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Sample records for emery-dreifuss muscular dystrophy

  1. Atrial paralysis in a patient with Emery-Dreifuss muscular dystrophy.

    PubMed

    Marshall, T M; Huckell, V F

    1992-02-01

    Emery-Dreifuss disease is a benign X-linked muscular dystrophy characterized by a distinct pattern of muscle weakness, which is of insidious onset and slow progression. It is associated with atrial paralysis that results in sudden death in early adulthood if left untreated. The authors report the documentation of electrical and mechanical silence confined to the atria in a patient with this disease. Electrocardiography and electrophysiological study document the absence of electrical atrial activity, and inability to pace the atria. Hemodynamic studies demonstrate the absence of A waves, and angiography revealed immobility of the atria. This patient has done well following the institution of permanent ventricular pacing. His brother, who also had muscular dystrophy, died a sudden cardiac death at the age of 29 after refusing medical intervention. Emery-Dreifuss muscular dystrophy is particularly worthy of recognition because of the preventable occurrence of sudden death in young patients with an otherwise excellent prognosis. Permanent ventricular pacing is indicated. PMID:1372411

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

    PubMed

    Madej-Pilarczyk, A; Kotruchow, K; Kabzinska, D; Cegielska, J; Kochanski, A; Hausmanowa-Petrusewicz, I

    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

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

    PubMed Central

    ZHANG, LI; SHEN, HONGRUI; ZHAO, ZHE; BING, QI; HU, JING

    2015-01-01

    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

  4. 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.

  5. 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.

  6. 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 ...

  7. doi:10.1093/brain/awl023 Brain (2006), 129, 9961013 Nuclear envelope dystrophies show a

    E-print Network

    Shneiderman, Ben

    2006-01-01

    Mutations of lamin A/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery­Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X

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

    MedlinePLUS

    ... to live with muscles that grow weaker over time, but you don’t have to let MD keep you from pursuing an education, career, family, travel — anything you want. People with disabilities have more ...

  9. Muscular Dystrophy

    MedlinePLUS

    ... Coping Center Writing a Paper Abusive Relationships Dynamic Stretching A Guy's Guide to Body Image Muscular Dystrophy KidsHealth > Teens > Diseases & Conditions > Bones, Muscles & Joints > Muscular ...

  10. 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 ...

  11. Muscular Dystrophy

    MedlinePLUS

    ... in Duchenne muscular dystrophy. Dev. Med. Child Neurol. Mar 1995;37(3):260-269. 4. Centers for ... DM1) . The International Myotonic Dystrophy Consortium (IDMC). Neurology. Mar 28 2000;54(6):1218-1221. 5. Harper ...

  12. 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. ...

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

    PubMed

    Szmidt-Sa?kowska, El?bieta; Gawe?, Ma?gorzata; 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

  14. Phenotype–Genotype 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. Phenotype–genotype analysis determines that some mutations are well correlated with LMNA-related MD. PMID:26098624

  15. Becker muscular dystrophy

    MedlinePLUS

    ... and wheelchairs may improve movement and self-care. Genetic counseling may be recommended. Daughters of a man with ... Genetic counseling may be advised if there is a family history of Becker muscular dystrophy.

  16. 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)

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

    PubMed

    Herrada, Isaline; Samson, Camille; Velours, Christophe; Renault, Louis; Östlund, 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

  18. Muscular Dystrophy-Associated SUN1 and SUN2 Variants Disrupt Nuclear-Cytoskeletal Connections and Myonuclear Organization

    PubMed Central

    Antoku, Susumu; Columbaro, Marta; Straatman, Kees R.; Worman, Howard J.; Gundersen, Gregg G.; Lattanzi, Giovanna; Wehnert, Manfred; Shackleton, Sue

    2014-01-01

    Proteins of the nuclear envelope (NE) are associated with a range of inherited disorders, most commonly involving muscular dystrophy and cardiomyopathy, as exemplified by Emery-Dreifuss muscular dystrophy (EDMD). EDMD is both genetically and phenotypically variable, and some evidence of modifier genes has been reported. Six genes have so far been linked to EDMD, four encoding proteins associated with the LINC complex that connects the nucleus to the cytoskeleton. However, 50% of patients have no identifiable mutations in these genes. Using a candidate approach, we have identified putative disease-causing variants in the SUN1 and SUN2 genes, also encoding LINC complex components, in patients with EDMD and related myopathies. Our data also suggest that SUN1 and SUN2 can act as disease modifier genes in individuals with co-segregating mutations in other EDMD genes. Five SUN1/SUN2 variants examined impaired rearward nuclear repositioning in fibroblasts, confirming defective LINC complex function in nuclear-cytoskeletal coupling. Furthermore, myotubes from a patient carrying compound heterozygous SUN1 mutations displayed gross defects in myonuclear organization. This was accompanied by loss of recruitment of centrosomal marker, pericentrin, to the NE and impaired microtubule nucleation at the NE, events that are required for correct myonuclear arrangement. These defects were recapitulated in C2C12 myotubes expressing exogenous SUN1 variants, demonstrating a direct link between SUN1 mutation and impairment of nuclear-microtubule coupling and myonuclear positioning. Our findings strongly support an important role for SUN1 and SUN2 in muscle disease pathogenesis and support the hypothesis that defects in the LINC complex contribute to disease pathology through disruption of nuclear-microtubule association, resulting in defective myonuclear positioning. PMID:25210889

  19. Muscular dystrophy family Most common of the dystrophies

    E-print Network

    Brutlag, Doug

    ". Muscular Dystrophy Campaign. 2008. Torchbox. 29 Sep 2008. dystrophy.org> "MyotonicLidia Park #12; Muscular dystrophy family Most common of the dystrophies Myotonia- inability dystrophies #12;#12; Still being researched Strong conservation in other animals = high research potential 3

  20. Duchenne and Becker Muscular Dystrophies

    MedlinePLUS

    ... muscular dystrophy (DMD) was first described by the French neurologist Guillaume Benjamin Amand Duchenne in the 1860s. ... Children with the disorder are often late in learning to walk. In toddlers, parents may notice enlarged ...

  1. [Therapeutic strategy for muscular dystrophies].

    PubMed

    Shin, Jin-Hong; Takeda, Shin'ichi

    2007-04-01

    A successful cure for muscular dystrophies has yet to be demonstrated, but we could notice spectacular progress for the past few years. Advances have been made in methods of delivering foreign genes into muscle cells, either as naked plasmid DNA or via viral vectors. Among the virus-based methods, results with adeno-associated viral vectors have been the most promising. Systemic administration of anti-sense oligonucleotides has shown incredible success in inducing dystrophin expression and ameliorating muscle pathology via exon skipping in canine models of muscular dystrophy. Biochemical and functional rescue of dystrophic muscle has also been demonstrated with the transplantation of normal or genetically modified myogenic stem cells, as well as with a number of pharmacological approaches in animal models. Here we review the current researches on the treatment of muscular dystrophies and clinical trials on Duchenne muscular dystrophy. PMID:17447528

  2. 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...

  3. Wasting mechanisms in muscular dystrophy.

    PubMed

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

    2013-10-01

    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. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting. PMID:23669245

  4. Duchenne and Becker muscular dystrophies.

    PubMed

    Flanigan, Kevin M

    2014-08-01

    The dystrophinopathies Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most common inherited disorders of muscle. Improvements in cardiac care, attention to respiratory function, and judicious use of spinal correction surgery have led to increased survival in the DMD population. Meanwhile, advances in molecular therapeutics have led to promising therapies that are in or are entering clinical trials. An understanding of the dystrophinopathies, and recent advances in their molecular diagnosis and treatment, is of benefit to practicing neurologists. PMID:25037084

  5. 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 ...

  6. Duchenne muscular dystrophy: current cell therapies

    PubMed Central

    Sienkiewicz, Dorota; Okurowska-Zawada, Bo?ena; Paszko-Patej, Gra?yna; 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

  7. 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

  8. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    MedlinePLUS

    ... normal function. Without functional ?-dystroglycan to stabilize muscle cells, muscle fibers become damaged as they repeatedly contract ... hypotonia ; incidence ; infection ; inherited ; joint ; mental retardation ; motor ; muscle cells ; muscle tone ; muscular dystrophy ; mutation ; nervous system ; neuronal ...

  9. Genetics Home Reference: Tibial muscular dystrophy

    MedlinePLUS

    ... skeletal muscles) and in heart (cardiac) muscle. Within muscle cells, titin is an essential component of structures called ... cardiac ; cell ; contraction ; distal ; foot drop ; gene ; inherited ; muscle cells ; muscular dystrophy ; myosin ; protein ; sign ; wasting You may ...

  10. 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

  11. Duchenne muscular dystrophy and epilepsy.

    PubMed

    Pane, M; Messina, S; Bruno, C; D'Amico, A; Villanova, M; Brancalion, B; Sivo, S; Bianco, F; Striano, P; Battaglia, D; Lettori, D; Vita, G L; Bertini, E; Gualandi, F; Ricotti, V; Ferlini, A; Mercuri, E

    2013-04-01

    Cognitive and behavioral difficulties occur in approximately a third of patients with Duchenne muscular dystrophy. The aim of our study was to assess the prevalence of epilepsy in a cohort of 222 DMD patients. Epileptic seizures were found in 14 of the 222 DMD patients (6.3%). The age of onset ranged from 3 months to 16 years (mean 7.8). Seizures were more often focal epilepsy (n=6), generalized tonic-clonic seizures (n=4) or absences (n=4). They were present in 12 of the 149 boys with normal IQ (8.1%) and in two of the 73 with mental retardation (2.7%). In two cases the parents did not report any past or present history of seizures but only 'staring episodes' interpreted as a sign of 'poor attention'. In both patients EEG showed the typical pattern observed in childhood absence epilepsy. Our results suggest that the prevalence of epilepsy in our study (6.3%) is higher than in the general pediatric population (0.5-1%). The risk of epilepsy does not appear to increase in patients with mental retardation. PMID:23465656

  12. 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 ...

  13. Genetics Home Reference: LAMA2-related muscular dystrophy

    MedlinePLUS

    ... It is considered part of a class of muscle disorders called congenital muscular dystrophies and is sometimes called ... are similar to those of a group of muscle disorders classified as limb-girdle muscular dystrophies. In late- ...

  14. INTRODUCTION Duchenne muscular dystrophy (DMD) is a progressive, X-

    E-print Network

    Campbell, Kevin P.

    ). Both DMD and the more benign Becker muscular dystrophy (BMD) are caused by mutations in the geneINTRODUCTION Duchenne muscular dystrophy (DMD) is a progressive, X- linked disease in muscular dystrophy. Furthermore a reduction in laminin 2, 1 and 2 chains has been observed in other

  15. 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

  16. Muscular Dystrophy: Hope Through Research

    MedlinePLUS

    ... that may apply to multiple types of MD. Gene replacement therapy Gene therapy has the potential for directly addressing the primary ... myotonic dystrophy), researchers are developing and fine-tuning gene therapy vectors (a way to deliver genetic materials to ...

  17. 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…

  18. Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies

    PubMed Central

    Fogel, Paul; Duvallet, Angélique; Poupiot, Jérôme; Charrier, Sabine; Arock, Michel; Montus, Marie; Nelson, Isabelle; Richard, Isabelle; Carrier, Lucie; Servais, Laurent; Voit, Thomas; Bonne, Gisèle; Israeli, David

    2013-01-01

    Biomarkers are critically important for disease diagnosis and monitoring. In particular, close monitoring of disease evolution is eminently required for the evaluation of therapeutic treatments. Classical monitoring methods in muscular dystrophies are largely based on histological and molecular analyses of muscle biopsies. Such biopsies are invasive and therefore difficult to obtain. The serum protein creatine kinase is a useful biomarker, which is however not specific for a given pathology and correlates poorly with the severity or course of the muscular pathology. The aim of the present study was the systematic evaluation of serum microRNAs (miRNAs) as biomarkers in striated muscle pathologies. Mouse models for five striated muscle pathologies were investigated: Duchenne muscular dystrophy (DMD), limb-girdle muscular dystrophy type 2D (LGMD2D), limb-girdle muscular dystrophy type 2C (LGMD2C), Emery-Dreifuss muscular dystrophy (EDMD) and hypertrophic cardiomyopathy (HCM). Two-step RT-qPCR methodology was elaborated, using two different RT-qPCR miRNA quantification technologies. We identified miRNA modulation in the serum of all the five mouse models. The most highly dysregulated serum miRNAs were found to be commonly upregulated in DMD, LGMD2D and LGMD2C mouse models, which all exhibit massive destruction of striated muscle tissues. Some of these miRNAs were down rather than upregulated in the EDMD mice, a model without massive myofiber destruction. The dysregulated miRNAs identified in the HCM model were different, with the exception of one dysregulated miRNA common to all pathologies. Importantly, a specific and distinctive circulating miRNA profile was identified for each studied pathological mouse model. The differential expression of a few dysregulated miRNAs in the DMD mice was further evaluated in DMD patients, providing new candidates of circulating miRNA biomarkers for DMD. PMID:23418438

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

    PubMed

    Kanitkar, Shubhangi A; 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. Gower's 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

  20. 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. Gower’s 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

  1. Assembly of the Sarcoglycan INSIGHTS FOR MUSCULAR DYSTROPHY*

    E-print Network

    Campbell, Kevin P.

    of sarco- lemma integrity. A shared feature of four types of auto- somal recessive limb girdle muscular dystrophy (LGMD) is that mutations in a single sarcoglycan gene result in the loss of all sarcoglycans in -, -, -, and -SG cause autosomal recessive limb girdle muscular dystrophy (LGMD) types LGMD2D (5), LGMD2E (6, 7

  2. Action Plan for the Muscular Dystrophies DEPARTMENT OF HEALTH AND HUMAN SERVICES

    E-print Network

    Ungerleider, Leslie G.

    . Introduction 10 B. Recent Research Advances 11 Duchenne/Becker Muscular Dystrophy 11 Myotonic Dystrophy 13 Glycosylation 25 26 Development of Mutation Testing for Myotonic Dystrophy Type 2 27 Improved Diagnostic TestingAction Plan for the Muscular Dystrophies DEPARTMENT OF HEALTH AND HUMAN SERVICES Muscular Dystrophy

  3. 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

  4. 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

  5. Cognitive and psychological profile of males with Becker muscular dystrophy.

    PubMed

    Young, Helen K; Barton, Belinda A; Waisbren, Susan; Portales Dale, Lourdes; Ryan, Monique M; Webster, Richard I; North, Kathryn N

    2008-02-01

    Duchenne and Becker muscular dystrophy are allelic X-linked disorders causing progressive muscle weakness in males. Duchenne muscular dystrophy is caused by absence of dystrophin in muscle and brain; boys with Duchenne muscular dystrophy have a static cognitive impairment with mean Full Scale IQ approximately 1 standard deviation below the mean. Less is known of the cognitive profile of males with Becker muscular dystrophy, which is associated with variable alterations in the amount or size of the dystrophin protein. The aim of this study was to describe the cognitive and psychological profile of males with Becker muscular dystrophy. This was a prospective cohort study. Clinical data collected included age at diagnosis and assessment, socioeconomic status, serum creatine kinase level, and site of gene deletion/mutation (by exon number). The following psychological tests were used to assess general intellectual functioning, academic achievement, incidence and nature of behavioral problems: The Wechsler Intelligence Scales, The Wide Range Achievement Test-Revised, The Developmental Test of Visual-Motor Integration, The Child Behavior Checklist, and The Conner's Parent Rating Scale. Twenty-four males were enrolled. The Wechsler Full Scale IQ was normally distributed with a mean of 95.6 (SD 23.3), which did not differ significantly from the population mean. The frequency of learning difficulties for reading was 21%, for spelling was 32%, and for arithmetic was 26%, significantly higher than the frequency in the general population. The frequency of total behavioral problems in the clinical range was 67%, and the frequency of autism was 8.3%. Patients with Becker muscular dystrophy demonstrate a less homogeneous cognitive phenotype than that seen in Duchenne muscular dystrophy. Males with Becker muscular dystrophy have a high incidence of learning difficulties. Autism and behavioral and attention problems are also more common in Becker muscular dystrophy than in the general population. PMID:18056690

  6. 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

  7. 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

  8. Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability

    E-print Network

    Mallela, Krishna M. G.

    Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability of functional dystrophin protein in muscle cells causes muscular dystrophy (MD). More than 50% of missense, thereby decreasing the net functional dystrophin concentration. actin binding domain Becker muscular

  9. 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

  10. 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…

  11. 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

  12. Facioscapulohumeral muscular dystrophy: consequences of chromatin relaxation

    PubMed Central

    van der Maarel, Silvère 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. 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.

  15. 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

  16. 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

  17. 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

  18. 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

  19. Exon-Skipped Dystrophins for Treatment of Duchenne Muscular Dystrophy: Mass Spectrometry Mapping of Most

    E-print Network

    Discher, Dennis

    --that shorten dystro- phin's central rod domain can lead to more mild forms of Becker muscular dystrophy (BMDExon-Skipped Dystrophins for Treatment of Duchenne Muscular Dystrophy: Mass Spectrometry Mapping such as Duchenne muscular dystrophy (DMD) which arises in the absence of the linkage protein dys- trophin

  20. Dystrophin, its interactions with other proteins, and implications for muscular dystrophy

    E-print Network

    Ervasti, James M.

    into the molecular basis for Duchenne muscular dystrophy were greatly facilitated by seminal studies in the 1980sDa protein product of the gene defective in Duchenne muscular dystrophy [1,2]. Dystrophin is comprisedReview Dystrophin, its interactions with other proteins, and implications for muscular dystrophy

  1. Gene Therapy for Muscular Dystrophy: Moving the Field Forward

    PubMed Central

    Al-Zaidy, Samiah; Rodino-Klapac, Louise; Mendell, Jerry R

    2014-01-01

    Gene therapy for the muscular dystrophies has evolved as a promising treatment for this progressive group of disorders. While corticosteroids and/or supportive treatments remain standard of care for Duchenne muscular dystrophy (DMD), loss of ambulation, respiratory failure and compromised cardiac function is the inevitable outcome. Recent developments in genetically mediated therapies have allowed for personalized treatments that strategically target individual muscular dystrophy subtypes based on disease pathomechanism and phenotype. In this review, we highlight therapeutic progress with emphasis on evolving pre-clinical data and our own experience in completed clinical trials, and others currently underway. We also discuss the lessons we have learned along the way and the strategies developed to overcome limitations and obstacles in this field. PMID:25439576

  2. 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

  3. ?-Sarcoglycan-deficient muscular dystrophy: from discovery to therapeutic approaches

    PubMed Central

    2011-01-01

    Mutations in the ?-sarcoglycan gene cause limb-girdle muscular dystrophy 2F (LGMD2F), an autosomal recessive disease that causes progressive weakness and wasting of the proximal limb muscles and often has cardiac involvement. Here we review the clinical implications of LGMD2F and discuss the current understanding of the putative mechanisms underlying its pathogenesis. Preclinical research has benefited enormously from various animal models of ?-sarcoglycan deficiency, which have helped researchers to explore therapeutic approaches for both muscular dystrophy and cardiomyopathy. PMID:21798091

  4. Cell, Vol. 80, 675-679, March 10, 1995, Copyright 1995 by Cell Press Three Muscular Dystrophies: Review

    E-print Network

    Campbell, Kevin P.

    to the extracellular matrix in skeletal muscle. DMD and Becker Muscular Dystrophy DMD and Becker muscular dystrophyCell, Vol. 80, 675-679, March 10, 1995, Copyright © 1995 by Cell Press Three Muscular Dystrophies 52242 Muscular dystrophies are a group of diseases that primar- ily affect skeletal muscle

  5. 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

  6. Cardiac involvement in Duchenne and Becker muscular dystrophy.

    PubMed

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

    2015-07-26

    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

  7. 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…

  8. 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…

  9. Dysferlin and the plasma membrane repair in muscular dystrophy

    E-print Network

    Campbell, Kevin P.

    to contraction-induced injuries [6]. Skeletal muscle cells are very susceptible to plasma membrane injuries of the skeletal muscle cells. Muscular dystrophy includes a diverse group of inherited myogenic disorders disrupts the stability of the whole complex, which in turn makes the muscle cell membrane susceptible

  10. 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…

  11. 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.

  12. 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…

  13. 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).…

  14. Social Behavior Problems in Boys with Duchenne Muscular Dystrophy

    E-print Network

    Social Behavior Problems in Boys with Duchenne Muscular Dystrophy VERONICA J. HINTON, PH with DMD. Parental ratings of boys with DMD (n = 181) on the Child Behavior Checklist behavior scales were of boys with DMD (n = 86), and children with cerebral palsy (CP) (n = 42). Increased ratings of general

  15. Characterization of aquaporin-4 in muscle and muscular dystrophy

    E-print Network

    Campbell, Kevin P.

    in -, -, -, or -sarcoglycan result in autosomal recessive limb girdle muscular dystrophy (AR-LGMD) types 2D, 2E, 2C, and 2F­sarcospan subcomplex, although cases of partial sarcoglycan loss have been reported (16). Mouse models for DMD and AR-LGMD

  16. 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…

  17. 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

  18. A Unifying Genetic Model for Facioscapulohumeral Muscular Dystrophy

    PubMed Central

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

    2015-01-01

    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 (SNPs) 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

  19. A unifying genetic model for facioscapulohumeral muscular dystrophy.

    PubMed

    Lemmers, Richard J L F; van der Vliet, Patrick J; Klooster, Rinse; Sacconi, Sabrina; Camaño, 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, Silvère 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

  20. Fat Embolism Syndrome following minor trauma in Duchenne muscular dystrophy.

    PubMed

    McAdam, Laura C; Rastogi, Anjali; Macleod, Kathleen; Douglas Biggar, W

    2012-12-01

    We describe five patients with Duchenne muscular dystrophy who presented with acute neurologic and respiratory symptoms following minor trauma. Four of the five deteriorated rapidly and died within 36 h after falling. X-rays for fractures were negative. Four of the five patients were taking corticosteroids daily. All five patients fulfilled the clinical criteria for Fat Embolism Syndrome. Autopsy findings were consistent with fat embolism in two cases. Fat Embolism Syndrome needs to be considered in patients with Duchenne muscular dystrophy following minor trauma even without fractures. Early recognition of Fat Embolism Syndrome and aggressive resuscitation are important to improve survival. This report serves as an important reminder that seatbelts need to be used at all times. PMID:22920089

  1. Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy.

    PubMed

    Govoni, Alessandra; Magri, Francesca; Brajkovic, Simona; Zanetta, Chiara; Faravelli, Irene; Corti, Stefania; Bresolin, Nereo; Comi, Giacomo P

    2013-12-01

    Muscular dystrophy is a heterogeneous group of genetic disorders characterised by progressive muscle tissue degeneration. No effective treatment has been discovered for these diseases. Preclinical and clinical studies aimed at the development of new therapeutic approaches have been carried out, primarily in subjects affected with dystrophinopathies (Duchenne and Becker muscular dystrophy). In this review, we outline the current therapeutic approaches and past and ongoing clinical trials, highlighting both the advantages and limits of each one. The experimental designs of these trials were based on different rationales, including immunomodulation, readthrough strategies, exon skipping, gene therapy, and cell therapy. We also provide an overview of available outcome measures, focusing on their reliability in estimating meaningful clinical improvement in order to aid in the design of future trials. This perspective is extremely relevant to the field considering the recent development of novel therapeutic approaches that will result in an increasing number of clinical studies over the next few years. PMID:23775131

  2. Update on the genetics of limb girdle muscular dystrophy.

    PubMed

    Mitsuhashi, Satomi; Kang, Peter B

    2012-12-01

    Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders characterized by progressive muscle weakness with dystrophic muscle pathology caused by autosomal dominant or recessive gene mutations. Recently, several novel causative gene mutations have been associated with LGMD, due in part to recent scientific advances such as next generation sequencing. Interestingly, some of these novel forms of LGMD are allelic with other muscle diseases such as the dystroglycanopathy subtype of congenital muscular dystrophy. For the clinical diagnosis of LGMD, a comprehensive approach is typically needed, which may include a thorough evaluation by an experienced clinician, serum creatine kinase measurements, genetic testing, and muscle biopsy. On a research basis, the continued discovery of novel LGMD genes will be expedited with the increasing use of next generation sequencing technologies in combination with traditional approaches such as linkage analysis. PMID:23245554

  3. [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

  4. Revised genetic classification of Limb Girdle Muscular Dystrophies.

    PubMed

    Magri, F; Brajkovic, S; Govoni, A; Brusa, R; Comi, G P

    2014-10-10

    Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited progressive muscle disorders affecting predominantly the shoulder and pelvic girdle muscles. They present both with autosomal dominant and autosomal recessive patterns of inheritance. Recent development, including results from Next Generation Sequencing technology, expanded the number of recognised forms. Therefore a revised genetic classification that takes into account the novel entities is needed, allowing clinicians and researchers to refer to a common nomenclature for diagnostic and research purposes. PMID:25323878

  5. 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

  6. 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

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

    PubMed

    Comim, Clarissa M; Mathia, Gisiane B; Hoepers, Andreza; Tuon, Lisiane; Kapczinski, Flávio; Dal-Pizzol, Felipe; Quevedo, João; 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

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

    PubMed

    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

  14. 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

  15. Myoferlin, a candidate gene and potential modifier of muscular dystrophy.

    PubMed

    Davis, D B; Delmonte, A J; Ly, C T; McNally, E M

    2000-01-22

    Dysferlin, the gene product of the limb girdle muscular dystrophy (LGMD) 2B locus, encodes a membrane-associated protein with homology to Caenorhabditis elegans fer-1. Humans with mutations in dysferlin ( DYSF ) develop muscle weakness that affects both proximal and distal muscles. Strikingly, the phenotype in LGMD 2B patients is highly variable, but the type of mutation in DYSF cannot explain this phenotypic variability. Through electronic database searching, we identified a protein highly homologous to dysferlin that we have named myoferlin. Myoferlin mRNA was highly expressed in cardiac muscle and to a lesser degree in skeletal muscle. However, antibodies raised to myoferlin showed abundant expression of myoferlin in both cardiac and skeletal muscle. Within the cell, myoferlin was associated with the plasma membrane but, unlike dysferlin, myoferlin was also associated with the nuclear membrane. Ferlin family members contain C2 domains, and these domains play a role in calcium-mediated membrane fusion events. To investigate this, we studied the expression of myoferlin in the mdx mouse, which lacks dystrophin and whose muscles undergo repeated rounds of degeneration and regeneration. We found upregulation of myoferlin at the membrane in mdx skeletal muscle. Thus, myoferlin ( MYOF ) is a candidate gene for muscular dystrophy and cardiomyopathy, or possibly a modifier of the muscular dystrophy phenotype. PMID:10607832

  16. 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…

  17. 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

  18. 1997 Oxford University Press 747752Human Molecular Genetics, 1997, Vol. 6, No. 5 Mild congenital muscular dystrophy in two patients

    E-print Network

    Campbell, Kevin P.

    this protein. This situation presents a striking analogy with Becker muscular dystrophy, where in muscular dystrophy in two patients with an internally deleted laminin 2-chain Valérie Allamand1, Yoshihide; Revised and Accepted January 31, 1997 Congenital muscular dystrophy (CMD) is a group of clinically

  19. 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

  20. [Surgical treatment of spinal deformities in Duchenne muscular dystrophy].

    PubMed

    Bellen, P; Hody, J L; Clairbois, J; Denis, N; Soudon, P

    1992-01-01

    Forty seven Duchenne Muscular Dystrophy patients, operated on for spinal deformity with segmental spinal instrumentation according to Luque's technique, are reviewed with a mean post-operative follow up of 4 years 4 months. The study of the results obviously showed the interest of Luque Galveston technique for the treatment of severe curves with pelvic obliquity, whereas Dove's rectangle is an interesting choice for the early instrumentation. A total spinal arthrodesis can probably be avoided in these patients, which often demonstrate a satisfying spontaneous fusion after instrumentation. The general and mechanical complications are described, according to the consequences they have on the management technique of these patients. PMID:1306582

  1. 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

  2. Fibrogenic Cell Plasticity Blunts Tissue Regeneration and Aggravates Muscular Dystrophy

    PubMed Central

    Pessina, Patrizia; Kharraz, Yacine; Jardí, Mercè; Fukada, So-ichiro; Serrano, Antonio L.; Perdiguero, Eusebio; Muñoz-Cánoves, Pura

    2015-01-01

    Summary Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGF?-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component. PMID:25981413

  3. 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

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy

    PubMed Central

    Kharraz, Yacine; Guerra, Joana; Serrano, Antonio L.; Muñoz-Cánoves, Pura

    2014-01-01

    Fibrosis is the aberrant deposition of extracellular matrix (ECM) components during tissue healing leading to loss of its architecture and function. Fibrotic diseases are often associated with chronic pathologies and occur in a large variety of vital organs and tissues, including skeletal muscle. In human muscle, fibrosis is most readily associated with the severe muscle wasting disorder Duchenne muscular dystrophy (DMD), caused by loss of dystrophin gene function. In DMD, skeletal muscle degenerates and is infiltrated by inflammatory cells and the functions of the muscle stem cells (satellite cells) become impeded and fibrogenic cells hyperproliferate and are overactivated, leading to the substitution of skeletal muscle with nonfunctional fibrotic tissue. Here, we review new developments in our understanding of the mechanisms leading to fibrosis in DMD and several recent advances towards reverting it, as potential treatments to attenuate disease progression. PMID:24877152

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

    PubMed

    van der Maarel, Silvère 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

  16. Assessment of hand function in Duchenne muscular dystrophy.

    PubMed

    Wagner, M B; Vignos, P J; Carlozzi, C; Hull, A L

    1993-08-01

    Eighteen boys with Duchenne muscular dystrophy (DMD) were assessed for their ability to perform tasks involving wrist and hand function. Each subject was assessed using the Jebsen Test of Hand Function, range of motion measurements, and muscle strength tests. Writing and simulated page turning were performed successfully by boys in all age groups. Boys over age 15 had difficulty completing simulated feeding and picking up large and small objects. The muscle strength of the wrist extensors and the radial deviation range of motion at the wrist were found to be strongly correlated with six of the seven tasks assessed. These two clinical assessments appear to be good indicators of overall wrist and hand function. Life expectancy with DMD is increasing with advances in respiratory care making preservation of wrist and hand function, the major activity remaining with advanced disease, increasingly important. PMID:8347064

  17. 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

  18. 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

  19. 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

  20. [Erythrocytes' deformations in primitive muscular dystrophies (author's transl)].

    PubMed

    Marchini, C; Grassi, E; Rossi, G L; Ottonello, S; Parma, M; Lucci, B

    1976-01-01

    On the light of previous reports on a possible correlation between echinocytogenesis and primitive muscular dystrophies, we have investigated the presence and time dependent development of echinocytes in the blood of normal subjects, patients and healthy carriers of D.M.D. A very few echinocytes are present in the fresh blood of all the patients and some carriers, but not in the blood of control normal subjects. With time, more echinocytes develop in all cases but much more markedly for sick people and carriers. These results might explain conflicting data on the echinocyte content in the blood reported in the literatura and provide a guideline for a correct analysis of the phenomenon and its possible relevance in the eugenetic diagnosis of carriers. PMID:1021148

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

    PubMed Central

    de Greef, J.C.; Lemmers, R.J.L.F.; Camaño, 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

  2. 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

  3. Diagnosis and cell-based therapy for Duchenne muscular dystrophy in humans, mice, and zebrafish

    PubMed Central

    Kunkel, Louis M.; Bachrach, Estanislao; Bennett, Richard R.; Guyon, Jeffrey; Steffen, Leta

    2012-01-01

    The muscular dystrophies are a heterogeneous group of genetically caused muscle degenerative disorders. The Kunkel laboratory has had a longstanding research program into the pathogenesis and treatment of these diseases. Starting with our identification of dystrophin as the defective protein in Duchenne muscular dystrophy (DMD), we have continued our work on normal dystrophin function and how it is altered in muscular dystrophy. Our work has led to the identification of the defective genes in three forms of limb girdle muscular dystrophy (LGMD) and a better understanding of how muscle degenerates in many of the different dystrophies. The identification of mutations causing human forms of dystrophy has lead to improved diagnosis for patients with the disease. We are continuing to improve the molecular diagnosis of the dystrophies and have developed a high-throughput sequencing approach for the low-cost rapid diagnosis of all known forms of dystrophy. In addition, we are continuing to work on therapies using available animal models. Currently, there are a number of mouse models of the human dystrophies, the most notable being the mdx mouse with dystrophin deficiency. These mice are being used to test possible therapies, including stem-cell-based approaches. We have been able to systemically deliver human dystrophin to these mice via the arterial circulation and convert 8% of dystrophin-deficient fibers to fibers expressing human dystrophin. We are now expanding our research to identify new forms of LGMD by analyzing zebrafish models of muscular dystrophy. Currently, we have 14 different zebrafish mutants exhibiting various phenotypes of muscular dystrophy, including muscle weakness and inactivity. One of these mutants carries a stop codon mutation in dystrophin, and we have recently identified another carrying a mutation in titin. We are currently positionally cloning the disease-causative mutation in the remaining 12 mutant strains. We hope that one of these new mutant strains of fish will have a mutation in a gene not previously implicated in human muscular dystrophy. This gene would become a candidate gene to be analyzed in patients which do not carry a mutation in any of the known dystrophy-associated genes. By studying both disease pathology and investigating potential therapies, we hope to make a positive difference in the lives of people living with muscular dystrophy. PMID:16583129

  4. Adhalin Gene Mutations in Patients with Autosomal Recessive Childhood Onset Muscular Dystrophy with Adhalin Deficiency

    E-print Network

    Campbell, Kevin P.

    Adhalin Gene Mutations in Patients with Autosomal Recessive Childhood Onset Muscular Dystrophy Neurology, National Sanatorium Tokushima Hospital, Oegun, Tokushima 776, Japan; gLaboratoryof Gene Research Homozygous adhalim gene mutations were found in three patients from two consanguineousfamilies with autosomal

  5. 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

  6. 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.

  7. 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

  8. People with a form of muscular dystrophy may have elevated cancer risk

    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. The scientists suggest that some of the genetic changes that lead to MMD may also be responsible for the observed increase in cancer risk, but more research is needed to confirm this hypothesis. The study appeared Dec.

  9. 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)

  10. 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…

  11. Patterns of late gadolinium enhancement in Duchenne muscular dystrophy carriers

    PubMed Central

    2014-01-01

    Background This study was designed to assess whether cardiovascular magnetic resonance imaging (CMR) in Duchenne muscular dystrophy carriers (DMDc) may index any cell milieu elements of LV dysfunction and whether this cardiac phenotype may be related to genotype. The null hypothesis was that myocardial fibrosis, assessed by late gadolinium enhancement (LGE), might be similarly accounted for in DMDc and gender and age-matched controls. Methods Thirty DMDc patients had CMR and genotyping with 37 gender and age-matched controls. Systolic and diastolic LV function was assessed by 2D-echocardiography. Results Absolute and percent LGE were higher in muscular symptomatic (sym) than asymptomatic (asy) DMDc (1.77?±?0.27 vs 0.76?±?0.17 ml; F =?19.6, p

  12. 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

  13. Duchenne muscular dystrophy gene therapy: Lost in translation?

    PubMed Central

    Duan, Dongsheng

    2011-01-01

    A milestone of molecular medicine is the identification of dystrophin gene mutation as the cause of Duchenne muscular dystrophy (DMD). Over the last 2 decades, major advances in dystrophin biology and gene delivery technology have created an opportunity to treat DMD with gene therapy. Remarkable success has been achieved in treating dystrophic mice. Several gene therapy strategies, including plasmid transfer, exon skipping, and adeno-associated virus-mediated microdystrophin therapy, have entered clinical trials. However, therapeutic benefit has not been realized in DMD patients. Bridging the gap between mice and humans is no doubt the most pressing issue facing DMD gene therapy now. In contrast to mice, dystrophin-deficient dogs are genetically and phenotypically similar to human patients. Preliminary gene therapy studies in the canine model may offer critical insights that cannot be obtained from murine studies. It is clear that the canine DMD model may represent an important link between mice and humans. Unfortunately, our current knowledge of dystrophic dogs is limited, and the full picture of disease progression remains to be clearly defined. We also lack rigorous outcome measures (such as in situ force measurement) to monitor therapeutic efficacy in dystrophic dogs. Undoubtedly, maintaining a dystrophic dog colony is technically demanding, and the cost of dog studies cannot be underestimated. A carefully coordinated effort from the entire DMD community is needed to make the best use of the precious dog resource. Successful DMD gene therapy may depend on valid translational studies in dystrophin-deficient dogs. PMID:21691429

  14. 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

  15. 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

  16. Dropped-head in recessive oculopharyngeal muscular dystrophy.

    PubMed

    Garibaldi, Matteo; Pennisi, Elena Maria; Bruttini, Mirella; Bizzarri, Veronica; Bucci, Elisabetta; Morino, Stefania; Talerico, Caterina; Stoppacciaro, Antonella; Renieri, Alessandra; Antonini, Giovanni

    2015-11-01

    A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD). There are a few reports of the recessive form, which has a later disease onset with milder symptoms and higher clinical variability than the typical dominantly inherited form. This patient, who is the first Italian and the eighth worldwide reported case of recessive OPMD, is also the first case of OPMD with dropped-head syndrome, which thus expands the clinical phenotype of recessive OPMD. PMID:26494409

  17. 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

  18. 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?

