically expressed in slow-twitch muscle fibers and mitochondrial malate dehydrogenase 2 (MDH2) and electron transfer flavoprotein A (ETFA). Using age-matched sub-cohorts, 9 protein profiles correlating with disease progression and severity were identified, which hold promise for the development of new clinical tools for management of dystrophinopathies. PMID:24920607

  20. Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy

    PubMed Central

    Kaspar, Rita Wen; Allen, Hugh D.; Montanaro, Federica

    2013-01-01

    Purpose To review the current understanding of the pathophysiology of dilated cardiomyopathy (DCM) in patients with Duchenne and Becker muscular dystrophies, assessment of cardiac dysfunction for these patients, and the recommended pharmacological treatment options and ongoing research directions. Data sources Reviews and original research articles from scholarly journals and books. Conclusions Duchenne and Becker muscular dystrophies are debilitating neuromuscular disorders, both caused by mutations in the dystrophin gene. Most patients develop DCM as part of the disease course; in fact, DCM is the leading cause of death among these patients. Cardiac surveillance, including routine monitoring of electrocardiograms, echocardiograms, and appropriate blood biomarkers, may detect early DCM development. Although previous studies have shown that early administration of cardiac medications may delay the development of DCM, current standard of care does not emphasize cardiac surveillance and timely treatment. This, in turn, limits clinicians, including advanced practice nurses, to be optimally engaged in providing the most aggressive and proactive patient care. Implications for practice Implementing a routine cardiac assessment and timely pharmacological treatment in primary or specialty care settings is high-lighted as an important step to optimize cardiac health among patients with Duchenne and Becker muscular dystrophies. PMID:19432907

  1. Muscular Dystrophy associated with alpha-dystroglycan deficiency in Sphynx and Devon Rex cats

    PubMed Central

    Martin, Paul T; Diane Shelton, G.; Dickinson, Peter J; Sturges, Beverly K; Xu, Rui; LeCouteur, Richard A; Guo, Ling T; Grahn, Robert A; Lo, Harriet P; North, Kathryn N; Malik, Richard; Engvall, Eva; Lyons, Leslie A

    2008-01-01

    Recent studies have identified a number of forms of muscular dystrophy, termed dystroglycanopathies, which are associated with loss of natively glycosylated ?dystroglycan. Here we identify a new animal model for this class of disorders in Sphynx and Devon Rex cats. Affected cats displayed a slowly progressive myopathy with clinical and histologic hallmarks of muscular dystrophy including skeletal muscle weakness with no involvement of peripheral nerves or CNS. Skeletal muscles had myopathic features and reduced expression of ?dystroglycan, while ?dystroglycan, sarcoglycans, and dystrophin were expressed at normal levels. In the Sphynx cat, analysis of laminin and lectin binding capacity demonstrated no loss in overall glycosylation or ligand binding for the ?-dystroglycan protein, only a loss of protein expression. A reduction in laminin-?2 expression in the basal lamina surrounding skeletal myofibers was also observed. Sequence analysis of translated regions of the feline dystroglycan gene (DAG1) in affected cats did not identify a causative mutation, and levels of DAG1 mRNA determined by real-time QRT-PCR did not differ significantly from normal controls. Reduction in the levels of glycosylated ?dystroglycan by immunoblot was also identified in an affected Devon Rex cat. These data suggest that muscular dystrophy in Sphynx and Devon Rex cats results from a deficiency in ?-dystroglycan protein expression, and as such may represent a new type of dystroglycanopathy where expression, but not glycosylation, is affected. PMID:18990577

  2. From proteins to genes: immunoanalysis in the diagnosis of muscular dystrophies

    PubMed Central

    2011-01-01

    Muscular dystrophies are a large heterogeneous group of inherited diseases that cause progressive muscle weakness and permanent muscle damage. Very few muscular dystrophies show sufficient specific clinical features to allow a definite diagnosis. Because of the currently limited capacity to screen for numerous genes simultaneously, muscle biopsy is a time and cost-effective test for many of these disorders. Protein analysis interpreted in correlation with the clinical phenotype is a useful way of directing genetic testing in many types of muscular dystrophies. Immunohistochemistry and western blot are complementary techniques used to gather quantitative and qualitative information on the expression of proteins involved in this group of diseases. Immunoanalysis has a major diagnostic application mostly in recessive conditions where the absence of labelling for a particular protein is likely to indicate a defect in that gene. However, abnormalities in protein expression can vary from absence to very subtle reduction. It is good practice to test muscle biopsies with antibodies for several proteins simultaneously and to interpret the results in context. Indeed, there is a degree of direct or functional association between many of these proteins that is reflected by the presence of specific secondary abnormalities that are of value, especially when the diagnosis is not straightforward. PMID:21798100

  3. Memory or amnesia: the dilemma of stem cell therapy in muscular dystrophies.

    PubMed

    Sandri, Marco

    2015-12-01

    Muscular dystrophies are monogenetic diseases that are often characterized by the degeneration of both cardiac and skeletal muscle. Gene therapy to correct the mutated gene has shown promise in both animal models and clinical trials; however, current gene delivery strategies are limited to the introduction of the corrected gene into only one tissue. Strategies to target multiple striated muscle types would provide a much-needed improvement for the treatment of muscular dystrophies. In this issue of the JCI, Quattrocelli and colleagues demonstrate that induced pluripotent stem cells (iPSCs) with a myogenic propensity are able to engraft into both cardiac and skeletal muscles. The authors also identified a novel pool of mesodermal iPSC-derived progenitors (MiPs). Moreover, the authors show that these MiPs are amenable to gene correction and can restore function in murine dystrophic models. Together, the results of this study provide an important advance in improving gene delivery to treat patients with muscular dystrophy. PMID:26571391

  4. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function

    PubMed Central

    Bibee, Kristin P.; Cheng, Ya-Jian; Ching, James K.; Marsh, Jon N.; Li, Allison J.; Keeling, Richard M.; Connolly, Anne M.; Golumbek, Paul T.; Myerson, Jacob W.; Hu, Grace; Chen, Junjie; Shannon, William D.; Lanza, Gregory M.; Weihl, Conrad C.; Wickline, Samuel A.

    2014-01-01

    Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.Bibee, K. P., Cheng, Y.-J., Ching, J. K., Marsh, J. N., Li, A. J., Keeling, R. M., Connolly, A. M., Golumbek, P. T., Myerson, J. W., Hu, G., Chen, J., Shannon, W. D., Lanza, G. M., Weihl, C. C., Wickline, S. A. Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function. PMID:24500923

  5. Concise Review: Mesoangioblast and Mesenchymal Stem Cell Therapy for Muscular Dystrophy: Progress, Challenges, and Future Directions

    PubMed Central

    2015-01-01

    Mesenchymal stem cells (MSCs) and mesoangioblasts (MABs) are multipotent cells that differentiate into specialized cells of mesodermal origin, including skeletal muscle cells. Because of their potential to differentiate into the skeletal muscle lineage, these multipotent cells have been tested for their capacity to participate in regeneration of damaged skeletal muscle in animal models of muscular dystrophy. MSCs and MABs infiltrate dystrophic muscle from the circulation, engraft into host fibers, and bring with them proteins that replace the functions of those missing or truncated. The potential for systemic delivery of these cells increases the feasibility of stem cell therapy for the large numbers of affected skeletal muscles in patients with muscular dystrophy. The present review focused on the results of preclinical studies with MSCs and MABs in animal models of muscular dystrophy. The goals of the present report were to (a) summarize recent results, (b) compare the efficacy of MSCs and MABs derived from different tissues in restoration of protein expression and/or improvement in muscle function, and (c) discuss future directions for translating these discoveries to the clinic. In addition, although systemic delivery of MABs and MSCs is of great importance for reaching dystrophic muscles, the potential concerns related to this method of stem cell transplantation are discussed. PMID:25391645

  6. Progress and prospects of gene therapy clinical trials for the muscular dystrophies.

    PubMed

    Bengtsson, Niclas E; Seto, Jane T; Hall, John K; Chamberlain, Jeffrey S; Odom, Guy L

    2016-04-15

    Clinical trials represent a critical avenue for new treatment development, where early phases (I, I/II) are designed to test safety and effectiveness of new therapeutics or diagnostic indicators. A number of recent advances have spurred renewed optimism toward initiating clinical trials and developing refined therapies for the muscular dystrophies (MD's) and other myogenic disorders. MD's encompass a heterogeneous group of degenerative disorders often characterized by progressive muscle weakness and fragility. Many of these diseases result from mutations in genes encoding proteins of the dystrophin-glycoprotein complex (DGC). The most common and severe form among children is Duchenne muscular dystrophy, caused by mutations in the dystrophin gene, with an average life expectancy around 25 years of age. Another group of MD's referred to as the limb-girdle muscular dystrophies (LGMDs) can affect boys or girls, with different types caused by mutations in different genes. Mutation of the α-sarcoglycan gene, also a DGC component, causes LGMD2D and represents the most common form of LGMD. Early preclinical and clinical trial findings support the feasibility of gene therapy via recombinant adeno-associated viral vectors as a viable treatment approach for many MDs. In this mini-review, we present an overview of recent progress in clinical gene therapy trials of the MD's and touch upon promising preclinical advances. PMID:26450518

  7. Comparison of Pulmonary Functions at Onset of Ventilatory Insufficiency in Patients With Amyotrophic Lateral Sclerosis, Duchenne Muscular Dystrophy, and Myotonic Muscular Dystrophy

    PubMed Central

    Cho, Han Eol; Lee, Jang Woo; Kang, Seong Woong; Choi, Won Ah; Oh, Hyeonjun

    2016-01-01

    Objective To evaluate pulmonary functions of patients with amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD), and myotonic muscular dystrophy (MMD) at the onset of ventilatory insufficiency. Methods This retrospective study included ALS, DMD, and MMD patients with regular outpatient clinic follow-up in the Department of Rehabilitation Medicine at Gangnam Severance Hospital before the application of non-invasive positive pressure ventilation (NIPPV). The patients were enrolled from August 2001 to March 2014. If patients experienced ventilatory insufficiency, they were treated with NIPPV, and their pulmonary functions were subsequently measured. Results Ninety-four DMD patients, 41 ALS patients, and 21 MMD patients were included in the study. The mean SpO2 was lower in the MMD group than in the other two groups. The mean forced vital capacity (FVC) in the supine position was approximately low to mid 20% on average in DMD and ALS patients, whereas it was 10% higher in MMD patients. ALS patients showed a significantly lower FVC in the supine position than in the sitting position. Maximal insufflation capacity, unassisted peak cough flow, maximum inspiratory pressure (MIP), and maximum expiratory pressure (MEP) were significantly higher in MMD group than in the other groups. MEP was significantly the lowest in DMD patients, followed by in ALS, and MMD patients, in order. Conclusion Disease-specific values of pulmonary function, including FVC, MEP, and MIP, can be accurately used to assess the onset of ventilatory insufficiency in patients with ALS, DMD, and MMD. PMID:26949672

  8. Orthodontic treatment in a patient with unilateral open-bite and Becker muscular dystrophy. A 5-year follow-up

    PubMed Central

    Aristizabal, Juan Fernando; Smit, Rosana Martnez

    2014-01-01

    INTRODUCTION: Becker muscular dystrophy is an X-chromosomal linked anomaly characterized by progressive muscle wear and weakness. This case report shows the orthodontic treatment of a Becker muscular dystrophy patient with unilateral open bite. METHODS: To correct patient's malocclusion, general anesthesia and orthognathic surgery were not considered as an option. Conventional orthodontic treatment with intermaxillary elastics and muscular functional therapy were employed instead. RESULTS: After 36 months, open bite was corrected. The case remains stable after a 5-year post-treatment retention period. PMID:25628078

  9. 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.

  10. The zebrafish runzel muscular dystrophy is linked to the titin gene.

    PubMed

    Steffen, Leta S; Guyon, Jeffrey R; Vogel, Emily D; Howell, Melanie H; Zhou, Yi; Weber, Gerhard J; Zon, Leonard I; Kunkel, Louis M

    2007-09-15

    Titin (also called connectin) acts as a scaffold for signaling proteins in muscle and is responsible for establishing and maintaining the structure and elasticity of sarcomeres in striated muscle. Several human muscular dystrophies and cardiomyopathies have previously been linked to mutations in the titin gene. This study reports linkage of the runzel homozygous lethal muscular dystrophy in the zebrafish Danio rerio to a genomic interval containing the titin gene. Analysis of the genomic sequence suggests that zebrafish contain two adjacent titin loci. One titin locus lies within the genetic linkage interval and its expression is significantly reduced in runzel mutants by both immunofluorescence and protein electrophoresis. Morpholino downregulation of this same titin locus in wild-type embryos results in decreased muscle organization and mobility, phenocopying runzel mutants. Additional protein analysis demonstrates that, in wild-type zebrafish, titin isoform sizes are rapidly altered during the development of striated muscle, likely requiring a previously unrecognized need for vertebrate sarcomere remodeling to incorporate developmentally regulated titin isoforms. Decreases of affected titin isoforms in runzel mutants during this time correlate with a progressive loss of sarcomeric organization and suggest that the unaffected titin proteins are capable of sarcomerogenesis but not sarcomere maintenance. In addition, microarray analysis of the ruz transcriptome suggests a novel mechanism of dystrophy pathogenesis, involving mild increases in calpain-3 expression and upregulation of heat shock proteins. These studies should lead to a better understanding of titin's role in normal and diseased muscle. PMID:17678642

  11. A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy.

    PubMed

    Riisager, M; Duno, M; Hansen, F Juul; Krag, T O; Vissing, C R; Vissing, J

    2013-07-01

    Defects in glycosylations of ?-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of ?-dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal <150 IU/L). A homozygous, novel c.917A>G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far. PMID:23746544

  12. 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. PMID:24594375

  13. Exome Sequencing Identifies a DNAJB6 Mutation in a Family with Dominantly-Inherited Limb-Girdle Muscular Dystrophy

    PubMed Central

    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.

    2014-01-01

    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. PMID:24594375

  14. Mutations in GDP-mannose pyrophosphorylase B cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of ?-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; Bnnemann, 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 ?-dystroglycan (?-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 ?-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 ?-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including ?-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced ?-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 ?-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 ?-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of ?-DG. PMID:23768512

  15. Overexpression of the Cytotoxic T Cell (CT) Carbohydrate Inhibits Muscular Dystrophy in the dyW Mouse Model of Congenital Muscular Dystrophy 1A

    PubMed Central

    Xu, Rui; Chandrasekharan, Kumaran; Yoon, Jung Hae; Camboni, Marybeth; Martin, Paul T.

    2007-01-01

    A number of recent studies have demonstrated therapeutic effects of transgenes on the development of muscle pathology in the mdx mouse model for Duchenne muscular dystrophy, but none have been shown also to be effective in mouse models for laminin ?2-deficient congenital muscular dystrophy (MDC1A). Here, we show that overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) is effective in inhibiting the development of muscle pathology in the dyW mouse model of MDC1A, much as we had previously shown in mdx animals. Embryonic overexpression of Galgt2 in skeletal muscles using transgenic mice or postnatal overexpression using adeno-associated virus both reduced the extent of muscle pathology in dyW/dyW skeletal muscle. As with mdx mice, embryonic overexpression of the Galgt2 transgene in dyW/dyW myofibers inhibited muscle growth, whereas postnatal overexpression did not. Both embryonic and postnatal overexpression of Galgt2 in dyW/dyW muscle increased the expression of agrin, a protein that, in recombinant form, has been shown to ameliorate disease, whereas laminin ?1, another disease modifier, was not expressed. Galgt2 over-expression also stimulated the glycosylation of a glycolipid with the CT carbohydrate, and glycolipids accounted for most of the CT-reactive material in postnatal overexpression experiments. These experiments demonstrate that Galgt2 overexpression is effective in altering disease progression in skeletal muscles of dyW mice and should be considered as a therapeutic target in MDC1A. PMID:17591965

  16. Diagnosis of Muscular Dystrophy Using Western Blot with Micro-sample of Muscle.

    PubMed

    Wu, Dong-Yan; Chen, Lin; Zhao, Yan-Huan; Ren, Hai-Tao; Guan, Hong-Zhi; Wei, Yan-Ping; Liu, Zhi; Qian, Min; Guo, Yu-Pu; Cui, Li-Ying; Jiao, Jin-Song

    2015-12-25

    Objective To diagnose muscular dystrophy using Western blot (WB) by improving the method of the protein extraction. Method Firstly,we compared the effect of different sample buffer solutions and processing Methods on the extraction of muscle protein in rats,then selected the appropriate extracting method and the process of the muscular protein. Results We put the selected sample buffer into the micro-sample,then mixed. The concentration of the extracting protein was much more,and the loss during the process was much less. We extracted enough protein in 62 cases. The protein bands were showed clearly by WB,and the abnormal protein bands were shown in some patients. Compared with the Results of immunohistochemical staining detected the severe abnormal expressions of Dys-R,Dys-C,and Dys-N in the specimens,we did not detect the corresponding target band in WB. We detected the target protein band of the specimens were abnormal position,light or normal staining in WB,while Dys were mildly expressed in immunohistochemical staining. Conclusions The improved protein extraction method can save the muscle tissue,and the protein bands can be used for diagnosing the muscular dystrophy. For clinically suspected patients with dystrophinopathy,if normal or mild deficiency is shown by immunohistochemistry,WB should be applied to detect the dystrophin protein band. PMID:26725394

  17. 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

  18. Clinical and genetic analysis of Korean patients with facioscapulohumeral muscular dystrophy.

    PubMed

    Ki, Chang-Seok; Lee, Seung-Tae; Kim, Kyung-Sook; Kim, Jong-Won; Hong, Yoon-Ho; Sung, Jung-Joon; Park, Kyung Seok; Lee, Kwang-Woo

    2008-12-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominantly inherited muscular disorder, which is characterized by weakness of facial, shoulder and hip girdle, humeral, and anterior distal leg muscles. The FSHD gene has been mapped to 4q35 and a deletion of integral copies of a 3.3-kb DNA repeat motif named D4Z4 was known to be the genetic background of the disorder. Although FSHD is the second most common muscular dystrophy in adulthood, there were few reports on the genetically confirmed patients in Korea. Recently, we experienced four Korean patients with clinical features resembling FSHD. In order to confirm the diagnosis, conventional Southern blot (SB) analysis by using double digestion with EcoRI and BlnI and hybridization with p13E-11 probe was performed in three patients and newly developed long polymerase chain reaction (PCR) method was used for one patient because genomic DNA was not enough for conventional SB for this patient. All patients were demonstrated to have shortened D4Z4 repeats that were consistent with FSHD. Therefore, we could confirm the diagnosis of FSHD in four Korean patients and appropriate genetic counseling was done for the patients and their families. It is of note that long-PCR method could be a good alternative for conventional SB when D4Z4 repeats were less than 5. PMID:19119436

  19. Evaluation of 2'-Deoxy-2'-fluoro Antisense Oligonucleotides for Exon Skipping in Duchenne Muscular Dystrophy.

    PubMed

    Jirka, Silvana M G; Tanganyika-de Winter, Christa L; Boertje-van der Meulen, Joke W; van Putten, Maaike; Hiller, Monika; Vermue, Rick; de Visser, Peter C; Aartsma-Rus, Annemieke

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder typically caused by frame-shifting mutations in the DMD gene. Restoration of the reading frame would allow the production of a shorter but partly functional dystrophin protein as seen in Becker muscular dystrophy patients. This can be achieved with antisense oligonucleotides (AONs) that induce skipping of specific exons during pre-mRNA splicing. Different chemical modifications have been developed to improve AON properties. The 2'-deoxy-2'-fluoro (2F) RNA modification is attractive for exon skipping due to its ability to recruit ILF2/3 proteins to the 2F/pre-mRNA duplex, which resulted in enhanced exon skipping in spinal muscular atrophy models. In this study, we examined the effect of two different 2'-substituted AONs (2'-F phosphorothioate (2FPS) and 2'-O-Me phosphorothioate (2OMePS)) on exon skipping in DMD cell and animal models. In human cell cultures, 2FPS AONs showed higher exon skipping levels than their isosequential 2OMePS counterparts. Interestingly, in the mdx mouse model, 2FPS was less efficient than 2OMePS and suggested safety issues as evidenced by increased spleen size and weight loss. Our results do not support a clinical application for 2FPS AON. PMID:26623937

  20. Muscle Quantitative MR Imaging and Clustering Analysis in Patients with Facioscapulohumeral Muscular Dystrophy Type 1

    PubMed Central

    Lareau-Trudel, Emilie; Le Troter, Arnaud; Ghattas, Badih; Pouget, Jean; Attarian, Shahram; Bendahan, David; Salort-Campana, Emmanuelle

    2015-01-01

    Background Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest. Methods and Findings Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI) combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score) on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS) scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ± 20.4%) than in volunteers (3.6 ± 2.8%) (p<0.001). In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001). However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p≤0.01) and was inversely correlated with MMT score, MFM subscore D1 (p≤0.01) further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy. Conclusion The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients. PMID:26181385

  1. Carrier detection in Becker muscular dystrophy using creatine kinase estimation and DNA analysis.

    PubMed

    Kingston, H M; Sarfarazi, M; Newcombe, R G; Willis, N; Harper, P S

    1985-04-01

    Serum creatine kinase levels in 39 control females and 59 obligate carriers of Becker muscular dystrophy (BMD) have been used to construct likelihood ratios for carrier detection. In 24 possible carriers of BMD, analysis of DNA with X chromosome specific DNA probes linked to the dystrophy gene, has been used in conjunction with creatine kinase measurement to calculate final risk estimates of carrier status. Incorporation of information from probe genotype into the Bayesian calculation, enables a substantially lower risk to be deliniated for some possible carriers of the BMD gene. Thus, although the existing DNA probes are not sufficiently closely linked to BMD to be used in prenatal diagnosis, they can make a major contribution to genetic counseling by refining the estimated probability of carrier status. PMID:3995787

  2. Spectrin extractability from erythrocytes in Duchenne muscular dystrophy patients and carriers and in other myopathies.

    PubMed

    Gargioni, G; Chiaffoni, G; Bonadonna, G; Corradini, P; Lechi, C; de Grandis, D; Zatti, M

    1985-02-15

    Spectrin extractability was measured in the erythrocyte membranes from patients with Duchenne Muscular Dystrophy (DMD), from DMD definite carriers (in whom serum creatine kinase (CK) was also measured) and patients affected by other myopathies. After the extraction of spectrin from ghosts with EDTA, membrane proteins were examined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Spectrin extractability was also investigated in the presence of an excess of calcium. Spectrin extraction from erythrocyte ghosts was significantly reduced with respect to controls in DMD patients, in DMD definite carriers and in patients affected by limb-girdle dystrophy, but not in patients suffering from other non-dystrophic myopathies. Fifty percent of DMD definite carriers showed a reduced extraction of spectrin and some of them had normal serum CK. Reduced extractability was also observed in red blood cells incubated in media containing excess calcium. Our results could suggest that reduced spectrin extractability is connected with a modification of intracellular calcium levels. PMID:3987029

  3. Generation of Induced Pluripotent Stem Cells from Muscular Dystrophy Patients: Efficient Integration-free Reprogramming of Urine Derived Cells

    PubMed Central

    Afzal, Muhammad Z.; Strande, Jennifer L.

    2015-01-01

    Dystrophic cardiomyopathy is a poorly understood consequence of muscular dystrophy. Generating induced Pluripotent Stem Cells (iPSCs) from patients with muscular dystrophy is an invaluable cellular source for in vitro disease model systems and can be used for drug screening studies. Patient-derived urine cells have been used in successful reprogramming into induced pluripotent stem cells in order to model dystrophic cardiomyopathy1. Addressing the safety concerns of integrating vector systems, we present a protocol using a non-integrating Sendai virus vector for transduction of Yamanaka factors into urine cells collected from patients with muscular dystrophy. This protocol generates fully reprogrammed clones within 23 weeks. The pluripotent cells are vector-free by passage-13. These dystrophic iPSCs can be differentiated into cardiomyocytes and used either to study disease mechanisms or for drug screening. PMID:25650629

  4. Congenital muscular dystrophy with dropped head phenotype and cognitive impairment due to a novel mutation in the LMNA gene.

    PubMed

    Bonati, Ulrike; Bechtel, Nina; Heinimann, Karl; Rutz, Erich; Schneider, Jacques; Frank, Stephan; Weber, Peter; Fischer, Dirk

    2014-06-01

    Mutations in A-type nuclear lamins are known to cause a variety of diseases, which can affect almost all organs of the human body including striated muscle. For lamin-related congenital muscular dystrophy two different phenotypes are known to date. Here, we describe a 3-year-old, white Caucasian girl with a novel de novo mutation in the LMNA gene with marked hypotonia of neck and trunk muscles with dropped head posture, loss of cervical lordosis and marked joint laxity. In addition to this novel mutation, the patient also had cerebral white matter lesions on MRI and cognitive impairment on developmental testing. This is only the second A-type lamin-related congenital muscular dystrophy patient in which white matter lesions are described. Thus, white matter involvement might be a feature in A-type lamin-related congenital muscular dystrophy, warranting screening of these patients for both white matter lesions and cognitive impairment. PMID:24684859

  5. Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy

    PubMed Central

    Winston, Jincy; Duerden, Laura; Mort, Matthew; Frayling, Ian M; Rogers, Mark T; Upadhyaya, Meena

    2015-01-01

    Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD. PMID:24755953

  6. Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy.

    PubMed

    Reyes, Nicholas L; Banks, Glen B; Tsang, Mark; Margineantu, Daciana; Gu, Haiwei; Djukovic, Danijel; Chan, Jacky; Torres, Michelle; Liggitt, H Denny; Hirenallur-S, Dinesh K; Hockenbery, David M; Raftery, Daniel; Iritani, Brian M

    2015-01-13

    Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. PMID:25548157

  7. Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy

    PubMed Central

    Reyes, Nicholas L.; Banks, Glen B.; Tsang, Mark; Margineantu, Daciana; Gu, Haiwei; Djukovic, Danijel; Chan, Jacky; Torres, Michelle; Liggitt, H. Denny; Hirenallur-S, Dinesh K.; Hockenbery, David M.; Raftery, Daniel; Iritani, Brian M.

    2015-01-01

    Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I “red” slow twitch and type II “white” fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. PMID:25548157

  8. Identification of two novel SMCHD1 sequence variants in families with FSHD-like muscular dystrophy.

    PubMed

    Winston, Jincy; Duerden, Laura; Mort, Matthew; Frayling, Ian M; Rogers, Mark T; Upadhyaya, Meena

    2015-01-01

    Facioscapulohumeral muscular dystrophy 1 (FSHD1) is caused by a contraction in the number of D4Z4 repeats on chromosome 4, resulting in relaxation of D4Z4 chromatin causing inappropriate expression of DUX4 in skeletal muscle. Clinical severity is inversely related to the number of repeats. In contrast, FSHD2 patients also have inappropriate expression of DUX4 in skeletal muscle, but due to constitutional mutations in SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1), which cause global hypomethylation and hence general relaxation of chromatin. Thirty patients originally referred for FSHD testing were screened for SMCHD1 mutations. Twenty-nine had >11 D4Z4 repeats. SMCHD1 c.1040+1G>A, a pathogenic splice-site variant, was identified in a FSHD1 family with a borderline number of D4Z4 repeats (10) and a variable phenotype (in which a LMNA1 sequence variant was previously described), and SMCHD1 c.2606 G>T, a putative missense variant (p.Gly869Val) with strong in vitro indications of pathogenicity, was identified in a family with an unusual muscular dystrophy with some FSHD-like features. The two families described here emphasise the genetic complexity of muscular dystrophies. As SMCHD1 has a wider role in global genomic methylation, the possibility exists that it could be involved in other complex undiagnosed muscle disorders. Thus far, only 15 constitutional mutations have been identified in SMCHD1, and these two sequence variants add to the molecular and phenotypic spectrum associated with FSHD. PMID:24755953

  9. Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy.

    PubMed

    Richards, C S; Watkins, S C; Hoffman, E P; Schneider, N R; Milsark, I W; Katz, K S; Cook, J D; Kunkel, L M; Cortada, J M

    1990-04-01

    One of female MZ twins presented with muscular dystrophy. Physical examination, creatine phosphokinase levels, and muscle biopsy were consistent with Duchenne muscular dystrophy (DMD). However, because of her sex she was diagnosed as having limb-girdle muscular dystrophy. With cDNA probes to the DMD gene, a gene deletion was detected in the twins and their mother. The de novo mutation which arose in the mother was shown by novel junction fragments generated by HindIII, PstI, or TaqI when probed with cDNA8. Additional evidence of a large gene deletion was given by novel SfiI junction fragments detected by probes p20, J-Bir, and J-66 on pulsed-field gel electrophoresis (PFGE). Immunoblot analysis of muscle from the affected twin showed dystrophin of normal size but of reduced amount. Immunofluorescent visualization of dystrophin revealed foci of dystrophin-positive fibers adjacent to foci of dystrophin-negative fibers. These data indicate that the affected twin is a manifesting carrier of an abnormal DMD gene, her myopathy being a direct result of underexpression of dystrophin. Cytogenetic analysis revealed normal karyotypes, eliminating the possibility of a translocation affecting DMD gene function. Both linkage analysis and DNA fingerprint analysis revealed that each twin has two different X chromosomes, eliminating the possibility of uniparental disomy as a mechanism for DMD expression. On the basis of methylation differences of the paternal and maternal X chromosomes in these MZ twins, we propose uneven lyonization (X chromosome inactivation) as the underlying mechanism for disease expression in the affected female. PMID:2180286

  10. Non-Invasive Biomarkers for Duchenne Muscular Dystrophy and Carrier Detection.

    PubMed

    Anaya-Segura, Monica Alejandra; Garca-Martnez, Froylan Arturo; Montes-Almanza, Luis Angel; Daz, Benjamn-Gomez; Avila-Ramrez, Guillermina; Alvarez-Maya, Ikuri; Coral-Vazquez, Ramn Mauricio; Mondragn-Tern, Paul; Escobar-Cedillo, Rosa Elena; Garca-Caldern, Noem; Vazquez-Cardenas, Norma Alejandra; Garca, Silvia; Lpez-Hernandez, Luz Berenice

    2015-01-01

    Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 and matrix metalloproteinase 2, tissue inhibitor of metalloproteinases 1, myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid nave patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p < 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p < 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression. PMID:26091074

  11. ANGIOTENSIN-DEPENDENT AUTONOMIC DYSREGULATION PRECEDES DILATED CARDIOMYOPATHY IN A MOUSE MODEL OF MUSCULAR DYSTROPHY

    PubMed Central

    Sabharwal, Rasna; Weiss, Robert M.; Zimmerman, Kathy; Domenig, Oliver; Cicha, Michael Z.; Chapleau, Mark W.

    2015-01-01

    Sarcoglycan mutations cause muscular dystrophy. Patients with muscular dystrophy develop autonomic dysregulation and dilated cardiomyopathy (DCM), but the temporal relationship and mechanism of autonomic dysregulation are not well understood. We hypothesized that activation of the renin-angiotensin system (RAS) causes autonomic dysregulation prior to development of DCM in sarcoglycan-delta (Sgcd) deficient mice, and that the severity of autonomic dysfunction at a young age predicts the severity of DCM at older ages. At 10-12 weeks of age, when left ventricular function assessed by echocardiography remained normal, Sgcd−/− mice exhibited decreases in arterial pressure, locomotor activity, baroreflex sensitivity (BRS) and cardiovagal tone, and increased sympathetic tone compared with age-matched C57BL/6 control mice (P<0.05). Systemic and skeletal muscle RAS were activated, and angiotensin II type 1 receptor (AT1R) expression, superoxide and fibrosis were increased in dystrophic skeletal muscle (P<0.05). Treatment with the AT1R blocker losartan for 7-9 weeks beginning at 3 weeks of age prevented or strongly attenuated the abnormalities in Sgcd−/− mice (P<0.05). Repeated assessment of phenotypes between 10 and 75 weeks of age demonstrated worsening of autonomic function, progressive cardiac dysfunction and DCM, and increased mortality in Sgcd−/− mice. High sympathetic tone predicted subsequent left ventricular dysfunction. We conclude that RAS activation causes severe autonomic dysregulation in young Sgcd−/− mice, which portends a worse long-term prognosis. Therapeutic targeting of RAS at a young age may improve autonomic function and slow disease progression in muscular dystrophy. PMID:25921929

  12. Compound heterozygous PLEC mutations in a patient of consanguineous parentage with epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia.

    PubMed

    Yin, Jinghua; Ren, Yali; Lin, Zhimiao; Wang, Huijun; Zhou, Yun; Yang, Yong

    2015-02-01

    Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM 226670) is an autosomal recessive form of EBS, characterized by skin blistering at birth and delayed onset of muscle dystrophy. Mutations in PLEC, the gene encoding plectin, have been identified to be causal for EBS-MD. We report a case of EBS-MD with diffuse alopecia. Genetic study revealed the patient carrying compound heterozygous mutations in PLEC despite the consanguineous parentage. PMID:25209331

  13. Metabogenic and Nutriceutical Approaches to Address Energy Dysregulation and Skeletal Muscle Wasting in Duchenne Muscular Dystrophy

    PubMed Central

    Rybalka, Emma; Timpani, Cara A.; Stathis, Christos G.; Hayes, Alan; Cooke, Matthew B.

    2015-01-01

    Duchenne Muscular Dystrophy (DMD) is a fatal genetic muscle wasting disease with no current cure. A prominent, yet poorly treated feature of dystrophic muscle is the dysregulation of energy homeostasis which may be associated with intrinsic defects in key energy systems and promote muscle wasting. As such, supplementative nutriceuticals that target and augment the bioenergetical expansion of the metabolic pathways involved in cellular energy production have been widely investigated for their therapeutic efficacy in the treatment of DMD. We describe the metabolic nuances of dystrophin-deficient skeletal muscle and review the potential of various metabogenic and nutriceutical compounds to ameliorate the pathological and clinical progression of the disease. PMID:26703720

  14. The Molecular Basis of Muscular Dystrophy in the mdx Mouse: A Point Mutation

    NASA Astrophysics Data System (ADS)

    Sicinski, Piotr; Geng, Yan; Ryder-Cook, Allan S.; Barnard, Eric A.; Darlison, Mark G.; Barnard, Pene J.

    1989-06-01

    The mdx mouse is an X-linked myopathic mutant, an animal model for human Duchenne muscular dystrophy. In both mouse and man the mutations lie within the dystrophin gene, but the phenotypic differences of the disease in the two species confer much interest on the molecular basis of the mdx mutation. The complementary DNA for mouse dystrophin has been cloned, and the sequence has been used in the polymerase chain reaction to amplify normal and mdx dystrophin transcripts in the area of the mdx mutation. Sequence analysis of the amplification products showed that the mdx mouse has a single base substitution within an exon, which causes premature termination of the polypeptide chain.

  15. Rapid carrier and prenatal diagnosis of Duchenne and Becker muscular dystrophy

    SciTech Connect

    Roberts, R.G.; Cole, C.G.; Hart, K.A.; Bobrow, M.; Bentley, D.R. )

    1989-01-25

    Carrier and prenatal diagnosis of Duchenne and Becker muscular dystrophy (DMD and BMD) by DNA methods uses Southern blotting to detect either the informative segregation of restriction fragment length polymorphisms (RFLPs) or the absence of restriction fragments in affected males. Recently, the use of the polymerase chain reaction (PCR) for rapid detection of deletions in some affected males was reported eliminating the need for Southern blotting of 37% of all samples. This approach is not applicable, however, to non-deletion cases or for carrier diagnosis. The authors have used PCR for rapid analysis of intragenic RFLPs to permit both carrier and prenatal diagnosis in the majority of familial cases.

  16. Occurrence of two different intragenic deletions in two male relatives affected with Duchenne muscular dystrophy

    SciTech Connect

    Mostacciuolo, M.L.; Miorin, M.; Vitiello, L.; Rampazzo, A.; Fanin, M.; Angelini, C.; Danieli, G.A.

    1994-03-01

    The occurrence of 2 different intragenic deletions (exons 10-44 and exon 45, respectively) is reported in 2 male relatives affected with Duchenne muscular dystrophy, both showing the same haplotype for DNA markers not included in the deleted segment. The 2 different deletions seem to have occurred independently in the same X chromosome. This finding, together with other reports, suggests possibly an increased predisposition to mutations within the DMD locus in some families. Therefore, when dealing with prenatal diagnosis, the investigation on fetal DNA cannot be restricted only to the region in which a mutation was previously identified in the family. 14 refs., 1 fig.

  17. Conservation of the Duchenne muscular dystrophy gene in mice and humans

    SciTech Connect

    Hoffman, E.P.; Monaco, A.P.; Feener, C.C.; Kunkel, L.M.

    1987-10-16

    A portion of the Duchenne muscular dystrophy (DMD) gene transcript from human fetal skeletal muscle and mouse adult heart was sequence, representing approximately 25 percent of the total, 14-kb DMD transcript. The nucleic acid and predicted amino acid sequences from the two species are nearly 90 percent homologous. The amino acid sequence that is predicted from this portion of the DMD gene indicates that the protein product might serve a structural role in muscle, but the abundance and tissue distribution of the messenger RNA suggest that the DMD protein is not nebulin.

  18. Extreme variability of expression in monozygotic twins with FSH muscular dystrophy.

    PubMed

    Tawil, R; Storvick, D; Feasby, T E; Weiffenbach, B; Griggs, R C

    1993-02-01

    We describe monozygotic twins who are either discordant or show extreme variability in the expression of facioscapulohumeral muscular dystrophy (FSHD). One twin was severely incapacitated by FSHD. The asymptomatic twin demonstrated equivocal facial weakness on physical examination, but no difference on quantitative myometry when compared with normal controls. High-resolution cytogenetic analysis showed no chromosomal abnormalities. Five polymorphic 4q35 markers known to be linked to FSHD showed identical RFLP patterns, indicating that submicroscopic chromosomal rearrangement is unlikely. We conclude that this set of twins represents an extreme case of variability in the expression of the FSHD gene. PMID:8094896

  19. Human artificial chromosomes for Duchenne muscular dystrophy and beyond: challenges and hopes.

    PubMed

    Tedesco, Francesco Saverio

    2015-02-01

    Safe and efficacious vectors able to carry large or several transgenes are of key importance for gene therapy. Human artificial chromosomes can fulfil this essential requirement; moreover, they do not integrate into the host genome. However, drawbacks such as the low efficiency of chromosome transfer and their relatively complex engineering still limit their widespread use. In this article, I summarise the key steps that brought human artificial chromosomes into preclinical research for Duchenne muscular dystrophy, an X-linked, monogenic disorder. I will also review possible future pre-clinical and clinical perspectives for this technology. PMID:25596829

  20. Duchenne muscular dystrophy: a 30-year population-based incidence study.

    PubMed

    Dooley, Joseph; Gordon, Kevin E; Dodds, Linda; MacSween, Judith

    2010-02-01

    Duchenne muscular dystrophy (DMD) is among the most common lethal genetic diseases. It has been proposed that genetic counseling and prenatal diagnosis have begun to lower the incidence. We reviewed the records of all patients with confirmed DMD who were born between 1969 and 2008. Statistics Canada data on annual male births in Nova Scotia were obtained for each year.The overall incidence of 1 per 4700 male births remained stable during the 30-year period of the study. Similarly, the age at diagnosis did not change during that time. PMID:20080524

  1. Metabogenic and Nutriceutical Approaches to Address Energy Dysregulation and Skeletal Muscle Wasting in Duchenne Muscular Dystrophy.

    PubMed

    Rybalka, Emma; Timpani, Cara A; Stathis, Christos G; Hayes, Alan; Cooke, Matthew B

    2015-01-01

    Duchenne Muscular Dystrophy (DMD) is a fatal genetic muscle wasting disease with no current cure. A prominent, yet poorly treated feature of dystrophic muscle is the dysregulation of energy homeostasis which may be associated with intrinsic defects in key energy systems and promote muscle wasting. As such, supplementative nutriceuticals that target and augment the bioenergetical expansion of the metabolic pathways involved in cellular energy production have been widely investigated for their therapeutic efficacy in the treatment of DMD. We describe the metabolic nuances of dystrophin-deficient skeletal muscle and review the potential of various metabogenic and nutriceutical compounds to ameliorate the pathological and clinical progression of the disease. PMID:26703720

  2. Risks in a Trial of an Innovative Treatment of Duchenne Muscular Dystrophy.

    PubMed

    Bos, Wendy; Westra, Anna E; Pinxten, Wim; Mayer, Matthew P; Lantos, John D

    2015-12-01

    Studies of innovative therapies for muscular dystrophy raise unique ethical issues. The disease is currently untreatable and relentlessly progressive. A number of potentially efficacious treatments are being developed, but like all treatments, they may have unforeseen adverse effects. Nevertheless, patients and families, facing a bleak future, may be willing to take the gamble and try the treatments. Many doctors are eager to study them. But should institutional review boards approve them? This article discusses these issues and recounts the ways that one such study elicited different responses from different institutional review boards. PMID:26553189

  3. Merosin-deficient congenital muscular dystrophy: A novel homozygous mutation in the laminin-2 gene.

    PubMed

    Turner, Clinton; Mein, Rachael; Sharpe, Cynthia; Love, Donald R

    2015-12-01

    Merosin deficient congenital muscular dystrophy (MDC1A) is an autosomal recessive disorder characterized by mutations in the LAMA2 gene at chromosome 6q22-23. This gene spans 65 exons and encodes the ?2 chain subunit of laminin-2. A variety of deletions, missense, nonsense and splice site mutations have been described in the LAMA2 gene, with resultant MDC1A. We describe a novel LAMA2 homozygous sequence variant in a Samoan patient with MDC1A and confirm its pathogenic effect with merosin immunohistochemistry on skeletal muscle biopsy. The likely effect of the sequence variant is modeled using in silico analysis. PMID:26249246

  4. Emery–Dreifuss muscular dystrophy: a test case for precision medicine

    PubMed Central

    Pillers, De-Ann M; Von Bergen, Nicholas H

    2016-01-01

    Emery–Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of scapulohumeroperoneal muscle weakness, joint contractures, and cardiac defects that include arrhythmias and dilated cardiomyopathy. Although there is a defining group of clinical findings, the proteins responsible and their underlying gene defects leading to EDMD are varied. A common aspect of the gene defects is their involvement in, or with, the nuclear envelope. Treatment approaches are largely based on clinical symptoms. The genetic diversity of EDMD predicts that a cure will ultimately depend upon the individual’s defect at the gene level, making this an ideal candidate for a precision medicine approach. PMID:26966385

  5. Discovery of 2-arylbenzoxazoles as upregulators of utrophin production for the treatment of Duchenne muscular dystrophy.

    PubMed

    Chancellor, Daniel R; Davies, Kay E; De Moor, Olivier; Dorgan, Colin R; Johnson, Peter D; Lambert, Adam G; Lawrence, Daniel; Lecci, Cristina; Maillol, Carole; Middleton, Penny J; Nugent, Gary; Poignant, Sverine D; Potter, Allyson C; Price, Paul D; Pye, Richard J; Storer, Richard; Tinsley, Jonathon M; van Well, Renate; Vickers, Richard; Vile, Julia; Wilkes, Fraser J; Wilson, Francis X; Wren, Stephen P; Wynne, Graham M

    2011-05-12

    A series of novel 2-arylbenzoxazoles that upregulate the production of utrophin in murine H2K cells, as assessed using a luciferase reporter linked assay, have been identified. This compound class appears to hold considerable promise as a potential treatment for Duchenne muscular dystrophy. Following the delineation of structure-activity relationships in the series, a number of potent upregulators were identified, and preliminary ADME evaluation is described. These studies have resulted in the identification of 1, a compound that has been progressed to clinical trials. PMID:21456623

  6. 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

  7. G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy.

    PubMed

    Hayashiji, Nozomi; Yuasa, Shinsuke; Miyagoe-Suzuki, Yuko; Hara, Mie; Ito, Naoki; Hashimoto, Hisayuki; Kusumoto, Dai; Seki, Tomohisa; Tohyama, Shugo; Kodaira, Masaki; Kunitomi, Akira; Kashimura, Shin; Takei, Makoto; Saito, Yuki; Okata, Shinichiro; Egashira, Toru; Endo, Jin; Sasaoka, Toshikuni; Takeda, Shin'ichi; Fukuda, Keiichi

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a chronic and life-threatening disease that is initially supported by muscle regeneration but eventually shows satellite cell exhaustion and muscular dysfunction. The life-long maintenance of skeletal muscle homoeostasis requires the satellite stem cell pool to be preserved. Asymmetric cell division plays a pivotal role in the maintenance of the satellite cell pool. Here we show that granulocyte colony-stimulating factor receptor (G-CSFR) is asymmetrically expressed in activated satellite cells. G-CSF positively affects the satellite cell population during multiple stages of differentiation in ex vivo cultured fibres. G-CSF could be important in developing an effective therapy for DMD based on its potential to modulate the supply of multiple stages of regenerated myocytes. This study shows that the G-CSF-G-CSFR axis is fundamentally important for long-term muscle regeneration, functional maintenance and lifespan extension in mouse models of DMD with varying severities. PMID:25865621

  8. [Congenital muscular dystrophy with laminin-a2 deficiency in early infancy: diagnosis and long-term follow-up].

    PubMed

    Panteliadis, C; Karatza, E; Xinias, I; Flaris, N; Tzitiridou, M; Ramantani, G

    2005-01-01

    Congenital muscular dystrophy (CMD) is a heterogeneous group of neuromuscular disorders characterized by muscle weakness and hypotonia at birth or within the first few months of life. It is inherited in an autosomal recessive pattern. About half of the patients have a deficiency of the alpha-2-chain of laminin (merosin). We describe a case of congenital muscular dystrophy in an infant with laminin-a2-chain deficiency, which appeared hypotonia in early infancy. Diagnosis was made by clinical features and the histological and immunohistochemical studies on muscle biopsy. PMID:16167276

  9. Air stacking: effects on pulmonary function in patients with spinal muscular atrophy and in patients with congenital muscular dystrophy*,**

    PubMed Central

    Marques, Tanyse Bahia Carvalho; Neves, Juliana de Carvalho; Portes, Leslie Andrews; Salge, Joo Marcos; Zanoteli, Edmar; Reed, Umbertina Conti

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (ten with CMD and eight with SMA) were submitted to routine daily air-stacking maneuvers at home with manual resuscitators for four to six months, undergoing pulmonary function tests before and after that period. The pulmonary function tests included measurements of FVC; PEF; maximum insufflation capacity (MIC); and assisted and unassisted peak cough flow (APCF and UPCF, respectively) with insufflations. RESULTS: After the use of home air-stacking maneuvers, there were improvements in the APCF and UPCF. In the patients without scoliosis, there was also a significant increase in FVC. When comparing patients with and without scoliosis, the increases in APCF and UPCF were more pronounced in those without scoliosis. CONCLUSIONS: Routine daily air-stacking maneuvers with a manual resuscitator appear to increase UPCF and APCF in patients with NMD, especially in those without scoliosis. PMID:25410841

  10. Nitric oxide donors improve prednisone effects on muscular dystrophy in the mdx mouse diaphragm.

    PubMed

    Mizunoya, Wataru; Upadhaya, Ritika; Burczynski, Frank J; Wang, Guqi; Anderson, Judy E

    2011-05-01

    In Duchenne muscular dystrophy (DMD), palliative glucocorticoid therapy can produce myopathy or calcification. Since increased nitric oxide synthase activity in dystrophic mice promotes regeneration, the outcome of two nitric oxide (NO) donor drugs, MyoNovin (M) and isosorbide dinitrate (I), on the effectiveness of the anti-inflammatory drug prednisone (P) in alleviating progression of dystrophy was tested. Dystrophic mdx mice were treated (18 days) as controls or with an NO donor P. Fiber permeability and DNA synthesis were labeled by Evans blue dye (EBD) and bromodeoxyuridine uptake, respectively. P decreased body weight gain, M increased quadriceps mass, and I increased heart mass. P increased fiber permeability (%EBD+ fibers) and calcification in diaphragm. Treatment with NO donors + P (M+P, I+P) reduced %EBD+ fibers and calcification vs. P alone. %EBD+ fibers in M+P diaphragm did not differ from control. NO donor treatment reduced proliferation and the population of c-met+ cells and accelerated fiber regeneration. Concurrent with P, NO donor treatment suppressed two important detrimental effects of P in mice, possibly by accelerating regeneration, rebalancing satellite cell quiescence and activation in dystrophy, and/or increasing perfusion. Results suggest that NO donors could improve current therapy for DMD. PMID:21270295

  11. Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping.

    PubMed

    Gao, Quan Q; Wyatt, Eugene; Goldstein, Jeff A; LoPresti, Peter; Castillo, Lisa M; Gazda, Alec; Petrossian, Natalie; Earley, Judy U; Hadhazy, Michele; Barefield, David Y; Demonbreun, Alexis R; Bönnemann, Carsten; Wolf, Matthew; McNally, Elizabeth M

    2015-11-01

    Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations. PMID:26457733

  12. Effects of an immunosuppressive treatment in the GRMD dog model of Duchenne muscular dystrophy.

    PubMed

    Barthlmy, Ins; Uriarte, Ane; Drougard, Carole; Unterfinger, Yves; Thibaud, Jean-Laurent; Blot, Stphane

    2012-01-01

    The GRMD (Golden retriever muscular dystrophy) dog has been widely used in pre-clinical trials targeting DMD (Duchenne muscular dystrophy), using in many cases a concurrent immune-suppressive treatment. The aim of this study is to assess if such a treatment could have an effect on the disease course of these animals. Seven GRMD dogs were treated with an association of cyclosporine A (immunosuppressive dosage) and prednisolone (2 mg/kg/d) during 7 months, from 2 to 9 months of age. A multi-parametric evaluation was performed during this period which allowed us to demonstrate that this treatment had several significant effects on the disease progression. The gait quality as assessed by 3D-accelerometry was dramatically improved. This was consistent with the evolution of other parameters towards a significant improvement, such as the clinical motor score, the post-tetanic relaxation and the serum CK levels. In contrast the isometric force measurement as well as the histological evaluation argued in favor of a more severe disease progression. In view of the disease modifying effects which have been observed in this study it should be concluded that immunosuppressive treatments should be used with caution when carrying out pre-clinical studies in this canine model of DMD. They also highlight the importance of using a large range of multi-parametric evaluation tools to reliably draw any conclusion from trials involving dystrophin-deficient dogs, which reproduce the complexity of the human disease. PMID:23185260

  13. From representation to mediation: the shaping of collective mobilization on muscular dystrophy in France.

    PubMed

    Rabeharisoa, Vololona

    2006-02-01

    How, and to what extent, do patient organisations renew traditional forms of social participation and protest? This question is examined, drawing on a socio-historical case study of the Association Franaise contre les Myopathies--French Muscular Dystrophy Organisation (AFM). The originality of the AFM is that it has not been content to endorse the classic role of representation of people with muscular dystrophy (MD) and their families. It has also articulated and structured different social spaces that allow people suffering from genetic diseases and severe disabilities to be considered as fully-fledged human beings, persons, and citizens within those spaces. Based on quantitative data and methods, this paper aims to characterize this reconfiguration of social spaces that the AFM has undertaken. My contention is that it has given shape to a different form of collective mobilization, one in which the patient organisation is a mediator between different social actors, as much as a patients' representative. It helps a new issue, here MD, to emerge so that the largest possible collective designate it as a general public concern. As we shall discuss, this renews the question of patients' collective identity and citizenship. PMID:16051407

  14. Where do we stand in trial readiness for autosomal recessive limb girdle muscular dystrophies?

    PubMed

    Straub, Volker; Bertoli, Marta

    2016-02-01

    Autosomal recessive limb girdle muscular dystrophies (LGMD2) are a group of genetically heterogeneous diseases that are typically characterised by progressive weakness and wasting of the shoulder and pelvic girdle muscles. Many of the more than 20 different conditions show overlapping clinical features with other forms of muscular dystrophy, congenital, myofibrillar or even distal myopathies and also with acquired muscle diseases. Although individually extremely rare, all types of LGMD2 together form an important differential diagnostic group among neuromuscular diseases. Despite improved diagnostics and pathomechanistic insight, a curative therapy is currently lacking for any of these diseases. Medical care consists of the symptomatic treatment of complications, aiming to improve life expectancy and quality of life. Besides well characterised pre-clinical tools like animal models and cell culture assays, the determinants of successful drug development programmes for rare diseases include a good understanding of the phenotype and natural history of the disease, the existence of clinically relevant outcome measures, guidance on care standards, up to date patient registries, and, ideally, biomarkers that can help assess disease severity or drug response. Strong patient organisations driving research and successful partnerships between academia, advocacy, industry and regulatory authorities can also help accelerate the elaboration of clinical trials. All these determinants constitute aspects of translational research efforts and influence patient access to therapies. Here we review the current status of determinants of successful drug development programmes for LGMD2, and the challenges of translating promising therapeutic strategies into effective and accessible treatments for patients. PMID:26810373

  15. Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy

    SciTech Connect

    Roberds, S.L.; Anderson, R.D.; Lim, L.E.

    1994-09-01

    Adhalin, the 50-kDa dystrophin-associated glycoprotein, is deficient in skeletal muscle of patients having severe childhood autosomal recessive muscular dystrophy (SCARMD). In several North African families, SCARMD has been linked to markers in the pericentromeric region of chromosome l3q, but SCARMD has been excluded from linkage to this locus in other families. To determine whether the adhalin gene might be involved in SCARMD, human adhalin cDNA and large portions of the adhalin gene were cloned. Adhalin is a transmembrane glycoprotein with an extracellular domain bearing limited homology to domains of entactin and nerve growth factor receptor, suggesting that adhalin may serve as a receptor for an extracellular matrix protein. The adhalin gene was mapped to chromosome 17q12-q21.33, excluding the gene from involvement in 13q-linked SCARMD. A polymorphic microsatellite was identified within intron 6 of the adhalin gene, and one allelic variant of this marker cosegregated with the disease phenotype in a large French family with a lod score of 3.61 at 0 recombination. Adhalin is undetectable in skeletal muscle from affected members of this family. Missense mutations were identified within the adhalin gene that might cause SCARMD in this family. Thus, genetic defects in at least two components, dystrophin and adhalin, of the dystrophin-glycoprotein complex can independently cause muscular dystrophies.