  19. This work was supported by the Muscular Dystrophy Association (2916, D.E.), the General Clinic Research Center (M01-

    E-print Network

    This work was supported by the Muscular Dystrophy Association (2916, D.E.), the General Clinic al. Clinical trial in Duchenne dystrophy. I. The design of the protocol. Muscle Nerve 1981. A randomized efficacy and safety trial of oxandrolone in the treatment of Duchenne dystrophy. Neurology 2001

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

    PubMed

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

    2014-01-01

    Achondroplasia, Duchenne muscular dystrophy, and osteogenesis imperfecta are among the most frequent rare genetic disorders affecting the musculoskeletal system in children. Rare genetic disorders are severely disabling and can have substantial impacts on families, children, and on healthcare systems. This literature review aims to classify, summarize and compare these non-medical impacts of achondroplasia, Duchenne muscular dystrophy and osteogenesis imperfecta. PMID:25649344

  1. 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

  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. 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

  4. 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.

  5. INVITED REVIEW ABSTRACT: Muscular dystrophies represent a heterogeneous group of disorders, which have been largely classified by clinical phenotype. In the

    E-print Network

    Campbell, Kevin P.

    - phosphatase; AD-EMD, autosomal dominant EMD; BMD, Becker muscu- lar dystrophy; CMD, congenital muscularINVITED REVIEW ABSTRACT: Muscular dystrophies represent a heterogeneous group of disorders, which pathogenesis of these disorders. A large number of genes involved in muscular dystrophy encode components

  6. Muscular dystrophy in adults: a five-year follow-up.

    PubMed

    Dahlbom, K; Ahlström, G; Barany, M; Kihlgren, A; Gunnarsson, L G

    1999-09-01

    The aim was to describe the natural history of adults with hereditary muscular dystrophies, including myotonic dystrophy, with respect to muscular function, ventilation and electrocardiogram. In a prospective study, 46 subjects were followed over a period of five years. In 1991 and 1996, their muscle function was assessed according to an observation scheme and their lung vital capacity was measured by spirometer. Electrocardiograms were obtained in 1991, 1993 and 1996. Deterioration of muscular function was seen with regard to both the functional muscle tests and the vital capacity. The proportion of pathological electrocardiograms increased from 38% in 1991 to 54% in 1996 in the 26 patients with myotonic dystrophy without an increase in clinically detected cardiac abnormalities. Timely examinations using standard methods can reveal medically important information on deterioration, which often passes clinically unnoticed because of the insidious progress of the diseases. PMID:10458316

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

    PubMed Central

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

    2013-01-01

    Three adhesion complexes span the sarcolemma and facilitate critical connections between the extracellular matrix and the actin cytoskeleton: the dystrophin- and utrophin-glycoprotein complexes and ?7?1 integrin. Loss of individual protein components results in a loss of the entire protein complex and muscular dystrophy. Muscular dystrophy is a progressive, lethal wasting disease characterized by repetitive cycles of myofiber degeneration and regeneration. Protein replacement therapy offers a promising approach for the treatment of muscular dystrophy. Recently, we demonstrated that sarcospan facilitates protein-protein interactions amongst the adhesion complexes and is an important therapeutic target. Here, we review current protein replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

  8. 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.

  9. 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.

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

    PubMed

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

    2014-09-01

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

  11. Merosin-negative congenital muscular dystrophy: diffusion-weighted imaging findings of brain.

    PubMed

    Alkan, Alpay; Sigirci, Ahmet; Kutlu, Ramazan; Aslan, Mehmet; Doganay, Selim; Yakinci, Cengiz

    2007-05-01

    Merosin-negative congenital muscular dystrophy is a rare genetic disease of childhood involving the central and peripheral nervous system. There were high signal intensities throughout the centrum semiovale, periventricular, and sub-cortical white matters on T2-weighted images in a 4-year-old girl with merosin-negative congenital muscular dystrophy. An apparent diffusion coefficient map revealed increased signal intensity and apparent diffusion coefficient values in the periventricular and deep white matters. It may be attributable to increased water content in the white matter because of an abnormal blood-brain barrier rather than to decreased or abnormal myelination. PMID:17690079

  12. 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

  13. 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; López, José 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

  14. 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...

  15. 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

  16. 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…

  17. 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…

  18. 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.

  19. The sarcoglycan complex in limb-girdle muscular dystrophy Leland E. Lim and Kevin P. Campbell ,

    E-print Network

    Campbell, Kevin P.

    :443-452 Abbreviations CFTR cystic fibrosis transmembraneconductance regulator DGC dystrophin-glycoproteincomplex LGMD-girdle muscular dystrophy (LGMD), are caused by mutations in genes that encode sarcolemmal proteins. LGMD groups [1,2]. The nomenclature for LGMD has changed over the years; other terms for this condition have

  20. 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 ?-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 ?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

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

    PubMed

    Plantié, 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

  3. 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

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

    PubMed

    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

  5. A comprehensive genetic diagnosis of Chinese muscular dystrophy and congenital myopathy patients by targeted next-generation sequencing.

    PubMed

    Dai, Yi; Wei, Xiaoming; Zhao, Yanhuan; Ren, Haitao; Lan, Zhangzhang; Yang, Yun; Chen, Lin; Cui, Liying

    2015-08-01

    Muscular dystrophies and congenital myopathies are a large group of heterogeneous inherited muscle disorders. The spectrum of muscular dystrophies and congenital myopathies extends to more than 50 diseases today, even excluding the common forms Duchenne Muscular Dystrophy, Myotonic Dystrophy and Facioscapulohumeral Dystrophy. Unfortunately, even by critical clinical evaluation and muscle pathology, diagnosis is still difficult. To potentially remediate this difficulty, we applied a microarray-based targeted next-generation sequencing (NGS) technology to diagnose these patients. There were 55 consecutive unrelated patients who underwent the test, 36 of which (65%) were found to have a causative mutation. Our result shows the accuracy and efficiency of next-generation sequencing in clinical circumstances and reflects the features and relative distribution of inherited myopathies in the Chinese population. PMID:25987458

  6. 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.

  7. Muscular dystrophy due to a sarcoglycan deficiency in a female Dobermann dog.

    PubMed

    Munday, J S; Shelton, G D; Willox, S; Kingsbury, D D

    2015-06-01

    A four-month-old female Dobermann presented with myalgia, dysphagia, progressive weakness and loss of body condition. Diagnostic evaluation at nine months of age revealed markedly elevated serum creatine kinase activity, electromyographic abnormalities and histological evidence of chronic-active muscle necrosis. Imaging confirmed dysphagia and aspiration pneumonia. Muscular dystrophy was suspected and immunohistochemical staining of muscle cryosections demonstrated reduced sarcoglycans. Treatment consisted of gastrostomy, and over the next 5 months the dog gained weight, despite continued loss of muscle mass. The dog died at 14 months of age after developing clinical signs of aspiration pneumonia. To the authors' knowledge, this is the first report of muscular dystrophy in a Dobermann and only the second detailed report of a canine sarcoglycanopathy. Supportive care resulted in an acceptable quality of life for 10 months after clinical signs were first observed. PMID:25482856

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. RNAi-based gene therapy for dominant Limb Girdle Muscular Dystrophies.

    PubMed

    Liu, Jian; Harper, Scott Q

    2012-08-01

    Limb Girdle Muscular Dystrophy (LGMD) refers to a group of 25 genetic diseases linked by common clinical features, including wasting of muscles supporting the pelvic and shoulder girdles. Cardiac involvement may also occur. Like other muscular dystrophies, LGMDs are currently incurable, but prospective gene replacement therapies targeting recessive forms have shown promise in pre-clinical and clinical studies. In contrast, little attention has been paid to developing gene therapy approaches for dominant forms of LGMD, which would likely benefit from disease gene silencing. Despite the lack of focus to date on developing gene therapies for dominant LGMDs, the field is not starting at square one, since translational studies on recessive LGMDs provided a framework that can be applied to treating dominant forms of the disease. In this manuscript, we discuss the prospects of treating dominantly inherited forms of LGMD with gene silencing approaches. PMID:22856606

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. TNF-?-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy.

    PubMed

    Fiorillo, Alyson A; Heier, Christopher R; Novak, James S; Tully, Christopher B; Brown, Kristy J; Uaesoontrachoon, Kitipong; Vila, Maria C; Ngheim, Peter P; Bello, Luca; Kornegay, Joe N; Angelini, Corrado; Partridge, Terence A; Nagaraju, Kanneboyina; Hoffman, Eric P

    2015-09-01

    The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-? increases microRNA levels in vitro whereas NF?B inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression. PMID:26321630

  18. QRS Prolongation in Myotonic Muscular Dystrophy and Diffuse Fibrosis on Cardiac Magnetic Resonance

    PubMed Central

    Nazarian, Saman; Bluemke, David A.; Wagner, Kathryn R.; Zviman, Menekhem M.; Turkbey, Evrim; Caffo, Brian S.; Shehata, Monda; Edwards, David; Butcher, Barbara; Calkins, Hugh; Berger, Ronald D.; Halperin, Henry R.; Tomaselli, Gordon F.

    2011-01-01

    Current noninvasive surrogates of cardiac involvement in myotonic muscular dystrophy have low positive predictive value for sudden death. We hypothesized that the cardiac MR signal-to-noise ratio variance (SNRV) is a surrogate of the spatial heterogeneity of myocardial fibrosis and correlates with electrocardiography changes in myotonic muscular dystrophy. The SNRV for contrast enhanced cardiac MR images was calculated over the entire left ventricle in 43 patients with myotonic muscular dystrophy. All patients underwent standard electrocardiography, and a subset of 23 patients underwent signal averaged electrocardiography. After correcting for body mass index, age, and ejection fraction, SNRV was predictive of QRS duration on standard electrocardiography (1.35-msec increased QRS duration/unit increase in SNRV, P < 0.001). SNRV was also predictive of the low-amplitude late-potential duration (1.49-msec increased low-amplitude late-potential duration/unit increase in SNRV, P < 0.001). Ten-fold cross-validation yielded an area under the receiver operating characteristic curve of 0.87 for the predictive value of SNRV for QRS duration greater than 120 msec. The SNRV of the left ventricle is associated with QRS prolongation, likely due to late depolarization of tissue within islands of patchy fibrosis. The association of SNRV with future clinical events warrants further study. PMID:20572151

  19. Defective Ca2+ metabolism in Duchenne muscular dystrophy: effects on cellular and viral growth.

    PubMed Central

    Fingerman, E; Campisi, J; Pardee, A B

    1984-01-01

    Normal fibroblasts in medium containing 0.02 mM CaCl2 arrested growth within 24 hr, whereas Duchenne muscular dystrophy fibroblasts continued to grow for 5 days, albeit at 40% of their rate in standard medium (1.8 mM CaCl2). Moreover, Duchenne cells in calcium-deficient medium showed an enhanced rate of protein synthesis (60% over the rate in standard medium), whereas normal cells were unaffected. Previously we described a general assay for detection of mutant cells by using herpes simplex virus I replication as a probe of cellular function. By altering the growth medium, one can elicit changes in viral DNA replication that depend upon cellular differences. Duchenne fibroblasts in calcium-deficient low-serum (0.5%) medium supported viral replication at a rate 7- to 10-fold greater than did normal cells infected under the same conditions. Using this viral assay, we have successfully identified all 10 samples of a blind coded set of Duchenne muscular dystrophy, normal, and heterozygote cells. In addition, differences of a lower magnitude were found between these cell strains as measured by cellular growth or protein synthesis. Therefore, a cell's ability to grow and support viral replication in calcium-deficient medium can be used to readily distinguish Duchenne muscular dystrophy fibroblasts from normal ones. These results suggest that the viral assay could be used as a prenatal diagnostic test. A defect related to calcium metabolism may be fundamental to this disease. PMID:6095311

  20. Report of a patient with limb-girdle muscular dystrophy, ptosis and ophthalmoparesis caused by plectinopathy.

    PubMed

    Fattahi, Zohreh; Kahrizi, Kimia; Nafissi, Shahriar; Fadaee, Mahsa; Abedini, Seyedeh Sedigheh; Kariminejad, Ariana; Akbari, Mohammad R; Najmabadi, Hossein

    2015-01-01

    Mutations in plectin, a widely expressed giant cytolinker protein can lead to different diseases mostly with signs of muscular dystrophy (MD) and skin blistering. The only report of plectin-related disease without skin involvement is limb-girdle muscular dystrophy type 2Q (LGMD2Q) phenotype, showing early-onset limb-girdle muscular dystrophy symptoms with progressive manner and no cranial muscle involvement. Here, we report a non-consanguineous Iranian family with two affected sisters showing progressive limb and ocular muscle weakness. Whole Exome Sequencing (WES) led to identification of a compound heterozygous mutations, p.Gln1022Ter (c.3064C>T) and p.Gly3835Ser (c.11503G>A), in PLEC gene. To the best of our knowledge, this would be the first report of a patient with LGMD and myasthenic symptoms without any skin involvement, caused by plectinopathy. This observation extends the phenotypic spectrum of PLEC related diseases and suggests a variable expression of the PLEC- related symptoms. PMID:25556389

  1. Scapuloperoneal muscular dystrophy phenotype due to TRIM32-sarcotubular myopathy in South Dakota Hutterite.

    PubMed

    Liewluck, Teerin; Tracy, Jennifer A; Sorenson, Eric J; Engel, Andrew G

    2013-02-01

    Scapuloperoneal muscular dystrophy is a group of genetically heterogeneous disorders that share the phenotype of progressive weakness of scapular and anterior distal leg muscles. Recessive mutations in C-terminal domains of TRIM32 result in limb-girdle muscular dystrophy 2H and sarcotubular myopathy, a rare congenital myopathy commonly seen in Hutterites. A scapuloperoneal phenotype has never been reported in sarcotubular myopathy. We here report a 23-year-old Hutterite man with a one-year history of progressive weakness predominantly involving the anterior tibial and left scapular muscles, and hyperCKemia. Biopsy of the anterior tibial muscle showed an active myopathy with non-rimmed vacuoles and mild denervation atrophy associated with reinnervation. The vacuoles are similar to those described in sarcotubular myopathy. TRIM32 sequencing revealed the common c.1459G>A mutation at homozygosity. A search for mutations in TRIM32 should be considered in patients with scapuloperoneal muscular dystrophy, and especially in patients of Hutterite origin or with an atypical vacuolar myopathy. PMID:23142638

  2. The value of mammalian models for duchenne muscular dystrophy in developing therapeutic strategies.

    PubMed

    Banks, Glen B; Chamberlain, Jeffrey S

    2008-01-01

    Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. There is no effective treatment and patients typically die in approximately the third decade. DMD is an X-linked recessive disease caused by mutations in the dystrophin gene. There are three mammalian models of DMD that have been used to understand better the pathogenesis of disease and develop therapeutic strategies. The mdx mouse is the most widely used model of DMD that displays some features of muscle degeneration, but the pathogenesis of disease is comparatively mild. The severity of disease in mice lacking both dystrophin and utrophin is similar to DMD, but one has to account for the discrete functions of utrophin. Canine X-linked muscular dystrophy (cxmd) is the best representation of DMD, but the phenotype of the most widely used golden retriever (GRMD) model is variable, making functional endpoints difficult to ascertain. Although each mammalian model has its limitations, together they have been essential for the development of several treatment strategies for DMD that target dystrophin replacement, disease progression, and muscle regeneration. PMID:19186250

  3. 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

  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. 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

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

    PubMed

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

    2014-06-01

    Recent studies in patients with muscular dystrophies suggest positive effects of aerobic and strength training. These studies focused training on using bicycle ergometers and conventional strength training, which precludes more severely affected patients from participating, because of their weakness. We investigated the functional effects of combined aerobic and strength training in patients with Becker and limb-girdle muscular dystrophies with knee muscle strength levels as low as 3% of normal strength. Eight patients performed 10 weeks of aerobic and strength training on an anti-gravity treadmill, which offered weight support up to 80% of their body weight. Six minute walking distance, dynamic postural balance, and plasma creatine kinase were assessed 10 weeks prior to training, immediately before training and after 10 weeks of training. Training elicited an improvement of walking distance by 8±2% and dynamic postural balance by 13±4%, indicating an improved physical function. Plasma creatine kinase remained unchanged. These results provide evidence that a combination of aerobic and strength training during anti-gravity has the potential to safely improve functional ability in severely affected patients with Becker and limb-girdle muscular dystrophies. PMID:24684860

  7. 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.

  8. 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; Bönnemann, Carsten G; Abdenur, Jose E; Grosmann, Carla M; Kesari, Akanchha; Punetha, Jaya; Quinlivan, Ros; Waddell, Leigh B; Young, Helen K; Wraige, Elizabeth; Yau, Shu; Brodd, Lina; Feng, Lucy; Sewry, Caroline; MacArthur, Daniel G; North, Kathryn N; Hoffman, Eric; Stemple, Derek L; Hurles, Matthew E; van Bokhoven, Hans; Campbell, Kevin P; Lefeber, Dirk J; Lin, Yung-Yao; Muntoni, Francesco

    2013-07-11

    Congenital muscular dystrophies with hypoglycosylation of ?-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

  9. 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

  10. Characterization of Dystrophin Deficient Rats: A New Model for Duchenne Muscular Dystrophy

    PubMed Central

    Tesson, Laurent; Remy, Séverine; Thepenier, Virginie; François, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maéva; Guigand, Lydie; Toumaniantz, Gilles; De Cian, Anne; Boix, Charlotte; Renaud, Jean-Baptiste; Cherel, Yan; Giovannangeli, Carine; Concordet, Jean-Paul; Anegon, Ignacio; Huchet, Corinne

    2014-01-01

    A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD. PMID:25310701

  11. [A case of limb-girdle muscular dystrophy 2M diagnosed by the occurence of dilated cardiomyopathy].

    PubMed

    Matsui, Misa; Endo, Takuyuki; Matsumura, Tsuyoshi; Saito, Toshio; Fujimura, Harutoshi

    2015-01-01

    We report a 24-year-old Japanese man initially suspected to have Becker's muscular dystrophy at the age of 6 years, because of a high level of creatine kinase in serum, though he discontinued visiting the hospital. At the age of 23, he was admitted to the hospital for severe dilated cardiomyopathy, and subsequently diagnosed with limb-girdle muscular dystrophy2M (LGMD2M) based on muscle biopsy and gene analysis. It was recently reported that some patients with fukutinopathy develop LGMD. Most of the cases reported in Japan showed mild skeletal muscle involvement despite serious cardiomyopathy, which may sometimes the initial symptom of the disease. Since muscular dystrophy patients can develop severe cardiac failure, irrespective of the severity of skeletal muscle involvement, regular examinations of cardiopulmonary function are necessary. PMID:26050665

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

    PubMed

    Anaya-Segura, Monica Alejandra; García-Martínez, Froylan Arturo; Montes-Almanza, Luis Angel; Díaz, Benjamín-Gomez; Avila-Ramírez, Guillermina; Alvarez-Maya, Ikuri; Coral-Vazquez, Ramón Mauricio; Mondragón-Terán, Paul; Escobar-Cedillo, Rosa Elena; García-Calderón, Noemí; Vazquez-Cardenas, Norma Alejandra; García, Silvia; López-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 naïve 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

  13. 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

  14. 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.

  15. Muscle ribosomal protein synthesis in normal pregnancy: implication for carrier detection in Duchenne muscular dystrophy

    PubMed Central

    Ionasescu, Victor; White, Charles; Zellweger, Hans; Lewis, Ruth; Conway, Thomas W.

    1974-01-01

    Muscle samples of rectus abdominis were obtained from 11 normal pregnant women 21-30 years old during elective Caesarean section and from 10 normal, non-pregnant controls of comparable age. The in-vitro amino-acid incorporation of polyribosomes extracted from the muscle homogenates of the pregnant women showed high activity for the synthesis of non-collagen protein in six cases, while control values were found in five cases. These results indicate that carrier detection in Duchenne muscular dystrophy based on increased muscle ribosomal protein synthesis cannot be done accurately during pregnancy, unless adequate values for known carriers at a comparable stage of gestation are available. PMID:4841079

  16. 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.

  17. 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.

  18. 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.

  19. Cardiac resynchronization therapy in a young patient with Duchenne muscular dystrophy

    PubMed Central

    Kono, Tamami; Ogimoto, Akiyoshi; Nishimura, Kazuhisa; Yorozuya, Toshihiro; Okura, Takafumi; Higaki, Jitsuo

    2015-01-01

    A 32-year-old man with Duchenne muscular dystrophy (DMD) was admitted to the hospital because of worsening dyspnea and general fatigue. He had received medication therapy for cardiomyopathy with heart failure and home mechanical ventilation for respiratory failure. An electrocardiogram on admission showed intermittent third-degree atrioventricular block. Echocardiography showed global mild left ventricular systolic dysfunction with dyssynchrony (ejection fraction: 45%). He underwent implantation of a cardiac resynchronization therapy–defibrillator. His B-type natriuretic peptide level was improved after cardiac resynchronization therapy–defibrillator implantation, and he remains asymptomatic. The incidence of cardiomyopathy increases with age. By adulthood, 100% of patients have cardiac involvement. PMID:26346252

  20. LIMS2 mutations are associated with a novel muscular dystrophy, severe cardiomyopathy and triangular tongues.

    PubMed

    Chardon, Jodi Warman; Smith, A C; Woulfe, J; Pena, E; Rakhra, K; Dennie, C; Beaulieu, C; Huang, Lijia; Schwartzentruber, J; Hawkins, C; Harms, M B; Dojeiji, S; Zhang, M; Majewski, J; Bulman, D E; Boycott, K M; Dyment, D A

    2015-12-01

    Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of genetic disorders leading to progressive muscle degeneration and often associated with cardiac complications. We present two adult siblings with childhood-onset of weakness progressing to a severe quadriparesis with the additional features of triangular tongues and biventricular cardiac dysfunction. Whole exome sequencing identified compound heterozygous missense mutations that are predicted to be pathogenic in LIMS2. Biopsy of skeletal muscle demonstrated disrupted immunostaining of LIMS2. This is the first report of mutations in LIMS2 and resulting disruption of the integrin linked kinase (ILK)-LIMS-parvin complex associated with LGMD. PMID:25589244

  1. 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

  2. Therapy of Genetic Disorders—Novel Therapies for Duchenne Muscular Dystrophy

    PubMed Central

    Seto, Jane T.; Bengtsson, Niclas E.; Chamberlain, Jeffrey S.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is an inherited, progressive muscle wasting disorder caused by mutations in the dystrophin gene. An increasing variety of approaches are moving towards clinical testing that all aim to restore dystrophin production and to enhance or preserve muscle mass. Gene therapy methods are being developed to replace the defective dystrophin gene or induce dystrophin production from mutant genes. Stem cell approaches are being developed to replace lost muscle cells while also bringing in new dystrophin genes. This review summarizes recent progress in the field with an emphasis on clinical applications. PMID:24883236

  3. 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

  4. 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

  5. Treatable renal failure found in non-ambulatory Duchenne muscular dystrophy patients.

    PubMed

    Motoki, Takahiro; Shimizu-Motohashi, Yuko; Komaki, Hirofumi; Mori-Yoshimura, Madoka; Oya, Yasushi; Takeshita, Eri; Ishiyama, Akihiko; Saito, Takashi; Nakagawa, Eiji; Sugai, Kenji; Murata, Miho; Sasaki, Masayuki

    2015-10-01

    Duchenne muscular dystrophy (DMD) is a progressive muscular disorder in which respiratory and heart failures are the main causes of death. Intensive intervention in respiratory and cardiac function has dramatically improved the prognosis; however, dysfunction in other multiple organs may emerge in the later stages of the disease. We report the case of four non-ambulatory DMD patients who presented with renal failure. Common findings included decreased fluid intake, use of diuretics, and presence of chronic heart failure. The levels of serum cystatin C (CysC), a marker of kidney function unaffected by reduced muscle mass, were elevated in all four patients. In two patients, renal failure improved by increasing fluid intake, and discontinuing or reducing the dose of diuretics. The findings suggest that non-ambulatory DMD patients are at a risk of reduced kidney perfusion, which potentially leads to prerenal failure. Therefore, in DMD patients, dehydration signs and CysC levels should be monitored. PMID:26298609

  6. Towards the control of a powered orthosis for people with muscular dystrophy.

    PubMed

    Rahman, T; Ramanathan, R; Stroud, S; Sample, W; Seliktar, R; Harwin, W; Alexander, M; Scavina, M

    2001-01-01

    The paper describes the development of a passive/active orthosis for people with limited anti-gravity strength in their arms. This is symptomatic of conditions such as muscular dystrophy and spinal muscular atrophy. A passive orthosis was designed and developed using linear elastic elements. The system is being tested with children with disabilities and preliminary results are encouraging. An RT200 robot was also used as a test-bed for an active orthosis. The robot was instrumented with a six-axis force/torque sensor at the end-effector. The force acted as the input to the robot. The robot kinematics and dynamics were modelled. A number of control schemes were implemented on the test-bed including force proportional to velocity and acceleration; these schemes were evaluated with two subjects. PMID:11436269

  7. Multisystem disorder and limb girdle muscular dystrophy caused by LMNA p.R28W mutation.

    PubMed

    Türk, Matthias; Wehnert, Manfred; Schröder, Rolf; Chevessier, Frédéric

    2013-07-01

    Primary laminopathies caused by mutations in the LMNA gene typically display an extremely pleiotropic clinical presentation including cardiac, muscular and metabolic phenotypes. Additionally, many atypical laminopathies have been described combining features of two or more of the distinctive disorders or syndromes associated with LMNA mutations. We report on a 46-year-old female patient with a heterozygous p.R28W LMNA mutation, who presented with a novel clinical phenotype comprising severe limb-girdle muscular dystrophy, pronounced partial lipodystrophy, cardiac conduction defect, polycystic ovary disease and a metabolic syndrome with insulin-resistant diabetes mellitus and hypertriglyceridemia. On examination, her 23-year old daughter solely showed early signs of a LGMD phenotype. PMID:23746545

  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. 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

  10. 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

  11. Genitourinary health in a population-based cohort of males with Duchenne and Becker muscular dystrophies

    PubMed Central

    Zhu, Yong; Romitti, Paul A.; Conway, Kristin M. Caspers; Kim, Sunkyung; Zhang, Ying; Yang, Michele; Mathews, Katherine D.

    2015-01-01

    Introduction Genitourinary (GU) health among patients with Duchenne and Becker muscular dystrophies (DBMD) has not been explored using population-based data. Methods Medical records of 918 males ascertained by the Muscular Dystrophy Surveillance, Tracking, and Research Network were reviewed for documentation of GU-related hospitalizations and prescribed medications. Percentages of males who received these medical interventions were calculated, hazard ratios (HR) and 95% confidence intervals (CI) were estimated for associations with sociodemographics (study site, race/ethnicity), symptoms (early-versus late-onset, ambulation status, scoliosis), and treatments (respiratory support, steroids). Results Among the 918 males, 81 (9%) had a GU condition; voiding dysfunction (n=40), GU tract infection (n=19), and kidney/ureter calculus (n=9) were most common. A Kaplan-Meier curve produced a cumulative probability of 27%. Cox regression showed GU conditions were more common when males were non-ambulatory (HR=2.7, 95% CI=1.3-5.6). Discussion These findings highlight increased awareness of GU health and multidisciplinary care of DBMD patients. PMID:25297835

  12. Diagnostic and clinical characteristics of early-manifesting females with Duchenne or Becker muscular dystrophy.

    PubMed

    Imbornoni, Lauren; Price, Elinora T; Andrews, Jennifer; Meaney, F John; Ciafaloni, Emma; Cunniff, Christopher

    2014-11-01

    Manifestations of Duchenne and Becker muscular dystrophy (DBMD) are present in up to 40% of heterozygous females, but there are few reports of females who exhibit skeletal muscle symptoms in childhood. From the Muscular Dystrophy Surveillance Tracking and Research Network, a multi-site population-based surveillance network for dystrophinopathy, nine symptomatic female heterozygotes with onset of symptoms prior to age 9 years were identified. The median age at diagnosis was 8.3 years, and the median interval from first symptoms to diagnosis was 1.35 years. Of the nine female heterozygotes, four had a positive family history, seven had intellectual disability and five had at least one mental health disorder. Mental health concerns included attention deficit hyperactivity disorder (ADHD), autism spectrum features, bipolar disorder, and depression. The frequency of intellectual and mental health problems in this group is higher than previously reported for affected males and for symptomatic females. These findings may have implications for diagnosis of early manifesting heterozygotes and for their health supervision. PMID:25125379

  13. 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.

  14. 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.

  15. 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

  16. ERG phenotype of a dystrophin mutation in heterozygous female carriers of Duchenne muscular dystrophy

    PubMed Central

    Fitzgerald, K.; Cibis, G.; Gettel, A. H.; Rinaldi, R.; Harris, D.; White, R.

    1999-01-01

    PURPOSE—Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). DMD is associated with an abnormal electroretinogram (ERG) if the mutation disrupts the translation of retinal dystrophin (Dp260). Our aim was to determine if incomplete ERG abnormalities would be associated with heterozygous carriers of dystrophin gene mutations.?METHODS—Ganzfeld ERGs were obtained under scotopic and photopic testing conditions from a family which includes the heterozygous maternal grandmother, the heterozygous mother, and her children, two affected boys and dizygotic twin sibs, an unaffected male and heterozygous female. Southern blot analyses were done to characterise the dystrophin mutation.?RESULTS—The dystrophin gene was found to contain a deletion encompassing exon 50. The ERGs in the two affected boys were abnormal, consistent with the DMD ERG phenotype. Serial ERGs of the heterozygous females were abnormal; however, they were less severely affected than the DMD boys. The ERG of the female sib showed a greater abnormality than her mother and maternal grandmother. The unaffected twin had a normal ERG.?CONCLUSIONS—The ERG shows abnormalities associated with carrier status in this family with a single exon deletion. A large study of confirmed obligate carriers is planned to clarify further the value of the ERG in detecting female heterozygous carriers of dystrophin gene mutations.???Keywords: muscular dystrophy; electroretinography; retina; dystrophin PMID:10227401

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

    PubMed

    Barthélémy, Inès; Uriarte, Ane; Drougard, Carole; Unterfinger, Yves; Thibaud, Jean-Laurent; Blot, Stéphane

    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

  18. 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 ?-sarcoglycan is functional. We generated an internally truncated ?-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 ?-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking ?-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 ?-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in ?-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with ?-sarcoglycan gene mutations. PMID:26457733

  19. 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.

  20. 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.

  1. 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.; Bönnemann, 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

  2. Therapeutic Potential of Proteasome Inhibition in Duchenne and Becker Muscular Dystrophies

    PubMed Central

    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

    2010-01-01

    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, ?-sarcoglycan, and ?-dystroglycan protein levels in explants from BMD patients, whereas it increases the proteins of the dystrophin glycoprotein complex in DMD cases. PMID:20304949

  3. Limb-girdle muscular dystrophy type 2I is not rare in Taiwan.

    PubMed

    Liang, Wen-Chen; Hayashi, Yukiko K; Ogawa, Megumu; Wang, Chien-Hua; Huang, Wan-Ting; Nishino, Ichizo; Jong, Yuh-Jyh

    2013-08-01

    Alpha-dystroglycanopathy is caused by the glycosylation defects of ?-dystroglycan (?-DG). The clinical spectrum ranges from severe congenital muscular dystrophy (CMD) to later-onset limb girdle muscular dystrophy (LGMD). Among all ?-dystroglycanopathies, LGMD type 2I caused by FKRP mutations is most commonly seen in Europe but appears to be rare in Asia. We screened uncategorized 40 LGMD and 10 CMD patients by immunohistochemistry for ?-DG and found 7 with reduced ?-DG immunostaining. Immunoblotting with laminin overlay assay confirmed the impaired glycosylation of ?-DG. Among them, five LGMD patients harbored FKRP mutations leading to the diagnosis of LGMD2I. One common mutation, c.948delC, was identified and cardiomyopathy was found to be very common in our cohort. Muscle images showed severe involvement of gluteal muscles and posterior compartment at both thigh and calf levels, which is helpful for the differential diagnosis. Due to the higher frequency of LGMD2I with cardiomyopathy in our series, the early introduction of mutation analysis of FKRP in undiagnosed Taiwanese LGMD patients is highly recommended. PMID:23800702

  4. Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

    PubMed

    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

    2012-12-01

    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

  5. 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

  6. 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: 0.25–3 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

  7. 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

  8. 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 proteins5–8 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

  9. 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

  10. A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1

    E-print Network

    Campbell, Kevin P.

    ,m,n , Steven A. Moore o , Sidney M. Gospe Jr. p,q,r, a Division of Genetic Medicine, Department of Pediatrics in severity from Walker­Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, agesGlyfsÃ8) associated with Walker­Warburg syndrome and a novel missense mutation in a highly conserved

  11. 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…

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

    E-print Network

    Straight, Aaron

    . Introduction Autosomal dominant limb-girdle muscular dystrophies (LGMD1) are a genetically and clinically heterogeneous group of disorders. LGMD1 often presents with progressive proximal muscle weakness of the upper associated with LGMD1, including the MYOT gene encoding myotilin in LGMD1A [2], the LMNA gene encoding lamin

  13. 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 8–15 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

  14. 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; Sertié, 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

  15. 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.

  16. Dystromirs as Serum Biomarkers for Monitoring the Disease Severity in Duchenne Muscular Dystrophy

    PubMed Central

    Zaharieva, Irina T.; Calissano, Mattia; Scoto, Mariacristina; Preston, Mark; Cirak, Sebahattin; Feng, Lucy; Collins, James; Kole, Ryszard; Guglieri, Michela; Straub, Volker; Bushby, Kate; Ferlini, Alessandra; Morgan, Jennifer E.; Muntoni, Francesco

    2013-01-01

    Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy (BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls. We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials. Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD. PMID:24282529

  17. 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 ...

  18. Changes in pain-related beliefs, coping, and catastrophizing predict changes in pain intensity, pain interference, and psychological functioning in individuals with Myotonic Muscular Dystrophy and Facioscapulohumeral Dystrophy

    PubMed Central

    Nieto, Rubén; Raichle, Katherine A.; Jensen, Mark P.; Miró, Jordi

    2011-01-01

    Objectives The primary aim of this study was to test hypothesized associations between changes in psychological variables (i.e., pain beliefs, catastrophizing and coping strategies) and changes in pain intensity and related adjustment (i.e., pain interference and psychological functioning) in individuals with Myotonic Muscular Dystrophy (MMD) and Facioscapulohumeral Muscular Dystrophy (FSHD). Methods A sample of 107 adults with a diagnosis of MMD or FSHD, reporting pain in the past three months, completed assessments at two time-points, separated by about 24 months. Results Results showed that changes in pain-related psychological variables were significantly associated with changes in psychological functioning, pain intensity and pain interference. Specifically, increases in the belief that emotion influences pain, and catastrophizing were associated with decreases in psychological functioning. Increases in the coping strategies of asking for assistance and resting, and the increases of catastrophizing were associated with increases in pain intensity. Finally, increases in pain intensity and asking for assistance were associated with increases in pain interference. Discussion The results support the utility of the biopsychosocial model of pain for understanding pain and its impact in individuals with MMD or FSHD. These findings may inform the design and implementation of psychosocial pain treatments for people with muscular dystrophy and chronic pain. PMID:21642844

  19. 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

  20. 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

  1. 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

  2. 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.

  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 45–47, 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 82 bp 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. Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient.

    PubMed

    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

    2015-07-01

    We report a dystrophinopathy patient with an in-frame deletion of DMD exons 45-47, 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 82 bp 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

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. The Growing Family of Limb-Girdle Muscular Dystrophies: Old and Newly Identified Members.

    PubMed

    Bastian, Alexandra; Mageriu, V; Micu, Gianina; Manole, Emilia

    2015-01-01

    Limb-girdle muscular dystrophies (LGMD) are an extremely heterogeneous and rapidly expanding group of diseases characterized by progressive weakness of pelvic, scapular and trunk muscles with sparing of facial and distal musculature in most of the subtypes, onset in childhood or in adults of both sexes, very variable clinical severity ranging from mild to severe phenotypes, some associated with cardio-pulmonary and extraskeletal impairment and high serum creatine-kinase (CK) levels. In the past years, huge advances have been recorded in the various identification methods and new distinct entities were discovered. However, it is not yet clear why some muscle groups are affected and others spared in a specific subtype of LGMD, why similar clinical pictures are associated with different genes and mutations, while the same gene or mutation may present with very various clinical phenotypes. In this review we summarize the main aspects of positive and differential diagnosis in LGMD. PMID:26076556

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy and Hypoglycosylation of ?-Dystroglycan

    PubMed Central

    Stevens, Elizabeth; Carss, Keren J.; Cirak, Sebahattin; Foley, A. Reghan; Torelli, Silvia; Willer, Tobias; Tambunan, Dimira E.; Yau, Shu; Brodd, Lina; Sewry, Caroline A.; Feng, Lucy; Haliloglu, Goknur; Orhan, Diclehan; Dobyns, William B.; Enns, Gregory M.; Manning, Melanie; Krause, Amanda; Salih, Mustafa A.; Walsh, Christopher A.; Hurles, Matthew; Campbell, Kevin P.; Manzini, M. Chiara; Stemple, Derek; Lin, Yung-Yao; Muntoni, Francesco

    2013-01-01

    Mutations in several known or putative glycosyltransferases cause glycosylation defects in ?-dystroglycan (?-DG), an integral component of the dystrophin glycoprotein complex. The hypoglycosylation reduces the ability of ?-DG to bind laminin and other extracellular matrix ligands and is responsible for the pathogenesis of an inherited subset of muscular dystrophies known as the dystroglycanopathies. By exome and Sanger sequencing we identified two individuals affected by a dystroglycanopathy with mutations in ?-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2). B3GALNT2 transfers N-acetyl galactosamine (GalNAc) in a ?-1,3 linkage to N-acetyl glucosamine (GlcNAc). A subsequent study of a separate cohort of individuals identified recessive mutations in four additional cases that were all affected by dystroglycanopathy with structural brain involvement. We show that functional dystroglycan glycosylation was reduced in the fibroblasts and muscle (when available) of these individuals via flow cytometry, immunoblotting, and immunocytochemistry. B3GALNT2 localized to the endoplasmic reticulum, and this localization was perturbed by some of the missense mutations identified. Moreover, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy phenotype with reduced motility, brain abnormalities, and disordered muscle fibers with evidence of damage to both the myosepta and the sarcolemma. Functional dystroglycan glycosylation was also reduced in the b3galnt2 knockdown zebrafish embryos. Together these results demonstrate a role for B3GALNT2 in the glycosylation of ?-DG and show that B3GALNT2 mutations can cause dystroglycanopathy with muscle and brain involvement. PMID:23453667

  15. 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

  16. 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

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

    PubMed

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

    2015-03-01

    In-frame exon deletions of the Duchenne muscular dystrophy (DMD) gene produce internally truncated proteins that typically lead to Becker muscular dystrophy (BMD), a milder allelic disorder of DMD. We hypothesized that differences in the structure of mutant dystrophin may be responsible for the clinical heterogeneity observed in Becker patients and we studied four prevalent in-frame exon deletions, i.e. ?45-47, ?45-48, ?45-49 and ?45-51. Molecular homology modelling revealed that the proteins corresponding to deletions ?45-48 and ?45-51 displayed a similar structure (hybrid repeat) than the wild-type dystrophin, whereas deletions ?45-47 and ?45-49 lead to proteins with an unrelated structure (fractional repeat). All four proteins in vitro expressed in a fragment encoding repeats 16-21 were folded in ?-helices and remained highly stable. Refolding dynamics were slowed and molecular surface hydrophobicity were higher in fractional repeat containing ?45-47 and ?45-49 deletions compared with hybrid repeat containing ?45-48 and ?45-51 deletions. By retrospectively collecting data for a series of French BMD patients, we showed that the age of dilated cardiomyopathy (DCM) onset was delayed by 11 and 14 years in ?45-48 and ?45-49 compared with ?45-47 patients, respectively. A clear trend toward earlier wheelchair dependency (minimum of 11 years) was also observed in ?45-47 and ?45-49 patients compared with ?45-48 patients. Muscle dystrophin levels were moderately reduced in most patients without clear correlation with the deletion type. Disease progression in BMD patients appears to be dependent on the deletion itself and associated with a specific structure of dystrophin at the deletion site. PMID:25348330

  18. 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

  19. Predictive markers of clinical outcome in the GRMD dog model of Duchenne muscular dystrophy

    PubMed Central

    Barthélémy, Inès; Pinto-Mariz, Fernanda; Yada, Erica; Desquilbet, Loïc; Savino, Wilson; Silva-Barbosa, Suse Dayse; Faussat, Anne-Marie; Mouly, Vincent; Voit, Thomas; Blot, Stéphane; 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

  20. 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

  1. 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-?B, and in dystrophin-deficient mdx and utrophin/dystrophin (utrn-/-;mdx) double knock out (dko) mouse models, inhibition of NF-?B 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

  2. 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

  3. Hsp72 preserves muscle function and slows progression of severe muscular dystrophy.

    PubMed

    Gehrig, Stefan M; van der Poel, Chris; Sayer, Timothy A; Schertzer, Jonathan D; Henstridge, Darren C; Church, Jarrod E; Lamon, Severine; Russell, Aaron P; Davies, Kay E; Febbraio, Mark A; Lynch, Gordon S

    2012-04-19

    Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilizing protein dystrophin. Dystrophin-deficient muscle fibres are fragile and susceptible to an influx of Ca(2+), which activates inflammatory and muscle degenerative pathways. At present there is no cure for DMD, and existing therapies are ineffective. Here we show that increasing the expression of intramuscular heat shock protein 72 (Hsp72) preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy. Treatment with BGP-15 (a pharmacological inducer of Hsp72 currently in clinical trials for diabetes) improved muscle architecture, strength and contractile function in severely affected diaphragm muscles in mdx dystrophic mice. In dko mice, a phenocopy of DMD that results in severe spinal curvature (kyphosis), muscle weakness and premature death, BGP-15 decreased kyphosis, improved the dystrophic pathophysiology in limb and diaphragm muscles and extended lifespan. We found that the sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA, the main protein responsible for the removal of intracellular Ca(2+)) is dysfunctional in severely affected muscles of mdx and dko mice, and that Hsp72 interacts with SERCA to preserve its function under conditions of stress, ultimately contributing to the decreased muscle degeneration seen with Hsp72 upregulation. Treatment with BGP-15 similarly increased SERCA activity in dystrophic skeletal muscles. Our results provide evidence that increasing the expression of Hsp72 in muscle (through the administration of BGP-15) has significant therapeutic potential for DMD and related conditions, either as a self-contained therapy or as an adjuvant with other potential treatments, including gene, cell and pharmacological therapies. PMID:22495301

  4. 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, Frédéric; Miclau, Theodore; Marcucio, Ralph S; Colnot, Céline

    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

  5. Delayed bone regeneration is linked to chronic inflammation in murine muscular dystrophy

    PubMed Central

    Abou-Khalil, Rana; Yang, Frank; Mortreux, Marie; Lieu, Shirley; Yu, Yan-Yiu; Wurmser, Maud; Pereira, Catia; Relaix, Frédéric; Miclau, Theodore; Marcucio, Ralph S.; Colnot, Céline

    2013-01-01

    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 inhibitor in monocytes, partially rescued the bone repair defect through increasing cartilage deposition and decreasing macrophage number. 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

  6. Immobilization of Dystrophin and Laminin ?2-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 ?2-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 ?M). 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

  7. 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.

  8. 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.

  9. 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 ?–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

  10. A Novel Missense Mutation in POMT1 Modulates the Severe Congenital Muscular Dystrophy Phenotype Associated with POMT1 Nonsense Mutations

    PubMed Central

    Wallace, Stephanie E.; Conta, Jessie H.; Winder, Thomas L.; Willer, Tobias; Eskuri, Jamie M.; Haas, Richard; Patterson, Kathleen; Campbell, Kevin P.; Moore, Steven A.; Gospe, Sidney M.

    2014-01-01

    Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O-mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID:24491487

  11. 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.

  12. 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

  13. Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS

    PubMed Central

    Martins-Júnior, 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.; Ambrósio, 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

  14. A novel dystrophin deletion mutation in a becker muscular dystrophy patient with early-onset dilated cardiomyopathy.

    PubMed

    Guo, Xiaoxiao; Dai, Yi; Cui, Liying; Fang, Quan

    2014-08-01

    Becker muscular dystrophy (BMD) is a rare cause of dilated cardiomyopathy (DCM). We present a 23-year-old patient with BMD and early-onset DCM in whom cardiovascular magnetic resonance showed extensive myocardial late gadolinium enhancement and previously unreported findings of subepicardial fat infiltration in the lateral wall. In addition, this patient carried a rare mutation of dystrophin gene that might be a new genetic predisposition to early-onset DCM in BMD. PMID:24996370

  15. Profiles of Steroid Hormones in Canine X-Linked Muscular Dystrophy via Stable Isotope Dilution LC-MS/MS.

    PubMed

    Martins-Júnior, 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; Ambrósio, 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

  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. Limb-girdle muscular dystrophy with obesity for elective cesarean section: Anesthetic management and brief review of the literature

    PubMed Central

    Ranjan, R. V.; Ramachandran, T. R.; Manikandan, S.; John, Roshan

    2015-01-01

    Limb-girdle muscular dystrophy (LGMD) is an autosomal recessive disorder in which the pelvic or shoulder girdle musculature is predominantly or primarily involved. We report the management of a 27-year-old primigravida with LGMD associated with obesity posted for elective cesarean section. She was successfully managed with epidural anesthesia assisted with noninvasive positive pressure ventilation. She had an uncomplicated intra- and post-operative course. PMID:25886439

  18. Limb-girdle muscular dystrophy with obesity for elective cesarean section: Anesthetic management and brief review of the literature.

    PubMed

    Ranjan, R V; Ramachandran, T R; Manikandan, S; John, Roshan

    2015-01-01

    Limb-girdle muscular dystrophy (LGMD) is an autosomal recessive disorder in which the pelvic or shoulder girdle musculature is predominantly or primarily involved. We report the management of a 27-year-old primigravida with LGMD associated with obesity posted for elective cesarean section. She was successfully managed with epidural anesthesia assisted with noninvasive positive pressure ventilation. She had an uncomplicated intra- and post-operative course. PMID:25886439

  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. 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

  1. Retinal signal transmission in Duchenne muscular dystrophy: evidence for dysfunction in the photoreceptor/depolarizing bipolar cell pathway.

    PubMed Central

    Fitzgerald, K M; Cibis, G W; Giambrone, S A; Harris, D J

    1994-01-01

    There have been reports of abnormal retinal neurotransmission determined by electroretinography in boys with Duchenne and Becker muscular dystrophy. Dystrophin may play a role in transmitting signals between photoreceptors and the excitatory synapse of the ON-bipolar cell. These electroretinographic changes appeared to be limited to the rod ON-pathway but we felt there was also similar abnormality in the cone ON-pathway. We used long-duration stimuli to separate ON-(depolarizing bipolar cell) and OFF (hyperpolarizing bipolar cell) contributions to the cone-dominated ERG to better understand how the retina functions in boys with Duchenne muscular dystrophy. We recorded the electroretinograms of 11 boys with Duchenne muscular dystrophy and found abnormal signal transmission at the level of the photoreceptor and ON-bipolar cell in both the rod and cone generated responses. The OFF-bipolar cell that responds to the offset of the stimulus continues to function normally. The results support our hypothesis that retinal dystrophin plays a role in receptor function or controlling ion channels at the level of the photoreceptor and depolarizing bipolar cell. PMID:8200977

  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. Progressive muscular dystrophy--Duchenne type. Controversies of the kinesitherapy treatment.

    PubMed

    de Araujo Leitão, 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

  5. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy.

    PubMed

    Mendell, Jerry R; Sahenk, Zarife; Malik, Vinod; Gomez, Ana M; Flanigan, Kevin M; Lowes, Linda P; Alfano, Lindsay N; Berry, Katherine; Meadows, Eric; Lewis, Sarah; Braun, Lyndsey; Shontz, Kim; Rouhana, Maria; Clark, Kelly Reed; Rosales, Xiomara Q; Al-Zaidy, Samiah; Govoni, Alessandra; Rodino-Klapac, Louise R; Hogan, Mark J; Kaspar, Brian K

    2015-01-01

    Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype is variable with loss of ambulation in late teenage or late mid-life years. There is currently no treatment for this condition. In this BMD proof-of-principle clinical trial, a potent myostatin antagonist, follistatin (FS), was used to inhibit the myostatin pathway. Extensive preclinical studies, using adeno-associated virus (AAV) to deliver follistatin, demonstrated an increase in strength. For this trial, we used the alternatively spliced FS344 to avoid potential binding to off target sites. AAV1.CMV.FS344 was delivered to six BMD patients by direct bilateral intramuscular quadriceps injections. Cohort 1 included three subjects receiving 3?×?10(11) vg/kg/leg. The distance walked on the 6MWT was the primary outcome measure. Patients 01 and 02 improved 58 meters (m) and 125 m, respectively. Patient 03 showed no change. In Cohort 2, Patients 05 and 06 received 6?×?10(11) vg/kg/leg with improved 6MWT by 108 m and 29 m, whereas, Patient 04 showed no improvement. No adverse effects were encountered. Histological changes corroborated benefit showing reduced endomysial fibrosis, reduced central nucleation, more normal fiber size distribution with muscle hypertrophy, especially at high dose. The results are encouraging for treatment of dystrophin-deficient muscle diseases. PMID:25322757

  6. Living with severe physical impairment, Duchenne's muscular dystrophy and home mechanical ventilation

    PubMed Central

    Dreyer, Pia S.; Steffensen, Birgit F.; Pedersen, Birthe D.

    2010-01-01

    Aim To study life-experiences of people living with Duchenne's muscular dystrophy (DMD), home mechanical ventilation (HMV) and physical impairment. Background Since the introduction of invasive HMV in the late 1980s people with DMD in Denmark live longer and have the experience of adulthood and a high degree of physical dependency. Method Nineteen patients with DMD and invasive HMV were interviewed in 2007. The interviews were recorded, transcribed verbatim and analysed according to a method inspired by Ricoeur's theory of interpretation. Findings HMV not only extended the participants lifespan, it also gave them the capacity to live an active life. They were totally dependent in everyday living, but in spite of this, they did not see themselves as physically impaired. They realised that there were activities that were physically impossible, but they considered themselves to be just the same person they had always been. This dependency was described as “independent dependency”. Conclusion The lived-experience of physical impairment is found to be “independent dependency” in an active life. To solve problems with loneliness, society needs to work with prejudice and misunderstanding and for better physical accessibility to enable full participation. PMID:20689774

  7. 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; D’Amico, 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; D’Angelo, 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

  8. 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-?) 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-?), 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-? 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

  9. 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

  10. 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

  11. Dystrophin and the two related genetic diseases, Duchenne and Becker muscular dystrophies

    PubMed Central

    Rumeur, Elisabeth Le

    2015-01-01

    Mutations of the dystrophin DMD gene, essentially deletions of one or several exons, are the cause of two devastating and to date incurable diseases, Duchenne (DMD) and Becker (BMD) muscular dystrophies. Depending upon the preservation or not of the reading frame, dystrophin is completely absent in DMD, or present in either a mutated or a truncated form in BMD. DMD is a severe disease which leads to a premature death of the patients. Therapy approaches are evolving with the aim to transform the severe DMD in the BMD form of the disease by restoring the expression of a mutated or truncated dystrophin. These therapies are based on the assumption that BMD is a mild disease. However, this is not completely true as BMD patients are more or less severely affected and no molecular basis of this heterogeneity of the BMD form of the disease is yet understood. The aim of this review is to report for the correlation between dystrophin structures in BMD deletions in view of this heterogeneity and to emphasize that examining BMD patients in details is highly relevant to anticipate for DMD therapy effects. PMID:26295289

  12. Evidence of Insulin Resistance and Other Metabolic Alterations in Boys with Duchenne or Becker Muscular Dystrophy.

    PubMed

    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

  13. Dystrophin hydrophobic regions in the pathogenesis of Duchenne and Becker muscular dystrophies

    PubMed Central

    Liang, Yingyin; Chen, Songlin; Zhu, Jianzong; Zhou, Xiangxue; Yang, Chen; Yao, Lu; Zhang, Cheng

    2015-01-01

    The aim of our study was to determine the role of dystrophin hydrophobic regions in the pathogenesis of Duchenne (DMD) and Becker (BMD) muscular dystrophies, by the Kyte-Doolittle scale mean hydrophobicity profile and 3D molecular models. A total of 1038 cases diagnosed with DMD or BMD with the in-frame mutation were collected in our hospital and the Leiden DMD information database in the period 2002-2013. Correlation between clinical types and genotypes were determined on the basis of these two sources. In addition, the Kyte-Doolittle scale mean hydrophobicity of dystrophin was analyzed using BioEdit software and the models of the hydrophobic domains of dystrophin were constructed. The presence of four hydrophobic regions is confirmed. They include the calponin homology CH2 domain on the actin-binding domain (ABD), spectrin-type repeat 16, hinge III and the EF Hand domain. The severe symptoms of DMD usually develop as a result of the mutational disruption in the hydrophobic regions I, II and IV of dystrophin – those that bind associated proteins of the dystrophin-glycoprotein complex (DGC). On the other hand, when the hydrophobic region III is deleted, the connection of the ordered repeat domains of the central rod domain remains intact, resulting in the less severe clinical presentation. We conclude that mutational changes in the structure of hydrophobic regions of dystrophin play an important role in the pathogenesis of DMD. PMID:26042512

  14. Are all the previously reported genetic variants in limb girdle muscular dystrophy genes pathogenic?

    PubMed

    Di Fruscio, Giuseppina; Garofalo, Arcomaria; Mutarelli, Margherita; Savarese, Marco; Nigro, Vincenzo

    2016-01-01

    Hundreds of variants in autosomal genes associated with the limb girdle muscular dystrophies (LGMDs) have been reported as being causative. However, in most cases the proof of pathogenicity derives from their non-occurrence in hundreds of healthy controls and/or from segregation studies in small families. The limited statistics of the genetic variations in the general population may hamper a correct interpretation of the effect of variants on the protein. To clarify the meaning of low-frequency variants in LGMD genes, we have selected all variants described as causative in the Leiden Open Variation Database and the Human Gene Mutation Database. We have systematically searched for their frequency in the NHLBI GO Exome Sequencing Project (ESP) and in our internal database. Surprisingly, the ESP contains about 4% of the variants previously associated with a dominant inheritance and about 9% of those associated with a recessive inheritance. The putative disease alleles are much more frequent than those estimated considering the disease prevalence. In conclusion, we hypothesize that a number of disease-associated variants are non-pathogenic and that other variations are not fully penetrant, even if they affect the protein function, suggesting a more complex genetic mechanisms for such heterogeneous disorders. PMID:25898921

  15. 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

  16. Identification of de novo Mutations of Duchénnè/Becker Muscular Dystrophies in Southern Spain

    PubMed Central

    Garcia, Susana; de Haro, Tomás; Zafra-Ceres, Mercedes; Poyatos, Antonio; Gomez-Capilla, Jose A.; Gomez-Llorente, Carolina

    2014-01-01

    Background: Duchénnè/Becker muscular dystrophies (DMD/BMD) are X-linked diseases, which are caused by a de novo gene mutation in one-third of affected males. The study objectives were to determine the incidence of DMD/BMD in Andalusia (Spain) and to establish the percentage of affected males in whom a de novo gene mutation was responsible. Methods: Multiplex ligation-dependent probe amplification (MLPA) technology was applied to determine the incidence of DMD/BMD in 84 males with suspicion of the disease and 106 female relatives. Results: Dystrophin gene exon deletion (89.5%) or duplication (10.5%) was detected in 38 of the 84 males by MLPA technology; de novo mutations account for 4 (16.7%) of the 24 mother-son pairs studied. Conclusions: MLPA technology is adequate for the molecular diagnosis of DMD/BMD and establishes whether the mother carries the molecular alteration responsible for the disease, a highly relevant issue for genetic counseling. PMID:25076844

  17. 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

  18. CINRG Pilot trial of Coenzyme Q10 in steroid treated Duchenne Muscular Dystrophy

    PubMed Central

    Spurney, Christopher F.; Rocha, Carolina Tesi; Henricson, Erik; Florence, Julaine; Mayhew, Jill; Gorni, Ksenija; Pasquali, Livia; Pestronk, Alan; Martin, Gerard R.; Hu, Fengming; Nie, Lei; Connolly, Anne M.; Escolar, Diana M.

    2011-01-01

    Introduction Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin deficient muscle. Methods We performed an open label, “add-on” pilot study of CoQ10 in thirteen 5–10 year old DMD patients on steroids. The primary outcome measure was the total Quantitative Muscle Testing (QMT) score. Results Twelve of 16 children (mean age 8.03±1.64 years) completed the trial. Target serum levels of CoQ10 (?2.5 ?g/ml) were shown to be subject- and administration-dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in 8.5 % increase in muscle strength (p=0.03). Discussion This pilot study found the addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. PMID:21698649

  19. 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

  20. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2

    PubMed Central

    Mojumdar, Kamalika; Liang, Feng; Giordano, Christian; Lemaire, Christian; Danialou, Gawiyou; Okazaki, Tatsuma; Bourdon, Johanne; Rafei, Moutih; Galipeau, Jacques; Divangahi, Maziar; Petrof, Basil J

    2014-01-01

    Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6Chigh) MO recruitment and accumulation of CD11bhigh MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11bhigh MP population by impeding the release of Ly6Chigh MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. PMID:25312642

  1. Inflammatory monocytes promote progression of Duchenne muscular dystrophy and can be therapeutically targeted via CCR2.

    PubMed

    Mojumdar, Kamalika; Liang, Feng; Giordano, Christian; Lemaire, Christian; Danialou, Gawiyou; Okazaki, Tatsuma; Bourdon, Johanne; Rafei, Moutih; Galipeau, Jacques; Divangahi, Maziar; Petrof, Basil J

    2014-11-01

    Myofiber necrosis and fibrosis are hallmarks of Duchenne muscular dystrophy (DMD), leading to lethal weakness of the diaphragm. Macrophages (MPs) are required for successful muscle regeneration, but the role of inflammatory monocyte (MO)-derived MPs in either promoting or mitigating DMD is unclear. We show that DMD (mdx) mouse diaphragms exhibit greatly increased expression of CCR2 and its chemokine ligands, along with inflammatory (Ly6C(high)) MO recruitment and accumulation of CD11b(high) MO-derived MPs. Loss-of-function of CCR2 preferentially reduced this CD11b(high) MP population by impeding the release of Ly6C(high) MOs from the bone marrow but not the splenic reservoir. CCR2 deficiency also helped restore the MP polarization balance by preventing excessive skewing of MPs toward a proinflammatory phenotype. These effects were linked to amelioration of histopathological features and increased muscle strength in the diaphragm. Chronic inhibition of CCR2 signaling by mutated CCL2 secreted from implanted mesenchymal stem cells resulted in similar improvements. These data uncover a previously unrecognized role of inflammatory MOs in DMD pathogenesis and indicate that CCR2 inhibition could offer a novel strategy for DMD management. PMID:25312642

  2. A mixed methods study of age at diagnosis and diagnostic odyssey for Duchenne muscular dystrophy.

    PubMed

    Wong, Siaw H; McClaren, Belinda J; Archibald, Alison Dalton; Weeks, Alice; Langmaid, Tess; Ryan, Monique M; Kornberg, Andrew; Metcalfe, Sylvia A

    2015-10-01

    The delayed diagnosis of Duchenne muscular dystrophy (DMD) may be an ongoing problem internationally. We aimed to ascertain age at diagnosis and explore parents' experiences of the diagnosis of DMD in Australia. Using mixed methods, data were collected from laboratory and clinical record audits of testing for DMD in Victoria and Tasmania, interviews and a national survey of parents regarding their experiences from first noticing symptoms to receiving a diagnosis. The audits revealed that the median age at diagnosis for DMD was 5 years (n=49 during 2005-2010); this age had not changed substantially over this period. Fourteen parents interviewed reported age at diagnosis ranging from 2 to 8 years with a 6 month to 4 year delay between initial concerns about their child's development and receiving the DMD diagnosis. Sixty-two survey respondents reported the median age at diagnosis was 3 years and 9 months, while the median age when symptoms were noticed was 2 years and 9 months. Parents experienced many emotions in their search for a diagnosis and consulted with a wide range of health professionals. Half the survey respondents felt that their child could have been diagnosed earlier. Despite advances in testing technologies and increasing awareness of DMD, the age at diagnosis has remained constant in Australia. This mixed methods study shows that this diagnostic delay continues to have a negative impact on parents' experiences, places families at risk of having a second affected child and may have a deleterious effect on affected children's treatment. PMID:25626706

  3. Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging.

    PubMed

    Lang, Sean M; Shugh, Svetlana; Mazur, Wojciech; Sticka, Joshua J; Rattan, Mantosh S; Jefferies, John L; Taylor, Michael D

    2015-10-01

    The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children's Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction <55 %). Seven of 20 DMD carriers (35 %) were found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers. PMID:25976773

  4. Psychosocial challenges in family caregiving with children suffering from Duchenne muscular dystrophy.

    PubMed

    Thomas, Priya Treesa; Rajaram, Prakashi; Nalini, Atchayaram

    2014-08-01

    Families of children with Duchenne muscular dystrophy (DMD) go through significant challenges in dealing with the condition. Few studies have looked into the situation, especially in the sociocultural scenario that is unique to India. The authors' aim was to identify the psychosocial challenges for caregivers of children with DMD. A cross-sectional descriptive study was perfomed among the caregivers of 60 children with DMD who were attending the neuromuscular disorders clinic of a national tertiary referral center for neurological disorders. The knowledge and attitude, psychosocial needs, burden, and coping patterns were assessed in an interview. The findings showed that parents of children with DMD tended to have inadequate understanding of the disease but had a positive attitude, had a moderate family burden, and tended to rely more on religion, focus on and venting of emotions, and instrumental and emotional social support for coping. Caregivers of children with DMD would benefit from psychosocial intervention to address their understanding of and attitude toward the disease, as well as burden of dealing with it, and to help them develop their coping skills and meet their children's and their own needs. PMID:25095627

  5. Myogenic Enhancers Regulate Expression of the Facioscapulohumeral Muscular Dystrophy-Associated DUX4 Gene

    PubMed Central

    Himeda, Charis L.; Debarnot, Céline; 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. 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

  7. ?-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 ?-catenin as the main coordinator of FSHD-associated protein interaction signalling, with pathways including canonical Wnt, HIF1-? and TNF-? 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/?-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

  8. Biochemical and Functional Comparisons of mdx and Sgcg?/? Muscular Dystrophy Mouse Models

    PubMed Central

    Roberts, Nathan W.; Holley-Cuthrell, Jenan; Gonzalez-Vega, Magdalis; Mull, Aaron J.; Heydemann, Ahlke

    2015-01-01

    Mouse models have provided an essential platform to investigate facets of human diseases, from etiology, diagnosis, and prognosis, to potential treatments. Muscular dystrophy (MD) is the most common human genetic disease occurring in approximately 1 in 2500 births. The mdx mouse, which is dystrophin-deficient, has long been used to model this disease. However, this mouse strain displays a rather mild disease course compared to human patients. The mdx mice have been bred to additional genetically engineered mice to worsen the disease. Alternatively, other genes which cause human MD have been genetically disrupted in mice. We are now comparing disease progression from one of these alternative gene disruptions, the ?-sarcoglycan null mouse Sgcg?/? on the DBA2/J background, to the mdx mouse line. This paper aims to assess the time-course severity of the disease in the mouse models and determine which is best for MD research. The Sgcg?/? mice have a more severe phenotype than the mdx mice. Muscle function was assessed by plethysmography and echocardiography. Histologically the Sgcg?/? mice displayed increased fibrosis and variable fiber size. By quantitative Evan's blue dye uptake and hydroxyproline content two key disease determinants, membrane permeability and fibrosis respectively, were also proven worse in the Sgcg?/? mice. PMID:26064876

  9. Tongue pressure during swallowing is decreased in patients with Duchenne muscular dystrophy.

    PubMed

    Hamanaka-Kondoh, Sato; Kondoh, Jugo; Tamine, Ken-Ichi; Hori, Kazuhiro; Fujiwara, Shigehiro; Maeda, Yoshinobu; Matsumura, Tsuyoshi; Yasui, Kumiko; Fujimura, Harutoshi; Sakoda, Saburo; Ono, Takahiro

    2014-06-01

    Although dysphagia is a life-threatening problem in patients with Duchenne muscular dystrophy (DMD), the pathophysiology of oral stage dysphagia is yet to be understood. The present study investigated the tongue motor deficit during swallowing in patients with DMD and its relationship with disease-specific palatal morphology. Tongue pressure during swallowing water was recorded in 11 male patients with DMD and 11 age- and sex-matched healthy subjects using an intra-oral sensor with five measuring points, and the state of tongue pressure production was compared between the groups. Palatal morphology was assessed by a non-contact three-dimensional scanner on maxillary plaster models. In patients with DMD, the normal sequential order of tongue-palate contact was lost and the maximal magnitude and integrated value of tongue pressure on the mid-anterior part of palate were smaller than those in healthy subjects. The width of the palate in patients was greater than that in healthy subjects and the depth of the palate in patients had a negative correlation with tongue pressure magnitude on the median palate. Our results suggested that the deteriorated tongue motor kinetics prevented tongue movement during swallowing that was appropriate for the depth of the palate and affects the state of tongue pressure production during swallowing. PMID:24684858

  10. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy

    PubMed Central

    McGreevy, Joe W.; Hakim, Chady H.; McIntosh, Mark A.; Duan, Dongsheng

    2015-01-01

    Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder. It is caused by loss-of-function mutations in the dystrophin gene. Currently, there is no cure. A highly promising therapeutic strategy is to replace or repair the defective dystrophin gene by gene therapy. Numerous animal models of DMD have been developed over the last 30 years, ranging from invertebrate to large mammalian models. mdx mice are the most commonly employed models in DMD research and have been used to lay the groundwork for DMD gene therapy. After ~30 years of development, the field has reached the stage at which the results in mdx mice can be validated and scaled-up in symptomatic large animals. The canine DMD (cDMD) model will be excellent for these studies. In this article, we review the animal models for DMD, the pros and cons of each model system, and the history and progress of preclinical DMD gene therapy research in the animal models. We also discuss the current and emerging challenges in this field and ways to address these challenges using animal models, in particular cDMD dogs. PMID:25740330

  11. Muscle fatigue, nNOS and muscle fiber atrophy in limb girdle muscular dystrophy.

    PubMed

    Angelini, Corrado; Tasca, Elisabetta; Nascimbeni, Anna Chiara; Fanin, Marina

    2014-12-01

    Muscle fatigability and atrophy are frequent clinical signs in limb girdle muscular dystrophy (LGMD), but their pathogenetic mechanisms are still poorly understood. We review a series of different factors that may be connected in causing fatigue and atrophy, particularly considering the role of neuronal nitric oxide synthase (nNOS) and additional factors such as gender in different forms of LGMD (both recessive and dominant) underlying different pathogenetic mechanisms. In sarcoglycanopathies, the sarcolemmal nNOS reactivity varied from absent to reduced, depending on the residual level of sarcoglycan complex: in cases with complete sarcoglycan complex deficiency (mostly in beta-sarcoglycanopathy), the sarcolemmal nNOS reaction was absent and it was always associated with early severe clinical phenotype and cardiomyopathy. Calpainopathy, dysferlinopathy, and caveolinopathy present gradual onset of fatigability and had normal sarcolemmal nNOS reactivity. Notably, as compared with caveolinopathy and sarcoglycanopathies, calpainopathy and dysferlinopathy showed a higher degree of muscle fiber atrophy. Males with calpainopathy and dysferlinopathy showed significantly higher fiber atrophy than control males, whereas female patients have similar values than female controls, suggesting a gender difference in muscle fiber atrophy with a relative protection in females. In female patients, the smaller initial muscle fiber size associated to endocrine factors and less physical effort might attenuate gender-specific muscle loss and atrophy. PMID:25873780

  12. Stem Cell Transplantation for Muscular Dystrophy: The Challenge of Immune Response

    PubMed Central

    Noviello, Maddalena

    2014-01-01

    Treating muscle disorders poses several challenges to the rapidly evolving field of regenerative medicine. Considerable progress has been made in isolating, characterizing, and expanding myogenic stem cells and, although we are now envisaging strategies to generate very large numbers of transplantable cells (e.g., by differentiating induced pluripotent stem cells), limitations directly linked to the interaction between transplanted cells and the host will continue to hamper a successful outcome. Among these limitations, host inflammatory and immune responses challenge the critical phases after cell delivery, including engraftment, migration, and differentiation. Therefore, it is key to study the mechanisms and dynamics that impair the efficacy of cell transplants in order to develop strategies that can ultimately improve the outcome of allogeneic and autologous stem cell therapies, in particular for severe disease such as muscular dystrophies. In this review we provide an overview of the main players and issues involved in this process and discuss potential approaches that might be beneficial for future regenerative therapies of skeletal muscle. PMID:25054157

  13. Conserved expression of truncated telethonin in a patient with limb-girdle muscular dystrophy 2G.

    PubMed

    Barresi, Rita; Morris, Charlotte; Hudson, Judith; Curtis, Elizabeth; Pickthall, Clare; Bushby, Kate; Davies, Nicholas P; Straub, Volker

    2015-04-01

    Limb-girdle muscular dystrophy 2G is caused by mutations in the TCAP gene that encodes for telethonin. Here we describe a 49 year-old male patient of Indian descent presenting a classical LGMD phenotype. He had normal motor milestones but became noticeably slower in his early teens and was wheelchair bound by age 44. The muscle biopsy showed myopathic features and absence of labeling with an antibody to the C-terminal portion of telethonin. Sequence analysis of the TCAP gene revealed a novel homozygous mutation in exon 2, predicted to generate a truncated protein of 81 amino acids. Interestingly, an antibody for the full-length protein showed labeling on sections and a single band of ~10?kDa on Western blot. The truncated protein co-localized with filamin C at the Z-line. Our findings indicate that mutant telethonin can be incorporated into the sarcomere and that other LGMD2G patients with retention of telethonin expression may exist. PMID:25724973