  16. Fluorescent multiplex linkage analysis and carrier detection for Duchenne/Becker muscular dystrophy

    SciTech Connect

    Schwartz, L.S.; Hoffman, E.P. ); Tarleton, J. ); Popovich, B. ); Seltzer, W.K. )

    1992-10-01

    The authors have developed a fast and accurate PCR-based linkage and carrier detection protocol for families of Duchenne muscular dystrophy (DMD)/Becker muscular dystrophy (BMD) patients with or without detectable deletions of the dystrophin gene, using fluorescent PCR products analyzed on an automated sequencer. When a deletion is found in the affected male DMD/BMD patient by standard multiplex PCR, fluorescently labeled primers specific for the deleted and nondeleted exon(s) are used to amplify the DNA of at-risk female relatives by using multiplex PCR at low cycle number (20 cycles). The products are then quantitatively analyzed on an automatic sequencer to determine whether they are heterozygous for the deletion and thus are carriers. As a confirmation of the deletion data, and in cases in which a deletion is not found in the proband, fluorescent multiplex PCR linkage is done by using four previously described polymorphic dinucleotide sequences. The four (CA)[sub n] repeats are located throughout the dystrophin gene, making the analysis highly informative and accurate. The authors present the successful application of this protocol in families who proved refractory to more traditional analyses. 22 refs., 3 figs.

  17. Electrical impedance myography for the assessment of children with muscular dystrophy: a preliminary study

    NASA Astrophysics Data System (ADS)

    Rutkove, S. B.; Darras, B. T.

    2013-04-01

    Electrical impedance myography (EIM) provides a non-invasive approach for quantifying the severity of neuromuscular disease. Here we determine how well EIM data correlates to functional and ultrasound (US) measures of disease in children with Duchenne muscular dystrophy (DMD) and healthy subjects. Thirteen healthy boys, aged 2-12 years and 14 boys with DMD aged 4-12 years underwent both EIM and US measurements of deltoid, biceps, wrist flexors, quadriceps, tibialis anterior, and medial gastrocnemius. EIM measurements were performed with a custom-designed probe using a commercial multifrequency bioimpedance device. US luminosity data were quantified using a gray-scale analysis approach. Children also underwent the 6-minute walk test, timed tests and strength measurements. EIM and US data were combined across muscles. EIM 50 kHz phase was able to discriminate DMD children from healthy subjects with 98% accuracy. In the DMD patients, average EIM phase measurements also correlated well with standard functional measures. For example the 50 kHz phase correlated with the Northstar Ambulatory Assessment test (R = 0.83, p = 0.02). EIM 50 kHz phase and US correlated as well, with R = -0.79 (p < 0.001). These results show that EIM provides valuable objective measures Duchenne muscular dystrophy severity.

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

    SciTech Connect

    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, 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.

  19. Evidence-based guideline summary: Evaluation, diagnosis, and management of congenital muscular dystrophy

    PubMed Central

    Kang, Peter B.; Morrison, Leslie; Iannaccone, Susan T.; Graham, Robert J.; Bnnemann, Carsten G.; Rutkowski, Anne; Hornyak, Joseph; Wang, Ching H.; North, Kathryn; Oskoui, Maryam; Getchius, Thomas S.D.; Cox, Julie A.; Hagen, Erin E.; Gronseth, Gary; Griggs, Robert C.

    2015-01-01

    Objective: To delineate optimal diagnostic and therapeutic approaches to congenital muscular dystrophy (CMD) through a systematic review and analysis of the currently available literature. Methods: Relevant, peer-reviewed research articles were identified using a literature search of the MEDLINE, EMBASE, and Scopus databases. Diagnostic and therapeutic data from these articles were extracted and analyzed in accordance with the American Academy of Neurology classification of evidence schemes for diagnostic, prognostic, and therapeutic studies. Recommendations were linked to the strength of the evidence, other related literature, and general principles of care. Results: The geographic and ethnic backgrounds, clinical features, brain imaging studies, muscle imaging studies, and muscle biopsies of children with suspected CMD help predict subtype-specific diagnoses. Genetic testing can confirm some subtype-specific diagnoses, but not all causative genes for CMD have been described. Seizures and respiratory complications occur in specific subtypes. There is insufficient evidence to determine the efficacy of various treatment interventions to optimize respiratory, orthopedic, and nutritional outcomes, and more data are needed regarding complications. Recommendations: Multidisciplinary care by experienced teams is important for diagnosing and promoting the health of children with CMD. Accurate assessment of clinical presentations and genetic data will help in identifying the correct subtype-specific diagnosis in many cases. Multiorgan system complications occur frequently; surveillance and prompt interventions are likely to be beneficial for affected children. More research is needed to fill gaps in knowledge regarding this category of muscular dystrophies. PMID:25825463

  20. Enhanced Reprogramming Efficiency and Kinetics of Induced Pluripotent Stem Cells Derived from Human Duchenne Muscular Dystrophy

    PubMed Central

    Teotia, Pooja; Mohanty, Sujata; Kabra, Madhulika; Gulati, Sheffali; Airan, Balram

    2015-01-01

    The generation of disease-specific induced pluripotent stem cells (iPSCs) holds a great promise for understanding disease mechanisms and for drug screening. Recently, patient-derived iPSCs, containing identical genetic anomalies of the patient, have offered a breakthrough approach to studying Duchenne muscular dystrophy (DMD), a fatal disease caused by the mutation in the dystrophin gene. However, development of scalable and high fidelity DMD-iPSCs is hampered by low reprogramming efficiency, the addition of expensive growth factors and slow kinetics of disease-specific fibroblasts. Here, we show an efficient generation of DMD-iPSCs on bFGF secreting human foreskin fibroblast feeders (I-HFF) by employing single polycistronic lentiviral vector for delivering of transcription factors to DMD patient-specific fibroblast cells. Using this method, DMD-iPSCs generated on I-HFF feeders displayed pluripotent characteristics and disease genotype with improved reprogramming efficiency and kinetics over to mouse feeders. Moreover, we were able to maintain disease-specific iPSCs without additional supplementation of bFGF on I-HFF feeders. Our findings offer improvements in the generation of DMD-iPSCs and will facilitate in understanding of pathological mechanisms and screening of safer drugs for clinical intervention. Key Words: Duchenne Muscular Dystrophy, Reprogramming, Induced pluripotent Stem Cells, Immortalized Human Feeder, Basic Fibroblast Growth Factor, Stem Cell Cassette PMID:26579330

  1. Genetic mutations strengthen functional association of LAP1 with DYT1 dystonia and muscular dystrophy.

    PubMed

    Rebelo, Sandra; da Cruz E Silva, Edgar F; da Cruz E Silva, Odete A B

    2015-01-01

    Lamina-associated polypeptide 1 (LAP1) is a ubiquitously expressed integral protein of the inner nuclear membrane. It interacts physically with lamins, torsinA, emerin and protein phosphatase 1; potentially providing a pivotal mechanism for transducing signals across the inner nuclear membrane. In neurons a functional protein complex is formed, comprising LAP1 and torsinA and in skeletal muscle LAP1 and emerin likewise form a protein complex. Several isoforms of LAP1 have been reported across species. However, in humans only two isoforms have been described, LAP1B and LAP1C. The latter has only recently been reported, but its physiological function and mode of action are not clear. The first TOR1AIP1 (gene encoding LAP1) mutation identified is a single nucleotide deletion resulting in a frameshift and a putative truncated LAP1B protein (Turkish mutation). This has deleterious effects associated with a specific form of muscular dystrophy. A second point mutation, affecting both human LAP1 isoforms, was also recently described. This mutation involves the replacement of a single glutamic acid to alanine at position 482 (Moroccan Mutation), thereby causing severe dystonia, cerebellar atrophy and cardiomyopathy. This review focuses on the recently described human LAP1 isoform (LAP1C), the two recently reported LAP1 mutations and post-translational LAP1 modifications. The latter play an important role in regulating this protein. These scientific contributions strengthen the role of LAP1 in DYT1 dystonia and muscular dystrophy. PMID:26596547

  2. Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain.

    PubMed

    Allamand, V; Sunada, Y; Salih, M A; Straub, V; Ozo, C O; Al-Turaiki, M H; Akbar, M; Kolo, T; Colognato, H; Zhang, X; Sorokin, L M; Yurchenco, P D; Tryggvason, K; Campbell, K P

    1997-05-01

    Congenital muscular dystrophy (CMD) is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive mode. The alpha2-chain of laminin-2 (previously called merosin) has been shown by immunohistochemical and genetic analyses to be implicated in the pathogenesis of the 'classic' form of CMD. In the 'merosin-deficient' subgroup, which represents about half of the cases, more definite evidence of the involvement of the laminin alpha2-chain has recently been reported with the identification of mutations in the gene encoding the alpha2-chain of laminin 2 (LAMA2) in CMD patients. Here we report on two siblings from a consanguineous family expressing an internally deleted laminin alpha2-chain as a result of a splice site mutation in the LAMA2 gene which causes the splicing of exon 25. The predicted protein lacks 63 amino acids in domain IVa which forms a globular structure on the short arm of the alpha2-chain. Interestingly, these patients appear mildly affected compared to others who completely lack this protein. This situation presents a striking analogy with Becker muscular dystrophy, where in-frame deletions in the dystrophin gene result in the expression of a semi-functional protein and lead to a mild phenotype. PMID:9158149

  3. Generation of muscular dystrophy model rats with a CRISPR/Cas system

    PubMed Central

    Nakamura, Katsuyuki; Fujii, Wataru; Tsuboi, Masaya; Tanihata, Jun; Teramoto, Naomi; Takeuchi, Shiho; Naito, Kunihiko; Yamanouchi, Keitaro; Nishihara, Masugi

    2014-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked lethal muscle disorder caused by mutations in the Dmd gene encoding Dystrophin12. DMD model animals, such as mdx mice and canine X-linked muscular dystrophy dogs, have been widely utilized in the development of a treatment for DMD3. Here, we demonstrate the generation of Dmd-mutated rats using a clustered interspaced short palindromic repeats (CRISPR)/Cas system, an RNA-based genome engineering technique that is also adaptive to rats. We simultaneously targeted two exons in the rat Dmd gene, which resulted in the absence of Dystrophin expression in the F0 generation. Dmd-mutated rats exhibited a decline in muscle strength, and the emergence of degenerative/regenerative phenotypes in the skeletal muscle, heart, and diaphragm. These mutations were heritable by the next generation, and F1 male rats exhibited similar phenotypes in their skeletal muscles. These model rats should prove to be useful for developing therapeutic methods to treat DMD. PMID:25005781

  4. Development and psychometric analysis of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT).

    PubMed

    Landfeldt, Erik; Mayhew, Anna; Eagle, Michelle; Lindgren, Peter; Bell, Christopher F; Guglieri, Michela; Straub, Volker; Lochmller, Hanns; Bushby, Katharine

    2015-12-01

    The objective of this study was to describe the development and initial psychometric analysis of the UK English version of the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a patient-reported outcome (PRO) scale designed to measure functional ability in patients with Duchenne muscular dystrophy (DMD). Item selection was made by neuromuscular specialists and a Rasch analysis was performed to understand the psychometric properties of the DMDSAT. Instrument scores were also linked to cost of illness and health-related quality of life data. The administered version, completed by 186 UK patient-caregivers pairs, included eight items in four domains: Arm function, Mobility, Transfers, and Ventilation status. These items together successfully operationalized functional ability in DMD, with excellent targeting and reliability (Person Separation Index: 0.95; Cronbach's ?: 0.93), stable item locations, and good fit to the Rasch model (mean person/item fit residual: -0.21/-0.44, SD: 0.32/1.28). Estimated item difficulty was in excellent agreement with clinical opinion (Spearman's ?: 0.95) and instrument scores mapped well onto health economic outcomes. We show that the DMDSAT is a PRO instrument fit for purpose to measure functional ability in ambulant and non-ambulant patients with DMD. Rasch analysis augments clinical expertise in the development of robust rating scales. PMID:26483273

  5. Differences in Contraction-Induced Hemodynamics and Surface EMG in Duchenne Muscular Dystrophy.

    PubMed

    Van Ginderdeuren, Eva; Caicedo, Alexander; Taelmans, Joachim; Goemans, Nathalie; van den Hauwe, Marlen; Naulaers, Gunnar; Van Huffel, Sabine; Buyse, Gunnar

    2016-01-01

    Duchenne muscular dystrophy (DMD) is the most common and devastating type of muscular dystrophy worldwide. In this study we have investigated the potential of the combined use of non-invasive near-infrared spectroscopy (NIRS) and surface electromyography (sEMG) to assess contraction-induced changes in oxygenation and myoelectrical activity, respectively in the biceps brachii of eight DMD patients aged 9-12 years and 11 age-matched healthy controls. Muscle tissue oxygenation index (TOI), oxyhemoglobin (HbO2), and sEMG signals were continuously measured during a sustained submaximal contraction of 60% maximal voluntary isometric contraction, and post-exercise recovery period. Compared to controls, DMD subjects showed significantly smaller changes in TOI during the contraction. In addition, during the reoxygenation phase some dynamic parameters extracted from the HbO2 measurements were significantly different between the two groups, some of which were correlated with functional performances on a 6-min walking test. In conclusion, non-invasive continuous monitoring of skeletal muscle oxygenation by NIRS is feasible in young children, and significant differences in contraction-induced deoxygenation and reoxygenation patterns were observed between healthy controls and DMD children. PMID:26782197

  6. An autopsy study of a familial oculopharyngeal muscular dystrophy (OPMD) with distal spread and neurogenic involvement.

    PubMed

    Schmitt, H P; Krause, K H

    1981-01-01

    An 81-year-old man from a family with a history of oculopharyngeal muscular dystrophy (OPMD) involving 6 members over 4 generations is described. The patient first noted drooping of his eyelids at the age of 65. Dysphagia and dysarthria occurred soon thereafter. At age 78, impairment of gait developed and progressive wasting occurred in the limbs with an initial distal distribution. Electromyography of several limb muscles displayed a mixed myopathic and neurogenic pattern with giant potentials. Examination at autopsy revealed slight loss of neurons in the anterior horns of the spinal cord, with scanty ghost cells, neuronophagia, and central chromatolysis. By light microscopy the limb muscles showed moderate small-group atrophy with severe myopathy and target fibers. The viscerocranial muscles, including the ocular, vocal, and tongue muscles, demonstrated only myopathic change with the typical features of progressive muscular dystrophy. Advanced replacement by fibrous connective tissue and fat had occurred in both the viscerocranial and the lower limb muscles. The significance of neurogenic involvement in OPMD is discussed. PMID:7254232

  7. Muscle ERR? 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-? (ERR?), 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 ERR? selectively in the dystrophic muscles of the mdx mice restored metabolic and angiogenic gene expression compared with control mdx mice. Further, ERR? enhanced muscle oxidative myofibers, vasculature, and blood flow (by 33-66%) and improved exercise tolerance (by 75%) in the dystrophic mice. Restoring muscle ERR? pathway ameliorated muscle damage and also prevented DMD hallmarks of postexercise muscle damage, hypoxia, and fatigue in mdx mice. Notably, ERR? did not restore sarcolemmal DAG complex, which is thus dispensable for antidystrophic effects of ERR?. In summary, ERR?-dependent metabolic and angiogenic gene program is defective in DMD, and we demonstrate that its restoration is a potential strategy for treating muscular dystrophy. PMID:23781095

  8. Limb-girdle muscular dystrophy in the Agarwals: Utility of founder mutations in CAPN3 gene

    PubMed Central

    Khadilkar, Satish V.; Chaudhari, Chetan R.; Dastur, Rashna S.; Gaitonde, Pradnya S.; Yadav, Jayendra G.

    2016-01-01

    Background and Purpose: Diagnostic evaluation of limb-girdle muscular dystrophy type 2A (LGMD2A) involves specialized studies on muscle biopsy and mutation analysis. Mutation screening is the gold standard for diagnosis but is difficult as the gene is large and multiple mutations are known. This study evaluates the utility of two known founder mutations as a first-line diagnostic test for LGMD2A in the Agarwals. Materials and Methods: The Agarwals with limb-girdle muscular dystrophy (LGMD) phenotype were analyzed for two founder alleles (intron 18/exon 19 c.2051-1G>T and exon 22 c.2338G>C). Asymptomatic first-degree relatives of patients with genetically confirmed mutations and desirous of counseling were screened for founder mutations. Results: Founder alleles were detected in 26 out of 29 subjects with LGMD phenotype (89%). The most common genotype observed was homozygous for exon 22 c.2338 G>C mutation followed by compound heterozygosity. Single founder allele was identified in two. Single allele was detected in two of the five asymptomatic relatives. Conclusion: Eighty-nine percent of the Agarwals having LGMD phenotype have LGMD2A resulting from founder mutations. Founder allele analysis can be utilized as the initial noninvasive diagnostic step for index cases, carrier detection, and counseling. PMID:27011640

  9. An Intracellular Ca2+ Channel is Required For Sarcolemma Repair to Prevent Muscular Dystrophy

    PubMed Central

    Cheng, Xiping; Zhang, Xiaoli; Gao, Qiong; Samie, Mohammad Ali; Azar, Marlene; Tsang, Wai Lok; Dong, Libing; Sahoo, Nirakar; Li, Xinran; Zhuo, Yue; Garrity, Abigail G.; Wang, Xiang; Ferrer, Marc; Dowling, James; Xu, Li; Han, Renzhi; Xu, Haoxing

    2014-01-01

    The integrity of the plasma membrane is maintained through an active repair process, especially for skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo1,2. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness3,4. An important cause of MD is defective repair of sarcolemmal injuries, and sarcolemma repair requires Ca2+ sensor proteins58 and Ca2+-dependent delivery of intracellular vesicles to injury sites5,8,9. TRPML1 (ML1) is an endosomal and lysosomal Ca2+ channel and its human mutations cause Mucolipidosis IV, a neurodegenerative disease with motor disabilities10,11. Here, we report that ML1-null mice develop a primary, early-onset muscular dystrophy independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are normally expressed, membrane resealing was defective in ML1-null muscle fibers or upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca2+ release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, we have identified an intracellular Ca2+ channel that regulates membrane repair in skeletal muscle via Ca2+-dependent vesicle exocytosis. PMID:25216637

  10. Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression.

    PubMed

    Tian, L J; Cao, J H; Deng, X Q; Zhang, C L; Qian, T; Song, X X; Huang, B S

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy with no cure currently available. In this study, using two microarray data sets obtained from the Gene Expression Omnibus database, we conducted a dysfunctional pathway-enrichment analysis and investigated deregulated genes that are specific to different phases of the disease in order to determine pathogenic characteristics in the progression of DMD. We identified 41 and 33 dysfunctional pathways that were enriched with differentially expressed genes in presymptomatic patients and in symptomatic patients, respectively. Over 70% of pathways were shared between both phases and many of them involved the inflammatory process, suggesting that inflammatory cascades were induced soon after the birth of the patients. Further investigation showed that presymptomatic patients performed better with respect to muscle regeneration and cardiac muscle calcium homeostasis maintenance. Neuronal nitric oxide synthase, dihydropyridine receptors, sarcoplasmic/endoplasmic reticulum calcium ATPase, and phospholamban may serve as potential targets for further molecular diagnostic tests. Our results may provide a better understanding for the treatment of DMD. PMID:24634239

  11. Corticosteroid Treatments in Males With Duchenne Muscular Dystrophy: Treatment Duration and Time to Loss of Ambulation.

    PubMed

    Kim, Sunkyung; Campbell, Kimberly A; Fox, Deborah J; Matthews, Dennis J; Valdez, Rodolfo

    2015-09-01

    This population-based study examines the association between corticosteroid treatment and time to loss of ambulation, stratifying by treatment duration (short: 0.25-3 years, long: >3 years), among 477 Duchenne muscular dystrophy cases identified by the Muscular Dystrophy Surveillance Tracking and Research Network (MDSTARnet). Those cases who received short-term corticosteroid treatment had a time to loss of ambulation that was 0.8 years shorter (t test) and an annual risk of losing ambulation 77% higher than the untreated (Cox regression). Conversely, cases who received long-term corticosteroid treatment had a time to loss of ambulation that was 2 years longer and an annual risk of losing ambulation 82% lower than the untreated, up to age 11 years; after which the risks were not statistically different. The relationship of corticosteroids and time to loss of ambulation is more complex than depicted by previous studies limited to treatment responders or subjects who lost ambulation during study follow-up. PMID:25414237

  12. [Sugammadex, efficacious in reversing a neuromuscular block in a woman with Becker muscular dystrophy].

    PubMed

    Glvez Caellas, J L; Errando, C L; Ordez Arana, A; Falc, E; Mazzinari, G; Robles, D; Vila Snchez, M

    2011-12-01

    Becker muscular dystrophy affects mainly the musculoskeletal system, causing muscle wasting and progressive weakness. A 61-year-old woman with breast cancer, who had been diagnosed with Becker muscular dystrophy 45 years earlier, was scheduled for right mastectomy. We induced general anesthesia with propofol, fentanyl, and a nondepolarizing muscle blocker (rocuronium). Neuromuscular function was monitored continuously by acceleromyographic train-of-four ratio (TOFr) (Watch-SX monitor). The block was reversed with sugammadex. After preoxygenation with fentanyl and propofol, the device was calibrated and the baseline TOFr was recorded. We injected 1 mg/kg of rocuronium and assessed TOF responses every 15 seconds. The maximum decrease in TOF response (to 0 twitches) was at 52 seconds. Tracheal intubation was uneventful. Anesthesia was maintained by intravenous infusion. The operation lasted 74 minutes. The second TOF twitch (T2) reappeared 86 minutes after the initial dose. After we injected 2 mg/kg of sugammadex, a TOFr of 0.7 was reached at 79 seconds; a TOFr of 0.9 was reached at 108 seconds and a TOFr of 1.0 at 152 seconds. No electrocardiographic or hemodynamic abnormalities occurred during sugammadex administration and there were no signs of residual neuromuscular blockade on awakening or adverse events in the following 24 hours. PMID:22263407

  13. Therapeutic potential of proteasome inhibition in Duchenne and Becker muscular dystrophies.

    PubMed

    Gazzerro, Elisabetta; Assereto, Stefania; Bonetto, Andrea; Sotgia, Federica; Scarfì, Sonia; Pistorio, Angela; Bonuccelli, Gloria; Cilli, Michele; Bruno, Claudio; Zara, Federico; Lisanti, Michael P; Minetti, Carlo

    2010-04-01

    Duchenne muscular dystrophy (DMD) and its milder allelic variant, Becker muscular dystrophy (BMD), result from mutations of the dystrophin gene and lead to progressive muscle deterioration. Enhanced activation of proteasomal degradation underlies critical steps in the pathogenesis of the DMD/BMD dystrophic process. Previously, we demonstrated that treatment with the proteasome inhibitor MG-132 rescues the cell membrane localization of dystrophin and the dystrophin glycoprotein complex in mdx mice, a natural genetic mouse model of DMD. The current work aims to thoroughly define the therapeutic potential in dystrophinopathies of Velcade, a drug that selectively blocks the ubiquitin-proteasome pathway. Velcade is particularly intriguing since it has been approved for the treatment of multiple myeloma. Therefore, its side effects in humans have been explored. Velcade effects were analyzed through two independent methodological approaches. First, we administered the drug systemically in mdx mice over a 2-week period. In this system, Velcade restores the membrane expression of dystrophin and dystrophin glycoprotein complex members and improves the dystrophic phenotype. In a second approach, we treated with the compound explants from muscle biopsies of DMD or BMD patients. We show that the inhibition of the proteasome pathway up-regulates dystrophin, alpha-sarcoglycan, and beta-dystroglycan protein levels in explants from BMD patients, whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases. PMID:20304949

  14. Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data?

    PubMed Central

    Cwik, Valerie A.; Marshall, Bruce C.; Ciafaloni, Emma; Wolff, Jodi M.; Getchius, Thomas S.; Griggs, Robert C.

    2013-01-01

    Objective: To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care. Methods: We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery. Results: Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival. Conclusions: CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD. PMID:23382369

  15. Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy

    PubMed Central

    Bello, Luca; Melacini, Paola; Pezzani, Raffaele; D'Amico, Adele; Piva, Luisa; Leonardi, Emanuela; Torella, Annalaura; Soraru, Gianni; Palmieri, Arianna; Smaniotto, Gessica; Gavassini, Bruno F; Vianello, Andrea; Nigro, Vincenzo; Bertini, Enrico; Angelini, Corrado; Tosatto, Silvio C E; Pegoraro, Elena

    2012-01-01

    Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in ?-dystroglycan (?-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent ?-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function. PMID:22549409

  16. Studying the role of dystrophin-associated proteins in influencing Becker muscular dystrophy disease severity.

    PubMed

    van den Bergen, J C; Wokke, B H A; Hulsker, M A; Verschuuren, J J G M; Aartsma-Rus, A M

    2015-03-01

    Becker muscular dystrophy is characterized by a variable disease course. Many factors have been implicated to contribute to this diversity, among which the expression of several components of the dystrophin associated glycoprotein complex. Together with dystrophin, most of these proteins anchor the muscle fiber cytoskeleton to the extracellular matrix, thus protecting the muscle from contraction induced injury, while nNOS is primarily involved in inducing vasodilation during muscle contraction, enabling adequate muscle oxygenation. In the current study, we investigated the role of three components of the dystrophin associated glycoprotein complex (beta-dystroglycan, gamma-sarcoglycan and nNOS) and the dystrophin homologue utrophin on disease severity in Becker patients. Strength measurements, data about disease course and fresh muscle biopsies of the anterior tibial muscle were obtained from 24 Becker patients aged 19 to 66. The designation of Becker muscular dystrophy in this study was based on the mutation and not on the clinical severity. Contrary to previous studies, we were unable to find a relationship between expression of nNOS, beta-dystroglycan and gamma-sarcoglycan at the sarcolemma and disease severity, as measured by muscle strength in five muscle groups and age at reaching several disease milestones. Unexpectedly, we found an inverse correlation between utrophin expression at the sarcolemma and age at reaching disease milestones. PMID:25633150

  17. Corticosteroid Treatments in Males With Duchenne Muscular Dystrophy: Treatment Duration and Time to Loss of Ambulation

    PubMed Central

    Kim, Sunkyung; Campbell, Kimberly A.; Fox, Deborah J.; Matthews, Dennis J.; Valdez, Rodolfo

    2015-01-01

    This population-based study examines the association between corticosteroid treatment and time to loss of ambulation, stratifying by treatment duration (short: 0.253 years, long: >3 years), among 477 Duchenne muscular dystrophy cases identified by the Muscular Dystrophy Surveillance Tracking and Research Network (MDSTARnet). Those cases who received short-term corticosteroid treatment had a time to loss of ambulation that was 0.8 years shorter (t test) and an annual risk of losing ambulation 77% higher than the untreated (Cox regression). Conversely, cases who received long-term corticosteroid treatment had a time to loss of ambulation that was 2 years longer and an annual risk of losing ambulation 82% lower than the untreated, up to age 11 years; after which the risks were not statistically different. The relationship of corticosteroids and time to loss of ambulation is more complex than depicted by previous studies limited to treatment responders or subjects who lost ambulation during study follow-up. PMID:25414237

  18. 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

  19. Skeletal Muscle Homeostasis in Duchenne Muscular Dystrophy: Modulating Autophagy as a Promising Therapeutic Strategy

    PubMed Central

    De Palma, Clara; Perrotta, Cristiana; Pellegrino, Paolo; Clementi, Emilio; Cervia, Davide

    2014-01-01

    Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting. PMID:25104934

  20. [Successful perioperative management with non-invasive positive pressure ventilation in muscular dystrophy with thymoma; report of a case].