  14. Limb-girdle muscular dystrophies: where next after six decades from the first proposal (Review).

    PubMed

    Mahmood, Omar A; Jiang, Xin Mei

    2014-05-01

    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

  15. ANO5 mutations in the Dutch limb girdle muscular dystrophy population.

    PubMed

    van der Kooi, Anneke J; Ten Dam, Leroy; Frankhuizen, Wendy S; Straathof, Chiara S M; van Doorn, Pieter A; de Visser, Marianne; Ginjaar, Ieke B

    2013-06-01

    A Dutch cohort of 105 limb girdle muscular dystrophy (LGMD) patients were subject to subsequent genetic investigations. In half the families a causative mutation was found. Recently mutations were identified in ANO5 causing LGMD2L and Miyoshi-like myopathy (MMD3), but could also be found in patients with hyperCKemia only. Therefore, we analysed the index cases of the remaining 31 as yet undiagnosed families from our previously described cohort of LGMD patients for the presence of ANO5 mutations. Detailed history and neurological examination were available for all patients. Serum creatine kinase (CK) activity, skeletal muscle computed tomography (CT) and cardiological investigations were performed. Mutations in ANO5 were found in 16% of the families: 11 index patients and two sibs, eight males and five females. The founder mutation c.191dupA was present in 8 out of 13 patients. Ten different pathogenic mutations were identified of which seven were novel: five missense and two splice site mutations. The age of these patients ranged from 26 to 69 years and the age of onset varied from 21 to 57 years. Symptoms at onset were related to proximal leg weakness. The weakness was slowly progressive. Calf hypertrophy was present in three patients. Males were more severely affected than females. Serum CK activity was highly elevated in the early stage of disease and moderately increased in later stages. Muscle biopsy showed predominantly dystrophic changes. One patient had hypertrophic cardiomyopathy, two others had intraventricular septum thickening. PMID:23607914

  16. Fluoxetine prevents dystrophic changes in a zebrafish model of Duchenne muscular dystrophy

    PubMed Central

    Waugh, Trent A.; Horstick, Eric; Hur, Junguk; Jackson, Samuel W.; Davidson, Ann E.; Li, Xingli; Dowling, James J.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a common and relentlessly progressive muscle disease. Some interventions have been identified that modestly slow progression and prolong survival, but more meaningful therapies are lacking. The goal of this study is to identify new therapeutic pathways for DMD using a zebrafish model of the disease. To accomplish this, we performed a non-biased drug screen in sapje, a zebrafish line with a recessive nonsense mutation in dystrophin. We identified 6 positive hits (out of 640 total drugs tested) by their ability to prevent abnormal birefringence in sapje. Follow-up analyses demonstrated that fluoxetine, a selective serotonin reuptake inhibitor (SSRI), provided the most substantial benefit. Morpholino-based experimentation confirmed that modulation of the serotonin pathway alone can prevent the dystrophic phenotype, and transcriptomic analysis revealed changes in calcium homeostasis as a potential mechanism. In all, we demonstrate that monoamine agonists can prevent disease in a vertebrate model of DMD. Given the safe and widespread use of SSRIs in clinical practice, our study identifies an attractive target pathway for therapy development. PMID:24760771

  17. Gene expression profiling in tibial muscular dystrophy reveals unfolded protein response and altered autophagy.

    PubMed

    Screen, Mark; Raheem, Olayinka; Holmlund-Hampf, Jeanette; Jonson, Per Harald; Huovinen, Sanna; Hackman, Peter; Udd, Bjarne

    2014-01-01

    Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres. PMID:24618559

  18. Autologous Myoblast Transplantation for Oculopharyngeal Muscular Dystrophy: a Phase I/Iia Clinical Study

    PubMed Central

    Périé, Sophie; Trollet, Capucine; Mouly, Vincent; Vanneaux, Valérie; Mamchaoui, Kamel; Bouazza, Belaïd; Marolleau, Jean Pierre; Laforêt, Pascal; Chapon, Françoise; Eymard, Bruno; Butler-Browne, Gillian; Larghero, Jérome; St Guily, Jean Lacau

    2014-01-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant genetic disease mainly characterized by ptosis and dysphagia. We conducted a phase I/IIa clinical study (ClinicalTrials.gov NCT00773227) using autologous myoblast transplantation following myotomy in adult OPMD patients. This study included 12 patients with clinical diagnosis of OPMD, indication for cricopharyngeal myotomy, and confirmed genetic diagnosis. The feasibility and safety end points of both autologous myoblast transplantation and the surgical procedure were assessed by videoendoscopy in addition to physical examinations. Potential therapeutic benefit was also assessed through videoendoscopy and videofluoroscopy of swallowing, quality of life score, dysphagia grade, and a drink test. Patients were injected with a median of 178 million myoblasts following myotomy. Short and long-term (2 years) safety and tolerability were observed in all the patients, with no adverse effects. There was an improvement in the quality of life score for all 12 patients, and no functional degradation in swallowing was observed for 10 patients. A cell dose-dependant improvement in swallowing was even observed in this study. This trial supports the hypothesis that a local injection of autologous myoblasts in the pharyngeal muscles is a safe and efficient procedure for OPMD patients. PMID:23831596

  19. Behavioral Responses in Animal Model of Congenital Muscular Dystrophy 1D.

    PubMed

    Comim, Clarissa M; Schactae, Aryadnne L; Soares, Jaime A; Ventura, Letícia; Freiberger, Viviane; Mina, Francielle; Dominguini, Diogo; Vainzof, Mariz; Quevedo, João

    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

  20. The first exon duplication mouse model of Duchenne muscular dystrophy: A tool for therapeutic development.

    PubMed

    Vulin, Adeline; Wein, Nicolas; Simmons, Tabatha R; Rutherford, Andrea M; Findlay, Andrew R; Yurkoski, Jacqueline A; Kaminoh, Yuuki; Flanigan, Kevin M

    2015-11-01

    Exon duplication mutations account for up to 11% of all cases of Duchenne muscular dystrophy (DMD), and a duplication of exon 2 is the most common duplication in patients. For use as a platform for testing of duplication-specific therapies, we developed a mouse model that carries a Dmd exon 2 duplication. By using homologous recombination we duplicated exon 2 within intron 2 at a location consistent with a human duplication hotspot. mRNA analysis confirms the inclusion of a duplicated exon 2 in mouse muscle. Dystrophin expression is essentially absent by immunofluorescent and immunoblot analysis, although some muscle specimens show very low-level trace dystrophin expression. Phenotypically, the mouse shows similarities to mdx, the standard laboratory model of DMD. In skeletal muscle, areas of necrosis and phagocytosis are seen at 3 weeks, with central nucleation prominent by four weeks, recapitulating the "crisis" period in mdx. Marked diaphragm fibrosis is noted by 6 months, and remains unchanged at 12 months. Our results show that the Dup2 mouse is both pathologically (in degree and distribution) and physiologically similar to mdx. As it recapitulates the most common single exon duplication found in DMD patients, this new model will be a useful tool to assess the potential of duplicated exon skipping. PMID:26365037

  1. Phase 1 Gene Therapy for Duchenne Muscular Dystrophy Using a Translational Optimized AAV Vector

    PubMed Central

    Bowles, Dawn E; McPhee, Scott WJ; Li, Chengwen; Gray, Steven J; Samulski, Jade J; Camp, Angelique S; Li, Juan; Wang, Bing; Monahan, Paul E; Rabinowitz, Joseph E; Grieger, Joshua C; Govindasamy, Lakshmanan; Agbandje-McKenna, Mavis; Xiao, Xiao; Samulski, R Jude

    2012-01-01

    Efficient and widespread gene transfer is required for successful treatment of Duchenne muscular dystrophy (DMD). Here, we performed the first clinical trial using a chimeric adeno-associated virus (AAV) capsid variant (designated AAV2.5) derived from a rational design strategy. AAV2.5 was generated from the AAV2 capsid with five mutations from AAV1. The novel chimeric vector combines the improved muscle transduction capacity of AAV1 with reduced antigenic crossreactivity against both parental serotypes, while keeping the AAV2 receptor binding. In a randomized double-blind placebo-controlled phase I clinical study in DMD boys, AAV2.5 vector was injected into the bicep muscle in one arm, with saline control in the contralateral arm. A subset of patients received AAV empty capsid instead of saline in an effort to distinguish an immune response to vector versus minidystrophin transgene. Recombinant AAV genomes were detected in all patients with up to 2.56 vector copies per diploid genome. There was no cellular immune response to AAV2.5 capsid. This trial established that rationally designed AAV2.5 vector was safe and well tolerated, lays the foundation of customizing AAV vectors that best suit the clinical objective (e.g., limb infusion gene delivery) and should usher in the next generation of viral delivery systems for human gene transfer. PMID:22068425

  2. Laminin-?2 Chain-Deficient Congenital Muscular Dystrophy: Pathophysiology and Development of Treatment.

    PubMed

    Durbeej, Madeleine

    2015-01-01

    Laminin-211 is a major constituent of the skeletal muscle basement membrane. It stabilizes skeletal muscle and influences signal transduction events from the myomatrix to the muscle cell. Mutations in the gene encoding the ?2 chain of laminin-211 lead to congenital muscular dystrophy type 1A (MDC1A), a life-threatening disease characterized by severe hypotonia, progressive muscle weakness, and joint contractures. Common complications include severely impaired motor ability, respiratory failure, and feeding difficulties. Several adequate animal models for laminin-?2 chain deficiency exist and analyses of different MDC1A mouse models have led to a significant improvement in our understanding of MDC1A pathogenesis. Importantly, the animal models have been indispensable tools for the preclinical development of new therapeutic approaches for laminin-?2 chain deficiency, highlighting a number of important disease driving mechanisms that can be targeted by pharmacological approaches. In this chapter, I will describe laminin-211 and discuss the cellular and molecular pathophysiology of MDC1A as well as progression toward development of treatment. PMID:26610911

  3. A protein anomaly in erythrocyte membranes of patients with Duchenne muscular dystrophy.

    PubMed

    Wallach, D F; Verma, S P; Singer, W E

    1983-06-01

    Raman spectroscopic comparisons of erythrocyte membranes from 20 patients with Duchenne muscular dystrophy and 8 age-matched controls indicate a prominent and consistent protein anomaly in the patient samples. This was apparent in the following: (a) CH-stretching signals from control membranes reveal a thermotropic transition at 15.6 degrees C, attributable to a protein/lipid phase that is lacking in dystrophic membranes. (b) CH-stretching signals from control membranes also show a protein transition at 39 degrees C [pH 7.4] that is shifted to 45 degrees in dystrophic membranes. (c) A reduction in pH to 5.7 shifts this transition from 39 degrees C to 7 degrees C in normal membranes and from 45 degrees C to 24 degrees C in dystrophic membranes. (d) The Amide I/Amide III regions indicate a significant proportion of beta-structured peptide in dystrophic but not normal membranes. (e) Analysis of tyrosine signals indicates greater polar exposure of tyrosine hydroxyl groups in dystrophic vs normal membranes. All of the differences between dystrophic and normal membranes are highly significant (P less than 0.001). PMID:6854213

  4. 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

  5. Remodeling of Mitochondrial Flashes in Muscular Development and Dystrophy in Zebrafish

    PubMed Central

    Zhang, Meiling; Sun, Tao; Jian, Chongshu; Lei, Lei; Han, Peidong; Lv, Quanlong; Yang, Ran; Zhou, Xiaohai; Xu, Jiejia; Hu, Yingchun; Men, Yongfan; Huang, Yanyi; Zhang, Chuanmao; Zhu, Xiaojun; Wang, Xianhua; Cheng, Heping; Xiong, Jing-Wei

    2015-01-01

    Mitochondrial flash (mitoflash) is a highly-conserved, universal, and physiological mitochondrial activity in isolated mitochondria, intact cells, and live organisms. Here we investigated developmental and disease-related remodeling of mitoflash activity in zebrafish skeletal muscles. In transgenic zebrafish expressing the mitoflash reporter cpYFP, in vivo imaging revealed that mitoflash frequency and unitary properties underwent multiphasic and muscle type-specific changes, accompanying mitochondrial morphogenesis from 2 to 14 dpf. In particular, short (S)-type mitoflashes predominated in early muscle formation, then S-, transitory (T)- and regular (R)-type mitoflashes coexisted during muscle maturation, followed by a switch to R-type mitoflashes in mature skeletal muscles. In early development of muscular dystrophy, we found accelerated S- to R-type mitoflash transition and reduced mitochondrial NAD(P)H amidst a remarkable cell-to-cell heterogeneity. This study not only unravels a profound functional and morphological remodeling of mitochondria in developing and diseased skeletal muscles, but also underscores mitoflashes as a useful reporter of mitochondrial function in milieu of live animals under physiological and pathophysiological conditions. PMID:26186000

  6. Partial least squares based identification of Duchenne muscular dystrophy specific genes#

    PubMed Central

    An, Hui-bo; Zheng, Hua-cheng; Zhang, Li; Ma, Lin; Liu, Zheng-yan

    2013-01-01

    Large-scale parallel gene expression analysis has provided a greater ease for investigating the underlying mechanisms of Duchenne muscular dystrophy (DMD). Previous studies typically implemented variance/regression analysis, which would be fundamentally flawed when unaccounted sources of variability in the arrays existed. Here we aim to identify genes that contribute to the pathology of DMD using partial least squares (PLS) based analysis. We carried out PLS-based analysis with two datasets downloaded from the Gene Expression Omnibus (GEO) database to identify genes contributing to the pathology of DMD. Except for the genes related to inflammation, muscle regeneration and extracellular matrix (ECM) modeling, we found some genes with high fold change, which have not been identified by previous studies, such as SRPX, GPNMB, SAT1, and LYZ. In addition, downregulation of the fatty acid metabolism pathway was found, which may be related to the progressive muscle wasting process. Our results provide a better understanding for the downstream mechanisms of DMD. PMID:24190443

  7. Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program.

    PubMed

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han; Duan, Qiming; Sabeh, Mohamad; Prosdocimo, Domenick A; Lemieux, Madeleine E; Nordsborg, Nikolai; Russell, Aaron P; MacRae, Calum A; Gerber, Anthony N; Jain, Mukesh K; Haldar, Saptarsi M

    2015-12-01

    Classic physiology studies dating to the 1930s demonstrate that moderate or transient glucocorticoid (GC) exposure improves muscle performance. The ergogenic properties of GCs are further evidenced by their surreptitious use as doping agents by endurance athletes and poorly understood efficacy in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription factor KLF15, defining a downstream pathway distinct from that resulting in GC-related muscle atrophy. Furthermore, we establish that KLF15 deficiency exacerbates dystrophic severity and muscle GC-KLF15 signaling mediates salutary therapeutic effects in the mdx mouse model of DMD. Thus, although glucocorticoid receptor (GR)-mediated transactivation is often associated with muscle atrophy and other adverse effects of pharmacologic GC administration, our data define a distinct GR-induced gene regulatory pathway that contributes to therapeutic effects of GCs in DMD through proergogenic metabolic programming. PMID:26598680

  8. Computational Analysis of Muscular Dystrophy Sub-types Using A Novel Integrative Scheme

    PubMed Central

    Wang, Chen; Ha, Sook; Wang, Yue; Hoffman, Eric

    2012-01-01

    To construct biologically interpretable gene sets for muscular dystrophy (MD) sub-type classification, we propose a novel computational scheme to integrate protein-protein interaction (PPI) network, functional gene set information, and mRNA profiling data. The workflow of the proposed scheme includes the following three major steps: firstly, we apply an affinity propagation clustering (APC) approach to identify gene sub-networks associated with each MD sub-type, in which a new distance metric is proposed for APC to combine PPI network information and gene-gene co-expression relationship; secondly, we further incorporate functional gene set knowledge, which complements the physical PPI information, into our scheme for biomarker identification; finally, based on the constructed sub-networks and gene set features, we apply multi-class support vector machines (MSVMs) for MD sub-type classification, with which to highlight the biomarkers contributing to sub-type prediction. The experimental results show that our scheme can help identify sub-networks and gene sets that are more relevant to MD than those constructed by other conventional approaches. Moreover, our integrative strategy improves the prediction accuracy substantially, especially for those ’hard-to-classify’ sub-types. PMID:22773895

  9. Computational Analysis of Muscular Dystrophy Sub-types Using A Novel Integrative Scheme.

    PubMed

    Wang, Chen; Ha, Sook; Xuan, Jianhua; Wang, Yue; Hoffman, Eric

    2012-09-01

    To construct biologically interpretable gene sets for muscular dystrophy (MD) sub-type classification, we propose a novel computational scheme to integrate protein-protein interaction (PPI) network, functional gene set information, and mRNA profiling data. The workflow of the proposed scheme includes the following three major steps: firstly, we apply an affinity propagation clustering (APC) approach to identify gene sub-networks associated with each MD sub-type, in which a new distance metric is proposed for APC to combine PPI network information and gene-gene co-expression relationship; secondly, we further incorporate functional gene set knowledge, which complements the physical PPI information, into our scheme for biomarker identification; finally, based on the constructed sub-networks and gene set features, we apply multi-class support vector machines (MSVMs) for MD sub-type classification, with which to highlight the biomarkers contributing to sub-type prediction. The experimental results show that our scheme can help identify sub-networks and gene sets that are more relevant to MD than those constructed by other conventional approaches. Moreover, our integrative strategy improves the prediction accuracy substantially, especially for those 'hard-to-classify' sub-types. PMID:22773895

  10. Efficacy of Muscle Exercise in Patients with Muscular Dystrophy: A Systematic Review Showing a Missed Opportunity to Improve Outcomes

    PubMed Central

    Gianola, Silvia; Pecoraro, Valentina; Lambiase, Simone; Gatti, Roberto; Banfi, Giuseppe; Moja, Lorenzo

    2013-01-01

    Background Although muscular dystrophy causes muscle weakness and muscle loss, the role of exercise in the management of this disease remains controversial. Objective The purpose of this systematic review is to evaluate the role of exercise interventions on muscle strength in patients with muscular dystrophy. Methods We performed systematic electronic searches in Medline, Embase, Web of Science, Scopus and Pedro as well as a list of reference literature. We included trials assessing muscle exercise in patients with muscular dystrophy. Two reviewers independently abstracted data and appraised risk of bias. Results We identified five small (two controlled and three randomized clinical) trials comprising 242 patients and two ongoing randomized controlled trials. We were able to perform two meta-analyses. We found an absence of evidence for a difference in muscle strength (MD 4.18, 95% CIs - 2.03 to 10.39; p?=?0.91) and in endurance (MD ?0.53, 95% CIs –1.11 to 0.05; p?=?0.26). In both, the direction of effects favored muscle exercise. Conclusions The first included trial about the efficacy of muscular exercise was published in 1978. Even though some benefits of muscle exercise were consistently reported across studies, the benefits might be due to the small size of studies and other biases. Detrimental effects are still possible. After several decades of research, doctors cannot give advice and patients are, thus, denied basic information. A multi-center randomized trial investigating the strength of muscles, fatigue, and functional limitations is needed. PMID:23894268

  11. [Successful anesthetic management of laparoscopic rectopexy using rocuronium and sugammadex in a patient with Becker muscular dystrophy].

    PubMed

    Yamaguchi, Satoshi; Ohno, Giichiro; Kitamura, Jiro

    2014-10-01

    A 70-year-old man with Becker muscular dystrophy (BMD) underwent laparoscopic rectopexy under general anesthesia. For anesthetic induction, we administered total 0.6 mg · kg-1 of rocuronium with titration. Eight minutes later, train-of-four (TOF) count reached to 0 and the patient was intubated smoothly. One hundred and five minutes later, TOF ratio recovered to 100% and we administered rocuronium 10 mg additionally. Surgery was finished without any problems 95 minutes after thereafter. TOF ratio was 45% and we administered sugammadex 3 mg · kg-1, reversing neuromuscular blockade to TOF ratio 100% within 1.5 minute. The patient awoke clearly and respiratory condition was good. He was extubated without remaining neuromuscular blockade. Postoperative course was stable and there was no serious adverse effect on his muscular function intra- and post-operatively. In conclusion, rocuronium and sugammadex can be used safely and effectively in general anesthetic management for patients with muscular dystrophy. However, as the onset times and durations of these agents can be longer, we should administer these agents with titration carefully under periodic neuromuscular monitoring. PMID:25693344

  12. Nanoparticle Delivery of Antisense Oligonucleotides and Their Application in the Exon Skipping Strategy for Duchenne Muscular Dystrophy

    PubMed Central

    Falzarano, Maria Sofia; Passarelli, Chiara

    2014-01-01

    Antisense therapy is a powerful tool for inducing post-transcriptional modifications and thereby regulating target genes associated with disease. There are several classes of antisense oligonucleotides (AONs) with therapeutic use, such as double-stranded RNAs (interfering RNAs, utilized for gene silencing, and single-stranded AONs with various chemistries, which are useful for antisense targeting of micro-RNAs and mRNAs. In particular, the use of AONs for exon skipping, by targeting pre-mRNA, is proving to be a highly promising therapy for some genetic disorders like Duchenne muscular dystrophy and spinal muscular atrophy. However, AONs are unable to cross the plasma membrane unaided, and several other obstacles still remain to be overcome, in particular their instability due to their nuclease sensitivity and their lack of tissue specificity. Various drug delivery systems have been explored to improve the bioavailability of nucleic acids, and nanoparticles (NPs) have been suggested as potential vectors for DNA/RNA. This review describes the recent progress in AON conjugation with natural and synthetic delivery systems, and provides an overview of the efficacy of NP-AON complexes as an exon-skipping treatment for Duchenne muscular dystrophy. PMID:24506782

  13. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial

    PubMed Central

    Raman, Subha V; Hor, Kan N; Mazur, Wojciech; Halnon, Nancy J; Kissel, John T; He, Xin; Tran, Tam; Smart, Suzanne; McCarthy, Beth; Taylor, Michael D; Jefferies, John L; Rafael-Fortney, Jill A; Lowe, Jeovanna; Roble, Sharon L; Cripe, Linda H

    2015-01-01

    Summary Background Cardiomyopathy is a leading cause of death in patients with Duchenne muscular dystrophy and myocardial damage precedes decline in left ventricular systolic function. We tested the efficacy of eplerenone on top of background therapy in patients with Duchenne muscular dystrophy with early myocardial disease. Methods In this randomised, double-blind, placebo-controlled trial, boys from three centres in the USA aged 7 years or older with Duchenne muscular dystrophy, myocardial damage by late gadolinium enhancement cardiac MRI and preserved ejection fraction received either eplerenone 25 mg or placebo orally, every other day for the first month and once daily thereafter, in addition to background clinician-directed therapy with either angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Computer-generated randomisation was done centrally using block sizes of four and six, and only the study statistician and the investigational pharmacy had the preset randomisation assignments. The primary outcome was change in left ventricular circumferential strain (Ecc) at 12 months, a measure of contractile dysfunction. Safety was established through serial serum potassium levels and measurement of cystatin C, a non-creatinine measure of kidney function. This trial is registered with ClinicalTrials.gov, number NCT01521546. Findings Between Jan 26, 2012, and July 3, 2013, 188 boys were screened and 42 were enrolled. 20 were randomly assigned to receive eplerenone and 22 to receive placebo, of whom 20 in the eplerenone group and 20 in the placebo group completed baseline, 6-month, and 12-month visits. After 12 months, decline in left ventricular circumferential strain was less in those who received eplerenone than in those who received placebo (median ?Ecc 1.0 [IQR 0.3–2.2]vs2.2 [1.3–3.1]; p=0.020). Cystatin C concentrations remained normal in both groups, and all non-haemolysed blood samples showed normal potassium concentrations. One 23-year-old patient in the placebo group died of fat embolism, and another patient in the placebo group withdrew from the trial to address long-standing digestive issues. All other adverse events were mild: short-lived headaches coincident with seasonal allergies occurred in one patient given eplerenone, flushing occurred in one patient given placebo, and anxiety occurred in another patient given placebo. Interpretation In boys with Duchenne muscular dystrophy and preserved ejection fraction, addition of eplerenone to background ACEI or ARB therapy attenuates the progressive decline in left ventricular systolic function. Early use of available drugs warrants consideration in this population at high risk of cardiac death, but further studies are needed to determine the effect of combination cardioprotective therapy on event-free survival in Duchenne muscular dystrophy. Funding BallouSkies, Parent Project for Muscular Dystrophy, US National Center for Advancing Translational Sciences, and US National Institutes of Health. PMID:25554404

  14. Muscle MRS detects elevated PDE/ATP ratios prior to fatty infiltration in Becker muscular dystrophy.

    PubMed

    Wokke, B H; Hooijmans, M T; van den Bergen, J C; Webb, A G; Verschuuren, J J; Kan, H E

    2014-11-01

    Becker muscular dystrophy (BMD) is characterized by progressive muscle weakness. Muscles show structural changes (fatty infiltration, fibrosis) and metabolic changes, both of which can be assessed using MRI and MRS. It is unknown at what stage of the disease process metabolic changes arise and how this might vary for different metabolites. In this study we assessed metabolic changes in skeletal muscles of Becker patients, both with and without fatty infiltration, quantified via Dixon MRI and (31) P MRS. MRI and (31) P MRS scans were obtained from 25 Becker patients and 14 healthy controls using a 7 T MR scanner. Five lower-leg muscles were individually assessed for fat and muscle metabolite levels. In the peroneus, soleus and anterior tibialis muscles with non-increased fat levels, PDE/ATP ratios were higher (P < 0.02) compared with controls, whereas in all muscles with increased fat levels PDE/ATP ratios were higher compared with healthy controls (P ? 0.05). The Pi /ATP ratio in the peroneus muscles was higher in muscles with increased fat fractions (P = 0.005), and the PCr/ATP ratio was lower in the anterior tibialis muscles with increased fat fractions (P = 0.005). There were no other significant changes in metabolites, but an increase in tissue pH was found in all muscles of the total group of BMD patients in comparison with healthy controls (P < 0.05). These findings suggest that (31) P MRS can be used to detect early changes in individual muscles of BMD patients, which are present before the onset of fatty infiltration. PMID:25196814

  15. Disease course in mdx:utrophin+/? mice: comparison of three mouse models of Duchenne muscular dystrophy

    PubMed Central

    McDonald, Abby A; Hebert, Sadie L; Kunz, Matthew D; Ralles, Steven J; McLoon, Linda K

    2015-01-01

    The mdx mouse model of Duchenne muscular dystrophy (DMD) is used to study disease mechanisms and potential treatments, but its pathology is less severe than DMD patients. Other mouse models were developed to more closely mimic the human disease based on knowledge that upregulation of utrophin has a protective effect in mdx muscle. An mdx:utrophin?/? (dko) mouse was created, which had a severe disease phenotype and a shortened life span. An mdx:utrophin+/? mouse was also created, which had an intermediate disease phenotype compared to the mdx and dko mice. To determine the usefulness of mdx:utrophin+/? mice for long-term DMD studies, limb muscle pathology and function were assessed across the life span of wild-type, mdx, mdx:utrophin+/?, and dko mice. Muscle function assessment, specifically grip duration and rotarod performance, demonstrated that mdx:utrophin+/? mice were weaker for a longer time than mdx mice. Mean myofiber area was smaller in mdx:utrophin+/? mice compared to mdx mice at 12 months. Mdx:utrophin+/? mice had a higher percentage of centrally nucleated myofibers compared to mdx mice at 6 and 12 months. Collagen I and IV density was significantly higher in mdx:utrophin+/? muscle compared to mdx at most ages examined. Generally, mdx:utrophin+/? mice showed an intermediate disease phenotype over a longer time course compared to the mdx and dko mice. While they do not genetically mirror human DMD, mdx:utrophin+/? mice may be a more useful animal model than mdx or dko mice for investigating long-term efficacy of potential treatments when fibrosis or muscle function is the focus. PMID:25921779

  16. Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    González-Navarro, Félix F.; Belanche-Muñoz, Lluís A.; Silva-Colón, Karen A.

    2013-01-01

    The Facioscapulohumeral Muscular Dystrophy (FSHD) is an autosomal dominant neuromuscular disorder whose incidence is estimated in about one in 400,000 to one in 20,000. No effective therapeutic strategies are known to halt progression or reverse muscle weakness and atrophy. It is known that the FSHD is caused by modifications located within a D4ZA repeat array in the chromosome 4q, while recent advances have linked these modifications to the DUX4 gene. Unfortunately, the complete mechanisms responsible for the molecular pathogenesis and progressive muscle weakness still remain unknown. Although there are many studies addressing cancer databases from a machine learning perspective, there is no such precedent in the analysis of the FSHD. This study aims to fill this gap by analyzing two specific FSHD databases. A feature selection algorithm is used as the main engine to select genes promoting the highest possible classification capacity. The combination of feature selection and classification aims at obtaining simple models (in terms of very low numbers of genes) capable of good generalization, that may be associated with the disease. We show that the reported method is highly efficient in finding genes to discern between healthy cases (not affected by the FSHD) and FSHD cases, allowing the discovery of very parsimonious models that yield negligible repeated cross-validation error. These models in turn give rise to very simple decision procedures in the form of a decision tree. Current biological evidence regarding these genes shows that they are linked to skeletal muscle processes concerning specific human conditions. PMID:24349187

  17. Whole body periodic acceleration is an effective therapy to ameliorate muscular dystrophy in mdx mice.

    PubMed

    Altamirano, Francisco; Perez, Claudio F; Liu, Min; Widrick, Jeffrey; Barton, Elisabeth R; Allen, Paul D; Adams, Jose A; Lopez, Jose R

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca(2+) and Na(+) overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca(2+) and Na(+) overload, diminished abnormal sarcolemmal Ca(2+) entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway. PMID:25181488

  18. Dystropathology Increases Energy Expenditure and Protein Turnover in the Mdx Mouse Model of Duchenne Muscular Dystrophy

    PubMed Central

    Radley-Crabb, Hannah G.; Marini, Juan C.; Sosa, Horacio A.; Castillo, Liliana I.; Grounds, Miranda D.; Fiorotto, Marta L.

    2014-01-01

    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 dietary requirements for these macronutrients at different stages of the disease, are not well-understood. This study used juvenile (4- to 5- wk-old) and adult (12- to 14-wk-old) male dystrophic C57BL/10ScSn-mdx/J and age-matched C57BL/10ScSn/J control male mice to measure total and resting energy expenditure, food intake, spontaneous activity, body composition, whole body protein turnover, and muscle protein synthesis rates. In juvenile mdx mice that have extensive muscle damage, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were higher than in age-matched controls. Adaptations in food intake and decreased activity were insufficient to meet the increased energy and protein needs of juvenile mdx mice and resulted in stunted growth. In (non-growing) adult mdx mice with less severe dystropathology, energy expenditure, muscle protein synthesis, and whole body protein turnover rates were also higher than in age-matched controls. Food intake was sufficient to meet their protein and energy needs, but insufficient to result in fat deposition. These data show that dystropathology impacts the protein and energy needs of mdx mice and that tailored dietary interventions are necessary to redress this imbalance. If not met, the resultant imbalance blunts growth, and may limit the benefits of therapies designed to protect and repair dystrophic muscles. PMID:24586653

  19. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options

    PubMed Central

    LoMauro, Antonella; D’Angelo, Maria Grazia; Aliverti, Andrea

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting in progressive weakness and wasting of all the striated muscles including the respiratory muscles. The consequences are loss of ambulation before teen ages, cardiac involvement and breathing difficulties, the main cause of death. A cure for DMD is not currently available. In the last decades the survival of patients with DMD has improved because the natural history of the disease can be changed thanks to a more comprehensive therapeutic approach. This comprises interventions targeted to the manifestations and complications of the disease, particularly in the respiratory care. These include: 1) pharmacological intervention, namely corticosteroids and idebenone that significantly reduce the decline of spirometric parameters; 2) rehabilitative intervention, namely lung volume recruitment techniques that help prevent atelectasis and slows the rate of decline of pulmonary function; 3) scoliosis treatment, namely steroid therapy that is used to reduce muscle inflammation/degeneration and prolong ambulation in order to delay the onset of scoliosis, being an additional contribution to the restrictive lung pattern; 4) cough assisted devices that improve airway clearance thus reducing the risk of pulmonary infections; and 5) non-invasive mechanical ventilation that is essential to treat nocturnal hypoventilation, sleep disordered breathing, and ultimately respiratory failure. Without any intervention death occurs within the first 2 decades, however, thanks to this multidisciplinary therapeutic approach life expectancy of a newborn with DMD nowadays can be significantly prolonged up to his fourth decade. This review is aimed at providing state-of-the-art methods and techniques for the assessment and management of respiratory function in DMD patients. PMID:26451113

  20. Screening of Duchenne Muscular Dystrophy (DMD) Mutations and Investigating Its Mutational Mechanism in Chinese Patients

    PubMed Central

    Chen, Chen; Ma, Hongwei; Zhang, Feng; Chen, Lu; Xing, Xuesha; Wang, Shusen; Zhang, Xue; Luo, Yang

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43–55 and exon 10–23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements. PMID:25244321

  1. Sildenafil Does Not Improve Cardiomyopathy in Duchenne/Becker Muscular Dystrophy

    PubMed Central

    Leung, Doris G.; Herzka, Daniel A.; Thompson, W. Reid; He, Bing; Bibat, Genila; Tennekoon, Gihan; Russell, Stuart D.; Schuleri, Karl H.; Lardo, Albert C.; Kass, David A.; Thompson, Richard E.; Judge, Daniel P.; Wagner, Kathryn R.

    2014-01-01

    Objective Duchenne and Becker muscular dystrophy (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine if the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908). Methods Adults with DBMD and cardiomyopathy (ejection fraction ?50%) were randomized to receive sildenafil (20mg three times daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac MRI. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed. Results An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4/14) of subjects had a ?10% increase in LVESV after 6 months of sildenafil compared to 13% (1/8) of subjects receiving placebo. Subjects with LVESV >120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p=0.035). Due to the higher number of subjects worsening on sildenafil, the Data and Safety Monitoring Board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms. Interpretation Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD. PMID:25042693

  2. Reduced mandibular range of motion in Duchenne Muscular Dystrophy: predictive factors.

    PubMed

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

    2015-06-01

    Patients with Duchenne muscular dystrophy (DMD) experience negative effects upon feeding and oral health. We aimed to determine whether the mandibular range of motion in DMD is impaired and to explore predictive factors for the active maximum mouth opening (aMMO). 23 patients with DMD (mean age 16.7 ± 7.7 years) and 23 controls were assessed using a questionnaire about mandibular function and impairments. All participants underwent a clinical examination of the masticatory system, including measurement of mandibular range of motion and variables related to mandibular movements. In all patients, quantitative ultrasound of the digastric muscle and the geniohyoid muscle and the motor function measure (MFM) scale were performed. The patients were divided into early and late ambulatory stage (AS), early non-ambulatory stage (ENAS) and late non-ambulatory stage (LNAS). All mandibular movements were reduced in the patient group (P < 0.001) compared to the controls. Reduction in the aMMO (<40 mm) was found in 26% of the total patient group. LNAS patients had significantly smaller mandibular movements compared to AS and ENAS (P < 0.05). Multiple linear regression analysis for aMMO revealed a positive correlation with the body height and disease progression, with MFM total score as the strongest independent risk factor (R(2) = 0.71). Mandibular movements in DMD are significantly reduced and become more hampered with loss of motor function, including the sitting position, arm function, and neck and head control. We suggest that measurement of the aMMO becomes a part of routine care of patients with DMD. PMID:25600935

  3. Genetic analysis in a variant of limb girdle muscular dystrophy in an inbred aboriginal community

    SciTech Connect

    Greenberg, C.R.; Nylen, E.G.; Halliday, W.

    1994-09-01

    Limb girdle muscular dystrophy (LGMD) is a heterogeneous group of disorders with variable inheritance patterns, age-of-onset, rates of progression and patterns of muscle involvement. To date, 4 different chromosomal assignments have been described; LGMD1 to chromosome 5q, LGMD2 to chromosome 15q, SCARMD to chromosome 13q and a fourth locus on chromosome 2p. Because of this genetic heterogeneity, only large unambiguous multiplex families which are clearly linked to a particular locus can be utilized in a genetic analysis. We now report preliminary findings in a large highly inbred aboriginal kindred with 8 probands (5 females, 3 males) from 6 nuclear families with a progressive LMD. All presented in their mid- to late teens with gait disturbances. At time of presentation all except one had both proximal as well as distal muscle involvement, facial muscle sparing, CK levels 25 to 100 times normal (3762-20,400 U/l), dystrophic muscle biopsies and normal dystrophin and dystrophin-associated glycoprotein expression. We have studied the segregation of highly informative microsatellite markers for FBN1, D15S132 and the gene for thrombospondin on chromosome 15q and D2S134, D2S136, D2S147, and D2S166 on chromosome 2. Linkage to chromosome 15q has been excluded and two-point lod scores are not significant as yet to either confirm or exclude linkage to chromosome 2p. However, visual inspection reveals that affected individuals are not consistently homozygous for the chromosome 2p markers as would be predicted in such an inbred population. Clinically, SCARMD is unlikely and if the locus on chromosomes 2p and 5q can also be excluded, a genome-wide search using evenly spaced microsatellites will be initiated. A second geographically distinct aboriginal kindred with a similar clinical phenotype has now also been identified.

  4. Evolutionary analysis of the 3.3 kb tandem repeat sequence associated with facioscapulohumeral muscular dystrophy

    SciTech Connect

    Hewitt, J.E.; Clark, L.N.; Wienberg, J.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant progressive disorder affecting primarily the facial and shoulder girdle muscles. The FSHD gene has been localized to distal 4q35. Genetic and physical mapping has identified a polymorphic 3.3 kb tandem repeat (D4Z4) which is closely lined to the disease. In the majority of sporadic cases there are de novo DNA rearrangements resulting in loss of an integral number of D4Z4 repeats. Sequencing of D4Z4 showed it to contain two homeoboxes and a previously identified human repeat sequences (L Sau). At present, it is not known how these rearrangements affect the pathogenesis of FSHD; however, D4Z4 clearly has an important function. It is part of a complex, dispersed human tandem repeat family which is evolutionarily conserved with a marked difference in copy number in humans and great apes compared to other species. Given the unique structure and organization of the D4Z4 repeat and its role in the FSHD disease mechanism, we have further investigated the evolutionary conservation of D4Z4. Comparison of Southern blot data from Old and New World monkeys, great apes, and humans shows that this increase in the number of D4Z4-like loci occurred after the divergence of great apes and Old World monkeys. The localization of these loci in great apes has been investigated using fluorescent in situ hybridization. These studies provide evidence that the D4Z4 repeat has evolved very recently in the great ape lineage. An understanding of how this repeat family has arisen and identification of the ancestral locus in Old World monkeys should provide clues as to the role of this sequence in FSHD.

  5. Nutritional Status Evaluation in Patients Affected by Bethlem Myopathy and Ullrich Congenital Muscular Dystrophy

    PubMed Central

    Toni, Silvia; Morandi, Riccardo; Busacchi, Marcello; Tardini, Lucia; Merlini, Luciano; Battistini, Nino Carlo; Pellegrini, Massimo

    2014-01-01

    Collagen VI mutations lead to disabling myopathies like Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD). We have investigated the nutritional and metabolic status of one UCMD and seven BM patients (five female, three male, mean age 31?±?9?years) in order to find a potential metabolic target for nutritional intervention. For this study, we used standard anthropometric tools, such as BMI evaluation and body circumference measurements. All results were compared to dual-energy X-ray absorptiometry (DXA), considered the “gold standard” method. Energy intake of each patient was evaluated through longitudinal methods (7-day food diary) while resting energy expenditure (REE) was predicted using specific equations and measured by indirect calorimetry. Clinical evaluation included general and nutritional blood and urine laboratory analyses and quantitative muscle strength measurement by hand-held dynamometry. BM and UCMD patients showed an altered body composition, characterized by low free fat mass (FFM) and high fat mass (FM), allowing us to classify them as sarcopenic, and all but one as sarcopenic-obese. Another main result was the negative correlation between REE/FFM ratio (basal energy expenditure per kilograms of fat-free mass) and the severity of the disease, as defined by the muscle megascore (correlation coefficient ?0.955, P-value <0.001). We postulate that the increase of the REE/FFM ratio in relation to the severity of the disease may be due to an altered and pathophysiological loss of energetic efficiency at the expense of skeletal muscle. We show that a specific metabolic disequilibrium is related to the severity of the disease, which may represent a target for a nutritional intervention in these patients. PMID:25477818

  6. Assessment and management of respiratory function in patients with Duchenne muscular dystrophy: current and emerging options.

    PubMed

    LoMauro, Antonella; D'Angelo, Maria Grazia; Aliverti, Andrea

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting in progressive weakness and wasting of all the striated muscles including the respiratory muscles. The consequences are loss of ambulation before teen ages, cardiac involvement and breathing difficulties, the main cause of death. A cure for DMD is not currently available. In the last decades the survival of patients with DMD has improved because the natural history of the disease can be changed thanks to a more comprehensive therapeutic approach. This comprises interventions targeted to the manifestations and complications of the disease, particularly in the respiratory care. These include: 1) pharmacological intervention, namely corticosteroids and idebenone that significantly reduce the decline of spirometric parameters; 2) rehabilitative intervention, namely lung volume recruitment techniques that help prevent atelectasis and slows the rate of decline of pulmonary function; 3) scoliosis treatment, namely steroid therapy that is used to reduce muscle inflammation/degeneration and prolong ambulation in order to delay the onset of scoliosis, being an additional contribution to the restrictive lung pattern; 4) cough assisted devices that improve airway clearance thus reducing the risk of pulmonary infections; and 5) non-invasive mechanical ventilation that is essential to treat nocturnal hypoventilation, sleep disordered breathing, and ultimately respiratory failure. Without any intervention death occurs within the first 2 decades, however, thanks to this multidisciplinary therapeutic approach life expectancy of a newborn with DMD nowadays can be significantly prolonged up to his fourth decade. This review is aimed at providing state-of-the-art methods and techniques for the assessment and management of respiratory function in DMD patients. PMID:26451113

  7. High throughput screening in duchenne muscular dystrophy: from drug discovery to functional genomics.

    PubMed

    Gintjee, Thomas J J; Magh, Alvin S H; Bertoni, Carmen

    2014-01-01

    Centers for the screening of biologically active compounds and genomic libraries are becoming common in the academic setting and have enabled researchers devoted to developing strategies for the treatment of diseases or interested in studying a biological phenomenon to have unprecedented access to libraries that, until few years ago, were accessible only by pharmaceutical companies. As a result, new drugs and genetic targets have now been identified for the treatment of Duchenne muscular dystrophy (DMD), the most prominent of the neuromuscular disorders affecting children. Although the work is still at an early stage, the results obtained to date are encouraging and demonstrate the importance that these centers may have in advancing therapeutic strategies for DMD as well as other diseases. This review will provide a summary of the status and progress made toward the development of a cure for this disorder and implementing high-throughput screening (HTS) technologies as the main source of discovery. As more academic institutions are gaining access to HTS as a valuable discovery tool, the identification of new biologically active molecules is likely to grow larger. In addition, the presence in the academic setting of experts in different aspects of the disease will offer the opportunity to develop novel assays capable of identifying new targets to be pursued as potential therapeutic options. These assays will represent an excellent source to be used by pharmaceutical companies for the screening of larger libraries providing the opportunity to establish strong collaborations between the private and academic sectors and maximizing the chances of bringing into the clinic new drugs for the treatment of DMD. PMID:25405319

  8. Genetic basis of limb-girdle muscular dystrophies: the 2014 update.

    PubMed

    Nigro, Vincenzo; Savarese, Marco

    2014-05-01

    Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. Today, the list of genes to be screened is too large for the gene-by-gene approach and it is well suited for targeted next generation sequencing (NGS) panels that should include any gene that has been so far associated with a clinical picture of LGMD. The present review has the aim of recapitulating the genetic basis of LGMD ordering and of proposing a nomenclature for the orphan forms. This is useful given the pace of new discoveries. Thity-one loci have been identified so far, eight autosomal dominant and 23 autosomal recessive. The dominant forms (LGMD1) are: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin 3), LGMD1D (DNAJB6), LGMD1E (desmin), LGMD1F (transportin 3), LGMD1G (HNRPDL), LGMD1H (chr. 3). The autosomal recessive forms (LGMD2) are: LGMD2A (calpain 3), LGMD2B (dysferlin), LGMD2C (? sarcoglycan), LGMD2D (? sarcoglycan), LGMD2E (? sarcoglycan), LGMD2F (? sarcoglycan), LGMD2G (telethonin), LGMD2H (TRIM32), LGMD2I (FKRP), LGMD2J (titin), LGMD2K (POMT1), LGMD2L (anoctamin 5), LGMD2M (fukutin), LGMD2N (POMT2), LGMD2O (POMTnG1), LGMD2P (dystroglycan), LGMD2Q (plectin), LGMD2R (desmin), LGMD2S (TRAPPC11), LGMD2T (GMPPB), LGMD2U (ISPD), LGMD2V (Glucosidase, alpha ), LGMD2W (PINCH2). PMID:24843229

  9. Clinical and genetic spectrum in limb-girdle muscular dystrophy type 2E

    PubMed Central

    Semplicini, Claudio; Vissing, John; Dahlqvist, Julia R.; Stojkovic, Tanya; Bello, Luca; Witting, Nanna; Duno, Morten; Leturcq, France; Bertolin, Cinzia; D'Ambrosio, Paola; Eymard, Bruno; Angelini, Corrado; Politano, Luisa

    2015-01-01

    Objective: To determine the clinical spectrum of limb-girdle muscular dystrophy 2E (LGMD2E) and to investigate whether genetic or biochemical features can predict the phenotype of the disease. Methods: All LGMD2E patients followed in participating centers were included. A specific clinical protocol was created, including quantitative evaluation of motor, respiratory, and cardiac function. Phenotype was defined as severe or mild if the age at loss of ambulation occurred before or after 18 years. Molecular analysis of SGCB gene and biochemical features of muscle biopsies were reviewed. Results: Thirty-two patients were included (16 male, 16 female; age 7–67 years; 15 severe, 12 mild, and 5 unknown). Neurologic examination showed proximal muscle weakness in all patients, but distal involvement was also observed in patients with severe disease early in the disease course. Cardiac involvement was observed in 20 patients (63%) even before overt muscle involvement. Six patients had restrictive respiratory insufficiency requiring assisted ventilation (19%). Seventeen different mutations were identified, and 3 were recurrent. The c.377_384dup (13 alleles) was associated with the severe form, the c.-22_10dup (10) with the milder form, and the c.341C>T (9) with both. The entire sarcoglycan complex was undetectable by muscle immunohistochemistry or Western blot in 9/10 severe cases and reduced in 7/7 mild cases. The residual amount of sarcoglycan in muscle resulted a predictor of age at loss of ambulation. Conclusions: This study expands the spectrum of phenotype in ?-sarcoglycanopathy and provides strong evidence that severity of clinical involvement may be predicted by SGCB gene mutation and sarcoglycan protein expression. PMID:25862795

  10. Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic

    PubMed Central

    2014-01-01

    Background Autosomal recessive limb-girdle muscular dystrophies (LGMD2) include a number of disorders with heterogeneous etiology that cause predominantly weakness and wasting of the shoulder and pelvic girdle muscles. In this study, we determined the frequency of LGMD subtypes within a cohort of Czech LGMD2 patients using mutational analysis of the CAPN3, FKRP, SGCA, and ANO5 genes. Methods PCR-sequencing analysis; sequence capture and targeted resequencing. Results Mutations of the CAPN3 gene are the most common cause of LGMD2, and mutations in this gene were identified in 71 patients in a set of 218 Czech probands with a suspicion of LGMD2. Totally, we detected 37 different mutations of which 12 have been described only in Czech LGMD2A patients. The mutation c.550delA is the most frequent among our LGMD2A probands and was detected in 47.1% of CAPN3 mutant alleles. The frequency of particular forms of LGMD2 was 32.6% for LGMD2A (71 probands), 4.1% for LGMD2I (9 probands), 2.8% for LGMD2D (6 probands), and 1.4% for LGMD2L (3 probands). Further, we present the first results of a new approach established in the Czech Republic for diagnosis of neuromuscular diseases: sequence capture and targeted resequencing. Using this approach, we identified patients with mutations in the DYSF and SGCB genes. Conclusions We characterised a cohort of Czech LGMD2 patients on the basis of mutation analysis of genes associated with the most common forms of LGMD2 in the European population and subsequently compared the occurrence of particular forms of LGMD2 among countries on the basis of our results and published studies. PMID:25135358

  11. Muscular dystrophy with marked Dysferlin deficiency is consistently caused by primary dysferlin gene mutations

    PubMed Central

    Cacciottolo, Mafalda; Numitone, Gelsomina; Aurino, Stefania; Caserta, Imma Rosaria; Fanin, Marina; Politano, Luisa; Minetti, Carlo; Ricci, Enzo; Piluso, Giulio; Angelini, Corrado; Nigro, Vincenzo

    2011-01-01

    Dysferlin is a 237-kDa transmembrane protein involved in calcium-mediated sarcolemma resealing. Dysferlin gene mutations cause limb-girdle muscular dystrophy (LGMD) 2B, Miyoshi myopathy (MM) and distal myopathy of the anterior tibialis. Considering that a secondary Dysferlin reduction has also been described in other myopathies, our original goal was to identify cases with a Dysferlin deficiency without dysferlin gene mutations. The dysferlin gene is huge, composed of 55 exons that span 233?140?bp of genomic DNA. We performed a thorough mutation analysis in 65 LGMD/MM patients with ?20% Dysferlin. The screening was exhaustive, as we sequenced both genomic DNA and cDNA. When required, we used other methods, including real-time PCR, long PCR and array CGH. In all patients, we were able to recognize the primary involvement of the dysferlin gene. We identified 38 novel mutation types. Some of these, such as a dysferlin gene duplication, could have been missed by conventional screening strategies. Nonsense-mediated mRNA decay was evident in six cases, in three of which both alleles were only detectable in the genomic DNA but not in the mRNA. Among a wide spectrum of novel gene defects, we found the first example of a ‘nonstop' mutation causing a dysferlinopathy. This study presents the first direct and conclusive evidence that an amount of Dysferlin ?20% is pathogenic and always caused by primary dysferlin gene mutations. This demonstrates the high specificity of a marked reduction of Dysferlin on western blot and the value of a comprehensive molecular approach for LGMD2B/MM diagnosis. PMID:21522182

  12. Evaluation of skeletal muscle DTI in patients with duchenne muscular dystrophy.

    PubMed

    Hooijmans, M T; Damon, B M; Froeling, M; Versluis, M J; Burakiewicz, J; Verschuuren, J J G M; Niks, E H; Webb, A G; Kan, H E

    2015-11-01

    Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2 . The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2 , %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and ?3 (p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and ?3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and ?3 , these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2 , %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26449628

  13. Whole Body Periodic Acceleration Is an Effective Therapy to Ameliorate Muscular Dystrophy in mdx Mice

    PubMed Central

    Altamirano, Francisco; Perez, Claudio F.; Liu, Min; Widrick, Jeffrey; Barton, Elisabeth R.; Allen, Paul D.; Adams, Jose A.; Lopez, Jose R.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca2+ and Na+ overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca2+ and Na+ overload, diminished abnormal sarcolemmal Ca2+ entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway. PMID:25181488

  14. Ultrasound tissue characterization does not differentiate genotype, but indexes ejection fraction deterioration in becker muscular dystrophy.

    PubMed

    Giglio, Vincenzo; Puddu, Paolo Emilio; Holland, Mark R; Camastra, Giovanni; Ansalone, Gerardo; Ricci, Enzo; Mela, Julia; Sciarra, Federico; Di Gennaro, Marco

    2014-12-01

    The aims of the study were, first, to assess whether myocardial ultrasound tissue characterization (UTC) in Becker muscular dystrophy (BMD) can be used to differentiate between patients with deletions and those without deletions; and second, to determine whether UTC is helpful in diagnosing the evolution of left ventricular dysfunction, a precursor of dilated cardiomyopathy. Both cyclic variation of integrated backscatter and calibrated integrated backscatter (cIBS) were assessed in 87 patients with BMD and 70 controls. The average follow-up in BMD patients was 48 ± 12 mo. UTC analysis was repeated only in a subgroup of 40 BMD patients randomly selected from the larger overall group (15 with and 25 without left ventricular dysfunction). Discrimination between BMD patients with and without dystrophin gene deletion was not possible on the basis of UTC data: average cvIBS was 5.2 ± 1.2 and 5.5 ± 1.4 dB, and average cIBS was 29.9 ± 4.7 and 29.6 ± 5.8, respectively, significantly different (p < 0.001) only from controls (8.6 ± 0.5 and 24.6 ± 1.2 dB). In patients developing left ventricular dysfunction during follow-up, cIBS increased to 31.3 ± 5.4 dB, but not significantly (p = 0.08). The highest cIBS values (34.6 ± 5.3 dB, p < 0.09 vs. baseline, p < 0.01 vs BMD patients without left ventricular dysfunction) were seen in the presence of severe left ventricular dysfunction. Multivariate statistics indicated that an absolute change of 6 dB in cIBS is associated with a high probability of left ventricular dysfunction. UTC analysis does not differentiate BMD patients with or without dystrophin gene deletion, but may be useful in indexing left ventricular dysfunction during follow-up. PMID:25308949

  15. Analysis of dystrophin gene in Iranian Duchenne and Becker muscular dystrophies patients and identification of a novel mutation.

    PubMed

    Zamani, Gholam Reza; Karami, Fatemeh; Mehdizadeh, Mahshid; Movafagh, Abolfazl; Nilipour, Yalda; Zamani, Mahdi

    2015-11-01

    Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most frequent muscular dystrophies. Present study aimed to determine the frequency of dystrophin gene alterations in Iranian DMD/BMD patients using molecular techniques. 146 Iranian DMD/BMD patients have been analyzed using two devised sets of multiplex polymerase chain reaction (M-PCR) followed by multiple ligation-dependent probe amplification (MLPA). Two isolated DMD and BMD patients were analyzed by DNA sequencing. 30.9 % of patients had single-exon deletion while group and contiguous exon deletions were identified in 41 % of the patients. The most numerous exon deletions included exons 45-50 and were identified in the first M-PCR set. Deletion detection rate was 99 % in first M-PCR set and remaining deletions (1 %) were identified in the second M-PCR set. MLPA analysis showed that there were two exons 3-5 and 41-43 duplications (1.4 %) in a BMD and a DMD patient, respectively. Two nonsense mutations including c.633dupA and c.6283 C>T were, respectively, found in a DMD and BMD patient in which c.633dupA has not ever been reported in DMD mutation database and was pathogenic mutation. Besides the report of frequency of dystrophin gene alteration in a subset of Iranian DMD/BMD patients, it was revealed that the proposed M-PCR protocol can be useful in the initial step of molecular diagnosis of DMD/BMD. Exon sequencing would be the final step in determining the mutation status of DMD/BMD patients following MLPA. PMID:26081009

  16. Improving highly accelerated fat fraction measurements for clinical trials in muscular dystrophy: origin and quantitative effect of R2* changes.

    PubMed

    Loughran, Thomas; Higgins, David M; McCallum, Michelle; Coombs, Anna; Straub, Volker; Hollingsworth, Kieren G

    2015-05-01

    Purpose To investigate the effect of R2* modeling in conventional and accelerated measurements of skeletal muscle fat fraction in control subjects and patients with muscular dystrophy. Materials and Methods Eight patients with Becker muscular dystrophy and eight matched control subjects were recruited with approval from the Newcastle and North Tyneside 2 Research Ethics Committee and with written consent. Chemical-shift images with six widely spaced echo times (in 3.5-msec increments) were acquired to correlate R2* and muscle fat fraction. The effect of incorporating or neglecting R2* modeling on fat fraction magnitude and variance was evaluated in a typical three-echo protocol (with 0.78-msec increments). Accelerated acquisitions with this protocol with 3.65×, 4.94×, and 6.42× undersampling were reconstructed by using combined compressed sensing and parallel imaging and fat fraction maps produced with R2* modeling. Results Muscle R2* at 3.0 T (33-125 sec(-1)) depended on the morphology of fat replacement, the highest values occurring with the greatest interdigitation of fat. The inclusion of R2* modeling removed bias, which was greatest at low fat fraction, but did not increase variance. The 95% limits of agreement of the accelerated acquisitions were tight and not degraded by R2* modeling (1.65%, 1.95%, and 2.22% for 3.65×, 4.94×, and 6.42× acceleration, respectively). Conclusion Incorporating R2* modeling prevents systematic errors in muscle fat fraction by up to 3.5% without loss of precision and should be incorporated into all muscular dystrophy studies. Fat fraction measurements can be accelerated fivefold by using combined compressed sensing and parallel imaging, modeling for R2* without loss of fidelity. PMID:25575118

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

    SciTech Connect

    Miyake, Masashi; Nakahori, Yutaka; Matsushita, Ikumi

    1997-03-01

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

  18. Alterations in Notch signalling in skeletal muscles from mdx and dko dystrophic mice and patients with Duchenne muscular dystrophy.

    PubMed

    Church, Jarrod E; Trieu, Jennifer; Chee, Annabel; Naim, Timur; Gehrig, Stefan M; Lamon, Séverine; Angelini, Corrado; Russell, Aaron P; Lynch, Gordon S

    2014-04-01

    New Findings What is the central question of this study? The Notch signalling pathway plays an important role in muscle regeneration, and activation of the pathway has been shown to enhance muscle regeneration in aged mice. It is unknown whether Notch activation will have a similarly beneficial effect on muscle regeneration in the context of Duchenne muscular dystrophy (DMD). What is the main finding and its importance? Although expression of Notch signalling components is altered in both mouse models of DMD and in human DMD patients, activation of the Notch signalling pathway does not confer any functional benefit on muscles from dystrophic mice, suggesting that other signalling pathways may be more fruitful targets for manipulation in treating DMD. Abstract In Duchenne muscular dystrophy (DMD), muscle damage and impaired regeneration lead to progressive muscle wasting, weakness and premature death. The Notch signalling pathway represents a central regulator of gene expression and is critical for cellular proliferation, differentiation and apoptotic signalling during all stages of embryonic muscle development. Notch activation improves muscle regeneration in aged mice, but its potential to restore regeneration and function in muscular dystrophy is unknown. We performed a comprehensive examination of several genes involved in Notch signalling in muscles from dystrophin-deficient mdx and dko (utrophin- and dystrophin-null) mice and DMD patients. A reduction of Notch1 and Hes1 mRNA in tibialis anterior muscles of dko mice and quadriceps muscles of DMD patients and a reduction of Hes1 mRNA in the diaphragm of the mdx mice were observed, with other targets being inconsistent across species. Activation and inhibition of Notch signalling, followed by measures of muscle regeneration and function, were performed in the mouse models of DMD. Notch activation had no effect on functional regeneration in C57BL/10, mdx or dko mice. Notch inhibition significantly depressed the frequency-force relationship in regenerating muscles of C57BL/10 and mdx mice after injury, indicating reduced force at each stimulation frequency, but enhanced the frequency-force relationship in muscles from dko mice. We conclude that while Notch inhibition produces slight functional defects in dystrophic muscle, Notch activation does not significantly improve muscle regeneration in murine models of muscular dystrophy. Furthermore, the inconsistent expression of Notch targets between murine models and DMD patients suggests caution when making interspecies comparisons. PMID:24443351

  19. A clinical study shows safety and efficacy of autologous bone marrow mononuclear cell therapy to improve quality of life in muscular dystrophy patients.

    PubMed

    Sharma, Alok; Sane, Hemangi; Badhe, Prerna; Gokulchandran, Nandini; Kulkarni, Pooja; Lohiya, Mamta; Biju, Hema; Jacob, V C

    2013-01-01

    Muscular dystrophy is a genetic disorder with no definite cure. A study was carried out on 150 patients diagnosed with muscular dystrophy. These included Duchenne muscular dystrophy, limb-girdle muscular dystrophy, and Becker muscular dystrophy variants. They were administered autologous bone marrow-derived mononuclear cells intrathecally and intramuscularly at the motor points of the antigravity weak muscles followed by vigorous rehabilitation therapy. No significant adverse events were noted. Assessment after transplantation showed neurological improvements in trunk muscle strength, limb strength on manual muscle testing, gait improvements, and a favorable shift on assessment scales such as the Functional Independence Measure and the Brooke and Vignos Scales. Furthermore, imaging and electrophysiological studies also showed significant changes in selective cases. On a mean follow-up of 12 ± 1 months, overall 86.67% cases showed symptomatic and functional improvements, with six patients showing changes with respect to muscle regeneration and a decrease in fatty infiltration on musculoskeletal magnetic resonance imaging and nine showing improved muscle electrical activity on electromyography. Fifty-three percent of the cases showed an increase in trunk muscle strength, 48% showed an increase in upper limb strength, 59% showed an increase in lower limb strength, and approximately 10% showed improved gait. These data were statistically analyzed using Student's paired t test and found to be significant. The results show that this treatment is safe and efficacious and also improves the quality of life of patients having muscular dystrophy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation. PMID:24070109

  20. Characterization of genetic deletions in Becker muscular dystrophy using monoclonal antibodies against a deletion-prone region of dystrophin

    SciTech Connect

    Thanh, L.T.; Man, Nguyen Thi; Morris, G.E.

    1995-08-28

    We have produced a new panel of 20 monoclonal antibodies (mAbs) against a region of the dystrophin protein corresponding to a deletion-prone region of the Duchenne muscular dystrophy gene (exons 45-50). We show that immunohistochemistry or Western blotting with these {open_quotes}exon-specific{close_quotes} mAbs can provide a valuable addition to Southern blotting or PCR methods for the accurate identification of genetic deletions in Becker muscular dystrophy patients. The antibodies were mapped to the following exons: exon 45 (2 mAbs), exon 46 (6), exon 47 (1), exons 47/48 (4), exons 48-50 (6), and exon 50 (1). PCR amplification of single exons or groups of exons was used both to produce specific dystrophin immunogens and to map the mAbs obtained. PCR-mediated mutagenesis was also used to identify regions of dystrophin important for mAb binding. Because the mAbs can be used to characterize the dystrophin produced by individual muscle fibres, they will also be useful for studying {open_quotes}revertant{close_quotes} fibres in Duchenne muscle and for monitoring the results of myoblast therapy trials in MD patients with deletions in this region of the dystrophin gene. 27 refs., 7 figs., 3 tabs.

  1. Periodic sound-based 6-minute walk test forpatients with Duchenne muscular dystrophy:a preliminary study

    PubMed Central

    Nishizawa, Hitomi; Genno, Hirokazu; Shiba, Naoko; Nakamura, Akinori

    2015-01-01

    [Purpose] The purpose of this study was to verify if a periodic sound-based 6-minute walk test with the best periodic sound could be used to evaluate physical endurance more precisely than the conventional 6-minute walk test. [Subjects] The subjects were healthy subjects and 6 ambulant patients with Duchenne muscular dystrophy. [Methods] The subjects initially walked for 1 minute to a long-interval metronome sound, and the walking distance was measured. The sound interval was then gradually shortened, and the subjects walked for 1 minute for each of the intervals. The best periodic sound was considered to be the periodic sound used when the subject walked the longest distance in 1 minute, and the process of determining it was referred to as the period shortening walk test. This study administered the 6-minute walk test with the best periodic sound to twenty healthy subjects and 6 ambulant patients with Duchenne muscular dystrophy and compared the walking distance. [Results] The periodic sound-based 6-minute walk test distances in both the healthy subjects and the patients were significantly longer than the conventional 6-minute walk test distances. [Conclusion] The periodic sound-based 6-minute walk test provided a better indication of ambulatory potential in an evaluation of physical endurance than the conventional 6-minute walk test. PMID:26696721

  2. AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

    PubMed Central

    Bortolanza, Sergia; Nonis, Alessandro; Sanvito, Francesca; Maciotta, Simona; Sitia, Giovanni; Wei, Jessica; Torrente, Yvan; Di Serio, Clelia; Chamberlain, Joel R; Gabellini, Davide

    2011-01-01

    Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans. PMID:21829175

  3. Safe and bodywide muscle transduction in young adult Duchenne muscular dystrophy dogs with adeno-associated virus.

    PubMed

    Yue, Yongping; Pan, Xiufang; Hakim, Chady H; Kodippili, Kasun; Zhang, Keqing; Shin, Jin-Hong; Yang, Hsiao T; McDonald, Thomas; Duan, Dongsheng

    2015-10-15

    The ultimate goal of muscular dystrophy gene therapy is to treat all muscles in the body. Global gene delivery was demonstrated in dystrophic mice more than a decade ago using adeno-associated virus (AAV). However, translation to affected large mammals has been challenging. The only reported attempt was performed in newborn Duchenne muscular dystrophy (DMD) dogs. Unfortunately, AAV injection resulted in growth delay, muscle atrophy and contracture. Here we report safe and bodywide AAV delivery in juvenile DMD dogs. Three ?2-m-old affected dogs received intravenous injection of a tyrosine-engineered AAV-9 reporter or micro-dystrophin (?Dys) vector at the doses of 1.92-6.24 × 10(14) viral genome particles/kg under transient or sustained immune suppression. DMD dogs tolerated injection well and their growth was not altered. Hematology and blood biochemistry were unremarkable. No adverse reactions were observed. Widespread muscle transduction was seen in skeletal muscle, the diaphragm and heart for at least 4 months (the end of the study). Nominal expression was detected in internal organs. Improvement in muscle histology was observed in ?Dys-treated dogs. In summary, systemic AAV gene transfer is safe and efficient in young adult dystrophic large mammals. This may translate to bodywide gene therapy in pediatric patients in the future. PMID:26264580

  4. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy.

    PubMed

    Feng, Qing; Snider, Lauren; Jagannathan, Sujatha; Tawil, Rabi; van der Maarel, Silvère M; Tapscott, Stephen J; Bradley, Robert K

    2015-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy caused by inefficient epigenetic repression of the D4Z4 macrosatellite array and somatic expression of the DUX4 retrogene. DUX4 is a double homeobox transcription factor that is normally expressed in the testis and causes apoptosis and FSHD when misexpressed in skeletal muscle. The mechanism(s) of DUX4 toxicity in muscle is incompletely understood. We report that DUX4-triggered proteolytic degradation of UPF1, a central component of the nonsense-mediated decay (NMD) machinery, is associated with profound NMD inhibition, resulting in global accumulation of RNAs normally degraded as NMD substrates. DUX4 mRNA is itself degraded by NMD, such that inhibition of NMD by DUX4 protein stabilizes DUX4 mRNA through a double-negative feedback loop in FSHD muscle cells. This feedback loop illustrates an unexpected mode of autoregulatory behavior of a transcription factor, is consistent with 'bursts' of DUX4 expression in FSHD muscle, and has implications for FSHD pathogenesis. PMID:25564732

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

    PubMed Central

    2014-01-01

    Background Limb girdle muscular dystrophy type 2G (LGMD2G) is a subtype of autosomal recessive muscular dystrophy caused by mutations in the telethonin gene. There are few LGMD2G patients worldwide reported, and this is the first description associated with early tibialis anterior sparing on muscle image and myopathic-neurogenic motor unit potentials. Case presentation Here we report a 31 years old caucasian male patient with progressive gait disturbance, and severe lower limb proximal weakness since the age of 20 years, associated with subtle facial muscle weakness. Computed tomography demonstrated soleus, medial gastrocnemius, and diffuse thigh muscles involvement with tibialis anterior sparing. Electromyography disclosed both neurogenic and myopathic motor unit potentials. Muscle biopsy demonstrated large groups of atrophic and hypertrophic fibers, frequent fibers with intracytoplasmic rimmed vacuoles full of autophagic membrane and sarcoplasmic debris, and a total deficiency of telethonin. Molecular investigation identified the common homozygous c.157C?>?T in the TCAP gene. Conclusion This report expands the phenotypic variability of telethoninopathy/ LGMD2G, including: 1) mixed neurogenic and myopathic motor unit potentials, 2) facial weakness, and 3) tibialis anterior sparing. Appropriate diagnosis in these cases is important for genetic counseling and prognosis. PMID:25298746

  6. Whole Exome Sequencing Reveals DYSF, FKTN, and ISPD Mutations in Congenital Muscular Dystrophy Without Brain or Eye Involvement

    PubMed Central

    Ceyhan-Birsoy, Ozge; Talim, Beril; Swanson, Lindsay C.; Karakaya, Mert; Graff, Michelle A.; Beggs, Alan H.; Topaloglu, Haluk

    2015-01-01

    Background Congenital muscular dystrophies (CMDs) are a genetically and clinically heterogeneous group of neuromuscular disorders. Several genes encoding extracellular matrix, nuclear envelope, sarcolemmal proteins and glycosylation enzymes have been implicated in CMDs. The large overlap of clinical presentations due to mutations in different genes poses a challenge for clinicians in determining disease etiology for each patient. Objective We investigated the use of whole exome sequencing (WES) in identifying the genetic cause of disease in 5 CMD patients from 3 families who presented with highly similar clinical features, including early-onset rapidly progressive weakness without brain or eye abnormalities. Methods Whole exome sequencing was performed on DNA from affected individuals. Potential functional impacts of mutations were investigated by immunostaining on available muscle biopsies. Results Pathogenic mutations in 3 different genes, DYSF, FKTN, and ISPD were identified in each family. Mutation in DYSF led to absence of dysferlin protein in patient muscle. Mutations in ISPD led to impaired ISDP function, as demonstrated by deficiency of ?-dystroglycan glycosylation in patient muscle. Conclusions This study highlights the benefit of unbiased genomic approaches in molecular diagnosis of neuromuscular disorders with high clinical heterogeneity, such as the phenotypes observed in our patients. Our results suggest that dysferlin deficiency should be in the differential diagnosis of congenital and rapidly progressive muscular dystrophy, and therefore dysferlin antibody should be in the standard immunohistochemistry panel for muscle biopsies in cases with suspected CMD. PMID:25821721

  7. Angiogenesis as a novel therapeutic strategy for Duchenne muscular dystrophy through decreased ischemia and increased satellite cells

    PubMed Central

    Shimizu-Motohashi, Yuko; Asakura, Atsushi

    2014-01-01

    Duchenne muscular dystrophy (DMD) is the most common hereditary muscular dystrophy caused by mutation in dystrophin, and there is no curative therapy. Dystrophin is a protein which forms the dystrophin-associated glycoprotein complex (DGC) at the sarcolemma linking the muscle cytoskeleton to the extracellular matrix. When dystrophin is absent, muscle fibers become vulnerable to mechanical stretch. In addition to this, accumulating evidence indicates DMD muscle having vascular abnormalities and that the muscles are under an ischemic condition. More recent studies demonstrate decreased vascular densities and impaired angiogenesis in the muscles of murine model of DMD. Therefore, generation of new vasculature can be considered a potentially effective strategy for DMD therapy. The pro-angiogenic approaches also seem to be pro-myogenic and could induce muscle regeneration capacity through expansion of the satellite cell juxtavascular niche in the mouse model. Here, we will focus on angiogenesis, reviewing the background, vascular endothelial growth factor (VEGF)/VEGF receptor-pathway, effect, and concerns of this strategy in DMD. PMID:24600399

  8. Effects of yoga breathing exercises on pulmonary function in patients with Duchenne muscular dystrophy: an exploratory analysis*, **

    PubMed Central

    Rodrigues, Marcos Rojo; Carvalho, Celso Ricardo Fernandes; Santaella, Danilo Forghieri; Lorenzi-Filho, Geraldo; Marie, Suely Kazue Nagahashi

    2014-01-01

    OBJECTIVE: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in children, and children with DMD die prematurely because of respiratory failure. We sought to determine the efficacy and safety of yoga breathing exercises, as well as the effects of those exercises on respiratory function, in such children. METHODS: This was a prospective open-label study of patients with a confirmed diagnosis of DMD, recruited from among those followed at the neurology outpatient clinic of a university hospital in the city of São Paulo, Brazil. Participants were taught how to perform hatha yoga breathing exercises and were instructed to perform the exercises three times a day for 10 months. RESULTS: Of the 76 patients who entered the study, 35 dropped out and 15 were unable to perform the breathing exercises, 26 having therefore completed the study (mean age, 9.5 ± 2.3 years; body mass index, 18.2 ± 3.8 kg/m2). The yoga breathing exercises resulted in a significant increase in FVC (% of predicted: 82.3 ± 18.6% at baseline vs. 90.3 ± 22.5% at 10 months later; p = 0.02) and FEV1 (% of predicted: 83.8 ± 16.6% at baseline vs. 90.1 ± 17.4% at 10 months later; p = 0.04). CONCLUSIONS: Yoga breathing exercises can improve pulmonary function in patients with DMD. PMID:24831396

  9. Cardiac involvement in myotonic muscular dystrophy (Steinert's disease): a prospective study of 25 patients

    SciTech Connect

    Perloff, J.K.; Stevenson, W.G.; Roberts, N.K.; Cabeen, W.; Weiss, J.