    PubMed

    Motono, N; Aoki, T; Shimada, K; Nakayama, T; Yazawa, M

    2008-09-01

    We report a case of muscular dystrophy with thymoma that was detected by chance at the examination of his fatal arrhythmia. He has hypercapnea and restrictive pulmonary disfunction, but non-invasive positive pressure ventilation (NPPV) had not been introduced. Thymo-thymectomy was performed through reversed L-shaped mediansternotomy. NPPV was effective in his perioperative management. PMID:18788386

  1. Tl-201 myocardial SPECT in patients with Duchenne's muscular dystrophy: A long-term follow-up

    SciTech Connect

    Nagamachi, S.; Jinnouchi, S.; Ono, S.; Hoshi, H.; Inoue, K.; Watanabe, K. )

    1989-11-01

    Tl-201 SPECT was used to evaluate myocardial involvement in 13 patients with Duchenne's muscular dystrophy. Serial studies of 9 patients were done at two-year intervals. The hypoperfused areas of the left ventricle became more prominent with age and severity.

  2. Functional Behavioral Assessment for a Boy with Duchenne Muscular Dystrophy and Problem Behavior: A Case Study from Greece

    ERIC Educational Resources Information Center

    Theodoridou, Zoe; Koutsoklenis, Athanasios

    2013-01-01

    This article focuses on the application of functional behavioral assessment (FBA) to design a positive behavior intervention (PBI) for a boy with Duchenne muscular dystrophy (DMD) who encounters serious difficulties at the mainstream school because of behavioral problems and physical limitations. After the definition of problem behavior and its…

  3. A Splice Site Mutation in Laminin-?2 Results in a Severe Muscular Dystrophy and Growth Abnormalities in Zebrafish

    PubMed Central

    Gupta, Vandana A.; Kawahara, Genri; Myers, Jennifer A.; Chen, Aye T.; Hall, Thomas E.; Manzini, M. Chiara; Currie, Peter D.; Zhou, Yi; Zon, Leonard I.; Kunkel, Louis M.; Beggs, Alan H.

    2012-01-01

    Congenital muscular dystrophy (CMD) is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A) is a form of CMD caused by a defect in the laminin-?2 gene (LAMA2). Laminin-?2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC) complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 815 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-?2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-?2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD. PMID:22952766

  4. Age-Dependent Effect of Myostatin Blockade on Disease Severity in a Murine Model of Limb-Girdle Muscular Dystrophy

    PubMed Central

    Parsons, Stephanie A.; Millay, Douglas P.; Sargent, Michelle A.; McNally, Elizabeth M.; Molkentin, Jeffery D.

    2006-01-01

    Myostatin (MSTN) is a muscle-specific secreted peptide that functions to limit muscle growth through an autocrine regulatory feedback loop. Loss of MSTN activity in cattle, mice, and humans leads to a profound phenotype of muscle overgrowth, associated with more and larger fibers and enhanced regenerative capacity. Deletion of MSTN in the mdx mouse model of Duchenne muscular dystrophy enhances muscle mass and reduces disease severity. In contrast, loss of MSTN activity in the dyW/dyW mouse model of laminin-deficient congenital muscular dystrophy, a much more severe and lethal disease model, does not improve all aspects of muscle pathology. Here we examined disease severity associated with myostatin (mstn?/?) deletion in mice nullizygous for ?-sarcoglycan (scgd?/?), a model of limb-girdle muscular dystrophy. Early loss of MSTN activity achieved either by monoclonal antibody administration or by gene deletion each improved muscle mass, regeneration, and reduced fibrosis in scgd?/? mice. However, antibody-mediated inhibition of MSTN in late-stage dystrophic scgd?/? mice did not improve disease. These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition in severely affected or late-stage disease may be ineffective. PMID:16723712

  5. A 2009 perspective on the 2004 American Thoracic Society statement, "respiratory care of the patient with Duchenne muscular dystrophy".

    PubMed

    Finder, Jonathan D

    2009-05-01

    This is a summary of the presentation "A 2009 Perspective on the 2004 American Thoracic Society Statement, 'Respiratory Care of the Patient With Duchenne Muscular Dystrophy,'" presented as part of the program on pulmonary management of pediatric patients with neuromuscular disorders at the 30th annual Carrell-Krusen Neuromuscular Symposium on February 20, 2008. PMID:19420152

  6. Functional Behavioral Assessment for a Boy with Duchenne Muscular Dystrophy and Problem Behavior: A Case Study from Greece

    ERIC Educational Resources Information Center

    Theodoridou, Zoe; Koutsoklenis, Athanasios

    2013-01-01

    This article focuses on the application of functional behavioral assessment (FBA) to design a positive behavior intervention (PBI) for a boy with Duchenne muscular dystrophy (DMD) who encounters serious difficulties at the mainstream school because of behavioral problems and physical limitations. After the definition of problem behavior and its

  7. Motor and Cognitive Assessment of Infants and Young Boys with Duchenne Muscular Dystrophy; Results from the Muscular Dystrophy Association DMD Clinical Research Network

    PubMed Central

    Connolly, Anne M.; Florence, Julaine M.; Cradock, Mary M.; Malkus, Elizabeth C.; Schierbecker, Jeanine R.; Siener, Catherine A.; Wulf, Charlie O.; Anand, Pallavi; Golumbek, Paul T.; Zaidman, Craig M; Miller, J Philip; Lowes, Linda P; Alfano, Lindsay N.; Viollet-Callendret, Laurence; Flanigan, Kevin M.; Mendell, Jerry R.; McDonald, Craig M.; Goude, Erica; Johnson, Linda; Nicorici, Alina; Karachunski, Peter I.; Day, John W.; Dalton, Joline C.; Farber, Janey M.; Buser, Karen K.; Darras, Basil T.; Kang, Peter B.; Riley, Susan O.; Shriber, Elizabeth; Parad, Rebecca; Bushby, Kate; Eagle, Michelle

    2013-01-01

    Therapeutic trials in Duchenne Muscular dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley-III Scales of Infant and Toddler Development (Bayley-III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n=24; 1.9±0.7 years) were assessed. The mean Bayley-III motor composite score was low (82.8 ± 8; p=<.0001)(normal=100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p=<.0001). The mean cognitive comprehensive (p=.0002), receptive language (p=<.0001), and expressive language (p=.0001) were also low compared to normal children. Age was negatively associated with Bayley-III gross motor (r=−0.44 p=.02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n =18 boys; 2.2 ± 0.4years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley-III. PMID:23726376

  8. Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin ?2 Chain-Deficient Muscular Dystrophy.

    PubMed

    Krner, Zandra; Durbeej, Madeleine

    2016-01-01

    Congenital muscular dystrophy with laminin ?2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin ?2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin ?2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin ?2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin ?2 chain. PMID:26731667

  9. Bortezomib Does Not Reduce Muscular Dystrophy in the dy2J/dy2J Mouse Model of Laminin ?2 Chain-Deficient Muscular Dystrophy

    PubMed Central

    Krner, Zandra; Durbeej, Madeleine

    2016-01-01

    Congenital muscular dystrophy with laminin ?2 chain-deficiency, also known as MDC1A, is a severe neuromuscular disorder for which there is no cure. Patients with complete laminin ?2 chain-deficiency typically have an early onset disease with a more severe muscle phenotype while patients with residual laminin ?2 chain expression usually have a milder disease course. Similar genotype-phenotype correlations can be seen in the dy3K/dy3K and dy2J/dy2J mouse models of MDC1A, respectively, with dy3K/dy3K mice presenting the more severe phenotype. Recently, we demonstrated that the proteasome inhibitor bortezomib partially improves muscle morphology and increases lifespan in dy3K/dy3K mice. Here, we explore the use of bortezomib in dy2J/dy2J animals. However, bortezomib neither improved histological hallmarks of disease nor increased muscle strength and locomotive activity in dy2J/dy2J mice. Altogether our data suggest that proteasome inhibition does not mitigate muscle dysfunction caused by partial laminin ?2 chain-deficiency. Still, it is possible that proteasome inhibition could be useful as a supportive therapy in patients with complete absence of laminin ?2 chain. PMID:26731667

  10. The seventh form of autosomal recessive limb-girdle muscular dystrophy is mapped to 17q11-12.

    PubMed Central

    Moreira, E S; Vainzof, M; Marie, S K; Serti, A L; Zatz, M; Passos-Bueno, M R

    1997-01-01

    The group of autosomal recessive (AR) muscular dystrophies includes, among others, two main clinical entities, the limb-girdle muscular dystrophies (LGMDs) and the distal muscular dystrophies. The former are characterized mainly by muscle wasting of the upper and lower limbs, with a wide range of clinical severity. This clinical heterogeneity has been demonstrated at the molecular level, since the genes for six AR forms have been cloned and/or have been mapped to 15q15.1 (LGMD2A), 2p12-16 (LGMD2B), 13q12 (LGMD2C), 17q12-q21.33 (LGMD2D),4q12 (LGMD2E), and 5q33-34 (LGMD2F). The AR distal muscular dystrophies originally included two subgroups, Miyoshi myopathy, characterized mainly by extremely elevated serum creatine kinase (CK) activity and by a dystrophic muscle pattern, and Nonaka myopathy, which is distinct from the others because of the normal to slightly elevated serum CK levels and a myopathic muscle pattern with rimmed vacuoles. With regard to our unclassified AR LGMD families, analysis of the affected sibs from one of them (family LG61) revealed some clinical and laboratory findings (early involvement of the distal muscles, mildly elevated serum CK levels, and rimmed vacuoles in muscle biopsies) that usually are not observed in the analysis of patients with LGMD2A-LGMD2F. In the present investigation, through a genomewide search in family LG61, we demonstrated linkage of the allele causing this form of muscular dystrophy to a 3-cM region on 17q11-12. We suggest that this form, which, interestingly, clinically resembles AR Kugelberg-Welander disease, should be classified as LGMD2G. In addition, our results indicate the existence of still another locus causing severe LGMD. Images Figure 1 PMID:9245996

  11. Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis

    SciTech Connect

    Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K.

    2011-04-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin{sup -/-} (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of mpcs, the EOMCD34 cells, that are retained in significantly higher percentages in normal, mdx and DKO mice EOM, appear to be resistant to elevated levels of oxidative stress and toxins, and actively proliferate throughout life. Current studies are focused on further defining the EOMCD34 cell subtype molecularly, with the hopes that this may shed light on a cell type with potential therapeutic use in patients with sarcopenia, cachexia, or muscular dystrophy.

  12. Muscular Dystrophy

    MedlinePLUS

    ... A blood test can measure levels of serum creatine kinase , an enzyme that's released into the bloodstream when muscle fibers are breaking down. When serum creatine kinase levels are high, that indicates something is ...

  13. Muscular Dystrophy

    MedlinePLUS

    ... to improve mobility a ventilator to support breathing robotics to help perform routine daily tasks Physical Therapy ... to meet their needs as muscle deterioration advances. Robotic technologies also are under development to help kids ...

  14. α7β1 Integrin Does Not Alleviate Disease in a Mouse Model of Limb Girdle Muscular Dystrophy Type 2F

    PubMed Central

    Milner, Derek J.; Kaufman, Stephen J.

    2007-01-01

    Transgenic expression of the α7β1 integrin in the dystrophic mdx/utr−/− mouse decreases development of muscular dystrophy and enhances longevity. To explore the possibility that elevating α7β1 integrin expression could also ameliorate different forms of muscular dystrophy, we used transgenic technology to enhance integrin expression in mice lacking δ-sarcoglycan (δ sgc), a mouse model for human limb girdle muscular dystrophy type 2F. Unlike α7 transgenic mdx/utr−/− mice, enhanced α7β1 integrin expression in the δ sgc-null mouse did not alleviate muscular dystrophy in these animals. Expression of the transgene in the δ sgc-null did not alleviate dystrophic histopathology, nor did it decrease cardiomyopathy or restore exercise tolerance. One hallmark of integrin-mediated alleviation of muscular dystrophy in the mdx/utr−/− background is the restoration of myotendinous junction integrity. As assessed by atomic force microscopy, myotendinous junctions from normal and δ sgc-null mice were indistinguishable, thus suggesting the important influence of myotendinous junction integrity on the severity of muscular dystrophy and providing a possible explanation for the inability of enhanced integrin expression to alleviate dystrophy in the δ sgc-null mouse. These results suggest that distinct mechanisms underlie the development of the diseases that arise from deficiencies in dystrophin and sarcoglycan. PMID:17255329

  15. Limb-girdle muscular dystrophy type 2A in Brazilian children.

    PubMed

    Albuquerque, Marco Antnio Veloso de; Abath Neto, Osrio; Silva, Francisco Marcos Alencar da; Zanoteli, Edmar; Reed, Umbertina Conti

    2015-12-01

    Calpainopathy is an autosomal recessive limb girdle muscular dystrophy (LGMD2A) caused by mutations in CAPN3 gene. Objective To present clinical and histological findings in six children with a molecular diagnosis of LGMD2A and additionally the MRI findings in two of them. Method We retrospectively assessed medical records of 6 patients with mutation on CAPN3 gene. Results All patients were female (three to 12 years). The mean of age of disease onset was 9 years. All of them showed progressive weakness with predominance in lower limbs. Other findings were scapular winging, joint contractures and calf hypertrophy. One female had a more severe phenotype than her dizygotic twin sister that was confirmed by muscle MRI. Muscle biopsies showed a dystrophic pattern in all patients. Conclusion In this cohort of children with LGMD2A, the clinical aspects were similar to adults with the same disorder. PMID:26677118

  16. Deletion screening of the Duchenne muscular dystrophy locus via multiplex DNA amplification.

    PubMed

    Chamberlain, J S; Gibbs, R A; Ranier, J E; Nguyen, P N; Caskey, C T

    1988-12-01

    The application of recombinant DNA technology to prenatal diagnosis of many recessively inherited X-linked diseases is complicated by a high frequency of heterogeneous, new mutations (1). Partial gene deletions account for more than 50% of Duchenne muscular dystrophy (DMD) lesions, and approximately one-third of all cases result from a new mutation (2-5). We report the isolation and DNA sequence of several deletion prone exons from the human DMD gene. We also describe a rapid method capable of detecting the majority of deletions in the DMD gene. This procedure utilizes simultaneous genomic DNA amplification of multiple widely separated sequences and should permit deletion scanning at any hemizygous locus. We demonstrate the application of this multiplex reaction for prenatal and postnatal diagnosis of DMD. PMID:3205741

  17. Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: Deletion detection and familial diagnosis

    SciTech Connect

    Patino, A.; Garcia-Delgado, M.; Narbona, J.

    1995-11-06

    Deletion studies were performed in 26 Duchenne muscular dystrophy (DMD) patients through amplification of nine different exons by multiplex polymerase chain reaction (PCR). DNA from paraffin-embedded muscle biopsies was analyzed in 12 of the 26 patients studied. Optimization of this technique is of great utility because it enables analysis of material stored in pathology archives. PCR deletion detection, useful in DMD-affected boys, is problematic in determining the carrier state in female relatives. For this reason, to perform familial linkage diagnosis, we made use of a dinucleotide repeat polymorphism (STRP, or short tandem repeat polymorphism) located in intron 49 of the gene. We designed a new pair of primers that enabled the detection of 22 different alleles in relatives in the 14 DMD families studied. The use of this marker allowed familial diagnosis in 11 of the 14 DMD families and detection of de novo deletions in 3 of the probands. 8 refs., 5 figs., 2 tabs.

  18. 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.

  19. Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family

    SciTech Connect

    Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P.; Russo, L.S.; Riconda, D.L.

    1994-02-01

    Two male cousins with Duchenne muscular dystrophy were found to have different maternal dystrophin gene haplotypes and different deletion mutations. One propositus showed two noncontiguous deletions-one in the 5{prime}, proximal deletional hotspot region, and the other in the 3{prime}, more distal deletional hotspot region. The second propositus showed only the 5{prime} deletion. Using multiple fluorescent exon dosage and fluorescent multiplex CA repeat linkage analyses, the authors show that the mother of each propositus carries both deletions on the same grandmaternal X chromosome. This paradox is explained by a single recombinational event between the 2 deleted regions of one of the carrier`s dystrophin genes, giving rise to a son with a partially {open_quotes}repaired{close_quotes} gene retaining only the 5{prime} deletion. 20 refs., 4 figs.

  20. Dystrophin, utrophin and {beta}-dystroglycan expression in skeletal muscle from patients with Becker muscular dystrophy

    SciTech Connect

    Kawajiri, Masakazu; Mitsui, Takao; Kawai, Hisaomi

    1996-08-01

    The precise localization and semiquantitative correlation of dystrophin, utrophin and {beta}-dystroglycan expression on the sarcolemma of skeletal muscle cells obtained from patients with Becker muscular dystrophy (BMD) was studied using three types of double immunofluorescence. Staining intensity was measured using a confocal laser microscope. Each of these proteins was identified at the same locus on the sarcolemma. The staining intensities of dystrophin and utrophin were approximately reciprocal at sarcolemmal sites where dystrophin expression was obviously observed. The staining intensity of {beta}-dystroglycan was strong in areas where dystrophin staining was also strong and utrophin expression was weak. Quantitative analysis revealed that the staining intensity of {beta}-dystroglycan minus that of dystrophin approximated the staining intensity of utrophin, indicating that the sum of dystrophin and utrophin expression corresponds to that of {beta}-dystroglycan. These results suggest that utrophin may compensate for dystrophin deficiency found in BMD by binding to {beta}-dystroglycan. 35 refs., 3 figs., 1 tab.

  1. Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family

    SciTech Connect

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

    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 suggest 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.

  2. Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy

    SciTech Connect

    Speer, M.C.; Stajich, J.M.; Gaskell, P.C.

    1995-12-01

    Limb-girdle muscular dystrophy (LGMD) is a diagnostic classification encompassing a broad group of proximal myopathies. A gene for the dominant form of LGMD (LGMD1A) has recently been localized to a 7-cM region of chromosome 5q between D5S178 and IL9. We studied three additional dominant LGMD families for linkage to these two markers and excluded all from localization to this region, providing evidence for locus heterogeneity within the dominant form of LGMD. Although the patterns of muscle weakness were similar in all families studied, the majority of affected family members in the chromosome 5-linked pedigree have a dysarthric speech pattern, which is not present in any of the five unlinked families. The demonstration of heterogeneity within autosomal dominant LGMD is the first step in attempting to subclassify these families with similar clinical phenotypes on a molecular level. 33 refs., 1 fig., 2 tabs.

  3. Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient

    PubMed Central

    Greer, Kane; Mizzi, Kayla; Rice, Emily; Kuster, Lukas; Barrero, Roberto A; Bellgard, Matthew I; Lynch, Bryan J; Foley, Aileen Reghan; O Rathallaigh, Eoin; Wilton, Steve D; Fletcher, Sue

    2015-01-01

    We report a dystrophinopathy patient with an in-frame deletion of DMD exons 4547, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We characterized the deletion breakpoints and identified motifs that might influence selection of the pseudoexon. We concluded that the donor splice site was strengthened by juxtaposition of intron 47, and loss of intron 44 silencer elements, normally located downstream of the pseudoexon donor splice site, further enhanced pseudoexon selection and inclusion in the DMD transcript in this patient. PMID:26247048

  4. Endpoint measures in the mdx mouse relevant for muscular dystrophy pre-clinical studies

    PubMed Central

    Kobayashi, Yvonne M.; Rader, Erik P.; Crawford, Robert W.; Campbell, Kevin P.

    2011-01-01

    Loss of mobility influences the quality of life for patients with neuromuscular diseases. Common measures of mobility and chronic muscle damage are the six-minute walk test and serum creatine kinase. Despite extensive pre-clinical studies of therapeutic approaches, characterization of these measures is incomplete. To address this, a six-minute ambulation assay, serum creatine kinase, and myoglobinuria were investigated for the mdx mouse, a dystrophinopathy mouse model commonly used in pre-clinical studies. Mdx mice ambulated shorter distances than normal controls, a disparity accentuated after mild exercise. An asymmetric pathophysiology in mdx mice was unmasked with exercise, and peak measurements of serum creatine kinase and myoglobinuria were identified. Our data highlights the necessity to consider asymmetric pathology and timing of biomarkers when testing potential therapies for muscular dystrophy. PMID:22154712

  5. [Being a mother: encounters between mothers of children with Duchenne muscular dystrophy and nurses in Taiwan].

    PubMed

    Lee, Shu-Li; Chou, Fan-Hao; Chin, Chi-Chun

    2013-06-01

    The role of "mother" is understood and represented differently by people from different cultures. In traditional Taiwanese society, mothers demonstrate their existence value by giving birth to and raising sons able to continue her husband's familial line. Sons bear the patriarchal name and care for their parents in old age. However, a son stricken, paralyzed and eventually killed by Duchenne muscular dystrophy (DMD) can destroy a mother's perceived value in this traditional social context. Mothers are thus soundless sufferers. Nurses have a critical role to play in giving encouragement and hope to mothers of children with DMD. Through their own difficult situation, these mothers can also highlight the value and importance of Taiwan's nurses, who work in conditions marked by overloading, high stress, and under-appreciation. Caring for women in critical need of empathy and support help nurses realize their own positive capacity to empower sufferers. PMID:23729346

  6. Prevalence and psychosocial impact of lower urinary tract symptoms in patients with Duchenne muscular dystrophy.

    PubMed

    van Wijk, Evaline; Messelink, Bert J; Heijnen, Lily; de Groot, Imelda J M

    2009-11-01

    Patients with Duchenne muscular dystrophy (DMD) frequently report lower urinary tract symptoms at the outpatient rehabilitation clinic. The purpose of this study was to determine the prevalence of lower urinary tract symptoms in the Dutch male DMD population and their effect on quality of life. A postal questionnaire was sent to members of Dutch DMD patient organisations. 199 male patients with confirmed DMD and over the age of 3years were included. 170/199 (85%) patients reported one or more lower urinary tract symptoms. Generally, post micturition dribble, straining and feeling of incomplete emptying were most frequently mentioned. 42% of patients (range 18-76%) experienced the symptoms as a problem. In 49/170 (29%) patients, it reduced quality of life. In conclusion, lower urinary tract symptoms in DMD patients are under reported and under diagnosed. However, the vast majority of male DMD patients with symptoms experience them as a problem, often reducing quality of life. PMID:19853790

  7. Acute gastric dilatation in Duchenne muscular dystrophy: a case report and review of the literature.

    PubMed

    Bensen, E S; Jaffe, K M; Tarr, P I

    1996-05-01

    Duchenne muscular dystrophy (DMD) is the most common neuromuscular disorder of childhood. Its clinical characteristics that derive from skeletal muscle involvement have been well described. Less well known is that visceral smooth muscle is affected in DMD. We report a case of a 19-year-old man with DMD who presented with severe nonradiating epigastric pain. He was initially sent home from the emergency department with a diagnosis of costochondritis. Acute gastric dilation was not considered in the differential diagnosis despite supportive history, physical examination findings, and radiographs. The case illustrates the lack of familiarity by clinicians of the gastrointestinal manifestations of DMD, including gastric dilatation and intestinal pseudoobstruction. Following a case discussion, the literature relevant to acute gastric atony is reviewed. PMID:8629931

  8. Psychological Aspects in Children Affected by Duchenne De Boulogne Muscular Dystrophy

    PubMed Central

    Parisi, Lucia; Roccella, Michele

    2014-01-01

    Impairment of intelligence in Duchenne muscular dystrophy (DMD) patients was described by Duchenne de Boulogne himself in 1868. Further studies report intelligence disorders with mayor impairment of memory. The aim of the present study was to assess the presence of affective and personality disorders in a group of children affected by DMD. Twenty six male DMD patients, mean age eleven and four months years old, were assessed for their affective and personality disorder. Only eight subjects had a total IQ below average with major difficulties in verbal and visual-spatial memory, comprehension, arithmetic and vocabulary. All the subjects presented some disorders: tendency to marginalization and isolation, self-depreciation, sense of insecurity, hypochondriac thoughts and marked state of anxiety. These disorders are often a dynamic prolongation of a psychological process which starts when the diagnosis is made and continues, in a slow and latent fashion, throughout the evolution of the disease. PMID:25478112

  9. [Prenatal diagnosis of Duchenne and Becker muscular dystrophy by multiplex ligation-dependent probe amplification].

    PubMed

    Wang, Qian; Jin, Chun-Lian; Lin, Chang-Kun; Cui, Wan-Ting; Ma, Hong-Wei; Wu, Ying-Yu

    2009-06-01

    Duchenne/Becker muscular dystrophy (DMD/BMD) is an X-linked lethal recessive disease caused by mutation in the DMD gene. There is no efficient treatment for this serious and disabling disease. We established a combination method to detect carriers and performed prenatal diagnosis. Using multiplex ligation-dependent probe amplification (MLPA) and linkage analysis of short tandem repeats (STR) methods, 26 prenatal diagnosis were performed for pregnancies at risk of having a DMD/BMD baby through amniocentesis. Seven out of 26 male fetuses were affected and the pregnancies were terminated. Four out of 26 female fetuses were found to be carriers. MLPA can be the method of choice for initial screening of DMD/BMD patients for deletions and duplications mutations. When combined with STR-based analysis, it can improve the rate of DMD/BMD prenatal diagnosis. PMID:19586859

  10. Cultured muscle from myotonic muscular dystrophy patients: altered membrane electrical properties.

    PubMed Central

    Merickel, M; Gray, R; Chauvin, P; Appel, S

    1981-01-01

    Myotonic muscular dystrophy (MyD) is an inherited human disease involving skeletal muscle as well as many other organ systems. We have approached the study of this disorder by growing normal and diseased human muscle in a primary tissue culture system and investigating some of the electrical properties of the resulting myotubes. The most distinctive abnormality noted in MyD myotubes was an increased tendency to fire repetitive action potentials. A decreased action potential afterhyperpolarization amplitude and the presence of depolarizing afterpotentials were also noted, as were a decreased resting membrane potential, decreased action potential amplitude and overshoot, and decreased outward-going rectification. Although the ionic basis of these abnormal properties in vitro is not clearly defined, changes in the slow outward-going potassium current offer the best explanation. Furthermore, MyD cell culture offers a valuable model for critical analysis of the molecular mechanisms underlying MyD deficits. Images PMID:6941262

  11. Amelioration of laminin-?2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin

    PubMed Central

    Qiao, Chunping; Li, Jianbin; Zhu, Tong; Draviam, Romesh; Watkins, Simon; Ye, Xiaojing; Chen, Chunlian; Li, Juan; Xiao, Xiao

    2005-01-01

    Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-?2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-?2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD. PMID:16103356

  12. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy.