    1984-11-01

    The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically important cardiac manifestations of myotonic dystrophy reside in specialized tissues rather than in myocardium. Involvement is relatively specific, primarily assigned to the His-Purkinje system. The cardiac muscle disorder takes the form of dystrophy rather than myotonia, and is not selective, appearing with approximately equal distribution in all 4 chambers. Myocardial dystrophy seldom results in clinically overt ventricular failure, but may be responsible for atrial and ventricular arrhythmias. Since myotonic dystrophy is genetically transmitted, a primary biochemical defect has been proposed with complete expression of the gene toward striated muscle tissue, whether skeletal or cardiac. Specialized cardiac tissue and myocardium have close, if not identical, embryologic origins, so it is not surprising that the genetic marker affects both. Cardiac involvement is therefore an integral part of myotonic dystrophy, targeting particularly the infranodal conduction system, to a lesser extent the sinus node, and still less specifically, the myocardium.

  10. Under-recognition of Low Blood Pressure Readings in Patients with Duchenne Muscular Dystrophy.

    PubMed

    Masood, Syed Asif; Kazmouz, Suhaib; Heydemann, Peter; Li, Hong; Kenny, Damien

    2015-10-01

    Duchenne muscular dystrophy (DMD), a recessive sex-linked hereditary disorder, is characterized by degeneration, atrophy, and weakness of skeletal and cardiac muscle. The purpose of this study was to document the prevalence of abnormally low resting BP recordings in patients with DMD in our outpatient clinic. The charts of 31 patients with DMD attending the cardiology clinic at Rush University Medical Center were retrospectively reviewed. Demographic data, systolic, diastolic, and mean blood pressures along with current medications, echocardiograms, and documented clinical appreciation and management of low blood pressure were recorded in the form of 104 outpatient clinical visits. Blood pressure (BP) was classified as low if the systolic and/or mean BP was less than the fifth percentile for height for patients aged ?17 years (n = 23). For patients ?18 years (n = 8), systolic blood pressure (SBP) <90 mmHg or a mean arterial pressure (MAP) <60 mmHg was recorded as a low reading. Patients with other forms of myopathy or unclear diagnosis were excluded. Statistical analysis was done using PASW version 18. BP was documented at 103 (99.01 %) outpatient encounters. Low systolic and mean BP were recorded in 35 (33.7 %) encounters. This represented low recordings for 19 (61.3 %) out of a total 31 patients with two or more successive low recordings for 12 (38.7 %) patients. Thirty-one low BP encounters were in patients <18 years old. Hispanic patients accounted for 74 (71.2 %) visits and had low BP recorded in 32 (43.2 %) instances. The patients were non-ambulant in 71 (68.3 %) encounters. Out of 35 encounters with low BP, 17 patients (48.6 %) were taking heart failure medication. In instances when patients had low BP, 22 (66.7 %) out of 33 echocardiography encounters had normal left ventricular ejection fraction. Clinician comments on low BP reading were present in 11 (10.6 %) encounters, and treatment modification occurred in only 1 (1 %) patient. Age in years (p = .031) and ethnicity (p = .035) were independent predictors of low BP using stepwise multiple regression analysis. Low BP was recorded in a significant number of patient encounters in patients with DMD. Age 17 years or less and Hispanic ethnicity were significant predictors associated with low BP readings in our DMD cohort. Concomitant heart failure therapy was not a statistically significant association. There is a need for enhanced awareness of low BP in DMD patients among primary care and specialty physicians. The etiology and clinical impact of these findings are unclear but may impact escalation of heart failure therapy. PMID:25981564

  11. Effects of glucocorticoids and idebenone on respiratory function in patients with duchenne muscular dystrophy.

    PubMed

    Buyse, Gunnar M; Goemans, Nathalie; van den Hauwe, Marleen; Meier, Thomas

    2013-09-01

    In Duchenne muscular dystrophy (DMD) progressive weakness of respiratory muscles leads to a restrictive pulmonary syndrome that contributes to early morbidity and mortality. Currently no curative treatment exists for DMD. In a Phase II randomized placebo-controlled study (DELPHI) in 21 DMD boys at age 8-16 years, idebenone (450?mg/d) showed trends of efficacy for cardiac and respiratory endpoints. Since the DELPHI study population comprised both glucocorticoid-naïve subjects and glucocorticoid-users, we now report a post-hoc analysis investigating the effects of glucocorticoids and idebenone on markers of respiratory weakness, particularly peak expiratory flow (PEF) percent predicted (PEF%p). Baseline values of PEF%p correlated well with the percent predicted values for maximal inspiratory mouth pressure (MIP%p), forced vital capacity (FVC%p), and forced expired volume in 1?sec (FEV1%p). Baseline PEF%p and FVC%p were significantly higher in patients on concomitant glucocorticoids compared to glucocorticoid-naïve patients. In the latter subgroup, idebenone caused a 8.0?±?12.1% improvement in PEF%p, whilst patients on placebo declined by -12.3?±?17.9% (P?

  12. DUX4 promotes transcription of FRG2 by directly activating its promoter in facioscapulohumeral muscular dystrophy

    PubMed Central

    2014-01-01

    Background The most common form of facioscapulohumeral muscular dystrophy (FSHD) is caused by a genetic contraction of the polymorphic D4Z4 macrosatellite repeat array in the subtelomeric region of chromosome 4q. In some studies, genes centromeric to the D4Z4 repeat array have been reported to be over-expressed in FSHD, including FRG1 and FRG2, presumably due to decreased long-distance repression by the shorter array through a mechanism similar to position-effect variegation. Differential regulation of FRG1 in FSHD has never been unequivocally proven, however, FRG2 has been reproducibly shown to be induced in primary FSHD-derived muscle cells when differentiated in vitro. The molecular function of FRG2 and a possible contribution to FSHD pathology remain unclear. Recent evidence has identified the mis-expression of DUX4, located within the D4Z4 repeat unit, in skeletal muscle as the cause of FSHD. DUX4 is a double homeobox transcription factor that has been shown to be toxic when expressed in muscle cells. Methods We used a combination of expression analysis by qRT/PCR and RNA sequencing to determine the transcriptional activation of FRG2 and DUX4. We examined this in both differentiating control and FSHD derived muscle cell cultures or DUX4 transduced control cell lines. Next, we used ChIP-seq analysis and luciferase reporter assays to determine the potential DUX4 transactivation effect on the FRG2 promoter. Results We show that DUX4 directly activates the expression of FRG2. Increased expression of FRG2 was observed following expression of DUX4 in myoblasts and fibroblasts derived from control individuals. Moreover, we identified DUX4 binding sites at the FRG2 promoter by chromatin immunoprecipitation followed by deep sequencing and confirmed the direct regulation of DUX4 on the FRG2 promoter by luciferase reporter assays. Activation of luciferase was dependent on both DUX4 expression and the presence of the DUX4 DNA binding motifs in the FRG2 promoter. Conclusion We show that the FSHD-specific upregulation of FRG2 is a direct consequence of the activity of DUX4 protein rather than representing a regional de-repression secondary to fewer D4Z4 repeats. PMID:25789155

  13. Defective (U-14 C) palmitic acid oxidation in Duchenne muscular dystrophy

    SciTech Connect

    Carroll, J.E.; Norris, B.J.; Brooke, M.H.

    1985-01-01

    Compared with normal skeletal muscle, muscle from patients with Duchenne dystrophy had decreased (U-14 C) palmitic acid oxidation. (1-14 C) palmitic acid oxidation was normal. These results may indicate a defect in intramitochondrial fatty acid oxidation.

  14. A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G).

    PubMed

    Vieira, Natássia M; Naslavsky, Michel S; Licinio, Luciana; Kok, Fernando; Schlesinger, David; Vainzof, Mariz; Sanchez, Nury; Kitajima, João Paulo; Gal, Lihi; Cavaçana, Natale; Serafini, Peter R; Chuartzman, Silvia; Vasquez, Cristina; Mimbacas, Adriana; Nigro, Vincenzo; Pavanello, Rita C; Schuldiner, Maya; Kunkel, Louis M; Zatz, Mayana

    2014-08-01

    Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies. PMID:24647604

  15. More deletions in the 5{prime} region than in the central region of the dystrophin gene were identified among Filipino Duchenne and Becker muscular dystrophy patients

    SciTech Connect

    1995-11-06

    This report describes mutations in the dystrophin gene and the frequency of these mutations in Filipino pedigrees with Duchenne and Becker muscular dystrophy (DMD/BMD). The findings suggest the presence of genetic variability among DMD/BMD patients in different populations. 13 refs., 1 tab.

  16. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

    SciTech Connect

    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. ); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya )

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  17. Melanocytes from Patients Affected by Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy have Dysfunctional Mitochondria That Can be Rescued with Cyclophilin Inhibitors

    PubMed Central

    Zulian, Alessandra; Tagliavini, Francesca; Rizzo, Erika; Pellegrini, Camilla; Sardone, Francesca; Zini, Nicoletta; Maraldi, Nadir Mario; Santi, Spartaco; Faldini, Cesare; Merlini, Luciano; Petronilli, Valeria; Bernardi, Paolo; Sabatelli, Patrizia

    2014-01-01

    Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI (ColVI) genes, which encode an extracellular matrix protein; yet, mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high-conductance channel, which causes a shortage in ATP production. We find that melanocytes do not produce ColVI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myopathy patients display increased size, reduced matrix density, and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i) underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii) displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013), and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in ColVI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia. PMID:25477819

  18. P2RX7 Purinoceptor: A Therapeutic Target for Ameliorating the Symptoms of Duchenne Muscular Dystrophy

    PubMed Central

    Sinadinos, Anthony; Teti, Anna; Kalinski, Pawe?; Mohamad, Shafini; Tozzi, Gianluca; Jiang, Taiwen; Wurtz, Olivier; Lefebvre, Alexis; Shugay, Mikhail; Tong, Jie; Vaudry, David; Arkle, Stephen; doRego, Jean-Claude; Górecki, Dariusz C.

    2015-01-01

    Background Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease, leading to severe disability and death in young men. Death is caused by the progressive degeneration of striated muscles aggravated by sterile inflammation. The pleiotropic effects of the mutant gene also include cognitive and behavioral impairments and low bone density. Current interventions in DMD are palliative only as no treatment improves the long-term outcome. Therefore, approaches with a translational potential should be investigated, and key abnormalities downstream from the absence of the DMD product, dystrophin, appear to be strong therapeutic targets. We and others have demonstrated that DMD mutations alter ATP signaling and have identified P2RX7 purinoceptor up-regulation as being responsible for the death of muscles in the mdx mouse model of DMD and human DMD lymphoblasts. Moreover, the ATP–P2RX7 axis, being a crucial activator of innate immune responses, can contribute to DMD pathology by stimulating chronic inflammation. We investigated whether ablation of P2RX7 attenuates the DMD model mouse phenotype to assess receptor suitability as a therapeutic target. Methods and Findings Using a combination of molecular, histological, and biochemical methods and behavioral analyses in vivo we demonstrate, to our knowledge for the first time, that genetic ablation of P2RX7 in the DMD model mouse produces a widespread functional attenuation of both muscle and non-muscle symptoms. In dystrophic muscles at 4 wk there was an evident recovery in key functional and molecular parameters such as improved muscle structure (minimum Feret diameter, p < 0.001), increased muscle strength in vitro (p < 0.001) and in vivo (p = 0.012), and pro-fibrotic molecular signatures. Serum creatine kinase (CK) levels were lower (p = 0.025), and reduced cognitive impairment (p = 0.006) and bone structure alterations (p < 0.001) were also apparent. Reduction of inflammation and fibrosis persisted at 20 mo in leg (p = 0.038), diaphragm (p = 0.042), and heart muscles (p < 0.001). We show that the amelioration of symptoms was proportional to the extent of receptor depletion and that improvements were observed following administration of two P2RX7 antagonists (CK, p = 0.030 and p = 0.050) without any detectable side effects. However, approaches successful in animal models still need to be proved effective in clinical practice. Conclusions These results are, to our knowledge, the first to establish that a single treatment can improve muscle function both short and long term and also correct cognitive impairment and bone loss in DMD model mice. The wide-ranging improvements reflect the convergence of P2RX7 ablation on multiple disease mechanisms affecting skeletal and cardiac muscles, inflammatory cells, brain, and bone. Given the impact of P2RX7 blockade in the DMD mouse model, this receptor is an attractive target for translational research: existing drugs with established safety records could potentially be repurposed for treatment of this lethal disease. PMID:26461208

  19. Selenoproteins protect against avian nutritional muscular dystrophy by metabolizing peroxides and regulating redox/apoptotic signaling.

    PubMed

    Huang, Jia-Qiang; Ren, Fa-Zheng; Jiang, Yun-Yun; Xiao, Chen; Lei, Xin Gen

    2015-06-01

    Nutritional muscular dystrophy (NMD) of chicks is induced by dietary selenium (Se)/vitamin E (Vit. E) deficiencies and may be associated with oxidative cell damage. To reveal the underlying mechanisms related to the presumed oxidative cell damage, we fed four groups of 1-day-old broiler chicks (n = 40/group) with a basal diet (BD; 10 ?g Se/kg; no Vit. E added, -Se -Vit. E) or the BD plus all-rac-?-tocopheryl acetate at 50mg/kg (-Se +Vit. E), Se (as sodium selenite) at 0.3mg/kg (+Se -Vit. E), or both of these nutrients (+Se +Vit. E) for 6 weeks. High incidences of NMD (93%) and mortality (36%) of the chicks were induced by the BD, starting at week 3. Dietary Se deficiency alone also induced muscle fiber rupture and coagulation necrosis in the pectoral muscle of chicks at week 3 and thereafter, with increased (P < 0.05) malondialdehyde, decreased (P < 0.05) total antioxidant capacity, and diminished (P < 0.05) glutathione peroxidase activities in the muscle. To link these oxidative damages of the muscle cells to the Se-deficiency-induced NMD, we first determined gene expression of the potential 26 selenoproteins in the muscle of the chicks at week 2 before the onset of symptoms. Compared with the +Se chicks, the -Se chicks had lower (P < 0.05) muscle mRNA levels of Gpx1, Gpx3, Gpx4, Sepp1, Selo, Selk, Selu, Selh, Selm, Sepw1, and Sep15. The -Se chicks also had decreased (P < 0.05) production of 6 selenoproteins (long-form selenoprotein P (SelP-L), GPx1, GPx4, Sep15, SelW, and SelN), but increased levels (P < 0.05) of the short-form selenoprotein P in muscle at weeks 2 and 4. Dietary Se deficiency elevated (P < 0.05) muscle p53, cleaved caspase 3, cleaved caspase 9, cyclooxygenase 2 (COX2), focal adhesion kinase (FAK), phosphatidylinositol 3-kinase (PI3K), phospho-Akt, nuclear factor-?B (NF-?B), p38 mitogen-activated protein kinase (p38 MAPK), phospho-p38 MAPK, phospho-JNK, and phospho-ERK and decreased (P < 0.05) muscle procaspase 3, procaspase 9, and NF-?B inhibitor ?. In conclusion, the downregulation of SelP-L, GPx1, GPx4, Sep15, SelW, and SelN by dietary Se deficiency might account for induced oxidative stress and the subsequent peroxidative damage of chick muscle cells via the activation of the p53/caspase 9/caspase 3, COX2/FAK/PI3K/Akt/NF-?B, and p38 MAPK/JNK/ERK signaling pathways. Metabolism of peroxides and redox regulation are likely to be the mechanisms whereby these selenoproteins prevented the onset of NMD in chicks. PMID:25668720

  20. Erythrocytes in muscular dystrophy. Investigation with 31P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (31P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual 31P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which lead to lower steady-state concentrations of the intracellular phosphates.

  1. Erythrocytes in muscular dystrophy. Investigation with /sup 31/P nuclear magnetic resonance spectroscopy

    SciTech Connect

    Sarpel, G.; Lubansky, H.J.; Danon, M.J.; Omachi, A.

    1981-05-01

    Phosphorus 31 nuclear magnetic resonance (/sup 31/P NMR) signals were recorded from intact human erythrocytes for 16 hours. Total phosphate concentration, which was estimated as the sum of the individual /sup 31/P signals, was 25% lower in erythrocytes from men with myotonic dystrophy than in control erythrocytes. The inorganic-phosphate fraction contained the highest average phosphate concentration over the 16-hour period, and made the major contribution to the difference in total phosphate between the two groups. This result was not observed in erythrocytes from either women with myotonic dystrophy or patients with Duchenne's dystrophy and may be due to a change in cell membrane permeability to inorganic phosphate, which leads to lower steady-state concentrations of the intracellular phosphates.

  2. Successful surgery for scoliosis supported by pulmonary rehabilitation in a duchenne muscular dystrophy patient with forced vital capacity below 10%.

    PubMed

    Lee, Jang Woo; Won, Yu Hui; Choi, Won Ah; Lee, Soon Kyu; Kang, Seong Woong

    2013-12-01

    Low vital capacity is a risk factor for scoliosis correction operation in Duchenne muscular dystrophy (DMD) patients, but pulmonary rehabilitation, including noninvasive intermittent positive pressure ventilator application, air stacking exercise, and assisted coughing technique, reduces the pulmonary complications and perioperative mortality risk. In this case, the patient's preoperative forced vital capacity (FVC) was 8.6% of normal predicted value in sitting position and 9.4% in supine position. He started pulmonary rehabilitation before the operation and continued right after the operation. Scoliosis correction operation was successful without any pulmonary complications, and his discomfort in sitting position was improved. If pulmonary rehabilitative support is provided properly, FVC below 10% of normal predicted value is not a contraindication of scoliosis correction operation in DMD patients. PMID:24466523

  3. Successful Surgery for Scoliosis Supported by Pulmonary Rehabilitation in a Duchenne Muscular Dystrophy Patient With Forced Vital Capacity Below 10%

    PubMed Central

    Lee, Jang Woo; Won, Yu Hui; Choi, Won Ah; Lee, Soon Kyu

    2013-01-01

    Low vital capacity is a risk factor for scoliosis correction operation in Duchenne muscular dystrophy (DMD) patients, but pulmonary rehabilitation, including noninvasive intermittent positive pressure ventilator application, air stacking exercise, and assisted coughing technique, reduces the pulmonary complications and perioperative mortality risk. In this case, the patient's preoperative forced vital capacity (FVC) was 8.6% of normal predicted value in sitting position and 9.4% in supine position. He started pulmonary rehabilitation before the operation and continued right after the operation. Scoliosis correction operation was successful without any pulmonary complications, and his discomfort in sitting position was improved. If pulmonary rehabilitative support is provided properly, FVC below 10% of normal predicted value is not a contraindication of scoliosis correction operation in DMD patients. PMID:24466523

  4. Neuropsychological impairments and the impact of dystrophin mutations on general cognitive functioning of patients with Duchenne muscular dystrophy.

    PubMed

    Wingeier, Kevin; Giger, Elisabeth; Strozzi, Susi; Kreis, Roland; Joncourt, Franziska; Conrad, Bernard; Gallati, Sabina; Steinlin, Maja

    2011-01-01

    Mutations in the dystrophin gene have long been recognised as a cause of mental retardation. However, for reasons that are unclear, some boys with dystrophin mutations do not show general cognitive deficits. To investigate the relationship between dystrophin mutations and cognition, the general intellectual abilities of a group of 25 boys with genetically confirmed Duchenne muscular dystrophy were evaluated. Furthermore, a subgroup underwent additional detailed neuropsychological assessment. The results showed a mean full scale intelligence quotient (IQ) of 88 (standard deviation 24). Patients performed very poorly on various neuropsychological tests, including arithmetics, digit span tests and verbal fluency. No simple relationship between dystrophin mutations and cognitive functioning could be detected. However, our analysis revealed that patients who lack the dystrophin isoform Dp140 have significantly greater cognitive problems. PMID:21109441

  5. Mutation analysis in Duchenne and Becker muscular dystrophy patients from Bulgaria shows a peculiar distribution of breakpoints by intron

    SciTech Connect

    Todorova, A.; Bronzova, J.; Kremensky, I.

    1996-10-02

    For the first time in Bulgaria, a deletion/duplication screening was performed on a group of 84 unrelated Duchenne/Becker muscular dystrophy patients, and the breakpoint distribution in the dystrophin gene was analyzed. Intragenic deletions were detected in 67.8% of patients, and intragenic duplications in 2.4%. A peculiar distribution of deletion breakpoints was found. Only 13.2% of the deletion breakpoints fell in the {open_quotes}classical{close_quotes} hot spot in intron 44, whereas the majority (> 54%) were located within the segment encompassing introns 45-51, which includes intron 50, the richest in breakpoints (16%) in the Bulgarian sample. Comparison with data from Greece and Turkey points at the probable existence of a deletion hot spot within intron 50, which might be a characteristic of populations of the Balkan region. 17 refs., 2 figs.

  6. Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

    PubMed Central

    Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

    2008-01-01

    This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

  7. Increased mRNA expression of tissue inhibitors of metalloproteinase-1 and -2 in Duchenne muscular dystrophy.

    PubMed

    von Moers, Arpad; Zwirner, Angelika; Reinhold, Anke; Brückmann, Olaf; van Landeghem, Frank; Stoltenburg-Didinger, Gisela; Schuppan, Detlef; Herbst, Herrman; Schuelke, Markus

    2005-03-01

    In dystrophinopathies, disease severity is generally related to the extent of muscle fibrosis. To determine whether a decrease in matrix degradation contributes to the severe fibrosis seen in Duchenne muscular dystrophy (DMD), we quantified RNA transcript numbers for the fibrolytic matrix metalloproteinases (MMP)-1 and -2 and their natural tissue inhibitors (TIMP)-1 and -2 in DMD muscle as well as in pathological and normal controls. In addition, we investigated gelatinase (MMP-2) enzyme activity by zymography. We found an up-regulation of TIMP-1, TIMP-2 and MMP-2 RNA in DMD muscle. Zymography revealed an increase in MMP-2 activity in DMD muscle homogenates, which was absent in pathological and normal controls. Therefore, besides enhanced fibrogenesis, a disturbance of matrix degradation may play a significant role in muscle fibrosis in DMD. TIMP-1 should be investigated further as a promising target for pharmacological intervention to prevent muscle fibrosis in DMD. PMID:15616792

  8. Obesity and Premature Loss of Mobility in Two Adolescents with Becker Muscular Dystrophy After HeartMate II Implantation.

    PubMed

    Hollander, Seth A; Rizzuto, Sandra; Hollander, Amanda M; Lin, Aileen; Liu, Esther; Murray, Jenna M; Almond, Christopher S; Rosenthal, David N

    2016-01-01

    Weight gain is common after implantation of continuous-flow ventricular assist devices. Obesity can have a significant negative impact on mobility. For adolescents with Becker muscular dystrophy (BMD), for whom the ability to ambulate often persists into the mid-3rd decade, preservation of functional ability is critical. We report two cases of Thoratec HeartMate II left ventricular assist device (LVAD) implantation in adolescents with BMD for whom postoperative weight gain contributed significantly to an accelerated loss of ambulation and, in one case, driveline fracture in the context of repeated falls. As LVADs become an increasingly common therapy for endstage heart failure in adolescents with BMD, care must be focused not only on maintenance of device functionality, but also on management of aggressive weight, and preservation of ambulation, and skeletal muscle strength. PMID:26461240

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

    PubMed

    Fanin, Marina; Angelini, Corrado

    2015-08-01

    Limb girdle muscular dystrophy type 2A (LGMD2A) is the most frequent form of LGMD worldwide. Comprehensive clinical assessment and laboratory testing is essential for diagnosis of LGMD2A. Muscle immunoblot analysis of calpain-3 is the most useful tool to direct genetic testing, as detection of calpain-3 deficiency has high diagnostic value. However, calpain-3 immunoblot testing lacks sensitivity in about 30% of cases due to gene mutations that inactivate the enzyme. The best diagnostic strategy should be determined on a case-by-case basis, depending on which tissues are available, and which molecular and/or genetic methods are adopted. In this work we survey the current knowledge, advantages, limitations, and pitfalls of protein testing and mutation detection in LGMD2A and provide an update of genetic epidemiology. PMID:25900067

  10. Unexpected tracheal narrowing during general anesthesia in the prone position of Duchenne muscular dystrophy patient -A report of two cases-

    PubMed Central

    Lee, Dong Kyu; Lim, Byung Gun; Lee, Il-Ok; Oh, Hye-Ran; Lim, Sang Ho

    2013-01-01

    Unexpected tracheal narrowing was observed in a patient with Duchenne muscular dystrophy during a corrective operation for thoracolumbar scoliosis. As the operating time progressed, peak airway pressure and end-tidal CO2 increased gradually in the prone position. We found a floppy portion of the trachea using fiberoptic bronchoscopy (FB) in the prone position. We advanced a wire-reinforced tube toward the carina beyond the lesion. This allowed correction of the ventilatory abnormalities. We encountered another patient scheduled for the same operation. We performed FB in advance before the position change and observed a narrowed portion of trachea. We advanced the tracheal tube under FB beyond the pathologic portion and then moved the patient into the prone position. The operation was done successfully without any problems. PMID:23741571

  11. Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy.

    PubMed

    Wang, Yan; Yang, Yao; Liu, Jing; Chen, Xiao-Chun; Liu, Xin; Wang, Chun-Zhi; He, Xi-Yu

    2014-10-01

    Duchenne/Becker muscular dystrophies are the most frequent inherited neuromuscular diseases caused by mutations of the dystrophin gene. However, approximately 30% of patients with the disease do not receive a molecular diagnosis because of the complex mutational spectrum and the large size of the gene. The introduction and use of next-generation sequencing have advanced clinical genetic research and might be a suitable method for the detection of various types of mutations in the dystrophin gene. To identify the mutational spectrum using a single platform, whole dystrophin gene sequencing was performed using next-generation sequencing. The entire dystrophin gene, including all exons, introns and promoter regions, was target enriched using a DMD whole gene enrichment kit. The enrichment libraries were sequenced on an Illumina HiSeq 2000 sequencer using paired read 100 bp sequencing. We studied 26 patients: 21 had known large deletion/duplications and 5 did not have detectable large deletion/duplications by multiplex ligation-dependent probe amplification technology (MLPA). We applied whole dystrophin gene analysis by next-generation sequencing to the five patients who did not have detectable large deletion/duplications and to five randomly chosen patients from the 21 who did have large deletion/duplications. The sequencing data covered almost 100% of the exonic region of the dystrophin gene by ?10 reads with a mean read depth of 147. Five small mutations were identified in the first five patients, of which four variants were unreported in the dmd.nl database. The deleted or duplicated exons and the breakpoints in the five large deletion/duplication patients were precisely identified. Whole dystrophin gene sequencing by next-generation sequencing may be a useful tool for the genetic diagnosis of Duchenne and Becker muscular dystrophies. PMID:24770780

  12. Multi-Parametric MRI at 14T for Muscular Dystrophy Mice Treated with AAV Vector-Mediated Gene Therapy

    PubMed Central

    Park, Joshua; Wicki, Jacqueline; Knoblaugh, Sue E.; Chamberlain, Jeffrey S.; Lee, Donghoon

    2015-01-01

    The objective of this study was to investigate the efficacy of using quantitative magnetic resonance imaging (MRI) as a non-invasive tool for the monitoring of gene therapy for muscular dystrophy. The clinical investigations for this family of diseases often involve surgical biopsy which limits the amount of information that can be obtained due to the invasive nature of the procedure. Thus, other non-invasive tools may provide more opportunities for disease assessment and treatment responses. In order to explore this, dystrophic mdx4cv mice were systemically treated with a recombinant adeno-associated viral (AAV) vector containing a codon-optimized micro-dystrophin gene. Multi-parametric MRI of T2, magnetization transfer, and diffusion effects alongside 3-D volume measurements were then utilized to monitor disease/treatment progression. Mice were imaged at 10 weeks of age for pre-treatment, then again post-treatment at 8, 16, and 24 week time points. The efficacy of treatment was assessed by physiological assays for improvements in function and quantification of expression. Tissues from the hindlimbs were collected for histological analysis after the final time point for comparison with MRI results. We found that introduction of the micro-dystrophin gene restored some aspects of normal muscle histology and pathology such as decreased necrosis and resistance to contraction-induced injury. T2 relaxation values showed percentage decreases across all muscle types measured (tibialis anterior, gastrocnemius, and soleus) when treated groups were compared to untreated groups. Additionally, the differences between groups were statistically significant for the tibialis anterior as well. The diffusion measurements showed a wider range of percentage changes and less statistical significance while the magnetization transfer effect measurements showed minimal change. MR images displayed hyper-intense regions of muscle that correlated with muscle pathology in histological sections. T2 relaxation, alongside diffusion and magnetization transfer effects provides useful data towards the goal of non-invasively monitoring the treatment of muscular dystrophy. PMID:25856443

  13. Evaluation of a program for long-term treatment of Duchenne muscular dystrophy. Experience at the University Hospitals of Cleveland.

    PubMed

    Vignos, P J; Wagner, M B; Karlinchak, B; Katirji, B

    1996-12-01

    One hundred and forty-four boys who had Duchenne muscular dystrophy were managed at a single center between 1953 and 1994 and were followed for a mean of 8.9 years. The long duration of follow-up provided an opportunity to examine the effects of physical therapy and orthopaedic treatment on contractures of the lower extremities and on the duration of the ability to walk. Contractures of the lower extremities were controlled best when patients were managed with a combination of daily passive stretching exercises, prescribed periods of standing and walking, tenotomy of the Achilles tendon, posterior tibial-tendon transfer, and application of knee-ankle-foot orthoses. Approximately two years after bracing, the severity of the contracture of the heel cords was similar in the patients who had had an operation and those who had not. By the fourth year after bracing, however, the patients who had had an operation had less severe contractures than those who had had bracing alone. Five to seven years after the operation and bracing, control of contractures was still good, especially for the patients who had had posterior tibial-tendon transfer. Contracture of the knee was well controlled five to seven years after bracing in all patients who had had bracing, with or without an operation. The program enabled the patients who had been managed with bracing to walk until a mean age of 13.6 years. After loss of the ability to walk with bracing, the ability to stand continued for an additional two years with use of orthoses. The findings of the present study demonstrate the value of traditional methods of operative treatment and bracing for controlling contractures of the lower extremities in patients who have Duchenne muscular dystrophy and for prolonging their ability to walk. PMID:8986661

  14. Pregnancy-induced amelioration of muscular dystrophy phenotype in mdx mice via muscle membrane stabilization effect of glucocorticoid.