    PubMed

    Long, Chengzu; Amoasii, Leonela; Mireault, Alex A; McAnally, John R; Li, Hui; Sanchez-Ortiz, Efrain; Bhattacharyya, Samadrita; Shelton, John M; Bassel-Duby, Rhonda; Olson, Eric N

    2016-01-22

    CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associated virus-9 (AAV9) to deliver gene-editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intraperitoneal at postnatal day 1 (P1), intramuscular at P12, and retro-orbital at P18. Each of these methods restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees, and expression increased from 3 to 12 weeks after injection. Postnatal gene editing also enhanced skeletal muscle function, as measured by grip strength tests 4 weeks after injection. This method provides a potential means of correcting mutations responsible for DMD and other monogenic disorders after birth. PMID:26721683

  13. Positive effects of bisphosphonates on bone and muscle in a mouse model of Duchenne muscular dystrophy.

    PubMed

    Yoon, Sung-Hee; Sugamori, Kim S; Grynpas, Marc D; Mitchell, Jane

    2016-01-01

    Patients with Duchenne muscular dystrophy are at increased risk of decreased bone mineral density and bone fracture as a result of inactivity. To determine if antiresorptive bisphosphonates could improve bone quality and their effects on muscle we studied the Mdx mouse, treated with pamidronate during peak bone growth at 5 and 6 weeks of age, and examined the outcome at 13 weeks of age. Pamidronate increased cortical bone architecture and strength in femurs with increased resistance to fracture. While overall long bone growth was not affected by pamidronate, there was significant inhibition of remodeling in metaphyseal trabecular bone with evidence of residual calcified cartilage. Pamidronate treatment had positive effects on skeletal muscle in the Mdx mice with decreased serum and muscle creatine kinase and evidence of improved muscle histology and grip strength. PMID:26494410

  14. Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy.

    PubMed

    Chal, Jrome; Oginuma, Masayuki; Al Tanoury, Ziad; Gobert, Bndicte; Sumara, Olga; Hick, Aurore; Bousson, Fanny; Zidouni, Yasmine; Mursch, Caroline; Moncuquet, Philippe; Tassy, Olivier; Vincent, Stphane; Miyanari, Ayako; Bera, Agata; Garnier, Jean-Marie; Guevara, Getzabel; Hestin, Marie; Kennedy, Leif; Hayashi, Shinichiro; Drayton, Bernadette; Cherrier, Thomas; Gayraud-Morel, Barbara; Gussoni, Emanuela; Relaix, Frdric; Tajbakhsh, Shahragim; Pourqui, Olivier

    2015-09-01

    During embryonic development, skeletal muscles arise from somites, which derive from the presomitic mesoderm (PSM). Using PSM development as a guide, we establish conditions for the differentiation of monolayer cultures of mouse embryonic stem (ES) cells into PSM-like cells without the introduction of transgenes or cell sorting. We show that primary and secondary skeletal myogenesis can be recapitulated in vitro from the PSM-like cells, providing an efficient, serum-free protocol for the generation of striated, contractile fibers from mouse and human pluripotent cells. The mouse ES cells also differentiate into Pax7(+) cells with satellite cell characteristics, including the ability to form dystrophin(+) fibers when grafted into muscles of dystrophin-deficient mdx mice, a model of Duchenne muscular dystrophy (DMD). Fibers derived from ES cells of mdx mice exhibit an abnormal branched phenotype resembling that described in vivo, thus providing an attractive model to study the origin of the pathological defects associated with DMD. PMID:26237517

  15. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy

    PubMed Central

    Long, Chengzu; Amoasii, Leonela; Mireault, Alex A.; McAnally, John R.; Li, Hui; Sanchez-Ortiz, Efrain; Bhattacharyya, Samadrita; Shelton, John M.; Bassel-Duby, Rhonda; Olson, Eric N.

    2016-01-01

    CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associated virus9 (AAV9) to deliver gene-editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intraperitoneal at postnatal day 1 (P1), intramuscular at P12, and retro-orbital at P18. Each of these methods restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees, and expression increased from 3 to 12 weeks after injection. Postnatal gene editing also enhanced skeletal muscle function, as measured by grip strength tests 4 weeks after injection. This method provides a potential means of correcting mutations responsible for DMD and other monogenic disorders after birth. PMID:26721683

  16. Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents

    PubMed Central

    Wilton, Steve D; Fletcher, Sue

    2011-01-01

    The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD) was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms. PMID:23776365

  17. Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy

    PubMed Central

    Mankodi, Ami; Wheeler, Thurman M.; Shetty, Reena; Salceies, Kelly M.; Becher, Mark W.; Thornton, Charles A.

    2011-01-01

    The genetic basis of oculopharyngeal muscular dystrophy (OPMD) is a short expansion of a polyalanine tract (normal allele: 10 alanines, mutant allele: 1117 alanines) in the nuclear polyadenylate binding protein PABPN1 which is essential for controlling poly(A) tail length in messenger RNA. Mutant PABPN1 forms nuclear inclusions in OPMD muscle. To investigate the pathogenic role of mutant PABPN1 in vivo, we generated a ligand-inducible transgenic mouse model by using the mifepristone-inducible gene expression system. Induction of ubiquitous expression of mutant PABPN1 resulted in skeletal and cardiac myopathy. Histological changes of degenerative myopathy were preceded by nuclear inclusions of insoluble PABPN1. Downregulation of mutant PABPN1 expression attenuated the myopathy and reduced the nuclear burden of insoluble PABPN1. These results support association between mutant PABPN1 accumulation and degenerative myopathy in mice. Resolution of myopathy in mice suggests that the disease process in OPMD patients may be treatable. PMID:21964252

  18. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.

    PubMed

    Nelson, Christopher E; Hakim, Chady H; Ousterout, David G; Thakore, Pratiksha I; Moreb, Eirik A; Castellanos Rivera, Ruth M; Madhavan, Sarina; Pan, Xiufang; Ran, F Ann; Yan, Winston X; Asokan, Aravind; Zhang, Feng; Duan, Dongsheng; Gersbach, Charles A

    2016-01-22

    Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR-Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR-Cas9-based genome editing as a potential therapy to treat DMD. PMID:26721684

  19. A randomized comparative study of two methods for controlling Tendo Achilles contracture in Duchenne muscular dystrophy.

    PubMed

    Hyde, S A; Fl?ytrup, I; Glent, S; Kroksmark, A K; Salling, B; Steffensen, B F; Werlauff, U; Erlandsen, M

    2000-06-01

    A 30-month prospective randomized study of 27 Scandinavian boys with confirmed diagnosis of Duchenne muscular dystrophy was done to compare the effect of passive stretching combined with the use of night splints (group A) or passive stretching (group B) on the evolution of Tendo Achilles contractures. Assessments were based on the methodology of Scott et al. (Muscle Nerve 1982;5:291-301)Analysis of the pattern and mechanism of dropout was done to eliminate bias between the two groups. Logistic regression showed that Tendo Achilles contracture was the most important variable (P=0.0020) for dropout. Methods of statistical analysis for longitudinal data avoiding induced serial correlations were used in the analysis. The expected annual change in Tendo Achilles contracture was found to be 23% less in group A than in group B after equalization for total muscle strength (%MRC). PMID:10838252

  20. Psychological aspects in children affected by duchenne de boulogne muscular dystrophy.

    PubMed

    Filippo, Teresa Di; Parisi, Lucia; Roccella, Michele

    2012-07-26

    Impairment of intelligence in Duchenne muscular dystrophy (DMD) patients was described by Duchenne de Boulogne himself in 1868. Further studies report intelligence disorders with mayor impairment of memory. The aim of the present study was to assess the presence of affective and personality disorders in a group of children affected by DMD. Twenty six male DMD patients, mean age eleven and four months years old, were assessed for their affective and personality disorder. Only eight subjects had a total IQ below average with major difficulties in verbal and visual-spatial memory, comprehension, arithmetic and vocabulary. All the subjects presented some disorders: tendency to marginalization and isolation, self-depreciation, sense of insecurity, hypochondriac thoughts and marked state of anxiety. These disorders are often a dynamic prolongation of a psychological process which starts when the diagnosis is made and continues, in a slow and latent fashion, throughout the evolution of the disease. PMID:25478112

  1. Regenerative pharmacology in the treatment of genetic diseases: The paradigm of muscular dystrophy

    PubMed Central

    Mozzetta, Chiara; Minetti, Giulia; Puri, Pier Lorenzo

    2009-01-01

    Current evidence supports the therapeutic potential of pharmacological interventions that counter the progression of genetic disorders by promoting regeneration of the affected organs or tissues. The rationale behind this concept lies on the evidence that targeting key events downstream of the genetic defect can compensate, at least partially, the pathological consequence of the related disease. In this regard, the beneficial effect exerted on animal models of muscular dystrophy by pharmacological strategies that enhance muscle regeneration provides an interesting paradigm. In this review, we describe and discuss the potential targets of pharmacological strategies that promote regeneration of dystrophic muscles and alleviate the consequence of the primary genetic defect. Regenerative pharmacology provides an immediate and suitable therapeutic opportunity to slow down the decline of muscles in the present generation of dystrophic patients, with the perspective to hold them in conditions such that they could benefit of future, more definitive, therapies. PMID:18804548

  2. Myogenic Differentiation of Muscular Dystrophy-Specific Induced Pluripotent Stem Cells for Use in Drug Discovery

    PubMed Central

    Abujarour, Ramzey; Bennett, Monica; Valamehr, Bahram; Lee, Tom Tong; Robinson, Megan; Robbins, David; Le, Thuy; Lai, Kevin

    2014-01-01

    Human induced pluripotent stem cells (iPSCs) represent a scalable source of potentially any cell type for disease modeling and therapeutic screening. We have a particular interest in modeling skeletal muscle from various genetic backgrounds; however, efficient and reproducible methods for the myogenic differentiation of iPSCs have not previously been demonstrated. Ectopic myogenic differentiation 1 (MyoD) expression has been shown to induce myogenesis in primary cell types, but the same effect has been unexpectedly challenging to reproduce in human iPSCs. In this study, we report that optimization of culture conditions enabled direct MyoD-mediated differentiation of iPSCs into myoblasts without the need for an intermediate step or cell sorting. MyoD induction mediated efficient cell fusion of mature myocytes yielding multinucleated myosin heavy chain-positive myotubes. We applied the same approach to dystrophic iPSCs, generating 16 iPSC lines from fibroblasts of four patients with Duchenne and Becker muscular dystrophies. As seen with iPSCs from healthy donors, within 36 hours from MyoD induction there was a clear commitment toward the myogenic identity by the majority of iPSCs in culture (50%70%). The patient iPSC-derived myotubes successfully adopted the skeletal muscle program, as determined by global gene expression profiling, and were functionally responsive to treatment with hypertrophic proteins insulin-like growth factor 1 (IGF-1) and wingless-type MMTV integration site family, member 7A (Wnt7a), which are being investigated as potential treatments for muscular dystrophy in clinical and preclinical studies, respectively. Our results demonstrate that iPSCs have no intrinsic barriers preventing MyoD from inducing efficient and rapid myogenesis and thus providing a scalable source of normal and dystrophic myoblasts for use in disease modeling and drug discovery. PMID:24396035

  3. PKC Theta Ablation Improves Healing in a Mouse Model of Muscular Dystrophy

    PubMed Central

    Madaro, Luca; Pelle, Andrea; Nicoletti, Carmine; Crupi, Annunziata; Marrocco, Valeria; Bossi, Gianluca; Soddu, Silvia; Bouch, Marina

    2012-01-01

    Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C ? (PKC?) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKC? could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/??/?, where PKC? expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/??/? mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKC? expression in hematopoietic cells. These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKC? activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKC? can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches. PMID:22348094

  4. Canine Models of Duchenne Muscular Dystrophy and Their Use in Therapeutic Strategies

    PubMed Central

    Kornegay, Joe N.; Bogan, Janet R.; Bogan, Daniel J.; Childers, Martin K.; Li, Juan; Nghiem, Peter; Detwiler, David A.; Larsen, C. Aaron; Grange, Robert W.; Bhavaraju-Sanka, Ratna K.; Tou, Sandra; Keene, Bruce P.; Howard, James F.; Wang, Jiahui; Fan, Zheng; Schatzberg, Scott J.; Styner, Martin A.; Flanigan, Kevin M.; Xiao, Xiao; Hoffman, Eric P.

    2013-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry substantial risk, such as gene and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. We and others have developed various phenotypic tests to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. While some of these studies have largely provided general proof-of-concept for the treatment under study, others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. While confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified. PMID:22218699

  5. Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes

    PubMed Central

    Sormani, Maria Pia; Messina, Sonia; D?Amico, Adele; Carlesi, Adelina; Vita, Gianluca; Fanelli, Lavinia; Berardinelli, Angela; Torrente, Yvan; Lanzillotta, Valentina; Viggiano, Emanuela; D?Ambrosio, Paola; Cavallaro, Filippo; Frosini, Silvia; Barp, Andrea; Bonfiglio, Serena; Scalise, Roberta; De Sanctis, Roberto; Rolle, Enrica; Graziano, Alessandra; Magri, Francesca; Palermo, Concetta; Rossi, Francesca; Donati, Maria Alice; Sacchini, Michele; Arnoldi, Maria Teresa; Baranello, Giovanni; Mongini, Tiziana; Pini, Antonella; Battini, Roberta; Pegoraro, Elena; Previtali, Stefano; Bruno, Claudio; Politano, Luisa; Comi, Giacomo P.; Bertini, Enrico; Mercuri, Eugenio

    2014-01-01

    The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of ?15.8 (SD 77.3) m at 12 months, of ?58.9 (SD 125.7) m at 24 months and ?104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p?=?0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available. PMID:25271887

  6. MRI-based quantification of Duchenne muscular dystrophy in a canine model

    NASA Astrophysics Data System (ADS)

    Wang, Jiahui; Fan, Zheng; Kornegay, Joe N.; Styner, Martin A.

    2011-03-01

    Duchenne muscular dystrophy (DMD) is a progressive and fatal X-linked disease caused by mutations in the DMD gene. Magnetic resonance imaging (MRI) has shown potential to provide non-invasive and objective biomarkers for monitoring disease progression and therapeutic effect in DMD. In this paper, we propose a semi-automated scheme to quantify MRI features of golden retriever muscular dystrophy (GRMD), a canine model of DMD. Our method was applied to a natural history data set and a hydrodynamic limb perfusion data set. The scheme is composed of three modules: pre-processing, muscle segmentation, and feature analysis. The pre-processing module includes: calculation of T2 maps, spatial registration of T2 weighted (T2WI) images, T2 weighted fat suppressed (T2FS) images, and T2 maps, and intensity calibration of T2WI and T2FS images. We then manually segment six pelvic limb muscles. For each of the segmented muscles, we finally automatically measure volume and intensity statistics of the T2FS images and T2 maps. For the natural history study, our results showed that four of six muscles in affected dogs had smaller volumes and all had higher mean intensities in T2 maps as compared to normal dogs. For the perfusion study, the muscle volumes and mean intensities in T2FS were increased in the post-perfusion MRI scans as compared to pre-perfusion MRI scans, as predicted. We conclude that our scheme successfully performs quantitative analysis of muscle MRI features of GRMD.

  7. NBD delivery improves the disease phenotype of the golden retriever model of Duchenne muscular dystrophy

    PubMed Central

    2014-01-01

    Background Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and afflicts skeletal and cardiac muscles. Previous studies showed that DMD is associated with constitutive activation of NF-κB, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn-/-;mdx) double knock out (dko) mouse models, inhibition of NF-κB with the Nemo Binding Domain (NBD) peptide led to significant improvements in both diaphragm and cardiac muscle function. Methods A trial in golden retriever muscular dystrophy (GRMD) canine model of DMD was initiated with four primary outcomes: skeletal muscle function, MRI of pelvic limb muscles, histopathologic features of skeletal muscles, and safety. GRMD and wild type dogs at 2 months of age were treated for 4 months with NBD by intravenous infusions. Results were compared with those collected from untreated GRMD and wild type dogs through a separate, natural history study. Results Results showed that intravenous delivery of NBD in GRMD dogs led to a recovery of pelvic limb muscle force and improvement of histopathologic lesions. In addition, NBD-treated GRMD dogs had normalized postural changes and a trend towards lower tissue injury on magnetic resonance imaging. Despite this phenotypic improvement, NBD administration over time led to infusion reactions and an immune response in both treated GRMD and wild type dogs. Conclusions This GRMD trial was beneficial both in providing evidence that NBD is efficacious in a large animal DMD model and in identifying potential safety concerns that will be informative moving forward with human trials. PMID:25789154

  8. Skeletal muscle imaging in facioscapulohumeral muscular dystrophy, pattern and asymmetry of individual muscle involvement.

    PubMed

    Rijken, N H M; van der Kooi, E L; Hendriks, J C M; van Asseldonk, R J G P; Padberg, G W; Geurts, A C H; van Engelen, B G M

    2014-12-01

    To better understand postural and movement disabilities, the pattern of total body muscle fat infiltration was analyzed in a large group of patients with facioscapulohumeral muscular dystrophy. Additionally, we studied whether residual D4Z4 repeat array length adjusted for age and gender could predict the degree of muscle involvement. Total body computed tomography scans of 70 patients were used to assess the degree of fat infiltration of 42 muscles from neck to ankle level on a semi-quantitative scale. Groups of muscles that highly correlated regarding fat infiltration were identified using factor analysis. Linear regression analysis was performed using muscle fat infiltration as the dependent variable and D4Z4 repeat length and age as independent variables. A pattern of muscle fat infiltration in facioscapulohumeral muscular dystrophy could be constructed. Trunk muscles were most frequently affected. Of these, back extensors were more frequently affected than previously reported. Asymmetry in muscle involvement was seen in 45% of the muscles that were infiltrated with fat. The right-sided upper extremity showed significantly higher scores for fat infiltration compared to the left side, which could not be explained by handedness. It was possible to explain 29% of the fat infiltration based on D4Z4 repeat length, corrected for age and gender. Based on our results we conclude that frequent involvement of fat infiltration in back extensors, in addition to the abdominal muscles, emphasizes the extent of trunk involvement, which may have a profound impact on postural control even in otherwise mildly affected patients. PMID:25176503

  9. Emerging gene editing strategies for Duchenne muscular dystrophy targeting stem cells

    PubMed Central

    Bertoni, Carmen

    2014-01-01

    The progressive loss of muscle mass characteristic of many muscular dystrophies impairs the efficacy of most of the gene and molecular therapies currently being pursued for the treatment of those disorders. It is becoming increasingly evident that a therapeutic application, to be effective, needs to target not only mature myofibers, but also muscle progenitors cells or muscle stem cells able to form new muscle tissue and to restore myofibers lost as the result of the diseases or during normal homeostasis so as to guarantee effective and lost lasting effects. Correction of the genetic defect using oligodeoxynucleotides (ODNs) or engineered nucleases holds great potential for the treatment of many of the musculoskeletal disorders. The encouraging results obtained by studying in vitro systems and model organisms have set the groundwork for what is likely to become an emerging field in the area of molecular and regenerative medicine. Furthermore, the ability to isolate and expand from patients various types of muscle progenitor cells capable of committing to the myogenic lineage provides the opportunity to establish cell lines that can be used for transplantation following ex vivo manipulation and expansion. The purpose of this article is to provide a perspective on approaches aimed at correcting the genetic defect using gene editing strategies and currently under development for the treatment of Duchenne muscular dystrophy (DMD), the most sever of the neuromuscular disorders. Emphasis will be placed on describing the potential of using the patient own stem cell as source of transplantation and the challenges that gene editing technologies face in the field of regenerative biology. PMID:24795643

  10. PKC theta ablation improves healing in a mouse model of muscular dystrophy.

    PubMed

    Madaro, Luca; Pelle, Andrea; Nicoletti, Carmine; Crupi, Annunziata; Marrocco, Valeria; Bossi, Gianluca; Soddu, Silvia; Bouché, Marina

    2012-01-01

    Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C θ (PKCθ) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKCθ could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/θ(-/-), where PKCθ expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/θ(-/-) mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKCθ expression in hematopoietic cells.These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKCθ activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKCθ can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches. PMID:22348094

  11. Circulating Muscle-specific miRNAs in Duchenne Muscular Dystrophy Patients

    PubMed Central

    Li, Xihua; Li, Yuying; Zhao, Lei; Zhang, Duo; Yao, Xuan; Zhang, Huihui; Wang, Yu-cheng; Wang, Xin-yi; Xia, Hongfeng; Yan, Jun; Ying, Hao

    2014-01-01

    Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for Duchenne muscular dystrophy (DMD) patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the serum levels of six muscle-specific miRNAs (miR-1/206/133/499/208a/208b, also known as myomiRs) were all elevated in DMD patients (P < 0.01). The receiver operating characteristic curves of circulating miR-206, miR-499, miR-208b, and miR-133 levels reflected strong separation between Becker's muscular dystrophy (BMD) and DMD patients (P < 0.05). miR-206, miR-499, and miR-208b levels were positively correlated with both age and type IIc muscle fiber content in DMD patients (26 years), indicating that they might represent the stage of disease as well as the process of regeneration. miR-499 and miR-208b levels were correlated with slow and fast fiber content and might reflect the ratio of slow to fast fibers in DMD patient (>6 years). Fibroblast growth factor, transforming growth factor-?, and tumor necrosis factor-? could affect the secretion of myomiRs, suggesting that circulating myomiRs might reflect the effects of cytokines and growth factors on degenerating and regenerating muscles. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for DMD diagnosis and disease progression. PMID:25050825

  12. A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy.

    PubMed

    Whitehead, Nicholas P; Kim, Min Jeong; Bible, Kenneth L; Adams, Marvin E; Froehner, Stanley C

    2015-10-13

    Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID:26417069

  13. Pharmacologic Management of Duchenne Muscular Dystrophy: Target Identification and Preclinical Trials

    PubMed Central

    Kornegay, Joe N.; Spurney, Christopher F.; Nghiem, Peter P.; Brinkmeyer-Langford, Candice L.; Hoffman, Eric P.; Nagaraju, Kanneboyina

    2014-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked human disorder in which absence of the protein dystrophin causes degeneration of skeletal and cardiac muscle. For the sake of treatment development, over and above definitive genetic and cell-based therapies, there is considerable interest in drugs that target downstream disease mechanisms. Drug candidates have typically been chosen based on the nature of pathologic lesions and presumed underlying mechanisms and then tested in animal models. Mammalian dystrophinopathies have been characterized in mice (mdx mouse) and dogs (golden retriever muscular dystrophy [GRMD]). Despite promising results in the mdx mouse, some therapies have not shown efficacy in DMD. Although the GRMD model offers a higher hurdle for translation, dogs have primarily been used to test genetic and cellular therapies where there is greater risk. Failed translation of animal studies to DMD raises questions about the propriety of methods and models used to identify drug targets and test efficacy of pharmacologic intervention. The mdx mouse and GRMD dog are genetically homologous to DMD but not necessarily analogous. Subcellular species differences are undoubtedly magnified at the whole-body level in clinical trials. This problem is compounded by disparate cultures in clinical trials and preclinical studies, pointing to a need for greater rigor and transparency in animal experiments. Molecular assays such as mRNA arrays and genome-wide association studies allow identification of genetic drug targets more closely tied to disease pathogenesis. Genes in which polymorphisms have been directly linked to DMD disease progression, as with osteopontin, are particularly attractive targets. PMID:24936034

  14. A new therapeutic effect of simvastatin revealed by functional improvement in muscular dystrophy

    PubMed Central

    Whitehead, Nicholas P.; Kim, Min Jeong; Bible, Kenneth L.; Adams, Marvin E.; Froehner, Stanley C.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases. PMID:26417069

  15. Delayed bone regeneration is linked to chronic inflammation in murine muscular dystrophy.

    PubMed

    Abou-Khalil, Rana; Yang, Frank; Mortreux, Marie; Lieu, Shirley; Yu, Yan-Yiu; Wurmser, Maud; Pereira, Catia; Relaix, Frdric; Miclau, Theodore; Marcucio, Ralph S; Colnot, Cline

    2014-02-01

    Duchenne muscular dystrophy (DMD) patients exhibit skeletal muscle weakness with continuous cycles of muscle fiber degeneration/regeneration, chronic inflammation, low bone mineral density, and increased risks of fracture. Fragility fractures and associated complications are considered as a consequence of the osteoporotic condition in these patients. Here, we aimed to establish the relationship between muscular dystrophy and fracture healing by assessing bone regeneration in mdx mice, a model of DMD with absence of osteoporosis. Our results illustrate that muscle defects in mdx mice impact the process of bone regeneration at various levels. In mdx fracture calluses, both cartilage and bone deposition were delayed followed by a delay in cartilage and bone remodeling. Vascularization of mdx fracture calluses was also decreased during the early stages of repair. Dystrophic muscles are known to contain elevated numbers of macrophages contributing to muscle degeneration. Accordingly, we observed increased macrophage recruitment in the mdx fracture calluses and abnormal macrophage accumulation throughout the process of bone regeneration. These changes in the inflammatory environment subsequently had an impact on the recruitment of osteoclasts and the remodeling phase of repair. Further damage to the mdx muscles, using a novel model of muscle trauma, amplified both the chronic inflammatory response and the delay in bone regeneration. In addition, PLX3397 treatment of mdx mice, a cFMS (colony stimulating factor receptor 1) inhibitor in monocytes, partially rescued the bone repair defect through increasing cartilage deposition and decreasing the number of macrophages. In conclusion, chronic inflammation in mdx mice contributes to the fracture healing delay and is associated with a decrease in angiogenesis and a transient delay in osteoclast recruitment. By revealing the role of dystrophic muscle in regulating the inflammatory response during bone repair, our results emphasize the implication of muscle in the normal bone repair process and may lead to improved treatment of fragility fractures in DMD patients. PMID:23857747

  16. Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy

    PubMed Central

    Barthlmy, Ins; Pinto-Mariz, Fernanda; Yada, Erica; Desquilbet, Loc; Savino, Wilson; Silva-Barbosa, Suse Dayse; Faussat, Anne-Marie; Mouly, Vincent; Voit, Thomas; Blot, Stphane; Butler-Browne, Gillian

    2014-01-01

    In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4+CD49dhi T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease. PMID:25261568

  17. Intellectual Ability in the Duchenne Muscular Dystrophy and Dystrophin Gene Mutation Location

    PubMed Central

    Milic Rasic, V; Vojinovic, D; Pesovic, J; Mijalkovic, G; Lukic, V; Mladenovic, J; Kosac, A; Novakovic, I; Maksimovic, N; Romac, S; Todorovic, S; Savic Pavicevic, D

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy during childhood. Mutations in dystrophin (DMD) gene are also recognized as a cause of cognitive impairment. We aimed to determine the association between intelligence level and mutation location in DMD genes in Serbian patients with DMD. Forty-one male patients with DMD, aged 3 to 16 years, were recruited at the Clinic for Neurology and Psychiatry for Children and Youth in Belgrade, Serbia. All patients had defined DMD gene deletions or duplications [multiplex ligation-dependent probe amplification (MLPA), polymerase chain reaction (PCR)] and cognitive status assessment (Wechsler Intelligence Scale for Children, Brunet-Lezine scale, Vineland-Doll scale). In 37 patients with an estimated full scale intelligence quotient (FSIQ), six (16.22%) had borderline intelligence (70

  18. Immobilization of Dystrophin and Laminin α2-Chain Deficient Zebrafish Larvae In Vivo Prevents the Development of Muscular Dystrophy

    PubMed Central

    Li, Mei; Arner, Anders

    2015-01-01

    Muscular dystrophies are often caused by genetic alterations in the dystrophin-dystroglycan complex or its extracellular ligands. These structures are associated with the cell membrane and provide mechanical links between the cytoskeleton and the matrix. Mechanical stress is considered a pathological mechanism and muscle immobilization has been shown to be beneficial in some mouse models of muscular dystrophy. The zebrafish enables novel and less complex models to examine the effects of extended immobilization or muscle relaxation in vivo in different dystrophy models. We have examined effects of immobilization in larvae from two zebrafish strains with muscular dystrophy, the Sapje dystrophin-deficient and the Candyfloss laminin α2-chain-deficient strains. Larvae (4 days post fertilization, dpf) of both mutants have significantly lower active force in vitro, alterations in the muscle structure with gaps between muscle fibers and altered birefringence patterns compared to their normal siblings. Complete immobilization (18 hrs to 4 dpf) was achieved using a small molecular inhibitor of actin-myosin interaction (BTS, 50 μM). This treatment resulted in a significantly weaker active contraction at 4 dpf in both mutated larvae and normal siblings, most likely reflecting a general effect of immobilization on myofibrillogenesis. The immobilization also significantly reduced the structural damage in the mutated strains, showing that muscle activity is an important pathological mechanism. Following one-day washout of BTS, muscle tension partly recovered in the Candyfloss siblings and caused structural damage in these mutants, indicating activity-induced muscle recovery and damage, respectively. PMID:26536238

  19. Myocardial metabolism, perfusion, wall motion and electrical activity in Duchenne muscular dystrophy

    SciTech Connect

    Perloff, J.K.; Henze, E.; Schelbert, H.R.