    PubMed

    Shimizu-Motohashi, Yuko; Asakura, Yoko; Motohashi, Norio; Belur, Nandkishore R; Baumrucker, Michael G; Asakura, Atsushi

    2015-01-01

    Duchenne muscular dystrophy (DMD), the most common and severe type of dystrophinopathy, is an X-linked recessive genetic disease caused by the absence of dystrophin, which leads to fragility and vulnerability of the sarcolemma to mechanical stretching with increased membrane permeability. Currently, glucocorticoids such as prednisolone are the only medication available for DMD. However, molecular pathways responsible for this effect are still unclear. In addition, it remains unclear whether sex-related factors, including pregnancy and the postpartum period, affect the phenotype of dystrophinopathy. Here, we report the amelioration of muscle membrane permeability in the diaphragm muscle of pregnant and postpartum, but not in nulliparous, mdx mice, an animal model for DMD, during the physiological surge of corticosterone, the most abundant glucocorticoid in rodents. Cultures of single muscle fibers and myotubes isolated from mdx mouse diaphragm demonstrate resistance to hypo-osmotic shock when treated with corticosterone but not with estradiol or progesterone. This corticosterone-mediated resistance was diminished by an antagonist of corticosterone, indicating that the glucocorticoid-glucocorticoid receptor axis plays a role in this membrane stabilization effect on muscle. Moreover, subcutaneous injection of corticosterone into mdx mice showed decreased membrane permeability. This is the first report to demonstrate that pregnancy-related resistance to muscle fiber damage in mdx mice due to the membrane stabilization effect of corticosterone. We also propose that this membrane stabilization effect is exerted through annexin A1 up-regulation as the molecular mechanisms of glucocorticoid effects on DMD muscle. Furthermore, single muscle fiber culture studies provide a sensitive chemical screening platform for muscular dystrophies. PMID:25775477

  15. Pregnancy-Induced Amelioration of Muscular Dystrophy Phenotype in mdx Mice via Muscle Membrane Stabilization Effect of Glucocorticoid

    PubMed Central

    Shimizu-Motohashi, Yuko; Asakura, Yoko; Motohashi, Norio; Belur, Nandkishore R.; Baumrucker, Michael G.; Asakura, Atsushi

    2015-01-01

    Duchenne muscular dystrophy (DMD), the most common and severe type of dystrophinopathy, is an X-linked recessive genetic disease caused by the absence of dystrophin, which leads to fragility and vulnerability of the sarcolemma to mechanical stretching with increased membrane permeability. Currently, glucocorticoids such as prednisolone are the only medication available for DMD. However, molecular pathways responsible for this effect are still unclear. In addition, it remains unclear whether sex-related factors, including pregnancy and the postpartum period, affect the phenotype of dystrophinopathy. Here, we report the amelioration of muscle membrane permeability in the diaphragm muscle of pregnant and postpartum, but not in nulliparous, mdx mice, an animal model for DMD, during the physiological surge of corticosterone, the most abundant glucocorticoid in rodents. Cultures of single muscle fibers and myotubes isolated from mdx mouse diaphragm demonstrate resistance to hypo-osmotic shock when treated with corticosterone but not with estradiol or progesterone. This corticosterone-mediated resistance was diminished by an antagonist of corticosterone, indicating that the glucocorticoid-glucocorticoid receptor axis plays a role in this membrane stabilization effect on muscle. Moreover, subcutaneous injection of corticosterone into mdx mice showed decreased membrane permeability. This is the first report to demonstrate that pregnancy-related resistance to muscle fiber damage in mdx mice due to the membrane stabilization effect of corticosterone. We also propose that this membrane stabilization effect is exerted through annexin A1 up-regulation as the molecular mechanisms of glucocorticoid effects on DMD muscle. Furthermore, single muscle fiber culture studies provide a sensitive chemical screening platform for muscular dystrophies. PMID:25775477

  16. Promoter alteration causes transcriptional repression of the POMGNT1 gene in limb-girdle muscular dystrophy type 2O

    PubMed Central

    Raducu, Madalina; Baets, Jonathan; Fano, Oihane; Van Coster, Rudy; Cruces, Jesús

    2012-01-01

    Limb-girdle muscular dystrophy type 2O (LGMD2O) belongs to a group of rare muscular dystrophies named dystroglycanopathies, which are characterized molecularly by hypoglycosylation of ?-dystroglycan (?-DG). Here, we describe the first dystroglycanopathy patient carrying an alteration in the promoter region of the POMGNT1 gene (protein O-mannose ?-1,2-N-acetylglucosaminyltransferase 1), which involves a homozygous 9-bp duplication (-83_-75dup). Analysis of the downstream effects of this mutation revealed a decrease in the expression of POMGNT1 mRNA and protein because of negative regulation of the POMGNT1 promoter by the transcription factor ZNF202 (zinc-finger protein 202). By functional analysis of various luciferase constructs, we localized a proximal POMGNT1 promoter and we found a 75% decrease in luciferase activity in the mutant construct when compared with the wild type. Electrophoretic mobility shift assay (EMSA) revealed binding sites for the Sp1, Ets1 and GATA transcription factors. Surprisingly, the mutation generated an additional ZNF202 binding site and this transcriptional repressor bound strongly to the mutant promoter while failing to recognize the wild-type promoter. Although the genetic causes of dystroglycanopathies are highly variable, they account for only 50% of the cases described. Our results emphasize the importance of extending the mutational screening outside the gene-coding region in dystroglycanopathy patients of unknown aetiology, because mutations in noncoding regions may be the cause of disease. Our findings also underline the requirement to perform functional studies that may assist the interpretation of the pathogenic potential of promoter alterations. PMID:22419172

  17. Transcriptome Analysis of Ullrich Congenital Muscular Dystrophy Fibroblasts Reveals a Disease Extracellular Matrix Signature and Key Molecular Regulators

    PubMed Central

    Rodríguez, Maria Angels; Jou, Cristina; Puigdelloses, Montserrat; Ortez, Carlos I.; Diaz-Manera, Jordi; Gallardo, Eduardo; Colomer, Jaume; Nascimento, Andrés; Kalko, Susana G.; Jimenez-Mallebrera, Cecilia

    2015-01-01

    Background Collagen VI related myopathies encompass a range of phenotypes with involvement of skeletal muscle, skin and other connective tissues. They represent a severe and relatively common form of congenital disease for which there is no treatment. Collagen VI in skeletal muscle and skin is produced by fibroblasts. Aims & Methods In order to gain insight into the consequences of collagen VI mutations and identify key disease pathways we performed global gene expression analysis of dermal fibroblasts from patients with Ullrich Congenital Muscular Dystrophy with and without vitamin C treatment. The expression data were integrated using a range of systems biology tools. Results were validated by real-time PCR, western blotting and functional assays. Findings We found significant changes in the expression levels of almost 600 genes between collagen VI deficient and control fibroblasts. Highly regulated genes included extracellular matrix components and surface receptors, including integrins, indicating a shift in the interaction between the cell and its environment. This was accompanied by a significant increase in fibroblasts adhesion to laminin. The observed changes in gene expression profiling may be under the control of two miRNAs, miR-30c and miR-181a, which we found elevated in tissue and serum from patients and which could represent novel biomarkers for muscular dystrophy. Finally, the response to vitamin C of collagen VI mutated fibroblasts significantly differed from healthy fibroblasts. Vitamin C treatment was able to revert the expression of some key genes to levels found in control cells raising the possibility of a beneficial effect of vitamin C as a modulator of some of the pathological aspects of collagen VI related diseases. PMID:26670220

  18. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects

    PubMed Central

    Heier, Christopher R; Damsker, Jesse M; Yu, Qing; Dillingham, Blythe C; Huynh, Tony; Van der Meulen, Jack H; Sali, Arpana; Miller, Brittany K; Phadke, Aditi; Scheffer, Luana; Quinn, James; Tatem, Kathleen; Jordan, Sarah; Dadgar, Sherry; Rodriguez, Olga C; Albanese, Chris; Calhoun, Michael; Gordish-Dressman, Heather; Jaiswal, Jyoti K; Connor, Edward M; McCall, John M; Hoffman, Eric P; Reeves, Erica K M; Nagaraju, Kanneboyina

    2013-01-01

    Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-?B is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases. PMID:24014378

  19. From Innate to Adaptive Immune Response in Muscular Dystrophies and Skeletal Muscle Regeneration: The Role of Lymphocytes

    PubMed Central

    Madaro, Luca; Bouché, Marina

    2014-01-01

    Skeletal muscle is able to restore contractile functionality after injury thanks to its ability to regenerate. Following muscle necrosis, debris is removed by macrophages, and muscle satellite cells (MuSCs), the muscle stem cells, are activated and subsequently proliferate, migrate, and form muscle fibers restoring muscle functionality. In most muscle dystrophies (MDs), MuSCs fail to properly proliferate, differentiate, or replenish the stem cell compartment, leading to fibrotic deposition. However, besides MuSCs, interstitial nonmyogenic cells and inflammatory cells also play a key role in orchestrating muscle repair. A complete understanding of the complexity of these mechanisms should allow the design of interventions to attenuate MDs pathology without disrupting regenerative processes. In this review we will focus on the contribution of immune cells in the onset and progression of MDs, with particular emphasis on Duchenne muscular dystrophy (DMD). We will briefly summarize the current knowledge and recent advances made in our understanding of the involvement of different innate immune cells in MDs and will move on to critically evaluate the possible role of cell populations within the acquired immune response. Revisiting previous observations in the light of recent evidence will likely change our current view of the onset and progression of the disease. PMID:25028653

  20. Epigenetic effects on the mouse mandible: common features and discrepancies in remodeling due to muscular dystrophy and response to food consistency

    PubMed Central

    2010-01-01

    Background In wild populations phenotypic differentiation of skeletal structures is influenced by many factors including epigenetic interactions and plastic response to environmental influences, possibly blurring the expression of genetic differences. In contrast, laboratory animals provide the opportunity to separate environmental from genetic effects. The mouse mandible is particularly prone to such plastic variations because bone remodeling occurs late in postnatal ontogeny, in interaction with muscular loading. In order to understand the impact of this process on mandible morphology, we investigated how change in the masticatory function affects the mandible shape, and its pattern of variation. Breeding laboratory mice on food of different consistencies mimicked a natural variation in feeding ecology, whereas mice affected by the murine analogue of the Duchenne muscular dystrophy provided a case of pathological modification of the mastication process. Results Food consistency as well as dystrophy caused significant shape changes in the mouse mandible. Further differences were observed between laboratory strains and between sexes within strains, muscular dystrophy causing the largest morphological change. The directions of the morphological changes due to food consistency and muscular dystrophy were discrepant, despite the fact that both are related to bone remodeling. In contrast, directions of greatest variance were comparable among most groups, and the direction of the change due to sexual dimorphism was parallel to the direction of main variance. Conclusions Bone remodeling is confirmed as an important factor driving mandible shape differences, evidenced by differences due to both the consistency of the food ingested and muscular dystrophy. However, the resulting shape change will depend on how the masticatory function is affected. Muscular dystrophy caused shape changes distributed all over the mandible, all muscles being affected although possibly to a different degree. In contrast, the chewing function was mostly affected when the mice were fed on hard vs. soft food, whereas grinding likely occurred normally; accordingly, shape change was more localized. The direction of greatest variance, however, was remarkably comparable among groups, although we found a residual variance discarding age, sex, and food differences. This suggests that whatever the context in which bone remodeling occurs, some parts of the mandible such as the angular process are more prone to remodeling during late postnatal growth. PMID:20105331

  1. Abnormal expression of laminin suggests disturbance of sarcolemma-extracellular matrix interaction in Japanese patients with autosomal recessive muscular dystrophy deficient in adhalin.

    PubMed Central

    Higuchi, I; Yamada, H; Fukunaga, H; Iwaki, H; Okubo, R; Nakagawa, M; Osame, M; Roberds, S L; Shimizu, T; Campbell, K P

    1994-01-01

    Dystrophin is associated with several novel sarcolemmal proteins, including a laminin-binding extracellular glycoprotein of 156 kD (alpha-dystroglycan) and a transmembrane glycoprotein of 50 kD (adhalin). Deficiency of adhalin characterizes a severe autosomal recessive muscular dystrophy prevalent in Arabs. Here we report for the first time two mongoloid (Japanese) patients with autosomal recessive muscular dystrophy deficient in adhalin. Interestingly, adhalin was not completely absent and was faintly detectable in a patchy distribution along the sarcolemma in our patients. Although the M and B2 subunits of laminin were preserved, the B1 subunit was greatly reduced in the basal lamina surrounding muscle fibers. Our results raise a possibility that the deficiency of adhalin may be associated with the disturbance of sarcolemma-extracellular matrix interaction leading to sarcolemmal instability. Images PMID:8040315

  2. Distal mdx muscle groups exhibiting up-regulation of utrophin and rescue of dystrophin-associated glycoproteins exemplify a protected phenotype in muscular dystrophy

    NASA Astrophysics Data System (ADS)

    Dowling, Paul; Culligan, Kevin; Ohlendieck, Kay

    2002-02-01

    Unique unaffected skeletal muscle fibres, unlike necrotic torso and limb muscles, may pave the way for a more detailed understanding of the molecular pathogenesis of inherited neuromuscular disorders and help to develop new treatment strategies for muscular dystrophies. The sparing of extraocular muscle in Duchenne muscular dystrophy is mostly attributed to the special protective properties of extremely fast-twitching small-diameter fibres, but here we show that distal muscles also represent a particular phenotype that is more resistant to necrosis. Immunoblot analysis of membranes isolated from the well established dystrophic animal model mdx shows that, in contrast to dystrophic limb muscles, the toe musculature exhibits an up-regulation of the autosomal dystrophin homologue utrophin and a concomitant rescue of dystrophin-associated glycoproteins. Thus distal mdx muscle groups provide a cellular system that naturally avoids myofibre degeneration which might be useful in the search for naturally occurring compensatory mechanisms in inherited skeletal muscle diseases.

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

    PubMed

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

    2015-09-01

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

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

    PubMed Central

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

    2015-01-01

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

  5. A highly functional mini-dystrophin/GFP fusion gene for cell and gene therapy studies of Duchenne muscular dystrophy.

    PubMed

    Li, Sheng; Kimura, En; Ng, Rainer; Fall, Brent M; Meuse, Leonard; Reyes, Morayma; Faulkner, John A; Chamberlain, Jeffrey S

    2006-05-15

    A promising approach for treating Duchenne muscular dystrophy (DMD) is by autologous cell transplantation of myogenic stem cells transduced with a therapeutic expression cassette. Development of this method has been hampered by a low frequency of cellular engraftment, the difficulty of tracing transplanted cells, the rapid loss of autologous cells carrying marker genes that are unable to halt muscle necrosis and the difficulty of stable transfer of a large dystrophin gene into myogenic stem cells. We engineered a 5.7 kb miniDys-GFP fusion gene by replacing the dystrophin C-terminal domain (DeltaCT) with an eGFP coding sequence and removing much of the dystrophin central rod domain (DeltaH2-R19). In a transgenic mdx(4Cv) mouse expressing the miniDys-GFP fusion protein under the control of a skeletal muscle-specific promoter, the green fusion protein localized on the sarcolemma, where it assembled the dystrophin-glycoprotein complex and completely prevented the development of dystrophy in transgenic mdx(4Cv) muscles. When myogenic and other stem cells from these mice were transplanted into mdx(4Cv) recipients, donor cells can be readily identified in skeletal muscle by direct green fluorescence or by using antibodies against GFP or dystrophin. In mdx(4Cv) mice reconstituted with bone marrow cells from the transgenic mice, we monitored engraftment in various muscle groups and found the number of miniDys-GFP(+) fibers increased with time. We suggest that these transgenic mdx(4Cv) mice are highly useful for developing autologous cell therapies for DMD. PMID:16595609

  6. Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies

    E-print Network

    Campbell, Kevin P.

    ARTICLE Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O

  7. Reading impairment in Duchenne muscular dystrophy: A pilot study to investigate similarities and differences with developmental dyslexia.

    PubMed

    Astrea, Guja; Pecini, Chiara; Gasperini, Filippo; Brisca, Giacomo; Scutifero, Marianna; Bruno, Claudio; Santorelli, Filippo Maria; Cioni, Giovanni; Politano, Luisa; Chilosi, Anna Maria; Battini, Roberta

    2015-01-01

    Below-average reading performances have been reported in individuals with Duchenne muscular dystrophy (DMD), but literacy problems in these subjects have yet to be characterized. In this study, the presence and characteristics of literacy deficits in boys with DMD were investigated through a comparison with typically developing children and with children affected by developmental dyslexia, with the aim of clarifying whether DMD and developmental dyslexia have overlapping profiles of literacy deficits and whether these deficits are associated, as in children with dyslexia, with impairments in phonological processing and rapid lexical access. The results confirmed the high incidence of literacy problems in boys with DMD and revealed a profile less severe than, but qualitatively similar to, that of Italian children with developmental dyslexia. Both groups showed specific difficulties in reading and writing words and a reduced rapid automatized naming (RAN) speed. This is the first time that a RAN speed deficit has been documented in DMD. Moreover, the boys with DMD and the subgroup of dyslexic children with a previous language delay showed additional deficits in phonological processing. The impairments highlighted in this study could explain the reading difficulties observed in boys with DMD and suggest that there is a need for targeted preschool interventions. PMID:26255617

  8. The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

    PubMed Central

    Bladen, Catherine L; Salgado, David; Monges, Soledad; Foncuberta, Maria E; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Roy, Anna J; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Bariši?, Nina; Brabec, Petr; Lahdetie, Jaana; Walter, Maggie C; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Kimura, En; Koeks, Zaïda; van den Bergen, Janneke C; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Zimowski, Janusz; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Jeannet, Pierre-Yves; Joncourt, Franziska; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A Ay?e; Topalo?lu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V; Martin, Ann S; Peay, Holly L; Bellgard, Matthew I; Kirschner, Jan; Flanigan, Kevin M; Straub, Volker; Bushby, Kate; Verschuuren, Jan; Aartsma-Rus, Annemieke; Béroud, Christophe; Lochmüller, Hanns

    2015-01-01

    Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). PMID:25604253

  9. Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion

    SciTech Connect

    Shashi, V.; Golden, W.L.; Allinson, P.S.

    1996-06-01

    It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion. 50 refs., 7 figs., 1 tab.

  10. Nanopatterned muscle cell patches for enhanced myogenesis and dystrophin expression in a mouse model of muscular dystrophy.

    PubMed

    Yang, Hee Seok; Ieronimakis, Nicholas; Tsui, Jonathan H; Kim, Hong Nam; Suh, Kahp-Yang; Reyes, Morayma; Kim, Deok-Ho

    2014-02-01

    Skeletal muscle is a highly organized tissue in which the extracellular matrix (ECM) is composed of highly-aligned cables of collagen with nanoscale feature sizes, and provides structural and functional support to muscle fibers. As such, the transplantation of disorganized tissues or the direct injection of cells into muscles for regenerative therapy often results in suboptimal functional improvement due to a failure to integrate with native tissue properly. Here, we present a simple method in which biodegradable, biomimetic substrates with precisely controlled nanotopography were fabricated using solvent-assisted capillary force lithography (CFL) and were able to induce the proper development and differentiation of primary mononucleated cells to form mature muscle patches. Cells cultured on these nanopatterned substrates were highly-aligned and elongated, and formed more mature myotubes as evidenced by up-regulated expression of the myogenic regulatory factors Myf5, MyoD and myogenin (MyoG). When transplanted into mdx mice models for Duchenne muscular dystrophy (DMD), the proposed muscle patches led to the formation of a significantly greater number of dystrophin-positive muscle fibers, indicating that dystrophin replacement and myogenesis is achievable in vivo with this approach. These results demonstrate the feasibility of utilizing biomimetic substrates not only as platforms for studying the influences of the ECM on skeletal muscle function and maturation, but also to create transplantable muscle cell patches for the treatment of chronic and acute muscle diseases or injuries. PMID:24290810

  11. MicroRNA-486–dependent modulation of DOCK3/PTEN/AKT signaling pathways improves muscular dystrophy–associated symptoms

    PubMed Central

    Alexander, Matthew S.; Casar, Juan Carlos; Motohashi, Norio; Vieira, Natássia M.; Eisenberg, Iris; Marshall, Jamie L.; Gasperini, Molly J.; Lek, Angela; Myers, Jennifer A.; Estrella, Elicia A.; Kang, Peter B.; Shapiro, Frederic; Rahimov, Fedik; Kawahara, Genri; Widrick, Jeffrey J.; Kunkel, Louis M.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is caused by mutations in the gene encoding dystrophin, which results in dysfunctional signaling pathways within muscle. Previously, we identified microRNA-486 (miR-486) as a muscle-enriched microRNA that is markedly reduced in the muscles of dystrophin-deficient mice (Dmdmdx-5Cv mice) and in DMD patient muscles. Here, we determined that muscle-specific transgenic overexpression of miR-486 in muscle of Dmdmdx-5Cv mice results in reduced serum creatine kinase levels, improved sarcolemmal integrity, fewer centralized myonuclei, increased myofiber size, and improved muscle physiology and performance. Additionally, we identified dedicator of cytokinesis 3 (DOCK3) as a miR-486 target in skeletal muscle and determined that DOCK3 expression is induced in dystrophic muscles. DOCK3 overexpression in human myotubes modulated PTEN/AKT signaling, which regulates muscle hypertrophy and growth, and induced apoptosis. Furthermore, several components of the PTEN/AKT pathway were markedly modulated by miR-486 in dystrophin-deficient muscle. Skeletal muscle–specific miR-486 overexpression in Dmdmdx-5Cv animals decreased levels of DOCK3, reduced PTEN expression, and subsequently increased levels of phosphorylated AKT, which resulted in an overall beneficial effect. Together, these studies demonstrate that stable overexpression of miR-486 ameliorates the disease progression of dystrophin-deficient skeletal muscle. PMID:24789910

  12. Parallel Synthesis of Cell-Penetrating Peptide Conjugates of PMO Toward Exon Skipping Enhancement in Duchenne Muscular Dystrophy

    PubMed Central

    O'Donovan, Liz; Okamoto, Itaru; Arzumanov, Andrey A.; Williams, Donna L.; Deuss, Peter

    2015-01-01

    We describe two new methods of parallel chemical synthesis of libraries of peptide conjugates of phosphorodiamidate morpholino oligonucleotide (PMO) cargoes on a scale suitable for cell screening prior to in vivo analysis for therapeutic development. The methods represent an extension of the SELection of PEPtide CONjugates (SELPEPCON) approach previously developed for parallel peptide-peptide nucleic acid (PNA) synthesis. However, these new methods allow for the utilization of commercial PMO as cargo with both C- and N-termini unfunctionalized. The synthetic methods involve conjugation in solution phase, followed by rapid purification via biotin-streptavidin immobilization and subsequent reductive release into solution, avoiding the need for painstaking high-performance liquid chromatography purifications. The synthesis methods were applied for screening of PMO conjugates of a 16-member library of variants of a 10-residue ApoE peptide, which was suggested for blood-brain barrier crossing. In this work the conjugate library was tested in an exon skipping assay using skeletal mouse mdx cells, a model of Duchene's muscular dystrophy where higher activity peptide-PMO conjugates were identified compared with the starting peptide-PMO. The results demonstrate the power of the parallel synthesis methods for increasing the speed of optimization of peptide sequences in conjugates of PMO for therapeutic screening. PMID:25412073

  13. Implications for Cardiac Function Following Rescue of the Dystrophic Diaphragm in a Mouse Model of Duchenne Muscular Dystrophy

    PubMed Central

    Betts, Corinne A.; Saleh, Amer F.; Carr, Carolyn A.; Muses, Sofia; Wells, Kim E.; Hammond, Suzan M.; Godfrey, Caroline; McClorey, Graham; Woffindale, Caroline; Clarke, Kieran; Wells, Dominic J.; Gait, Michael J.; Wood, Matthew J. A.

    2015-01-01

    Duchenne muscular dystrophy (DMD) is caused by absence of the integral structural protein, dystrophin, which renders muscle fibres susceptible to injury and degeneration. This ultimately results in cardiorespiratory dysfunction, which is the predominant cause of death in DMD patients, and highlights the importance of therapeutic targeting of the cardiorespiratory system. While there is some evidence to suggest that restoring dystrophin in the diaphragm improves both respiratory and cardiac function, the role of the diaphragm is not well understood. Here using exon skipping oligonucleotides we predominantly restored dystrophin in the diaphragm and assessed cardiac function by MRI. This approach reduced diaphragmatic pathophysiology and markedly improved diaphragm function but did not improve cardiac function or pathophysiology, with or without exercise. Interestingly, exercise resulted in a reduction of dystrophin protein and exon skipping in the diaphragm. This suggests that treatment regimens may require modification in more active patients. In conclusion, whilst the diaphragm is an important respiratory muscle, it is likely that dystrophin needs to be restored in other tissues, including multiple accessory respiratory muscles, and of course the heart itself for appropriate therapeutic outcomes. This supports the requirement of a body-wide therapy to treat DMD. PMID:26113184

  14. [Genetic analysis and prenatal diagnosis of Xp deletion in a family with Duchenne/Becker muscular dystrophy].

    PubMed

    He, Jing; Wang, Lei; Tang, Xinhua; Yang, Bicheng; Su, Jie; Jiang, Fuman; Zhu, Baosheng; Zhang, Qi

    2015-10-01

    OBJECTIVE To delineate a deletional mutation of the Dystrophin gene on the short arm of chromosome X in a family affected with Duchenne/Becker muscular dystrophy. METHODS G-banded karyotyping, multiple ligation probe amplification (MLPA), array-based comparative genomic hybridization(array-CGH) and whole genome exon high-throughput sequencing were employed to delineate the mutation in the family. RESULTS GTG banding has demonstrated deletion of the terminal part of the short arm of chromosome X in the fetus. The same deletion was also found in its mother and maternal grandmother. MLPA analysis has revealed removal of exons 52 to 79 of the Dystrophin gene. A 30 Mb deletion in Xp22.33-p21.1 and a 10 Mb duplication in Xq27.2-q28 were identified by array-CGH and whole genome exon high-throughput sequencing. CONCLUSION The Xp deletion has led to deletion of exons 52 to 79 of the Dystrophin gene in the family. The female carriers also had certain features of Turner syndrome due to the same deletion. PMID:26418993

  15. Cognitive dysfunction in the dystrophin-deficient mouse model of Duchenne muscular dystrophy: A reappraisal from sensory to executive processes.

    PubMed

    Chaussenot, Rémi; Edeline, Jean-Marc; Le Bec, Benoit; El Massioui, Nicole; Laroche, Serge; Vaillend, Cyrille

    2015-10-01

    Duchenne muscular dystrophy (DMD) is associated with language disabilities and deficits in learning and memory, leading to intellectual disability in a patient subpopulation. Recent studies suggest the presence of broader deficits affecting information processing, short-term memory and executive functions. While the absence of the full-length dystrophin (Dp427) is a common feature in all patients, variable mutation profiles may additionally alter distinct dystrophin-gene products encoded by separate promoters. However, the nature of the cognitive dysfunctions specifically associated with the loss of distinct brain dystrophins is unclear. Here we show that the loss of the full-length brain dystrophin in mdx mice does not modify the perception and sensorimotor gating of auditory inputs, as assessed using auditory brainstem recordings and prepulse inhibition of startle reflex. In contrast, both acquisition and long-term retention of cued and trace fear memories were impaired in mdx mice, suggesting alteration in a functional circuit including the amygdala. Spatial learning in the water maze revealed reduced path efficiency, suggesting qualitative alteration in mdx mice learning strategy. However, spatial working memory performance and cognitive flexibility challenged in various behavioral paradigms in water and radial-arm mazes were unimpaired. The full-length brain dystrophin therefore appears to play a role during acquisition of associative learning as well as in general processes involved in memory consolidation, but no overt involvement in working memory and/or executive functions could be demonstrated in spatial learning tasks. PMID:26190833

  16. Wild-Type Mouse Models to Screen Antisense Oligonucleotides for Exon-Skipping Efficacy in Duchenne Muscular Dystrophy

    PubMed Central

    Cao, Limin; Han, Gang; Gu, Ben; Yin, HaiFang

    2014-01-01

    A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD), a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO)-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs. PMID:25365558

  17. Different mosaicism frequencies for proximal and distal Duchenne muscular dystrophy (DMD) mutations indicate difference in etiology and recurrence risk

    SciTech Connect

    Passos-Bueno, M.R.; Takata, R.I.; Rapaport, D.; Bakker, E.; Kneppers, A.L.J.; Dunnen, J.T. den; Ommen, J.B. van

    1992-11-01

    In about 65% of the cases of Duchenne muscular dystrophy (DMD) a partial gene deletion or duplication in the dystrophin gene can be detected. These mutations are clustered at two hot spots: 30% at the hot spot in the proximal part of the gene and about 70% at a more distal hot spot. Unexpectedly the authors observed a higher frequency of proximal gene rearrangements among proved germ line' mosaic cases. Of the 24 mosaic cases they are aware of, 19 (79%) have a proximal mutation, while only 5 (21%) have a distal mutation. This finding indicates that the mutations at the two hot spots in the dystrophin gene differ in origin. Independent support for the different mosaicism frequency was found by comparing the mutation spectra observed in isolated cases of DMD and familial cases (ratio 1:1). The authors conclude from these data that proximal deletions most likely occur early in embryonic development, causing them to have a higher chance of becoming familial, while distal deletions occur later and have a higher chance of causing only isolated cases. Finally, the findings have important consequences for the calculation of recurrence-risk estimates according to the site of the deletion: a [open quote]proximal[close quote] new mutant has an increased recurrence risk of approximately 30%, and a [open quote]distal[close quote] new mutant has a decreased recurrence risk of approximately 4%. 28 refs., 2 figs., 2 tabs.

  18. Clinical characteristics of megaconial congenital muscular dystrophy due to choline kinase beta gene defects in a series of 15 patients.

    PubMed

    Haliloglu, Goknur; Talim, Beril; Sel, Cigdem Genc; Topaloglu, Haluk

    2015-11-01

    A new form of congenital muscular dystrophy (CMD) with multisystem involvement and characteristic mitochondrial structural changes, due to choline kinase beta (CHKB) gene defects has been characterized by intellectual disability, autistic features, ichthyosis-like skin changes, and dilated cardiomyopathy. We define the clinical characteristics in 15 patients, from 14 unrelated families with so-called 'megaconial CMD', all having mutations in CHKB. Core clinical phenotype included global developmental delay prominent in gross-motor and language domains, severe intellectual disability (ID), and/or muscle weakness in all cases. Muscle biopsies were equivocally 'megaconial' in all. Other peculiarities were: ichthyosis-like skin changes (n?=?11), increased serum CK levels (n?=?12), microcephaly (n?=?6), dysmorphic facial features (n?=?7), neonatal hypotonia (n?=?3), seizures (n?=?3), epileptiform activity without clinically overt seizures (n?=?2), dilated cardiomyopathy (n?=?2), decreased left ventricular systolic function (n?=?2), congenital heart defects (n?=?3), sensorineural (n?=?1), and conductive hearing loss (n?=?1). Ten patients had cranial neuroimaging (MRI-MRS) study, which was notably normal in all, other than one patient having a decreased choline: creatine peak. Intra-familial variability in clinical expression of the disease is noted in four families. Two siblings from the same family, one presenting with global developmental delay and dilated cardiomyopathy, and the other with ichthyosis, ID and proximal weakness without cardiomyopathy died at the ages of 2 years 1 month, and 7 years 4 months respectively. Evolution was progressive (n?=?13) and static (n?=?2). PMID:26067811

  19. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis

    PubMed Central

    Jones, Takako Iida; Chen, Jennifer C. J.; Rahimov, Fedik; Homma, Sachiko; Arashiro, Patricia; Beermann, Mary Lou; King, Oliver D.; Miller, Jeffrey B.; Kunkel, Louis M.; Emerson, Charles P.; Wagner, Kathryn R.; Jones, Peter L.

    2012-01-01

    Facioscapulohumeral muscular dystrophy (FSHD), the most prevalent myopathy afflicting both children and adults, is predominantly associated with contractions in the 4q35-localized macrosatellite D4Z4 repeat array. Recent studies have proposed that FSHD pathology is caused by the misexpression of the DUX4 (double homeobox 4) gene resulting in production of a pathogenic protein, DUX4-FL, which has been detected in FSHD, but not in unaffected control myogenic cells and muscle tissue. Here, we report the analysis of DUX4 mRNA and protein expression in a much larger collection of myogenic cells and muscle biopsies derived from biceps and deltoid muscles of FSHD affected subjects and their unaffected first-degree relatives. We confirmed that stable DUX4-fl mRNA and protein were expressed in myogenic cells and muscle tissues derived from FSHD affected subjects, including several genetically diagnosed adult FSHD subjects yet to show clinical manifestations of the disease in the assayed muscles. In addition, we report DUX4-fl mRNA and protein expression in muscle biopsies and myogenic cells from genetically unaffected relatives of the FSHD subjects, although at a significantly lower frequency. These results establish that DUX4-fl expression per se is not sufficient for FSHD muscle pathology and indicate that quantitative modifiers of DUX4-fl expression and/or function and family genetic background are determinants of FSHD muscle disease progression. PMID:22798623

  20. The TREAT-NMD DMD Global Database: analysis of more than 7,000 Duchenne muscular dystrophy mutations.

    PubMed

    Bladen, Catherine L; Salgado, David; Monges, Soledad; Foncuberta, Maria E; Kekou, Kyriaki; Kosma, Konstantina; Dawkins, Hugh; Lamont, Leanne; Roy, Anna J; Chamova, Teodora; Guergueltcheva, Velina; Chan, Sophelia; Korngut, Lawrence; Campbell, Craig; Dai, Yi; Wang, Jen; Bariši?, Nina; Brabec, Petr; Lahdetie, Jaana; Walter, Maggie C; Schreiber-Katz, Olivia; Karcagi, Veronika; Garami, Marta; Viswanathan, Venkatarman; Bayat, Farhad; Buccella, Filippo; Kimura, En; Koeks, Zaïda; van den Bergen, Janneke C; Rodrigues, Miriam; Roxburgh, Richard; Lusakowska, Anna; Kostera-Pruszczyk, Anna; Zimowski, Janusz; Santos, Rosário; Neagu, Elena; Artemieva, Svetlana; Rasic, Vedrana Milic; Vojinovic, Dina; Posada, Manuel; Bloetzer, Clemens; Jeannet, Pierre-Yves; Joncourt, Franziska; Díaz-Manera, Jordi; Gallardo, Eduard; Karaduman, A Ay?e; Topalo?lu, Haluk; El Sherif, Rasha; Stringer, Angela; Shatillo, Andriy V; Martin, Ann S; Peay, Holly L; Bellgard, Matthew I; Kirschner, Jan; Flanigan, Kevin M; Straub, Volker; Bushby, Kate; Verschuuren, Jan; Aartsma-Rus, Annemieke; Béroud, Christophe; Lochmüller, Hanns

    2015-04-01

    Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations). PMID:25604253

  1. Towards the finer mapping of facioscapulohumeral muscular dystrophy at 4q35: Construction of a laser microdissection library

    SciTech Connect

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

    1995-06-19

    Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder which has been mapped to the 4q35 region. In order to saturate this distal 4q region with DNA markers, a laser-based chromosomal microdissection and microcloning procedure was used to construct a genomic library from the distal 20% of chromosome 4, derived from a single human metaphase spread. Of the 100 microclones analyzed from this library, 94 clones contained inserts sized from 80-800 bp, with an average size of 340 bp. Less than 20% of these clones hybridized to human repeat sequences. Seventy-two single-copy clones were further characterized by Southern blot hybridization against a DNA panel of somatic cell hybrids, containing various regions of chromosome 4. Forty-two clones mapped to chromosome 4, of which 8 clones mapped into the relevant 4q35 region. Twenty of these chromosome 4-specific clones were screened against {open_quotes}zoo-blots{close_quotes}; 11 clones, of which 3 mapped to 4q35, identified conserved sequences. This is the first report to describe the isolation of potential expressed sequences derived from the FSHD region. These chromosome region-specific microclones will be useful in the construction of the physical map of the region, the positional cloning of potential disease-associated genes, and the identification of additional polymorphic markers from within the distal 4q region. 47 refs., 6 figs., 1 tab.

  2. Comparison of Mutation Profiles in the Duchenne Muscular Dystrophy Gene among Populations: Implications for Potential Molecular Therapies

    PubMed Central

    López-Hernández, Luz Berenice; Gómez-Díaz, Benjamín; Luna-Angulo, Alexandra Berenice; Anaya-Segura, Mónica; Bunyan, David John; Zúñiga-Guzman, Carolina; Escobar-Cedillo, Rosa Elena; Roque-Ramírez, Bladimir; Ruano-Calderón, Luis Angel; Rangel-Villalobos, Héctor; López-Hernández, Julia Angélica; Estrada-Mena, Francisco Javier; García, Silvia; Coral-Vázquez, Ramón Mauricio

    2015-01-01

    Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations; Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p < 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations. PMID:25761239

  3. Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients.

    PubMed

    Magri, Francesca; Del Bo, Roberto; D'Angelo, Maria Grazia; Sciacco, Monica; Gandossini, Sandra; Govoni, Alessandra; Napoli, Laura; Ciscato, Patrizia; Fortunato, Francesco; Brighina, Erika; Bonato, Sara; Bordoni, Andreina; Lucchini, Valeria; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Comi, Giacomo Pietro

    2012-11-01

    Limb-girdle muscular dystrophy (LGMD) 2L, caused by mutations in the anoctamin 5 (ANO5) gene, is the third most common LGMD in Northern and Central Europe, where the c.191dupA mutation causes the majority of cases. We evaluated data from 228 Italian LGMD patients to determine the prevalence of LGMD2L and the c.191dupA mutation, and to describe the clinical, muscle biopsy, and magnetic resonance imaging findings in these patients. Forty-three patients who lacked molecular diagnosis were studied for ANO5 mutations, and four novel mutations were found in three probands. Only one proband carried the c.191dupA mutation, which was compound heterozygous with c.2516T>G. Two probands were homozygous for the c.1627dupA and c.397A>T mutations, respectively, while a fourth proband had a compound heterozygous status (c.220C>T and c.1609T>C). Therefore occurrence and molecular epidemiology of LGMD2L in this Italian cohort differed from those observed in other European countries. ANO5 mutations accounted for ?2% of our sample. Affected patients exhibited benign progression with variable onset and an absence of cardiac and respiratory impairment; muscle biopsy generally showed mild signs, except when performed on the quadriceps muscles; MRI showed predominant involvement of the posterior thigh. Overall these common clinical, morphological and imaging findings could be useful in differential diagnosis. PMID:22742934

  4. Independent living with Duchenne muscular dystrophy and home mechanical ventilation in areas of Japan with insufficient national welfare services

    PubMed Central

    Yamaguchi, Miku; Suzuki, Machiko

    2013-01-01

    In Japan, there is no national 24-hour home care system for people with severe impairments. Despite this fact, a small number of people with Duchenne muscular dystrophy on home mechanical ventilation pursue independent living. Therefore, our aim was to better understand the process by which these individuals arrived at this goal for independence (i.e., choosing to live at home in Japan instead of in special sanatoriums that provide sufficient support and care). Twenty-one participants were interviewed in 2011 and 2013. The interviews were recorded, transcribed, and analysed following a grounded theory approach. These individuals placed particular emphasis on their personal choice regarding where and how they live as well as on whom they depend. Therefore, the core element underlying participants’ goals for independent living was self-reliant independency. To improve their social inclusion, the strategies used by the participants to retain their autonomy in an underdeveloped Japanese welfare system by establishing relationships with people in their communities can prevent them from experiencing social isolation. This could serve as an example to their counterparts in other countries. PMID:23981723

  5. Fecal Transplant for Treatment of Toxic Megacolon Associated With Clostridium Difficile Colitis in a Patient With Duchenne Muscular Dystrophy.