    1982-01-01

    The cardiomyopathy of Duchenne's muscular dystrophy originates in the posterobasal left ventricle and extends chiefly to the contiguous lateral wall. Ultrastructural abnormalities in these regions precede connective tissue replacement. We postulated that a metabolic fault coincided with or antedated the subcellular abnormality. Accordingly, regional left ventricular metabolism, perfusion and wall motion were studied using positron computed tomography and metabolic isotopes supplemented by thallium perfusion scans, equilibrium radionuclide angiography and M-mode and two-dimensional echocardiography. To complete the assessment, electrocardiograms, vectorcardiograms, 24 hour taped electrocardiograms and chest x-rays were analyzed. Positron computed tomography utilizing F-18 2-fluoro 2-deoxyglucose (FDG) provided the first conclusive evidence supporting the hypothesis of a premorphologic regional metabolic fault. Thus, cardiac involvement in duchenne dystrophy emerges as a unique form of heart disease, genetically targeting specific regions of ventricular myocardium for initial metabolic and subcellular changes. Reported ultrastructural abnormalities of the impulse and conduction systems provide, at least in part, a basis for the clinically observed sinus node, intraatrial, internodal, AV nodal and infranodal disorders.

  20. Evaluation of myocardial involvement in muscular dystrophy with Thallium-201 emission computed tomography

    SciTech Connect

    Yamamoto, S.; Kawai, N.; Matsushima, H.; Okada, M.; Yamauchi, K.; Yokota, M.; Hayashi, H.; Sotobata, I.; Sakuma, S.

    1985-05-01

    The clinical usefulness of quantitative analysis of thallium-201 emission computed tomography (ECT) for evaluation of left ventricular myocardial fibrosis was assessed on 45 patients with Duchenne(D), facioscapulohumeral(FSH), limbgirdle(LG) and myotonic(M) dystrophy. Trans-,long- and short-axial images were interpreted quantitatively using circumferential profile analysis, and the fibrotic tissue size (%FIB) was estimated by integration of hypoperfused areas in 6 to 8 consecutive short-axial slices. Lung/mediastinum count ratios (L/M ratio) were also assessed. Distinct ECT defects were found in 42 patients (all cases of D, FSH and LG, and 2 of 5 MTs). ECT defects were observed specifically in the posterolateral wall (71%) and apex (58%) in D, and were scattered in all LV walls in FSHG, LG and MT. ECG and VCG underestimated the extent of myocardial fibrosis in 17 patients (40%). Percent FIBs coincided with fibrotic tissue sizes proven by autopsy. Body-surface ECG should be influenced by cardiac position and rotation in the thorax, which were often observed in these disease entities. These factors were also assessed with ECT. The authors conclude; ECT to be useful for non-invasive evaluation of myocardial fibrosis in patients with various types of muscular dystrophy.

  1. Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy

    PubMed Central

    Dadgar, Sherry; Wang, Zuyi; Johnston, Helen; Kesari, Akanchha; Nagaraju, Kanneboyina; Chen, Yi-Wen; Hill, D. Ashley; Partridge, Terence A.; Giri, Mamta; Freishtat, Robert J.; Nazarian, Javad; Xuan, Jianhua; Wang, Yue

    2014-01-01

    We sought to determine the mechanisms underlying failure of muscle regeneration that is observed in dystrophic muscle through hypothesis generation using muscle profiling data (human dystrophy and murine regeneration). We found that transforming growth factor β–centered networks strongly associated with pathological fibrosis and failed regeneration were also induced during normal regeneration but at distinct time points. We hypothesized that asynchronously regenerating microenvironments are an underlying driver of fibrosis and failed regeneration. We validated this hypothesis using an experimental model of focal asynchronous bouts of muscle regeneration in wild-type (WT) mice. A chronic inflammatory state and reduced mitochondrial oxidative capacity are observed in bouts separated by 4 d, whereas a chronic profibrotic state was seen in bouts separated by 10 d. Treatment of asynchronously remodeling WT muscle with either prednisone or VBP15 mitigated the molecular phenotype. Our asynchronous regeneration model for pathological fibrosis and muscle wasting in the muscular dystrophies is likely generalizable to tissue failure in chronic inflammatory states in other regenerative tissues. PMID:25313409

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

    PubMed Central

    Sabharwal, Rasna; Chapleau, MarkW.

    2015-01-01

    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. PMID:24334334

  3. A National Profile of Health Care and Family Impacts of Children With Muscular Dystrophy and Special Health Care Needs in the United States

    PubMed Central

    Ouyang, Lijing; Grosse, Scott D.; Fox, Michael H.; Bolen, Julie

    2015-01-01

    We used the 2005–2006 National Survey of Children with Special Health Care Needs to compare 3 types of outcomes between children with and those without parental reported muscular dystrophy: (1) functional limitations; (2) health care experiences in terms of the 5 components of a medical home; and (3) family impacts, including financial or out-of-pocket costs and parental employment and time use. We used weighted logistic regression to examine their associations with muscular dystrophy after adjustment for socio-demographic characteristics. Among children with special health care needs, children with reported muscular dystrophy were much more likely to have difficulties with ambulation and self-care. They were more likely to have family members who reported financial problems, reduced or stopped employment, and spent more than 10 hours weekly providing or coordinating care. Muscular dystrophy was not associated with the likelihood of having a medical home after adjustment for socioeconomic status and other socio-demographic characteristics. PMID:21954427

  4. Dysregulation of matricellular proteins is an early signature of pathology in laminin-deficient muscular dystrophy

    PubMed Central

    2014-01-01

    Background MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin ?2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies. Results We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1. We also saw a surge of inflammatory response at the first week, marked by high levels of infiltrating macrophages, nuclear factor ?B activation, osteopontin expression and overexpression of inflammatory cytokines. Fibrosis markers and related pathways were also observed to be elevated throughout early postnatal development in these mice, including periostin, collagen and fibronectin gene expression, as well as transforming growth factor ? signaling. Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development. Lastly, we observed upregulation in various genes related to angiotensin signaling. Methods We sought out to examine the dysregulation of various pathways throughout early development (postnatal weeks 1-4) in the DyW mouse, the most commonly used mouse model of laminin-deficient muscular dystrophy. Muscle function tests (stand-ups and retractions) as well as gene (qRT-PCR) and protein levels (western blot, ELISA), histology (H&E, picrosirius red staining) and immunohistochemistry (fibronectin, TUNEL assay) were used to assess dysregulation of matricelluar protieins. Conclusions Our results implicate the involvement of multiple signaling pathways in driving the earliest stages of pathology in DyW mice. As opposed to classical dystrophies, such as Duchenne muscular dystrophy, the dysregulation of various matricellular proteins appears to be a distinct feature of the early progression of DyW pathology. On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age. PMID:25075272

  5. Cognitive and adaptive deficits in young children with Duchenne muscular dystrophy (DMD).

    PubMed

    Cyrulnik, Shana E; Fee, Robert J; Batchelder, Abigail; Kiefel, Jacqueline; Goldstein, Edward; Hinton, Veronica J

    2008-09-01

    The goal of the current investigation was to examine adaptive behavior and cognitive skills in young children with Duchenne muscular dystrophy (DMD), a genetic disorder that causes progressive muscular weakness and concomitant cognitive deficits. Previous studies have documented specific language deficits in older children with DMD, but there are limited data on younger children. Twenty children with DMD who were between 3 and 6 years old and 20 unaffected family control children were recruited. Parents completed questionnaires relating to development and adaptive functioning, while children completed neuropsychological testing. Results of paired t tests indicate that children with DMD are rated as delayed relative to familial controls on measures of adaptive functioning, as assessed by the Vineland Adaptive Behavior Scales. Furthermore, children with DMD exhibit impairments on multiple measures of cognition, including measures of receptive language, expressive language, visuo-spatial skills, fine-motor skills, attention, and memory skills. Across all domains examined, the young children with DMD performed more poorly than their familial controls. These deficits appear to be more generalized than those reported in older children with this disorder. Dystrophin, a missing protein product, is hypothesized to be responsible for these cognitive and behavioral impairments. PMID:18764980

  6. Symptomatic female carriers of Duchenne muscular dystrophy (DMD): genetic and clinical characterization.

    PubMed

    Giliberto, Florencia; Radic, Claudia Pamela; Luce, Leonela; Ferreiro, Vernica; de Brasi, Carlos; Szijan, Irene

    2014-01-15

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the dystrophin gene and is characterized by muscle degeneration and death. DMD affects males; females being asymptomatic carriers of mutations. However, some of them manifest symptoms due to a translocation between X chromosome and an autosome or to a heterozygous mutation leading to inactivation of most of their normal X chromosome. Six symptomatic female carriers and two asymptomatic were analyzed by: I) Segregation of STRs-(CA)n and MLPA assays to detect a hemizygous alteration, and II) X chromosome inactivation pattern to uncover the reason for symptoms in these females. The symptomatic females shared mild but progressive muscular weakness and increased serum creatin kinase (CK) levels. Levels of dystrophin protein were below normal or absent in many fibers. Segregation of STRs-(CA)n revealed hemizygous patterns in three patients, which were confirmed by MLPA. In addition, this analysis showed a duplication in another patient. X chromosome inactivation assay revealed a skewed X inactivation pattern in the symptomatic females and a random inactivation pattern in the asymptomatic ones. Our results support the hypothesis that the DMD phenotype in female carriers of a dystrophin mutation has a direct correlation with a skewed X-chromosome inactivation pattern. PMID:24135430

  7. Long-Term Survival of Transplanted Stem Cells in Immunocompetent Mice with Muscular Dystrophy

    PubMed Central

    Wallace, Gregory Q.; Lapidos, Karen A.; Kenik, Jordan S.; McNally, Elizabeth M.

    2008-01-01

    Satellite cells refer to resident stem cells in muscle that are activated in response to damage or disease for the regeneration and repair of muscle fibers. The use of stem cell transplantation to treat muscular diseases has been limited by impaired donor cell survival attributed to rejection and an unavailable stem cell niche. We isolated a population of adult muscle mononuclear cells (AMMCs) from normal, strain-matched muscle and transplanted these cells into δ-sarcoglycan-null dystrophic mice. Distinct from other transplant studies, the recipient mice were immunocompetent with an intact endogenous satellite cell pool. We found that AMMCs were 35 times more efficient at restoring sarcoglycan compared with cultured myoblasts. Unlike cultured myoblasts, AMMC-derived muscle fibers expressed sarcoglycan protein throughout their entire length, consistent with enhanced migratory ability. We examined the capacity of single injections of AMMCs to provide long-term benefit for muscular dystrophy and found persistent regeneration after 6 months, consistent with augmentation of the endogenous stem cell pool. Interestingly, AMMCs were more effectively engrafted into aged dystrophic mice for the regeneration of large clusters of sarcoglycan-positive muscle fibers, which were protected from damage, suggesting that the stem cell niche in older muscle remains permissive. PMID:18711004

  8. Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy

    PubMed Central

    Hathout, Yetrib; Brody, Edward; Clemens, Paula R.; Cripe, Linda; DeLisle, Robert Kirk; Furlong, Pat; Gordish-Dressman, Heather; Hache, Lauren; Henricson, Erik; Hoffman, Eric P.; Kobayashi, Yvonne Monique; Lorts, Angela; Mah, Jean K.; McDonald, Craig; Mehler, Bob; Nelson, Sally; Nikrad, Malti; Singer, Britta; Steele, Fintan; Sterling, David; Sweeney, H. Lee; Williams, Steve; Gold, Larry

    2015-01-01

    Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy–Cincinnati Children’s Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. PMID:26039989

  9. Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy.

    PubMed

    Cossu, Giulio; Previtali, Stefano C; Napolitano, Sara; Cicalese, Maria Pia; Tedesco, Francesco Saverio; Nicastro, Francesca; Noviello, Maddalena; Roostalu, Urmas; Natali Sora, Maria Grazia; Scarlato, Marina; De Pellegrin, Maurizio; Godi, Claudia; Giuliani, Serena; Ciotti, Francesca; Tonlorenzi, Rossana; Lorenzetti, Isabella; Rivellini, Cristina; Benedetti, Sara; Gatti, Roberto; Marktel, Sarah; Mazzi, Benedetta; Tettamanti, Andrea; Ragazzi, Martina; Imro, Maria Adele; Marano, Giuseppina; Ambrosi, Alessandro; Fiori, Rossana; Sormani, Maria Pia; Bonini, Chiara; Venturini, Massimo; Politi, Letterio S; Torrente, Yvan; Ciceri, Fabio

    2015-01-01

    Intra-arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first-in-human, exploratory, non-randomized open-label phase I-IIa clinical trial of intra-arterial HLA-matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor-derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2-month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Twomonths after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor-derived dystrophin in 1. Intra-arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy. PMID:26543057

  10. Self-adjuvanted hyaluronate - antigenic peptide conjugate for transdermal treatment of muscular dystrophy.

    PubMed

    Kong, Won Ho; Sung, Dong Kyung; Kim, Hyemin; Yang, Jeong-A; Ieronimakis, Nicholas; Kim, Ki Su; Lee, Jeehun; Kim, Deok-Ho; Yun, Seok Hyun; Hahn, Sei Kwang

    2016-03-01

    Duchenne's muscular dystrophy (DMD) is a neuromuscular disorder accompanied with muscle weakness and wasting. Since myostatin was reported to be a key regulator of muscle wasting, myostatin inhibitors have been investigated as therapeutic candidates for the treatment of muscular diseases. Here, we report an antigenic peptide of myostatin fragment (MstnF) conjugated to hyaluronate (HA) with a low molecular weight (MW, 17 kDa) for transdermal immunotherapy of DMD. Facilitating the transdermal delivery, the low MW HA showed a boosting effect on the immunization of MstnF possibly by engaging both toll-like receptors and cluster of differentiation 44 (CD44). In vivo two-photon microscopy clearly visualized the effective transdermal penetration of HA-MstnF conjugates into deep intact skin layers. The transdermal immunization of mdx mice significantly increased antibody titers against myostatin. Furthermore, the mdx mice immunized with HA-MstnF conjugates resulted in statistically significant improvement in the biochemical and pathological status of skeletal musculature as well as functional behaviors. PMID:26724457

  11. Entire CAPN3 gene deletion in a patient with limb-girdle muscular dystrophy type 2A.

    PubMed

    Jaka, Oihane; Azpitarte, Margarita; Paisn-Ruiz, Coro; Zulaika, Miren; Casas-Fraile, Leire; Sanz, Ral; Trevisiol, Nathalie; Levy, Nicolas; Bartoli, Marc; Krahn, Martin; Lpez de Munain, Adolfo; Senz, Amets

    2014-09-01

    Limb-girdle muscular dystrophy type 2A (LGMD2A) due to mutations in the CAPN3 gene is one of the most common of autosomal recessive limb-girdle muscular dystrophies. We describe a patient who had a typical LGMD2A phenotype and posterior compartment involvement on MRI. Different genetic analyses were performed, including microarray analysis. There was an apparently homozygous mutation in exon 24, c.2465G>T, p.(*822Leuext62*), and a lack of correlation in the disease segregation analyses. This suggested the presence of a genomic rearrangement. In fact, a heterozygous deletion of the entire CAPN3 gene was found. This novel deletion comprised the terminal region of the GANC gene and the entire CAPN3 gene. This finding points out the need to reconsider and adapt our current strategy of molecular diagnosis in order to detect these types of genomic rearrangements that escape standard mutation screening procedures. PMID:24715573

  12. Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Klyen, Blake R.; Shavlakadze, Thea; Radley-Crabb, Hannah G.; Grounds, Miranda D.; Sampson, David D.

    2011-07-01

    Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with co-registered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology. OCT could identify morphological features of interest and necrotic lesions within the muscle tissue samples based on intrinsic optical contrast. These findings demonstrate the utility of 3D-OCT for the evaluation of small-animal skeletal muscle morphology and pathology, particularly for studies of mouse models of muscular dystrophy.

  13. Immunity and AAV-Mediated Gene Therapy for Muscular Dystrophies in Large Animal Models and Human Trials.

    PubMed

    Wang, Zejing; Tapscott, Stephen J; Chamberlain, Jeffrey S; Storb, Rainer

    2011-01-01

    Adeno-associated viral (AAV) vector-mediated gene replacement for the treatment of muscular dystrophy represents a promising therapeutic strategy in modern medicine. One major obstacle in using AAV vectors for in vivo gene delivery is the development of host immune responses to the viral capsid protein and transgene products as evidenced in animal models and human trials for a range of genetic diseases. Here, we review immunity against AAV vector and transgene in the context of gene delivery specific to muscles for treating muscular dystrophies and non-muscle diseases in large animal models and human trials, factors that influence the intensity of the immune responses, and immune modulatory strategies to prevent unwanted immune responses and induce tolerance to the vector and therapeutic gene for a successful gene therapy. PMID:21980317

  14. Assessment of a symptomatic Duchenne muscular dystrophy carrier 20 years after myoblast transplantation from her asymptomatic identical twin sister.

    PubMed

    Hogrel, Jean-Yves; Zagnoli, Fabien; Canal, Aurlie; Fraysse, Bodvael; Bouchard, Jean-Pierre; Skuk, Daniel; Fardeau, Michel; Tremblay, Jacques P

    2013-07-01

    Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects. PMID:23731976

  15. Cyclosporine A treatment for Ullrich congenital muscular dystrophy: a cellular study of mitochondrial dysfunction and its rescue.

    PubMed

    Hicks, D; Lampe, A K; Laval, S H; Allamand, V; Jimenez-Mallebrera, C; Walter, M C; Muntoni, F; Quijano-Roy, S; Richard, P; Straub, V; Lochmller, H; Bushby, K M D

    2009-01-01

    Mutations in COL6A1, COL6A2 and COL6A3, the genes which encode the extra-cellular matrix component collagen VI, lead to Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). Although the Col6a1(-/-) null mouse has an extremely mild neuromuscular phenotype, a mitochondrial defect has been demonstrated, linked to dysregulation of the mitochondrial permeability transition pore (PTP) opening. This finding has been replicated in UCMD muscle cells in culture, providing justification for a clinical trial using cyclosporine A, an inhibitor of PTP opening. We investigated whether PTP dysregulation could be detected in UCMD fibroblasts (the predominant source of muscle collagen VI), in myoblast cells from patients with other diseases and its response to rescue agents other than collagen VI. Although we confirm the presence of PTP dysregulation in muscle-derived cultures from two UCMD patients, fibroblasts from the same patients and the majority of fibroblasts from other well-characterized UCMD patients behave normally. PTP dysregulation is found in limb girdle muscular dystrophy (LGMD) type 2B myoblasts but not in myoblasts from patients with Bethlem myopathy, merosin-deficient congenital muscular dystrophy, LGMD2A, Duchenne muscular dystrophy and Leigh syndrome. In addition to rescue by cyclosporine A and collagen VI, this cellular phenotype was also rescued by other extra-cellular matrix constituents (laminin and collagen I). As the muscle derived cultures demonstrating PTP dysregulation shared poor growth in culture and lack of desmin labelling, we believe that PTP dysregulation may be a particular characteristic of the state of these cells in culture and is not specific to the collagen VI defect, and can in any case be rescued by a range of extra-cellular matrix components. Further work is needed on the relationship of PTP dysregulation with UCMD pathology. PMID:19015158

  16. Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p

    SciTech Connect

    Bashir, R.; Keers, S.; Strachan, T.

    1996-04-01

    The limb-girdle muscular dystrophies (LGMD) are a genetically heterogeneous group of disorders, different forms of which have been mapped to at least six distinct genetic loci. We have mapped to at least six distinct genetic loci. We have mapped an autosomal recessive form of LGMD (LGMD2B) to chromosome 2p13. Two other conditions have been shown to map to this region or to the homologous region in mouse: a gene for a form of autosomal recessive distal muscular dystrophy, Miyoshi myopathy, shows linkage to the same markers on chromosome 2p as LGMD2B, and an autosomal recessive mouse mutation mnd2, in which there is rapidly progressive paralysis and muscle atrophy, has been mapped to mouse chromosome 6 to a region showing conserved synteny with human chromosome 2p12-p13. We have assembled a 6-cM YAC contig spanning the LGMD2B locus and have mapped seven genes and 13 anonymous polymorphic microsatellites to it. Using haplotype analysis in the linked families, we have narrowed our region of interest to a 0-cM interval between D2S2113 and D2S145, which does not overlap with the critical region for mnd2 in mouse. Use of these most closely linked markers will help to determine the relationship between LGMD2B and Miyoshi myopathy. YACs selected from our contig will be the starting point for the cloning of the LGMD2B gene and thereby establish the biological basis for this form of muscular dystrophy and its relationship with the other limb-girdle muscular dystrophies. 26 refs., 6 figs.

  17. Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS

    PubMed Central

    Martins-Jnior, Helio A.; Simas, Rosineide C.; Brolio, Marina P.; Ferreira, Christina R.; Perecin, Felipe; Nogueira, Guilherme de P.; Miglino, Maria A.; Martins, Daniele S.; Eberlin, Marcos N.; Ambrsio, Carlos E.

    2015-01-01

    Golden retriever muscular dystrophy (GRMD) provides the best animal model for characterizing the disease progress of the human disorder, Duchenne muscular dystrophy (DMD). The purpose of this study was to determine steroid hormone concentration profiles in healthy golden retriever dogs (control group - CtGR) versus GRMD-gene carrier (CaGR) and affected female dogs (AfCR). Therefore, a sensitive and specific analytical method was developed and validated to determine the estradiol, progesterone, cortisol, and testosterone levels in the canine serum by isotope dilution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). To more accurately understand the dynamic nature of the serum steroid profile, the fluctuating levels of these four steroid hormones over the estrous cycle were compared across the three experimental groups using a multivariate statistical analysis. The concentration profiles of estradiol, cortisol, progesterone, and testosterone revealed a characteristic pattern for each studied group at each specific estrous phase. Additionally, several important changes in the serum concentrations of cortisol and estradiol in the CaGR and AfCR groups seem to be correlated with the status and progression of the muscular dystrophy. A comprehensive and quantitative monitoring of steroid profiles throughout the estrous cycle of normal and GRMD dogs were achieved. Significant differences in these profiles were observed between GRMD and healthy animals, most notably for estradiol. These findings contribute to a better understanding of both dog reproduction and the muscular dystrophy pathology. Our data open new venues for hormonal behavior studies in dystrophinopathies and that may affect the quality of life of DMD patients. PMID:26010907

  18. PAI-1regulated miR-21 defines a novel age-associated fibrogenic pathway in muscular dystrophy

    PubMed Central

    Ardite, Esther; Perdiguero, Eusebio; Vidal, Berta; Gutarra, Susana; Serrano, Antonio L.

    2012-01-01

    Disruption of skeletal muscle homeostasis by substitution with fibrotic tissue constitutes the principal cause of death in Duchenne muscular dystrophy (DMD) patients, yet the implicated fibrogenic mechanisms remain poorly understood. This study identifies the extracellular PAI-1/urokinase-type plasminogen activator (uPA) balance as an important regulator of microribonucleic acid (miR)21 biogenesis, controlling age-associated muscle fibrosis and dystrophy progression. Genetic loss of PAI-1 in mdx dystrophic mice anticipated muscle fibrosis through these sequential mechanisms: the alteration of collagen metabolism by uPA-mediated proteolytic processing of transforming growth factor (TGF)? in muscle fibroblasts and the activation of miR-21 expression, which inhibited phosphatase and tensin homologue and enhanced AKT signaling, thus endowing TGF-? with a remarkable cell proliferationpromoting potential. Age-associated fibrogenesis and muscle deterioration in mdx mice, as well as exacerbated dystrophy in young PAI-1?/? mdx mice, could be reversed by miR-21 or uPA-selective interference, whereas forced miR-21 overexpression aggravated disease severity. The PAI-1miR-21 fibrogenic axis also appeared dysregulated in muscle of DMD patients, providing a basis for effectively targeting fibrosis and muscular dystrophies in currently untreatable individuals. PMID:22213800

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

    PubMed Central

    2013-01-01

    Background Cardiomyopathy is reported in Duchenne and Becker muscle dystrophy patients and female carriers. Brain Natriuretic peptide (BNP) is a hormone produced mainly by ventricular cardiomyocytes and its production is up regulated in reaction to increased wall stretching. N-terminal-proBNP (NT-proBNP) has been shown to be a robust laboratory parameter to diagnose and monitor cardiac failure, and it may be helpful to screen for asymptomatic left ventricular dysfunction. Therefore we tested whether NT-proBNP can distinguish patients with Duchenne or Becker muscular dystrophy patients and carriers of a dystrophin mutation with a dilated cardiomyopathy from those without. Methods In a cohort of Duchenne and Becker muscle dystrophy patients (n?=?143) and carriers (n?=?219) NT-proBNP was measured, and echocardiography was performed to diagnose dilated cardiomyopathy (DCM). Results In total sixty-one patients (17%) fulfilled the criteria for DCM, whereas 283 patients (78%) had an elevated NT-pro BNP. The sensitivity of NT-proBNP for DCM in patients or carriers was 85%, the specificity 23%, area under the ROC-curve?=?0.56. In the specified subgroups there was also no association. Conclusion Measurement of NT-pro BNP in patients suffering from Duchenne or Becker muscular dystrophy and carriers does not distinguish between those with and without dilated cardiomyopathy. PMID:23870371

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

    SciTech Connect

    Toda, Tatsushi; Ikegawa, Shiro; Okui, Keiko; Nakamura, Yusuke; Kanazawa, Ichiro; Kondo, Eri; Saito, Kayoko; Fukuyama, Yukio; Yoshioka, Mieko; Kumagai, Toshiyuki

    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. 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.

  1. Fighting Against Disuse of the Masticatory System in Duchenne Muscular Dystrophy: A Pilot Study Using Chewing Gum.

    PubMed

    van Bruggen, H Willemijn; van den Engel-Hoek, Lenie; Steenks, Michel H; van der Bilt, Andries; Bronkhorst, Ewald M; Creugers, Nico H J; de Groot, Imelda J M; Kalaykova, Stanimira I

    2015-10-01

    Duchenne muscular dystrophy patients report masticatory problems. The aim was to determine the efficacy of mastication training in Duchenne muscular dystrophy using chewing gum for 4 weeks. In all, 17 patients and 17 healthy age-matched males participated. The masticatory performance was assessed using a mixing ability test and measuring anterior bite force before, shortly after and 1 month after the training. In the patient group the masticatory performance improved and remained after 1-month follow-up, no significant changes in anterior maximum bite force was observed after mastication training. In the healthy subject the bite force increased and remained at the 1-month follow-up; no significant differences in masticatory performance were observed. Mastication training by using sugar-free chewing gum in Duchenne muscular dystrophy patients improved their masticatory performance. Since bite force did not improve, the working mechanism of the improvement in chewing may relate to changes of the neuromuscular function and coordination, resulting in improvement of skills in performing mastication. PMID:25792431

  2. Automated DNA mutation detection using universal conditions direct sequencing: application to ten muscular dystrophy genes

    PubMed Central

    2009-01-01

    Background One of the most common and efficient methods for detecting mutations in genes is PCR amplification followed by direct sequencing. Until recently, the process of designing PCR assays has been to focus on individual assay parameters rather than concentrating on matching conditions for a set of assays. Primers for each individual assay were selected based on location and sequence concerns. The two primer sequences were then iteratively adjusted to make the individual assays work properly. This generally resulted in groups of assays with different annealing temperatures that required the use of multiple thermal cyclers or multiple passes in a single thermal cycler making diagnostic testing time-consuming, laborious and expensive. These factors have severely hampered diagnostic testing services, leaving many families without an answer for the exact cause of a familial genetic disease. A search of GeneTests for sequencing analysis of the entire coding sequence for genes that are known to cause muscular dystrophies returns only a small list of laboratories that perform comprehensive gene panels. The hypothesis for the study was that a complete set of universal assays can be designed to amplify and sequence any gene or family of genes using computer aided design tools. If true, this would allow automation and optimization of the mutation detection process resulting in reduced cost and increased throughput. Results An automated process has been developed for the detection of deletions, duplications/insertions and point mutations in any gene or family of genes and has been applied to ten genes known to bear mutations that cause muscular dystrophy: DMD; CAV3; CAPN3; FKRP; TRIM32; LMNA; SGCA; SGCB; SGCG; SGCD. Using this process, mutations have been found in five DMD patients and four LGMD patients (one in the FKRP gene, one in the CAV3 gene, and two likely causative heterozygous pairs of variations in the CAPN3 gene of two other patients). Methods and assay sequences are reported in this paper. Conclusion This automated process allows laboratories to discover DNA variations in a short time and at low cost. PMID:19835634

  3. POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking.

    PubMed

    Schindler, Roland F R; Scotton, Chiara; Zhang, Jianguo; Passarelli, Chiara; Ortiz-Bonnin, Beatriz; Simrick, Subreena; Schwerte, Thorsten; Poon, Kar-Lai; Fang, Mingyan; Rinné, Susanne; Froese, Alexander; Nikolaev, Viacheslav O; Grunert, Christiane; Müller, Thomas; Tasca, Giorgio; Sarathchandra, Padmini; Drago, Fabrizio; Dallapiccola, Bruno; Rapezzi, Claudio; Arbustini, Eloisa; Di Raimo, Francesca Romana; Neri, Marcella; Selvatici, Rita; Gualandi, Francesca; Fattori, Fabiana; Pietrangelo, Antonello; Li, Wenyan; Jiang, Hui; Xu, Xun; Bertini, Enrico; Decher, Niels; Wang, Jun; Brand, Thomas; Ferlini, Alessandra

    2016-01-01

    The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases. PMID:26642364

  4. Longitudinal assessment of grip strength using bulb dynamometer in Duchenne Muscular Dystrophy

    PubMed Central

    Pizzato, Tatiana M.; Baptista, Cyntia R. J. A.; Souza, Mariana A.; Benedicto, Michelle M. B.; Martinez, Edson Z.; Mattiello-Sverzut, Ana C.

    2014-01-01

    BACKGROUND: Grip strength is used to infer functional status in several pathological conditions, and the hand dynamometer has been used to estimate performance in other areas. However, this relationship is controversial in neuromuscular diseases and studies with the bulb dynamometer comparing healthy children and children with Duchenne Muscular Dystrophy (DMD) are limited. OBJECTIVE: The evolution of grip strength and the magnitude of weakness were examined in boys with DMD compared to healthy boys. The functional data of the DMD boys were correlated with grip strength. METHOD: Grip strength was recorded in 18 ambulant boys with DMD (Duchenne Group, DG) aged 4 to 13 years (mean 7.42.1) and 150 healthy volunteers (Control Group, CG) age-matched using a bulb dynamometer (North Coast- NC70154). The follow-up of the DG was 6 to 33 months (3-12 sessions), and functional performance was verified using the Vignos scale. RESULTS: There was no difference between grip strength obtained by the dominant and non-dominant side for both groups. Grip strength increased in the CG with chronological age while the DG remained stable or decreased. The comparison between groups showed significant difference in grip strength, with CG values higher than DG values (confidence interval of 95%). In summary, there was an increment in the differences between the groups with increasing age. Participants with 24 months or more of follow-up showed a progression of weakness as well as maintained Vignos scores. CONCLUSIONS: The amplitude of weakness increased with age in the DG. The bulb dynamometer detected the progression of muscular weakness. Functional performance remained virtually unchanged in spite of the increase in weakness. PMID:25003277

  5. Progressive muscular dystrophy--Duchenne type. Controversies of the kinesitherapy treatment.

    PubMed

    de Araujo Leito, A V; Duro, L A; de Andrade Penque, G M

    1995-01-01

    The authors carried out a study of children with progressive muscular dystrophy of Duchenne type (DMD), giving special attention to physiatrical follow-up, having in mind that the practice of exercises has been debated very much in the specialized literature. The goal of this study is to try to settle the limits for the utilization of kinesitherapy which should be applied only in specific situations, such as: after skeletal muscular trauma or when the respiratory system is at risk. In this situation the physiatrical procedure would be to restrict physical activity, with early use of wheelchairs and the exclusion of the use of orthoses for orthostatism. DMD, at present, has been considered a result of duplication (60%), deletion (5 to 6%) or point mutations at gen Xp21 (Zatz, 1994), that codifies a protein called Dystrophin (Hoffman et al., 1987). Dystrophin is a cytoskeletal sarcolemmic protein that constitutes about .002% of the total protein of the muscle, present in skeletal fibers concentrated in muscle tendinous joints, which supplies mechanical reinforcement to the surface of the membrane during stretching and shortening physical activity. This protein is absent in DMD cases, wherefore, the sarcolemma undergoes a segmentary necrosis losing its contractile property during eccentric and concentric physical activity. The importance of physiatrical follow-up for DMD patients is to avoid deformities and tendon shortening, to ameliorate the patient's quality of life, to provide respiratory assistance and general counseling to members of the patient's family. The objective of this study is to try to clarify the risks and possibilities of kinesitherapy applied to DMD cases. PMID:8729744

  6. Nitric oxide deficiency determines global chromatin changes in Duchenne muscular dystrophy.

    PubMed

    Colussi, Claudia; Gurtner, Aymone; Rosati, Jessica; Illi, Barbara; Ragone, Gianluca; Piaggio, Giulia; Moggio, Maurizio; Lamperti, Costanza; D'Angelo, Grazia; Clementi, Emilio; Minetti, Giulia; Mozzetta, Chiara; Antonini, Annalisa; Capogrossi, Maurizio C; Puri, Pier Lorenzo; Gaetano, Carlo

    2009-07-01

    The present study provides evidence that abnormal patterns of global histone modification are present in the skeletal muscle nuclei of mdx mice and Duchenne muscular dystrophy (DMD) patients. A combination of specific histone H3 modifications, including Ser-10 phosphorylation, acetylation of Lys 9 and 14, and Lys 79 methylation, were found enriched in muscle biopsies from human patients affected by DMD and in late-term fetuses, early postnatal pups, or adult mdx mice. In this context, chromatin immunoprecipitation experiments showed an enrichment of these modifications at the loci of genes involved in proliferation or inflammation, suggesting a regulatory effect on gene expression. Remarkably, the reexpression of dystrophin induced by gentamicin treatment or the administration of nitric oxide (NO) donors reversed the abnormal pattern of H3 histone modifications. These findings suggest an unanticipated link between the dystrophin-activated NO signaling and the remodeling of chromatin. In this context, the regulation of class IIa histone deacetylases (HDACs) 4 and 5 was found altered as a consequence of the reduced NO-dependent protein phosphatase 2A activity, indicating that both NO and class IIa HDACs are important for satellite cell differentiation and gene expression in mdx mice. In conclusion, this work provides the first evidence of a role for NO as an epigenetic regulator in DMD. PMID:19264835

  7. Genetic evidence in the mouse solidifies the calcium hypothesis of myofiber death in muscular dystrophy

    PubMed Central

    Burr, A R; Molkentin, J D

    2015-01-01

    Muscular dystrophy (MD) refers to a clinically and genetically heterogeneous group of degenerative muscle disorders characterized by progressive muscle wasting and often premature death. Although the primary defect underlying most forms of MD typically results from a loss of sarcolemmal integrity, the secondary molecular mechanisms leading to muscle degeneration and myofiber necrosis is debated. One hypothesis suggests that elevated or dysregulated cytosolic calcium is the common transducing event, resulting in myofiber necrosis in MD. Previous measurements of resting calcium levels in myofibers from dystrophic animal models or humans produced equivocal results. However, recent studies in genetically altered mouse models have largely solidified the calcium hypothesis of MD, such that models with artificially elevated calcium in skeletal muscle manifest fulminant dystrophic-like disease, whereas models with enhanced calcium clearance or inhibited calcium influx are resistant to myofiber death and MD. Here, we will review the field and the recent cadre of data from genetically altered mouse models, which we propose have collectively mostly proven the hypothesis that calcium is the primary effector of myofiber necrosis in MD. This new consensus on calcium should guide future selection of drugs to be evaluated in clinical trials as well as gene therapy-based approaches. PMID:26088163

  8. Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I.

    PubMed

    Palmieri, A; Manara, R; Bello, L; Mento, G; Lazzarini, L; Borsato, C; Bortolussi, L; Angelini, C; Pegoraro, E

    2011-07-01

    Limb-girdle muscular dystrophy 2I (LGMD2I) is a neuromuscular disorder with a heterogeneous phenotype. It is caused by mutations in the Fukutin Related Protein (FKRP) gene, which is ubiquitously expressed in human tissues. FKRP functions in CNS are largely unknown. To investigate possible cognitive impairment in LGMD2I and to describe brain MRI features. Ten LGMD2I patients (four males and six females, mean age 44 years, age range 19-69 years) were assessed with an extensive neuropsychological battery, psychopathological tests and neuromuscular specific quality-of-life questionnaire. Adults were compared with ten matched healthy controls. All patients underwent complete neurological examination, and nine underwent brain MRI scanning. Patients showed a fairly specific cognitive profile with mild impairment in executive functions and visuo-spatial planning without substantial impairment in global and logic IQ. MRI findings were heterogeneous: four patients showed non-specific white matter abnormalities; two patients showed moderate ventriculomegaly; three patients showed mild enlargement of subarachnoid spaces, without a specific pattern. Cerebellar atrophy was marked in one patient. Abnormal glycosylation of ?-dystroglycan in LGMD2I may interfere with brain development and cognitive performances involving the frontal and posterior parietal regions, but does not result in specific brain MRI abnormalities. PMID:21293871

  9. [Clinical-genetic characteristics of limb girdle-muscular dystrophy type 2A].

    PubMed

    Dadali, E L; Shagina, O A; Ryzhkova, O P; Rudenskaia, G E; Fedotov, V P; Poliakov, A V

    2010-01-01

    We present the results of the molecular genetic study of 26 patients, aged from 12 to 60 years, from 24 unrelated families with limb girdle-muscular dystrophy (LGMD) type 2A. The disease duration varied from 6 months to 30 years. The diagnosis of LGMD 2capital A, Cyrillic was confirmed by molecular genetic methods basing on the presence of a CAPN3 mutation in homozygous, compound-heterozygous and heterozygous state. The Leyden-Moebius variant that is characterized by the primary affection of muscles of pelvic girdle and shin with the gradual progression of the pathological process in shoulder girdle muscles was the most frequent in the Russian population. Tip-toe walking or difficulties in walking upstairs and running were the first symptoms reported by patients. In contrast to criteria of the European Neuromuscular Center, the characteristic symptoms of the disease were early contractures of ankle joints and pseudohypertrophy of gastrocnemius muscles. The major c.550delA mutation in the CAPN3 gene was identified in 70% of Russian patients. PMID:20517216

  10. Mitochondrial Dysfunction and Defective Autophagy in the Pathogenesis of Collagen VI Muscular Dystrophies

    PubMed Central

    Bernardi, Paolo; Bonaldo, Paolo

    2013-01-01

    Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy (BM), and Congenital Myosclerosis are diseases caused by mutations in the genes encoding the extracellular matrix protein collagen VI. A dystrophic mouse model, where collagen VI synthesis was prevented by targeted inactivation of the Col6a1 gene, allowed the investigation of pathogenesis, which revealed the existence of a Ca2+-mediated dysfunction of mitochondria and sarcoplasmic reticulum, and of defective autophagy. Key events are dysregulation of the mitochondrial permeability transition pore, an inner membrane high-conductance channel that for prolonged open times causes mitochondrial dysfunction, and inadequate removal of defective mitochondria, which amplifies the damage. Consistently, the Col6a1?/? myopathic mice could be cured through inhibition of cyclophilin D, a matrix protein that sensitizes the pore to opening, and through stimulation of autophagy. Similar defects contribute to disease pathogenesis in patients irrespective of the genetic lesion causing the collagen VI defect. These studies indicate that permeability transition pore opening and defective autophagy represent key elements for skeletal muscle fiber death, and provide a rationale for the use of cyclosporin A and its nonimmunosuppressive derivatives in patients affected by collagen VI myopathies, a strategy that holds great promise for treatment. PMID:23580791

  11. Limb-girdle muscular dystrophies: Where next after six decades from the first proposal (Review)

    PubMed Central

    MAHMOOD, OMAR A.; JIANG, XIN MEI

    2014-01-01

    Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders, which has led to certain investigators disputing its rationality. The mutual feature of LGMD is limb-girdle affection. Magnetic resonance imaging (MRI), perioral skin biopsies, blood-based assays, reverse-protein arrays, proteomic analyses, gene chips and next generation sequencing are the leading diagnostic techniques for LGMD and gene, cell and pharmaceutical treatments are the mainstay therapies for these genetic disorders. Recently, more highlights have been shed on disease biomarkers to follow up disease progression and to monitor therapeutic responsiveness in future trials. In this study, we review LGMD from a variety of aspects, paying specific attention to newly evolving research, with the purpose of bringing this information into the clinical setting to aid the development of novel therapeutic strategies for this hereditary disease. In conclusion, substantial progress in our ability to diagnose and treat LGMD has been made in recent decades, however enhancing our understanding of the detailed pathophysiology of LGMD may enhance our ability to improve disease outcome in subsequent years. PMID:24626787

  12. How to tackle the diagnosis of limb-girdle muscular dystrophy 2A.

    PubMed

    Fanin, Marina; Nascimbeni, Anna Chiara; Tasca, Elisabetta; Angelini, Corrado

    2009-05-01

    Limb-girdle muscular dystrophy (LGMD) 2A (calpainopathy) is the most frequent form of LGMD in many European countries. The increasing demand for a molecular diagnosis makes the identification of strategies to improve gene mutation detection crucial. We conducted both a quantitative analysis of calpain-3 protein in 519 muscles from patients with unclassified LGMD, unclassified myopathy and hyperCKemia, and a functional assay of calpain-3 autolytic activity in 108 cases with LGMD and normal protein quantity. Subsequently, screening of CAPN3 gene mutations was performed using allele-specific tests and simplified SSCP analysis. We diagnosed a total of 94 LGMD2A patients, carrying 66 different mutations (six are newly identified). The probability of diagnosing calpainopathy was very high in patients showing either a quantitative (80%) or a functional calpain-3 protein defect (88%). Our data show a high predictive value for reduced-absent calpain-3 or lost autolytic activity. These biochemical assays are powerful tools for otherwise laborious genetic screening of cases with a high probability of being primary calpainopathy. Our multistep diagnostic approach is rational and highly effective. This strategy has improved the detection rate of the disease and our extension of screening to presymptomatic phenotypes (hyperCKemia) has allowed us to obtain early diagnoses, which has important consequences for patient care and genetic counseling. PMID:18854869

  13. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms

    PubMed Central

    van Dijk, Gaby Pons; van der Kooi, Elly; Behin, Anthony; Smeets, Joep; Timmermans, Janneke; van der Maarel, Silvre; Padberg, George; Voermans, Nicol; van Engelen, Baziel

    2014-01-01

    Summary The exact prevalence and nature of cardiac involvement in facioscapulohumeral muscular dystrophy (FSHD) is unknown. Nevertheless, the current opinion is that symptomatic cardiac disease is rare. We performed a cardiac screening [electrocardiogram (ECG) and echocardiography in the event of ECG abnormalities] in 75 genetically confirmed, ambulant FSHD patients without cardiac symptoms, with an eight-year follow-up of 57 patients, and compared the findings with results of previously performed cardiac screenings in the normal population. Baseline ECG demonstrated incomplete right bundle branch block (RBBB) in 33%, complete RBBB in 4%, and other minor abnormalities in 16%. Echocardiography showed no abnormalities. No significant changes were found after eight years of follow-up. Comparison with ECG abnormalities in the normal population showed a higher prevalence of incomplete RBBB (9.7 times higher) and of complete RBBB (4.8 times higher) in FSHD patients. This study in cardiac asymptomatic FSHD patients shows i) increased prevalence of incomplete RBBB in the absence of cardiomyopathy; ii) no progression of these abnormalities during eight years of follow-up. We conclude that FSHD patients without cardiac complaints do not need specific cardiac screening or surveillance. Furthermore, the increased prevalence of incomplete RBBB in the absence of cardiomyopathy suggests a selective involvement of the His-Purkinje system in FSHD. PMID:25473735

  14. The mdx mouse model as a surrogate for Duchenne muscular dystrophy

    PubMed Central

    Partridge, Terence A.

    2014-01-01

    Research into fundamental principles and the testing of therapeutic hypotheses for treatment of human disease is commonly conducted on mouse models of human diseases. Although this is often the only practicable approach, it carries a number of caveats arising from differences between the two species. This article is centred on the example of skeletal muscle disease, in particular muscular dystrophy, to identify some of the principal classes of obstacle to the translation of data from mouse to man. Of these, the difference in scale is one of the most commonly ignored and is of particular interest because it has quite major repercussions for evaluation of some classes of intervention and of assessment criteria while having comparatively little bearing on others. Likewise, interspecies differences and similarities in cell and molecular biological mechanisms underlying development, growth and response to pathological processes should be considered on an individual basis. An awareness of such distinctions is crucial if we are to avoid misjudgement of the likely efficacy in man of results obtained on mouse models. PMID:23551987

  15. Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells

    PubMed Central

    Shoji, Emi; Sakurai, Hidetoshi; Nishino, Tokiko; Nakahata, Tatsutoshi; Heike, Toshio; Awaya, Tomonari; Fujii, Nobuharu; Manabe, Yasuko; Matsuo, Masafumi; Sehara-Fujisawa, Atsuko

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by a dystrophin deficiency. Effective suppression of the primary pathology observed in DMD is critical for treatment. Patient-derived human induced pluripotent stem cells (hiPSCs) are a promising tool for drug discovery. Here, we report an in vitro evaluation system for a DMD therapy using hiPSCs that recapitulate the primary pathology and can be used for DMD drug screening. Skeletal myotubes generated from hiPSCs are intact, which allows them to be used to model the initial pathology of DMD in vitro. Induced control and DMD myotubes were morphologically and physiologically comparable. However, electric stimulation of these myotubes for in vitro contraction caused pronounced calcium ion (Ca2+) influx only in DMD myocytes. Restoration of dystrophin by the exon-skipping technique suppressed this Ca2+ overflow and reduced the secretion of creatine kinase (CK) in DMD myotubes. These results suggest that the early pathogenesis of DMD can be effectively modelled in skeletal myotubes induced from patient-derived iPSCs, thereby enabling the development and evaluation of novel drugs. PMID:26290039

  16. Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy.

    PubMed

    Rodrguez-Cruz, Maricela; Sanchez, Ral; Escobar, Rosa E; Cruz-Guzmn, Oriana Del Roco; Lpez-Alarcn, Mardia; Bernabe Garca, Mariela; Coral-Vzquez, Ramn; Matute, Guadalupe; Velzquez Wong, Ana Claudia

    2015-01-01

    Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16-74.69) and 50 (OR = 8.73; 95% CI = 1.17-65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR. PMID:26089900

  17. The 6 Minute Walk Test and Performance of Upper Limb in Ambulant Duchenne Muscular Dystrophy Boys

    PubMed Central

    Pane, Marika; Mazzone, Elena Stacy; Sivo, Serena; Fanelli, Lavinia; De Sanctis, Roberto; DAmico, Adele; Messina, Sonia; Battini, Roberta; Bianco, Flaviana; Scutifero, Marianna; Petillo, Roberta; Frosini, Silvia; Scalise, Roberta; Vita, Gian Luca; Bruno, Claudio; Pedemonte, Marina; Mongini, Tiziana; Pegoraro, Elena; Brustia, Francesca; Gardani, Alice; Berardinelli, Angela; Lanzillotta, Valentina; Viggiano, Emanuela; Cavallaro, Filippo; Sframeli, Maria; Bello, Luca; Barp, Andrea; Busato, Fabio; Bonfiglio, Serena; Rolle, Enrica; Colia, Giulia; Bonetti, Annamaria; Palermo, Concetta; Graziano, Alessandra; DAngelo, Grazia; Pini, Antonella; Corlatti, Alice; Gorni, Ksenija; Baranello, Giovanni; Antonaci, Laura; Bertini, Enrico; Politano, Luisa; Mercuri, Eugenio

    2014-01-01

    The Performance of Upper Limb (PUL) test was specifically developed for the assessment of upper limbs in Duchenne muscular dystrophy (DMD). The first published data have shown that early signs of involvement can also be found in ambulant DMD boys. The aim of this longitudinal Italian multicentric study was to evaluate the correlation between the 6 Minute Walk Test (6MWT) and the PUL in ambulant DMD boys. Both 6MWT and PUL were administered to 164 ambulant DMD boys of age between 5.0 and 16.17 years (mean 8.82). The 6 minute walk distance (6MWD) ranged between 118 and 557 (mean: 376.38, SD: 90.59). The PUL total scores ranged between 52 and 74 (mean: 70.74, SD: 4.66). The correlation between the two measures was 0.499. The scores on the PUL largely reflect the overall impairment observed on the 6MWT but the correlation was not linear. The use of the PUL appeared to be less relevant in the very strong patients with 6MWD above 400 meters, who, with few exceptions had near full scores. In patients with lower 6MWD the severity of upper limb involvement was more variable and could not always be predicted by the 6MWD value or by the use of steroids. Our results confirm that upper limb involvement can already be found in DMD boys even in the ambulant phase. PMID:25642376

  18. Improved molecular diagnosis of facioscapulohumeral muscular dystrophy (FSHD): validation of the differential double digestion for FSHD.

    PubMed Central

    Upadhyaya, M; Maynard, J; Rogers, M T; Lunt, P W; Jardine, P; Ravine, D; Harper, P S

    1997-01-01

    A major advance in the molecular diagnosis of facioscapulohumeral muscular dystrophy is the recently reported elimination of confounding DNA fragments arising from homologous sequences located at 10q26. In order to evaluate the specificity and sensitivity of this important diagnostic test, we have compared a group of 130 patients fulfilling the diagnostic criteria for FSHD with 200 control subjects not known to have an increased risk of having an FSHD mutation. Among the FSHD cases the smallest BlnI/EcoRI fragment sizes ranged from 10 to > 48 kb with 94.6% (95% CI 89.2-97.8%) of cases having fragment sizes of 34 kb or less. Among the 400 chromosomes from controls the smallest BlnI/EcoRI fragment observed with the EcoRI/BlnI double restriction enzyme digest was 38 kb +/- 2 kb, suggesting a test specificity at a fragment size < 34 kb of or very near to 100% (lower 95% CI 98.2%). Test sensitivity at < 34 kb is estimated at 94.6% (95% CI 89.2-97.8%), all outliers having fragments > 38 kb. The Southern blot analysis with DNA probe p13E-11 has created a valuable molecular diagnostic test for FSHD. Images PMID:9192267

  19. Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan.

    PubMed

    Liang, Wen-Chen; Chou, Po-Ching; Hung, Chia-Cheng; Su, Yi-Ning; Kan, Tsu-Min; Chen, Wan-Zi; Hayashi, Yukiko K; Nishino, Ichizo; Jong, Yuh-Jyh

    2016-03-15

    Limb-girdle muscular dystrophy type 2D (LGMD2D), an autosomal-recessive inherited LGMD, is caused by the mutations in SGCA. SGCA encodes alpha-sarcoglycan (SG) that forms a heterotetramer with other SGs in the sarcolemma, and comprises part of the dystrophin-glycoprotein complex. The frequency of LGMD2D is variable among different ethnic backgrounds, and so far only a few patients have been reported in Asia. We identified five patients with a novel homozygous mutation of c.101G>T (p.Arg34Leu) in SGCA from a big aboriginal family ethnically consisting of two tribes in Taiwan. Patient 3 is the maternal uncle of patients 1 and 2. All their parents, heterozygous for c.101G>T, denied consanguineous marriages although they were from the same tribe. The heterozygous parents of patients 4 and 5 were from two different tribes, originally residing in different geographic regions in Taiwan. Haplotype analysis showed that all five patients shared the same mutation-associated haplotype, indicating the probability of a founder effect and consanguinity. The results suggest that the carrier rate of c.101G>T in SGCA may be high in Taiwan, especially in the aboriginal population regardless of the tribes. It is important to investigate the prevalence of LGMD2D in Taiwan for early diagnosis and treatment. PMID:26944168

  20. Genetic heterogeneity of limb-girdle muscular dystrophy in Amish populations

    SciTech Connect

    Beckmann, J.S.; Allamand, V.; Broux, O.

    1994-09-01

    The autosomal recessive form of limb-girdle muscular dystrophy (LGMD2) is characterized by onset in childhood, progressive weakness predominantly of shoulder, pelvic and trunk muscles with sparing of facial muscles. A gene for LGMD2 was localized to chromosome 15q by Beckmann et al. in 1991 in Isle La Reunion families, subsequently confirmed in Amish families and in Brazilian families where genetic heterogeneity has been demonstrated. Analysis of LGM2 families for recombination events permitted the gene region to be restricted to an interval of about 7 cM defined by flanking markers D15S129 and D15S143. Extended haplotypes were established in the families on the basis of the segregation of multiple markers within this interval. Although the nine northern Indiana Amish families showed linkage of the gene to chromosome 15 markers (maximum lod score of 7.58 at {theta}=0.06 for D15S129 and 12.57 at {theta}=0.046 for D15S143), six large southern Indiana families with LGMD2, clinically indistinguishable from the LGMD2 in northern Indiana, were found to have a disease neither linked to chromosome 15 nor to chromosome 2 where a second localization has been reported. Although these two Indiana Amish LGMD2 kindreds contain some common ancestors and are clinically similar, the LGMD2 appears to be genetically heterogeneous.

  1. Early pathogenesis of Duchenne muscular dystrophy modelled in patient-derived human induced pluripotent stem cells.

    PubMed

    Shoji, Emi; Sakurai, Hidetoshi; Nishino, Tokiko; Nakahata, Tatsutoshi; Heike, Toshio; Awaya, Tomonari; Fujii, Nobuharu; Manabe, Yasuko; Matsuo, Masafumi; Sehara-Fujisawa, Atsuko

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive and fatal muscle degenerating disease caused by a dystrophin deficiency. Effective suppression of the primary pathology observed in DMD is critical for treatment. Patient-derived human induced pluripotent stem cells (hiPSCs) are a promising tool for drug discovery. Here, we report an in vitro evaluation system for a DMD therapy using hiPSCs that recapitulate the primary pathology and can be used for DMD drug screening. Skeletal myotubes generated from hiPSCs are intact, which allows them to be used to model the initial pathology of DMD in vitro. Induced control and DMD myotubes were morphologically and physiologically comparable. However, electric stimulation of these myotubes for in vitro contraction caused pronounced calcium ion (Ca(2+)) influx only in DMD myocytes. Restoration of dystrophin by the exon-skipping technique suppressed this Ca(2+) overflow and reduced the secretion of creatine kinase (CK) in DMD myotubes. These results suggest that the early pathogenesis of DMD can be effectively modelled in skeletal myotubes induced from patient-derived iPSCs, thereby enabling the development and evaluation of novel drugs. PMID:26290039

  2. Histopathology of hereditary muscular dystrophy of the domestic turkey (Meleagris gallopavo).

    PubMed Central

    Schmitz, J A; Harper, J A

    1975-01-01

    The histopathology of hereditary muscular dystrophy was studied in homozygous dystrophic turkeys of various ages. Myopathy was severe at ten weeks of age but absent at seven weeks or less. Lesions at ten weeks consisted of variation in fiber size and contour with acute necrosis of individual muscle fibers. Myopathic characteristics were similar at 16 and 24 weeks but with fewer dystrophic fibers and slower fiber destruction. Fat deposition was mild at 24 weeks and there were disseminated foci or endomysial proliferation in dystrophic muscle at 16 and 24 weeks. Pectoral and alar muscles were dystrophic but no lesions were detected in gastrocnemius muscle, myocardium, central and peripheral nervous system tissue or visceral organs. Mean diameters and nuclear numbers of muscle fibers were significantly less in pectoral muscles of dystrophic turkeys than in controls and did not have increase significantly from ten to 24 weeks of age as did controls. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:1175075

  3. Behavioral Responses in Animal Model of Congenital Muscular Dystrophy 1D.

    PubMed

    Comim, Clarissa M; Schactae, Aryadnne L; Soares, Jaime A; Ventura, Letcia; Freiberger, Viviane; Mina, Francielle; Dominguini, Diogo; Vainzof, Mariz; Quevedo, Joo

    2016-01-01

    Congenital muscular dystrophies 1D (CMD1D) present a mutation on the LARGE gene and are characterized by an abnormal glycosylation of ?-dystroglycan (?-DG), strongly implicated as having a causative role in the development of central nervous system abnormalities such as cognitive impairment seen in patients. However, in the animal model of CMD1D, the brain involvement remains unclear. Therefore, the objective of this study is to evaluate the cognitive involvement in the Large(myd) mice. To this aim, we used adult homozygous, heterozygous, and wild-type mice. The mice underwent six behavioral tasks: habituation to an open field, step-down inhibitory avoidance, continuous multiple trials step-down inhibitory avoidance task, object recognition, elevated plus-maze, and forced swimming test. It was observed that Large(myd) individuals presented deficits on the habituation to the open field, step down inhibitory avoidance, continuous multiple-trials step-down inhibitory avoidance, object recognition, and forced swimming. This study shows the first evidence that abnormal glycosylation of ?-DG may be affecting memory storage and restoring process in an animal model of CMD1D. PMID:25465243

  4. PRO-051, an antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy.

    PubMed

    Hammond, Suzan M; Wood, Matthew Ja

    2010-08-01

    PRO-051 (GSK-2402968), being developed by GlaxoSmithKline plc, under license from Leiden University Medical Center and Prosensa Therapeutics BV, is a 2'-O-methyl phosphorothioate antisense oligonucleotide for the potential treatment of Duchenne muscular dystrophy (DMD). The PRO-051 oligonucleotide sequence induces skipping of exon 51 of the dystrophin gene by binding to a sequence within the dystrophin pre-mRNA and masking the exon inclusion signals that are used for splicing. Removal of exon 51 from an exon 45 to 50, 47 to 50, 48 to 50, 49 to 50, 50, 52 or 52 to 63 deleted transcript allows restoration of the open reading frame and synthesis of an internally truncated, semi-functional dystrophin protein. By targeting exon 51, approximately 13% of patients with DMD could be treated, the largest proportion of patients that could benefit from targeting a single dystrophin exon. A proof-of-concept clinical trial of PRO-051 in patients with DMD demonstrated that a single intramuscular administration of PRO-051 induced exon skipping within muscle fibers adjacent to the injection site, while biopsies revealed dystrophin expression in treated but not control muscle fibers. At the time of publication, a phase I/IIa trial to evaluate subcutaneous delivery of PRO-051 had been completed, although full results were yet to be published. PMID:20677099

  5. Myogenic Enhancers Regulate Expression of the Facioscapulohumeral Muscular Dystrophy-Associated DUX4 Gene

    PubMed Central

    Himeda, Charis L.; Debarnot, Cline; Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey B.

    2014-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite. However, this does not account for the tissue specificity of FSHD pathology, which requires stable expression of an alternative full-length mRNA splice form of DUX4 (DUX4-fl) from the D4Z4 array in skeletal muscle. Here, we describe the identification of two enhancers, DUX4 myogenic enhancer 1 (DME1) and DME2 which activate DUX4-fl expression in skeletal myocytes but not fibroblasts. Analysis of the chromatin revealed histone modifications and RNA polymerase II occupancy consistent with DME1 and DME2 being functional enhancers. Chromosome conformation capture analysis confirmed association of DME1 and DME2 with the DUX4 promoter in vivo. The strong interaction between DME2 and the DUX4 promoter in both FSHD and unaffected primary myocytes was greatly reduced in fibroblasts, suggesting a muscle-specific interaction. Nucleosome occupancy and methylome sequencing analysis indicated that in most FSHD myocytes, both enhancers are associated with nucleosomes but have hypomethylated DNA, consistent with a permissive transcriptional state, sporadic occupancy, and the observed DUX4 expression in rare myonuclei. Our data support a model in which these myogenic enhancers associate with the DUX4 promoter in skeletal myocytes and activate transcription when epigenetically derepressed in FSHD, resulting in the pathological misexpression of DUX4-fl. PMID:24636994

  6. The effects of electrical stimulation and exercise therapy in patients with limb girdle muscular dystrophy

    PubMed Central

    Kılınç, Muhammed; Yıldırım, Sibel A.; Tan, Ersin

    2015-01-01

    Objective: To evaluate and compare the effects of exercise therapy and electrical stimulation on muscle strength and functional activities in patients with limb-girdle muscular dystrophy (LGMD). Methods: This controlled clinical trial included 24 subjects who were diagnosed with LGMD by the Neurology Department of the Hacettepe University Hospital, Ankara, Turkey and were referred to the Physical Therapy Department between May 2013 and December 2014. Subjects were enrolled into an electrical stimulation (11 patients) group, or an exercise therapy (13 patients) group. Results: The mean age of patients was 31.62 years in the electrical stimulation group, and 30.14 years in the exercise therapy group. The most important results in this controlled clinical study were that the muscle strength in both groups was significantly decreased and post-treatment evaluation results indicated that muscle strength of the Deltoideus was higher in the electrical stimulation group, and the difference between the groups was maintained in the follow-up period (p<0.05). However, the muscle strength of quadriceps was similar in both groups, according to the post-treatment and follow-up evaluation results (p>0.05). Additionally, the electrical stimulation group presented more obvious overall improvements than the exercise therapy group according to muscle strength, endurance, and timed performance tests. Conclusions: Since no definitive treatments currently exist for patients with LGMD, these results provide important information on the role of exercise therapy and electrical stimulation for clinicians working in rehabilitation. PMID:26166595

  7. Selective Connexin43 Inhibition Prevents Isoproterenol-Induced Arrhythmias and Lethality in Muscular Dystrophy Mice

    PubMed Central

    Patrick Gonzalez, J.; Ramachandran, Jayalakshmi; Xie, Lai-Hua; Contreras, Jorge E.; Fraidenraich, Diego

    2015-01-01

    Duchenne muscular dystrophy (DMD) is caused by an X-linked mutation that leads to the absence of dystrophin, resulting in life-threatening arrhythmogenesis and associated heart failure. We targeted the gap junction protein connexin43 (Cx43) responsible for maintaining cardiac conduction. In mild mdx and severe mdx:utr mouse models of DMD, and human DMD tissues, Cx43 was found to be pathologically mislocalized to lateral sides of cardiomyocytes. In addition, overall Cx43 protein levels were markedly increased in mouse and human DMD heart tissues examined. Electrocardiography on isoproterenol challenged mice showed that both models developed arrhythmias and died within 24?hours, while wild-type mice were free of pathology. Administering peptide mimetics to inhibit lateralized Cx43 function prior to challenge protected mdx mice from arrhythmogenesis and death, while mdx:utr mice displayed markedly improved ECG scores. These findings suggest that Cx43 lateralization contributes significantly to DMD arrhythmogenesis and that selective inhibition may provide substantial benefit. PMID:26311238

  8. Clinical features and a mutation with late onset of limb girdle muscular dystrophy 2B

    PubMed Central

    Takahashi, Toshiaki; Aoki, Masashi; Suzuki, Naoki; Tateyama, Maki; Yaginuma, Chikako; Sato, Hitomi; Hayasaka, Miho; Sugawara, Hitomi; Ito, Mariko; Abe-Kondo, Emi; Shimakura, Naoko; Ibi, Tohru; Kuru, Satoshi; Wakayama, Tadashi; Sobue, Gen; Fujii, Naoki; Saito, Toshio; Matsumura, Tsuyoshi; Funakawa, Itaru; Mukai, Eiichiro; Kawanami, Toru; Morita, Mitsuya; Yamazaki, Mineo; Hasegawa, Takashi; Shimizu, Jun; Tsuji, Shoji; Kuzuhara, Shigeki; Tanaka, Hiroyasu; Yoshioka, Masaru; Konno, Hidehiko; Onodera, Hiroshi; Itoyama, Yasuto

    2013-01-01

    Objective and methods Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed. Results and conclusions Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations. PMID:23243261

  9. MRI/MRS Evaluation of a Female Carrier of Duchenne Muscular Dystrophy

    PubMed Central

    Forbes, Sean C.; Lott, Donovan J.; Finkel, Richard S.; Senesac, Claudia; Byrne, Barry J.; Sweeney, H. L.; Walter, Glenn A.; Vandenborne, Krista

    2012-01-01

    The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFCDMD) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFCDMD (47yr, 51kg) on four occasions within 21 months and in a control subject. Heterogeneity and asymmetry among muscles in the MFCDMD was observed in lipid fraction and mean transverse relaxation time (T2) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21 months a small decrease in CSAmax and increase in lipid fraction and T2 was observed in the MFCDMD in some muscles. In summary, this MFCDMD revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement. PMID:22980762

  10. β-Catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy.

    PubMed

    Banerji, Christopher R S; Knopp, Paul; Moyle, Louise A; Severini, Simone; Orrell, Richard W; Teschendorff, Andrew E; Zammit, Peter S

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development. PMID:25551153

  11. Loss of epigenetic silencing of the DUX4 transcription factor gene in facioscapulohumeral muscular dystrophy.

    PubMed

    Hewitt, Jane E

    2015-10-15

    Current genetic and molecular evidence best supports an epigenetic mechanism for facioscapulohumeral muscular dystrophy (FSHD), whereby de-repression of the D4Z4 macrosatellite array leads to aberrant expression of the DUX4 transcription factor in skeletal muscle. This de-repression is triggered by either array contraction or (more rarely) by mutation of the SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) gene. Activation of DUX4 targets, including germline genes and several mammalian retrotransposons, then drives pathogenesis. A direct role for DUX4 mRNA in suppression of nonsense-mediated decay pathways has recently been demonstrated and may also contribute to muscle pathology. Loss of D4Z4 repression in FSHD is observed as hypomethylation of the array accompanied by loss of repressive chromatin marks. The molecular mechanisms of D4Z4 repression are poorly understood, but recent data have identified an Argonaute (AGO)-dependent siRNA pathway. Targeting this pathway by exogenous siRNAs could be a therapeutic strategy for FSHD. PMID:26113644

  12. Hemizygosity for SMCHD1 in Facioscapulohumeral Muscular Dystrophy Type 2: Consequences for 18p Deletion Syndrome.

    PubMed

    Lemmers, Richard J L F; van den Boogaard, Marlinde L; van der Vliet, Patrick J; Donlin-Smith, Colleen M; Nations, Sharon P; Ruivenkamp, Claudia A L; Heard, Patricia; Bakker, Bert; Tapscott, Stephen; Cody, Jannine D; Tawil, Rabi; van der Maarel, Silvère M

    2015-07-01

    Facioscapulohumeral muscular dystrophy (FSHD) is most often associated with variegated expression in somatic cells of the normally repressed DUX4 gene within the D4Z4-repeat array. The most common form, FSHD1, is caused by a D4Z4-repeat array contraction to a size of 1-10 units (normal range 10-100 units). The less common form, FSHD2, is characterized by D4Z4 CpG hypomethylation and is most often caused by loss-of-function mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18p. The chromatin modifier SMCHD1 is necessary to maintain a repressed D4Z4 chromatin state. Here, we describe two FSHD2 families with a 1.2-Mb deletion encompassing the SMCHD1 gene. Numerical aberrations of chromosome 18 are relatively common and the majority of 18p deletion syndrome (18p-) cases have, such as these FSHD2 families, only one copy of SMCHD1. Our finding therefore raises the possibility that 18p- cases are at risk of developing FSHD. To address this possibility, we combined genome-wide array analysis data with D4Z4 CpG methylation and repeat array sizes in individuals with 18p- and conclude that approximately 1:8 18p- cases might be at risk of developing FSHD. PMID:25820463

  13. β-catenin is central to DUX4-driven network rewiring in facioscapulohumeral muscular dystrophy

    PubMed Central

    Banerji, Christopher R. S.; Knopp, Paul; Moyle, Louise A.; Severini, Simone; Orrell, Richard W.; Teschendorff, Andrew E.; Zammit, Peter S.

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an incurable disease, characterized by skeletal muscle weakness and wasting. Genetically, FSHD is characterized by contraction or hypomethylation of repeat D4Z4 units on chromosome 4, which causes aberrant expression of the transcription factor DUX4 from the last repeat. Many genes have been implicated in FSHD pathophysiology, but an integrated molecular model is currently lacking. We developed a novel differential network methodology, Interactome Sparsification and Rewiring (InSpiRe), which detects network rewiring between phenotypes by integrating gene expression data with known protein interactions. Using InSpiRe, we performed a meta-analysis of multiple microarray datasets from FSHD muscle biopsies, then removed secondary rewiring using non-FSHD datasets, to construct a unified network of rewired interactions. Our analysis identified β-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-α and TNF-α clearly perturbed. To detect transcriptional changes directly elicited by DUX4, gene expression profiling was performed using microarrays on murine myoblasts. This revealed that DUX4 significantly modified expression of the genes in our FSHD network. Furthermore, we experimentally confirmed that Wnt/β-catenin signalling is affected by DUX4 in murine myoblasts. Thus, we provide the first unified molecular map of FSHD signalling, capable of uncovering pathomechanisms and guiding therapeutic development. PMID:25551153

  14. Myoblast transplantation between monozygotic twin girl carriers of Duchenne muscular dystrophy.

    PubMed

    Tremblay, J P; Bouchard, J P; Malouin, F; Thau, D; Cottrell, F; Collin, H; Rouche, A; Gilgenkrantz, S; Abbadi, N; Tremblay, M

    1993-01-01

    Monozygotic twin girls, both carriers of Duchenne muscular dystrophy, only one a severe symptomatic carrier and the other asymptomatic due to opposite lyonization, were studied. Myoblast clones were obtained from a muscle biopsy of the asymptomatic carrier. PCR amplification showed that most (94%) of these clones produced normal dystrophin mRNA. Roughly 704 million myoblasts were produced from 119 clones. These myoblasts were transplanted into the extensor carpi radialis (ECR) and in the biceps of one arm of the manifesting carrier while the other arm acted as the control. The strength of the patient was evaluated in a series of pre- and post-tests and a biopsy was obtained about 1 yr after the transplantation. The myoblast injections produced a significant force gain (12%-31%) in wrist extension but no force gain for elbow flexion. Muscle biopsies on the injected and control muscles obtained 1 yr after the injections showed only a small increase in the number of dystrophin positive fibers and the presence of numerous small type II fibers. The small beneficial effect of this transplantation cannot be attributed to immune problems, the donor and the recipient being identical twins, but may be due to a low level of spontaneous muscle regeneration. PMID:8186717

  15. Duchenne muscular dystrophy in monozygotic twins: deletion of 5' fragments of the gene.

    PubMed

    Ionasescu, V V; Searby, C C; Ionasescu, R; Patil, S

    1989-05-01

    A recombinant DNA study for deletion evaluation was performed in a 4 generation family with Duchenne muscular dystrophy (DMD) in twins. The patients were 6 years old, had a history of progressive difficulty in walking since age 4, and showed weak gluteals, iliopsoas, latissimus dorsi, rhomboids, lower trapezius, sternocleidomastoids, pseudohypertrophic calves, and tight heelcords. Both patients had high serum creatine kinase of 19,000 and 11,000 IU, respectively, and the muscle biopsy of the left vastus lateralis showed dystrophic alterations. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing also detected the same antigens in both twins: A2, B44, DR4, and DR5. Cytogenetic studies were consistent with 46, XY male individuals with normal banding pattern. By cDNA probes the entire DMD gene was surveyed for missing or abnormal-sized restriction fragments. Both twin boys showed absence of 8.5, 8.0, 4.6, 4.2, and 3.1 kb fragments on Hind III blots and absence of 13.5, 3.7, 2.9, and 1.4 kb fragments on Bgl II blots both hybridized with cDNA 1-2a corresponding to most 5' region of the DMD gene. The mother and other relatives of the patient did not show deletion. These findings strongly suggest that the deletion in the DMD monozygotic twins represents a new mutation. PMID:2750778

  16. The clinical consequences of X-chromosome inactivation: Duchenne muscular dystrophy in one of monozygotic twins.

    PubMed

    Pena, S D; Karpati, G; Carpenter, S; Fraser, F C

    1987-07-01

    We have ascertained retrospectively a female patient, one of identical twins, who was diagnosed at age 23 years as having Duchenne muscular dystrophy (DMD). A muscle biopsy at that time showed a pattern in which large areas of destroyed muscle fibers replaced with adipose tissue were interspersed with normal-appearing muscle fascicles. The visualization of Barr bodies in the muscle biopsy, plus the patient's normal menstrual history served to rule out Turner's syndrome. The clinical expression of DMD in only one of monozygotic twins is strongly suggestive of uneven lyonization, with an excess of paternally derived X-chromosomes being inactivated in the patient. This view is supported by the appearance of the muscle biopsy. Twinning may conceivably predispose to uneven lyonization by reducing the size of the muscle cell anlage at the time of X-chromosome inactivation. Alternatively, lyonization may occur before the splitting of the embryonic mass, and by chance, the two embryonic centers could end up with a significantly different proportion of active maternal and paternal X-chromosomes. PMID:3612177

  17. Systemic Inflammation in Duchenne Muscular Dystrophy: Association with Muscle Function and Nutritional Status

    PubMed Central

    Cruz-Guzmán, Oriana del Rocío; Rodríguez-Cruz, Maricela; Escobar Cedillo, Rosa Elena

    2015-01-01

    Inflammation described in patients with Duchenne muscular dystrophy (DMD) may be related to loss of muscle function or to obesity. It is unknown if circulating proinflammatory cytokines (IL-6, IL-1, and TNF-α) levels are associated with muscle function. The purpose was to evaluate whether an association exists between systemic inflammation with muscle function and nutritional status in DMD patients. In 66 DMD patients without corticosteroid treatment, the following were evaluated in serum: cytokines (IL-1, IL-6, and TNF-α), C-reactive protein (CRP), leptin, adiponectin, and creatine kinase (CK). Muscle function was evaluated using Vignos Scale. Patients with better muscle function had the highest concentration of CK, IL-1, and TNF-α compared with less muscle function. No differences in IL-6 and adiponectin concentration were identified among groups with different levels of muscle function. Also, no differences were observed in the concentration of cytokines among groups with different nutritional status levels (underweight, normal weight, and overweight/obese). However, CRP and leptin were increased in the obese group compared with normal and underweight subjects. Systemic inflammation is increased in patients with better muscle function and decreases in DMD patients with poorer muscle function; nevertheless, systemic inflammation is similar among different levels of nutritional status in DMD patients. PMID:26380303

  18. Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy

    PubMed Central

    Rodríguez-Cruz, Maricela; Sanchez, Raúl; Escobar, Rosa E.; Cruz-Guzmán, Oriana del Rocío; López-Alarcón, Mardia; Bernabe García, Mariela; Coral-Vázquez, Ramón; Matute, Guadalupe; Velázquez Wong, Ana Claudia

    2015-01-01

    Aim. Our aim was (1) to determine the frequency of insulin resistance (IR) in patients with Duchenne/Becker muscular dystrophy (DMD/BMD), (2) to identify deleted exons of DMD gene associated with obesity and IR, and (3) to explore some likely molecular mechanisms leading to IR. Materials and Methods. In 66 patients with DMD/BMD without corticosteroids treatment, IR, obesity, and body fat mass were evaluated. Molecules involved in glucose metabolism were analyzed in muscle biopsies. Results show that 18.3%, 22.7%, and 68% were underweight, overweight, or obese, and with high adiposity, respectively; 48.5% and 36.4% presented hyperinsulinemia and IR, respectively. Underweight patients (27.3%) exhibited hyperinsulinemia and IR. Carriers of deletions in exons 45 (OR = 9.32; 95% CI = 1.16–74.69) and 50 (OR = 8.73; 95% CI = 1.17–65.10) from DMD gene presented higher risk for IR than noncarriers. We observed a greater staining of cytoplasmic aggregates for GLUT4 in muscle biopsies than healthy muscle tissue. Conclusion. Obesity, hyperinsulinemia, and IR were observed in DMD/BMD patients and are independent of corticosteroids treatment. Carriers of deletion in exons 45 or 50 from DMD gene are at risk for developing IR. It is suggested that alteration in GLUT4 in muscle fibers from DMD patients could be involved in IR. PMID:26089900

  19. Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy.

    PubMed Central

    Quan, F; Janas, J; Toth-Fejel, S; Johnson, D B; Wolford, J K; Popovich, B W

    1997-01-01

    Duchenne muscular dystrophy (DMD) is a severe, progressive, X-linked muscle-wasting disorder with an incidence of approximately 1/3,500 male births. Females are also affected, in rare instances. The manifestation of mild to severe symptoms in female carriers of dystrophin mutations is often the result of the preferential inactivation of the X chromosome carrying the normal dystrophin gene. The severity of the symptoms is dependent on the proportion of cells that have inactivated the normal X chromosome. A skewed pattern of X inactivation is also responsible for the clinical manifestation of DMD in females carrying X;autosome translocations, which disrupt the dystrophin gene. DMD may also be observed in females with Turner syndrome (45,X), if the remaining X chromosome carries a DMD mutation. We report here the case of a karyotypically normal female affected with DMD as a result of homozygosity for a deletion of exon 50 of the dystrophin gene. PCR analysis of microsatellite markers spanning the length of the X chromosome demonstrated that homozygosity for the dystrophin gene mutation was caused by maternal isodisomy for the entire X chromosome. This finding demonstrates that uniparental isodisomy of the X chromosome is an additional mechanism for the expression of X-linked recessive disorders. The proband's clinical presentation is consistent with the absence of imprinted genes (i.e., genes that are selectively expressed based on the parent of origin) on the X chromosome. Images Figure 1 Figure 2 PMID:8981959

  20. A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome

    PubMed Central

    2013-01-01

    Background The complexity of the skeletal muscle and the identification of numerous human disease-causing mutations in its constitutive proteins make it an interesting tissue for proteomic studies aimed at understanding functional relationships of interacting proteins in both health and diseases. Method We undertook a large-scale study using two-hybrid screens and a human skeletal-muscle cDNA library to establish a proteome-scale map of protein-protein interactions centered on proteins involved in limb-girdle muscular dystrophies (LGMD). LGMD is a group of more than 20 different neuromuscular disorders that principally affect the proximal pelvic and shoulder girdle muscles. Results and conclusion The interaction network we unraveled incorporates 1018 proteins connected by 1492 direct binary interactions and includes 1420 novel protein-protein interactions. Computational, experimental and literature-based analyses were performed to assess the overall quality of this network. Interestingly, LGMD proteins were shown to be highly interconnected, in particular indirectly through sarcomeric proteins. In-depth mining of the LGMD-centered interactome identified new candidate genes for orphan LGMDs and other neuromuscular disorders. The data also suggest the existence of functional links between LGMD2B/dysferlin and gene regulation, between LGMD2C/γ-sarcoglycan and energy control and between LGMD2G/telethonin and maintenance of genome integrity. This dataset represents a valuable resource for future functional investigations. PMID:23414517