    PubMed

    Yu, Shipeng; Abdelkarim, Ahmed; Nawras, Ali; Hinch, Bryan Thomas; Mbaso, Chimaka; Valavoor, Shahul; Safi, Fadi; Hammersley, Jeffrey; Tang, Jianlin; Assaly, Ragheb

    2014-05-22

    Clostridium difficile (C diff) colitis infection is the most common cause of nosocomial infectious diarrhea and the prevalence is increasing worldwide. Toxic megacolon is a severe complication of C diff colitis associated with high mortality. Gastrointestinal (GI) comorbidity and impaired smooth muscle contraction are risk factors for the development of C diff-associated toxic megacolon. We present a case of fulminant C diff colitis with toxic megacolon in a patient with Duchenne muscular dystrophy (DMD) in the intensive care unit. C diff colitis was diagnosed by clinical presentation and positive C diff DNA amplification test (polymerase chain reaction). The impairment of GI tract due to DMD predisposes these patients to severe C diff infection and toxic megacolon, as observed in this case report. For the same reason, the recovery of GI function in these patients can be prolonged. While surgery was conducted for relieving the pressure from toxic megacolon, fecal microbiota transplantation through colonoscopy resulted in successful resolution of the C diff symptoms, although the recovery is prolonged due to DMD. PMID:24858336

  6. Becker Muscular Dystrophy (BMD) caused by duplication of exons 3-6 of the dystrophin gene presenting as dilated cardiomyopathy

    SciTech Connect

    Tsai, A.C.; Allingham-Hawkins, D.J.; Becker, L.

    1994-09-01

    X-linked dilated cardiomyopathy (XLCM) is a progressive myocardial disease presenting with congestive heart failure in teenage males without clinical signs of skeletal myopathy. Tight linkage of XLCM to the DMD locus has been demonstrated; it has been suggested that, at least in some families, XLCM is a {open_quotes}dystrophinopathy.{close_quotes} We report a 14-year-old boy who presented with acute heart failure due to dilated cardiomyopathy. He had no history of muscle weakness, but physical examination revealed pseudohypertrophy of the calf muscles. He subsequently received a heart transplantation. Family history was negative. Serum CK level at the time of diagnosis was 10,416. Myocardial biopsy showed no evidence of carditis. Dystrophin staining of cardiac and skeletal muscle with anti-sera to COOH and NH{sub 2}termini showed a patchy distribution of positivity suggestive of Becker muscular dystrophy. Analysis of 18 of the 79 dystrophin exons detected a duplication that included exons 3-6. The proband`s mother has an elevated serum CK and was confirmed to be a carrier of the same duplication. A mutation in the muscle promotor region of the dystrophin gene has been implicated in the etiology of SLCM. However, Towbin et al. (1991) argued that other 5{prime} mutations in the dystrophin gene could cause selective cardiomyopathy. The findings in our patient support the latter hypothesis. This suggests that there are multiple regions in the dystrophin gene which, when disrupted, can cause isolated dilated cardiomyopathy.

  7. New splicing mutation in the choline kinase beta (CHKB) gene causing a muscular dystrophy detected by whole-exome sequencing.

    PubMed

    Oliveira, Jorge; Negrão, Luís; Fineza, Isabel; Taipa, Ricardo; Melo-Pires, Manuel; Fortuna, Ana Maria; Gonçalves, Ana Rita; Froufe, Hugo; Egas, Conceição; Santos, Rosário; Sousa, Mário

    2015-06-01

    Muscular dystrophies (MDs) are a group of hereditary muscle disorders that include two particularly heterogeneous subgroups: limb-girdle MD and congenital MD, linked to 52 different genes (seven common to both subgroups). Massive parallel sequencing technology may avoid the usual stepwise gene-by-gene analysis. We report the whole-exome sequencing (WES) analysis of a patient with childhood-onset progressive MD, also presenting mental retardation and dilated cardiomyopathy. Conventional sequencing had excluded eight candidate genes. WES of the trio (patient and parents) was performed using the ion proton sequencing system. Data analysis resorted to filtering steps using the GEMINI software revealed a novel silent variant in the choline kinase beta (CHKB) gene. Inspection of sequence alignments ultimately identified the causal variant (CHKB:c.1031+3G>C). This splice site mutation was confirmed using Sanger sequencing and its effect was further evaluated with gene expression analysis. On reassessment of the muscle biopsy, typical abnormal mitochondrial oxidative changes were observed. Mutations in CHKB have been shown to cause phosphatidylcholine deficiency in myofibers, causing a rare form of CMD (only 21 patients reported). Notwithstanding interpretative difficulties that need to be overcome before the integration of WES in the diagnostic workflow, this work corroborates its utility in solving cases from highly heterogeneous groups of diseases, in which conventional diagnostic approaches fail to provide a definitive diagnosis. PMID:25740612

  8. Menstrual Blood-derived Cells Confer Human Dystrophin Expression in the Murine Model of Duchenne Muscular Dystrophy via Cell Fusion and Myogenic Transdifferentiation

    PubMed Central

    Cui, Chang-Hao; Uyama, Taro; Miyado, Kenji; Terai, Masanori; Kyo, Satoru; Kiyono, Tohru

    2007-01-01

    Duchenne muscular dystrophy (DMD), the most common lethal genetic disorder in children, is an X-linked recessive muscle disease characterized by the absence of dystrophin at the sarcolemma of muscle fibers. We examined a putative endometrial progenitor obtained from endometrial tissue samples to determine whether these cells repair muscular degeneration in a murine mdx model of DMD. Implanted cells conferred human dystrophin in degenerated muscle of immunodeficient mdx mice. We then examined menstrual blood–derived cells to determine whether primarily cultured nontransformed cells also repair dystrophied muscle. In vivo transfer of menstrual blood–derived cells into dystrophic muscles of immunodeficient mdx mice restored sarcolemmal expression of dystrophin. Labeling of implanted cells with enhanced green fluorescent protein and differential staining of human and murine nuclei suggest that human dystrophin expression is due to cell fusion between host myocytes and implanted cells. In vitro analysis revealed that endometrial progenitor cells and menstrual blood–derived cells can efficiently transdifferentiate into myoblasts/myocytes, fuse to C2C12 murine myoblasts by in vitro coculturing, and start to express dystrophin after fusion. These results demonstrate that the endometrial progenitor cells and menstrual blood–derived cells can transfer dystrophin into dystrophied myocytes through cell fusion and transdifferentiation in vitro and in vivo. PMID:17314403

  9. 'Laminopathies': A wide spectrum of human diseases

    SciTech Connect

    Worman, Howard J. . E-mail: hjw14@columbia.edu; Bonne, Gisele

    2007-06-10

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

  10. Early-progressive dilated cardiomyopathy in a family with Becker muscular dystrophy related to a novel frameshift mutation in the dystrophin gene exon 27.

    PubMed

    Tsuda, Takeshi; Fitzgerald, Kristi; Scavena, Mena; Gidding, Samuel; Cox, Mary O; Marks, Harold; Flanigan, Kevin M; Moore, Steven A

    2015-03-01

    We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11 years; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAinsGG), in which seven base pairs are deleted and two are inserted. Although this predicts an amino-acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both the siblings developed progressive HF secondary to early-onset DCM. In addition, their 7-year-old nephew with delayed gross motor development, mild proximal muscle weakness and markedly elevated serum creatine kinase level (>13?000?IU?l(-1)) at 16 months was recently demonstrated to have the familial DMD mutation. Here, we report a novel genotype of BMD with early-onset DCM and progressive lethal HF during early adolescence. PMID:25537791

  11. Toward fully automated genotyping: Allele assignment, pedigree construction, phase determination, and recombination detection in Duchenne muscular dystrophy

    SciTech Connect

    Perlin, M.W.; Burks, M.B.; Hoop, R.C.; Hoffman, E.P.

    1994-10-01

    Human genetic maps have made quantum leaps in the past few years, because of the characterization of >2,000 CA dinucleotide repeat loci: these PCR-based markers offer extraordinarily high PIC, and within the next year their density is expected to reach intervals of a few centimorgans per marker. These new genetic maps open new avenues for disease gene research, including large-scale genotyping for both simple and complex disease loci. However, the allele patterns of many dinucleotide repeat loci can be complex and difficult to interpret, with genotyping errors a recognized problem. Furthermore, the possibility of genotyping individuals at hundreds or thousands of polymorphic loci requires improvements in data handling and analysis. The automation of genotyping and analysis of computer-derived haplotypes would remove many of the barriers preventing optimal use of dense and informative dinucleotide genetic maps. Toward this end, we have automated the allele identification, genotyping, phase determinations, and inheritance consistency checks generated by four CA repeats within the 2.5-Mbp, 10-cM X-linked dystrophin gene, using fluorescein-labeled multiplexed PCR products analyzed on automated sequencers. The described algorithms can deconvolute and resolve closely spaced alleles, despite interfering stutter noise; set phase in females; propagate the phase through the family; and identify recombination events. We show the implementation of these algorithms for the completely automated interpretation of allele data and risk assessment for five Duchenne/Becker muscular dystrophy families. The described approach can be scaled up to perform genome-based analyses with hundreds or thousands of CA-repeat loci, using multiple fluorophors on automated sequencers. 16 refs., 5 figs., 1 tab.

  12. Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging.

    PubMed

    Tandon, Animesh; Jefferies, John L; Villa, Chet R; Hor, Kan N; Wong, Brenda L; Ware, Stephanie M; Gao, Zhiqian; Towbin, Jeffrey A; Mazur, Wojciech; Fleck, Robert J; Sticka, Joshua J; Benson, D Woodrow; Taylor, Michael D

    2015-04-01

    Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies. PMID:25702278

  13. Protein and DNA analysis for the prenatal diagnosis of alpha2-laminin-deficient congenital muscular dystrophy.

    PubMed

    Yamamoto, Lydia U; Gollop, Thomas R; Naccache, Nadyr F; Pavanello, Rita C M; Zanoteli, Edmar; Zatz, Mayana; Vainzof, Mariz

    2004-09-01

    Congenital muscular dystrophies (CMD) are characterized by neonatal hypotonia and/or artrogriposis associated with a dystrophic muscle biopsy. The CMD1A form is caused by a deficiency of the alpha2 chain of laminin 2 (LAMA2 gene at 6q2), a protein present in the basal lamina of muscle fibers, in Schwann cells, epidermis, and in fetal trophoblastic tissue. This allows its study for prenatal diagnosis in the chorionic villous (CV), which was performed in a family with one deceased affected CMD1A child. Immunohistochemical analysis of the CV using antibodies against the C- and N-terminal domains of the alpha2-laminin protein showed a normal positive labeling for both antibodies in the "at-risk" CV, which did not differ from the normal control CV. The integrity of the CV membrane was confirmed through the analysis with antibodies against alpha1, beta1, and gamma1 laminins. DNA study using markers flanking the 6q2 region showed that the affected patient and the "at-risk" fetus did not share the same haplotype. Therefore, the fetus was considered normal through both methodologies, which was confirmed after the birth of a clinically normal male baby. As the LAMA2 gene is very large and the spectrum of mutations causing disease is wide, the analysis of the protein in muscle biopsy has been largely used for the diagnosis. Besides, the possibility to detect it in the chorionic villous, mainly using positive markers, also offers a powerful tool for prenatal diagnosis. PMID:15322429

  14. Use of epitope libraries to identify exon-specific monoclonal antibodies for characterization of altered dystrophins in muscular dystrophy

    SciTech Connect

    Nguyen thi Man; Morris, G.E. )

    1993-06-01

    The majority of mutations in Xp21-linked muscular dystrophy (MD) can be identified by PCR or Southern blotting, as deletions or duplications of groups of exons in the dystrophin gene, but it is not always possible to predict how much altered dystrophin, if any, will be produced. Use of exon-specific monoclonal antibodies (mAbs) on muscle biopsies from MD patients can, in principle, provide information on both the amount of altered dystrophin produced and, when dystrophin is present, the nature of the genetic deletion or point mutation. For this purpose, mAbs which recognize regions of dystrophin encoded by known exons and whose binding is unaffected by the absence of adjacent exons are required. To map mAbs to specific exons, random [open quotes]libraries[close quotes] of expressed dystrophin fragments were created by cloning DNAseI digestion fragments of a 4.3-kb dystrophin cDNA into a pTEX expression vector. The libraries were then used to locate the epitopes recognized by 48 mAbs to fragments of 25--60 amino acids within the 1,434-amino-acid dystrophin fragment used to produce the antibodies. This is sufficiently detailed to allow further refinement by using synthetic peptides and, in many cases, to identify the exon in the DMD (Duchenne MD) gene which encodes the epitope. To illustrate their use in dystrophin analysis, a Duchenne patient with a frameshift deletion of exons 42 and 43 makes a truncated dystrophin encoded by exons 1--41, and the authors now show that this can be detected in the sarcolemma by mAbs up to and including those specific for exon 41 epitopes but not by mAbs specific for exon 43 or later epitopes. 38 refs., 2 figs., 4 tabs.

  15. Sequence analysis of the breakpoint regions of an X;5 translocation in a female with Duchenne muscular dystrophy

    SciTech Connect

    Bakel, I. van; Holt, S.; Craig, I.

    1995-08-01

    X;autosome translocations in females with Duchenne muscular dystrophy (DMD) provide an opportunity to study the mechanisms responsible for chromosomal rearrangements that occur in the germ line. We describe here a detailed molecular analysis of the translocation breakpoints of an X;autosome reciprocal translocation, t(X;5) (p21;q31.1), in a female with DMD. Cosmid clones that contained the X-chromosome breakpoint region were identified, and subclones that hybridized to the translocation junction fragment in restriction digests of the patient`s DNA were isolated and sequenced. Primers designed from the X-chromosomal sequence were used to obtain the junction fragments on the der(X) and the der(5) by inverse PCR. The resultant clones were also cloned and sequenced, and this information used to isolate the chromosome 5 breakpoint region. Comparison of the DNA sequences of the junction fragments with those of the breakpoint regions on chromosomes X and 5 revealed that the translocation arose by nonhomologous recombination with an imprecise reciprocal exchange. Four and six base pairs of unknown origin are inserted at the exchange points of the der(X) and der(5), respectively, and three nucleotides are deleted from the X-chromosome sequence. Two features were found that may have played a role in the generation of the translocation. These were (1) a repeat motif with an internal homopyrimidine stretch 10 bp upstream from the X-chromosome breakpoint and (2) a 9-bp sequence of 78% homology located near the breakpoints on chromosomes 5 and X. 32 refs., 4 figs., 2 tabs.

  16. Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice

    PubMed Central

    Sanchez, Benjamin; Li, Jia; Yim, Sung; Pacheck, Adam; Widrick, Jeffrey J.; Rutkove, Seward B.

    2015-01-01

    Objectives Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx). Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters. Methods Eight wild-type (wt) and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg?1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed. Results As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p < 0.001 respectively) and muscle mass (25% p < 0.05 and 22% p < 0.001, respectively). The Cole impedance parameters in treated wt mice, showed a 24% lower central frequency (p < 0.05) and 19% higher resistance ratio (p < 0.05); no significant differences were observed in the mdx mice. These differences were consistent with those seen in maximum isometric force, which was greater in the wt animals (p < 0.05 at > 70 Hz), but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01). Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively). Conclusions Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials. PMID:26485280

  17. Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients.

    PubMed

    Hathout, Yetrib; Marathi, Ramya L; Rayavarapu, Sree; Zhang, Aiping; Brown, Kristy J; Seol, Haeri; Gordish-Dressman, Heather; Cirak, Sebahattin; Bello, Luca; Nagaraju, Kanneboyina; Partridge, Terry; Hoffman, Eric P; Takeda, Shin'ichi; Mah, Jean K; Henricson, Erik; McDonald, Craig

    2014-12-15

    It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-?52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials. PMID:25027324

  18. Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients

    PubMed Central

    Hathout, Yetrib; Marathi, Ramya L.; Rayavarapu, Sree; Zhang, Aiping; Brown, Kristy J.; Seol, Haeri; Gordish-Dressman, Heather; Cirak, Sebahattin; Bello, Luca; Nagaraju, Kanneboyina; Partridge, Terry; Hoffman, Eric P.; Takeda, Shin'ichi; Mah, Jean K.; Henricson, Erik; McDonald, Craig

    2014-01-01

    It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-?52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials. PMID:25027324

  19. Duchenne/Becker muscular dystrophy: A report on clinical, biochemical, and genetic study in Gujarat population, India

    PubMed Central

    Rao, Mandava V.; Sindhav, Gaurang M.; Mehta, Jitendra J.

    2014-01-01

    Objective: In India, various groups have studied different regions to find out deletion pattern of dystrophin gene. We have investigated its deletion pattern among Duchenne/Becker muscular dystrophy (D/BMD) patients across Gujarat. Moreover, in this study we also correlate the same with reading frame rule. However, we too consider various clinicopathological features to establish as adjunct indices when deletion detection fails. Materials and Methods: In this pilot study, a total of 88 D/BMD patients consulting at our centers in Gujarat, India were included. All patients were reviewed on basis of their clinical characteristics, tested by three primer sets of 10-plex, 9-plex, and 7-plex polymerase chain reaction (PCR) for genetic analysis; whereas, biochemical indices were measured using automated biochemical analyzers. Results: The diagnosis of D/BMD was confirmed by multiplex-PCR (M-PCR) in D/BMD patients. A number of 65 (73.86%) out of 88 patients showed deletion in dystrophin gene. The exon 50 (58.46%) was the most frequent deletion found in our study. The mean age of onset of DMD and BMD was 4.09 ± 0.15 and 7.14 ± 0.55 years, respectively. In patients, mean creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and myoglobin levels were elevated significantly (P < 0.05) in comparison to controls. Addition to CPK, LDH and myoglobin are good adjunct when deletion detection failed. These data are further in accordance with world literature when correlated with frame rule. Conclusion: The analysis has been carried out for the first time for a total of 88 D/BMD patients particularly from Gujarat, India. More research is essential to elucidate specific mutation pattern in association with management and therapies of proband. PMID:25221400

  20. Long-term systemic myostatin inhibition via liver-targeted gene transfer in golden retriever muscular dystrophy.

    PubMed

    Bish, Lawrence T; Sleeper, Meg M; Forbes, Sean C; Morine, Kevin J; Reynolds, Caryn; Singletary, Gretchen E; Trafny, Dennis; Pham, Jennifer; Bogan, Janet; Kornegay, Joe N; Vandenborne, Krista; Walter, Glenn A; Sweeney, H Lee

    2011-12-01

    Duchenne muscular dystrophy (DMD) is a lethal, X-linked recessive disease affecting 1 in 3,500 newborn boys for which there is no effective treatment or cure. One novel strategy that has therapeutic potential for DMD is inhibition of myostatin, a negative regulator of skeletal muscle mass that may also promote fibrosis. Therefore, our goal in this study was to evaluate systemic myostatin inhibition in the golden retriever model of DMD (GRMD). GRMD canines underwent liver-directed gene transfer of a self-complementary adeno-associated virus type 8 vector designed to express a secreted dominant-negative myostatin peptide (n = 4) and were compared with age-matched, untreated GRMD controls (n = 3). Dogs were followed with serial magnetic resonance imaging (MRI) for 13 months to assess cross-sectional area and volume of skeletal muscle, then euthanized so that tissue could be harvested for morphological and histological analysis. We found that systemic myostatin inhibition resulted in increased muscle mass in GRMD dogs as assessed by MRI and confirmed at tissue harvest. We also found that hypertrophy of type IIA fibers was largely responsible for the increased muscle mass and that reductions in serum creatine kinase and muscle fibrosis were associated with long-term myostatin inhibition in GRMD. This is the first report describing the effects of long-term, systemic myostatin inhibition in a large-animal model of DMD, and we believe that the simple and effective nature of our liver-directed gene-transfer strategy makes it an ideal candidate for evaluation as a novel therapeutic approach for DMD patients. PMID:21787232

  1. Evaluation of Post-Contrast Myocardial T1 in Duchenne Muscular Dystrophy Using Cardiac Magnetic Resonance Imaging

    PubMed Central

    Soslow, Jonathan H.; Damon, Bruce M.; Saville, Benjamin R.; Lu, Zengqi; Burnette, W Bryan; Lawson, Mark A.; Parra, David A.; Sawyer, Douglas B.; Markham, Larry W.

    2015-01-01

    Objectives Perform a retrospective pilot study to evaluate the potential of myocardial T1 in assessment of Duchenne muscular dystrophy (DMD) cardiomyopathy. Background Early identification of DMD cardiac disease, particularly myocardial fibrosis, would allow earlier therapy, potentially improving outcomes. Shortened myocardial T1 measured by cardiac MRI (CMR) is a measure of cardiac fibrosis that may be detected before late gadolinium enhancement (LGE). We hypothesized that the post-contrast T1 obtained from the Look-Locker sequences (T1LL), an easily obtainable surrogate of myocardial T1, would be abnormally shortened in DMD compared with controls. Methods T1LL measurement was performed on 21 DMD subjects and 11 controls; to account for individual variations in gadolinium distribution, myocardial T1LL was divided by blood pool T1LL, deriving T1LL ratios. Results DMD subjects had shorter mean T1LL ratio than controls (1.42 vs 1.72, p<0.001). Subset analyses in DMD subjects with normal LVEF and without LGE also demonstrated significantly shorter T1LL ratio (?0.28, p<0.001 and ?0.25, p=0.028). Conclusions Post-contrast T1LL ratio is abnormally shortened in DMD compared with controls, even in DMD patients with otherwise normal CMRs. The application of more aggressive therapy for those with shorter T1LL may favorably alter morbidity and improve mortality associated with DMD cardiomyopathy. These data suggest that further, prospective evaluation of myocardial T1 will be of benefit to patients with DMD. PMID:25070387

  2. In Silico Screening Based on Predictive Algorithms as a Design Tool for Exon Skipping Oligonucleotides in Duchenne Muscular Dystrophy

    PubMed Central

    Echigoya, Yusuke; Mouly, Vincent; Garcia, Luis; Yokota, Toshifumi; Duddy, William

    2015-01-01

    The use of antisense ‘splice-switching’ oligonucleotides to induce exon skipping represents a potential therapeutic approach to various human genetic diseases. It has achieved greatest maturity in exon skipping of the dystrophin transcript in Duchenne muscular dystrophy (DMD), for which several clinical trials are completed or ongoing, and a large body of data exists describing tested oligonucleotides and their efficacy. The rational design of an exon skipping oligonucleotide involves the choice of an antisense sequence, usually between 15 and 32 nucleotides, targeting the exon that is to be skipped. Although parameters describing the target site can be computationally estimated and several have been identified to correlate with efficacy, methods to predict efficacy are limited. Here, an in silico pre-screening approach is proposed, based on predictive statistical modelling. Previous DMD data were compiled together and, for each oligonucleotide, some 60 descriptors were considered. Statistical modelling approaches were applied to derive algorithms that predict exon skipping for a given target site. We confirmed (1) the binding energetics of the oligonucleotide to the RNA, and (2) the distance in bases of the target site from the splice acceptor site, as the two most predictive parameters, and we included these and several other parameters (while discounting many) into an in silico screening process, based on their capacity to predict high or low efficacy in either phosphorodiamidate morpholino oligomers (89% correctly predicted) and/or 2’O Methyl RNA oligonucleotides (76% correctly predicted). Predictions correlated strongly with in vitro testing for sixteen de novo PMO sequences targeting various positions on DMD exons 44 (R2 0.89) and 53 (R2 0.89), one of which represents a potential novel candidate for clinical trials. We provide these algorithms together with a computational tool that facilitates screening to predict exon skipping efficacy at each position of a target exon. PMID:25816009

  3. Upper Limb Strength and Function Changes during a One-Year Follow-Up in Non-Ambulant Patients with Duchenne Muscular Dystrophy: An Observational Multicenter Trial

    PubMed Central

    Seferian, Andreea Mihaela; Moraux, Amélie; Annoussamy, Mélanie; Canal, Aurélie; Decostre, Valérie; Diebate, Oumar; Le Moing, Anne-Gaëlle; Gidaro, Teresa; Deconinck, Nicolas; Van Parys, Frauke; Vereecke, Wendy; Wittevrongel, Sylvia; Mayer, Michèle; Maincent, Kim; Desguerre, Isabelle; Thémar-Noël, Christine; Cuisset, Jean-Marie; Tiffreau, Vincent; Denis, Severine; Jousten, Virginie; Quijano-Roy, Susana; Voit, Thomas; Hogrel, Jean-Yves; Servais, Laurent

    2015-01-01

    Introduction Upper limb evaluation of patients with Duchenne Muscular Dystrophy is crucially important to evaluations of efficacy of new treatments in non-ambulant patients. In patients who have lost ambulation, there are few validated and informative outcome measures. In addition, longitudinal data demonstrating sensitivity to clinical evolution of outcome measures over short-term periods are lacking. Patients and Methods We report here the results of a one-year multicenter study using specifically designed tools to assess grip, pinch strength, and hand function in wheelchair-bound patients. Our study assessed 53 non-ambulant patients with Duchenne muscular dystrophy aged 17.1 ± 4.8 years (range: 9 – 28.1 years). The average Brooke functional score of these patients was 4.6 ± 1.1. The average forced vital capacity was 44.5% predicted and 19 patients used non-invasive ventilation. Patients were assessed at baseline, 6 months, and one year using the Motor Function Measure and innovative devices (namely the MyoSet composed of MyoGrip, MyoPinch, and MoviPlate). Results Our study confirmed preliminary data previously reported regarding feasibility of use and of reliability of the MyoSet and the correlation at baseline between distal strength and clinical outcomes such as FVC, Brooke score, age, and duration since loss of ambulation. A significant correlation was observed between the distal upper limb strength and clinical variables. The sensitive dynamometers (MyoGrip and MyoPinch) and MoviPlate captured a 12-month change in non-ambulant Duchenne muscular dystrophy patients of all ages. Trial Registration ClinicalTrials.gov NCT00993161 NCT00993161 PMID:25643053

  4. Limb-girdle muscular dystrophy and Miyoshi myopathy in an aboriginal Canadian kindred map to LGMD2B and segregate with the same haplotype

    SciTech Connect

    Weiler, T.; Nylen, E.; Wrogemann, K.

    1996-10-01

    We report the results of our investigations of a large, inbred, aboriginal Canadian kindred with nine muscular dystrophy patients. The ancestry of all but two of the carrier parents could be traced to a founder couple, seven generations back. Seven patients presented with proximal myopathy consistent with limb girdle-type muscular dystrophy (LGMD), whereas two patients manifested predominantly distal wasting and weakness consistent with Miyoshi myopathy (distal autosomal recessive muscular dystrophy) (MM). Age at onset of symptoms, degree of creatine kinase elevation, and muscle histology were similar in both phenotypes. Segregation of LGMD/MM is consistent with autosomal recessive inheritance, and the putative locus is significantly linked (LOD scores >3.0) to six marker loci that span the region of the LGMD2B locus on chromosome 2p. Our initial hypothesis that the affected patients would all be homozygous by descent for microsatellite markers surrounding the disease locus was rejected. Rather, two different core haplotypes, encompassing a 4-cM region spanned by D2S291-D2S145-D2S286, segregated with the disease, indicating that there are two mutant alleles of independent origin in this kindred. There was no association, however, between the two different haplotypes and clinical variability; they do not distinguish between the LGMD and MM phenotypes. Thus, we conclude that LGMD and MM in our population are caused by the same mutation in LGMD2B and that additional factors, both genetic and nongenetic, must contribute to the clinical phenotype. 37 refs., 2 figs., 2 tabs.

  5. Retinal telangiectasis detected during a vision screening examination in a child with hearing loss led to the diagnosis of facioscapulohumeral muscular dystrophy.

    PubMed

    Lee, Gregory D; Chen, Vicki M; Barnes, Alexander C; Goldman, Darin R; Duker, Jay S

    2014-06-01

    A 2-year-old girl with congenital sensorineural hearing loss was found to have retinal exudation and subretinal fluid in her left eye. Further investigation revealed leaking retinal telangiectasias in her left eye and extensive areas of peripheral retinal nonperfusion in both eyes. A clinical diagnosis of facioscapulohumeral muscular dystrophy (FSHD) was confirmed by genetic testing. The patient was followed with serial intraoperative optical coherence tomography (OCT) scans, which demonstrated subretinal fluid in the macula and its subsequent resolution after treatment. She underwent 6 rounds of panretinal photocoagulation and 2 injections of intravitreal bevacizumab, which resolved the subretinal fluid and exudates. PMID:24924285

  6. The Rag2–Il2rb–Dmd– Mouse: a Novel Dystrophic and Immunodeficient Model to Assess Innovating Therapeutic Strategies for Muscular Dystrophies

    PubMed Central

    Vallese, Denis; Negroni, Elisa; Duguez, Stéphanie; Ferry, Arnaud; Trollet, Capucine; Aamiri, Ahmed; Vosshenrich, Christian AJ; Füchtbauer, Ernst-Martin; Di Santo, James P; Vitiello, Libero; Butler-Browne, Gillian; Mouly, Vincent

    2013-01-01

    The development of innovative therapeutic strategies for muscular dystrophies, particularly cell-based approaches, is still a developing field. Although positive results have been obtained in animal models, they have rarely been confirmed in patients and resulted in very limited clinical improvements, suggesting some specificity in humans. These findings emphasized the need for an appropriate animal model (i.e., immunodeficient and dystrophic) to investigate in vivo the behavior of transplanted human myogenic stem cells. We report a new model, the Rag2–Il2rb–Dmd– mouse, which lacks T, B, and NK cells, and also carries a mutant Dmd allele that prevents the production of any dystrophin isoform. The dystrophic features of this new model are comparable with those of the classically used mdx mouse, but with the total absence of any revertant dystrophin positive fiber. We show that Rag2–Il2rb–Dmd– mice allow long-term xenografts of human myogenic cells. Altogether, our findings indicate that the Rag2–Il2rb–Dmd– mouse represents an ideal model to gain further insights into the behavior of human myogenic stem cells in a dystrophic context, and can be used to assess innovative therapeutic strategies for muscular dystrophies. PMID:23975040

  7. Molecular evidence that the p55 gene is not responsible for either of two Xq28-linked disorders: Emery-Deifuss muscular dystrophy and dyskeratosis congenita

    SciTech Connect

    Metzenberg, A.B.; Pan, Y.; Das, S.; Gitschier, J. ); Pai, G.S. )

    1994-05-01

    Mapping studies have indicated that over two dozen genetic diseases lie on Xq28, the distal long arm of the X chromosome. In most cases the responsible gene has not yet been isolated. Most of these diseases occur at low frequency, and together with small family sizes and the lack of associated cytogenetic aberrations, this characteristic has made isolation of the genes difficult. Identification of the genes responsible for inherited disorders should eventually lead to a greater understanding of biochemical and developmental pathways. We and others are attempting to find these genes by examining genes that are candidates by virtue of their map location. One candidate is the Xq28-linked gene MPP-1, which encodes the p55 protein. In this study, we asked whether mutations in the p55 gene are present in patients affected with the Xq28-linked disorders dyskeratosis congenita and Emergy-Dreifuss muscular dystrophy. The p55 cDNA is [approx]2 kb in length. The strategy for mutation detection in this sequence involved reverse transciption (RT)-PCR amplification of patient and control cDNA, yielding five sets of overlapping fragments, each set consisting of 400 bp, followed by SSCP analysis of each fragment. In no case was a true mutation in the p55 gene discovered. Therefore, it is highly unlikely that mutations in the p55 gene are responsible for any cases of dyskeratosis congenita or Emergy-Dreifuss muscular dystrophy.

  8. Modeling and study of the mechanism of dilated cardiomyopathy using induced pluripotent stem cells derived from individuals with Duchenne muscular dystrophy

    PubMed Central

    Lin, Bo; Li, Yang; Han, Lu; Kaplan, Aaron D.; Ao, Ying; Kalra, Spandan; Bett, Glenna C. L.; Rasmusson, Randall L.; Denning, Chris; Yang, Lei

    2015-01-01

    ABSTRACT Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene (DMD), and is characterized by progressive weakness in skeletal and cardiac muscles. Currently, dilated cardiomyopathy due to cardiac muscle loss is one of the major causes of lethality in late-stage DMD patients. To study the molecular mechanisms underlying dilated cardiomyopathy in DMD heart, we generated cardiomyocytes (CMs) from DMD and healthy control induced pluripotent stem cells (iPSCs). DMD iPSC-derived CMs (iPSC-CMs) displayed dystrophin deficiency, as well as the elevated levels of resting Ca2+, mitochondrial damage and cell apoptosis. Additionally, we found an activated mitochondria-mediated signaling network underlying the enhanced apoptosis in DMD iPSC-CMs. Furthermore, when we treated DMD iPSC-CMs with the membrane sealant Poloxamer 188, it significantly decreased the resting cytosolic Ca2+ level, repressed caspase-3 (CASP3) activation and consequently suppressed apoptosis in DMD iPSC-CMs. Taken together, using DMD patient-derived iPSC-CMs, we established an in vitro model that manifests the major phenotypes of dilated cardiomyopathy in DMD patients, and uncovered a potential new disease mechanism. Our model could be used for the mechanistic study of human muscular dystrophy, as well as future preclinical testing of novel therapeutic compounds for dilated cardiomyopathy in DMD patients. PMID:25791035

  9. Screening Duchenne and Becker muscular dystrophy patients for deletions in 30 exons of the dystrophin gene by three-multiplex PCR

    SciTech Connect

    Risch, N. )

    1992-09-01

    Deletion mutations of the dystrophin gene may cause either the severe Duchenne muscular dystrophy (DMD) or the milder, allelic Becker muscular dystrophy (BMD) and are clustered in two high-frequency-deletion regions (HFDRs) located, respectively, 500 kb and 1,200 kb downstream from the 5[prime] end of the gene. Three PCR reactions described allowed the analysis of a total of 30 exons and led, to the identification of three additional deletions involving the following exons: (a) 42 only, (b) 28-42, and (c) 16 only, none of which were detected with the two original multiplex reactions. Therefore, the three modified multiplexes detected 95 of the 96 deletions identified among the 152 patients studied so far by using Southern analysis and cDNA probes. The only deletion that remained undetected with this system involves exons 22-25 and generates the junction fragment described elsewhere. The percentage of deletion mutations among DMS/BMD patients amounts to 63%, which is in agreement with similar estimates from other laboratories. When field-inversion gel electrophoresis is coupled to Southern analysis, the detection rate of deletion and duplication mutations reaches 65%.

  10. Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease.

    PubMed

    Palmio, Johanna; Jonson, Per Harald; Evilä, Anni; Auranen, Mari; Straub, Volker; Bushby, Kate; Sarkozy, Anna; Kiuru-Enari, Sari; Sandell, Satu; Pihko, Helena; Hackman, Peter; Udd, Bjarne

    2015-11-01

    DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T?>?A (p.F91I) and c.271T?>?C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation. PMID:26338452

  11. Dynamic distribution of muscle-specific calpain in mice has a key role in physical-stress adaptation and is impaired in muscular dystrophy

    PubMed Central

    Ojima, Koichi; Kawabata, Yukiko; Nakao, Harumi; Nakao, Kazuki; Doi, Naoko; Kitamura, Fujiko; Ono, Yasuko; Hata, Shoji; Suzuki, Hidenori; Kawahara, Hiroyuki; Bogomolovas, Julius; Witt, Christian; Ottenheijm, Coen; Labeit, Siegfried; Granzier, Henk; Toyama-Sorimachi, Noriko; Sorimachi, Michiko; Suzuki, Koichi; Maeda, Tatsuya; Abe, Keiko; Aiba, Atsu; Sorimachi, Hiroyuki

    2010-01-01

    Limb-girdle muscular dystrophy type 2A (LGMD2A) is a genetic disease that is caused by mutations in the calpain 3 gene (CAPN3), which encodes the skeletal muscle–specific calpain, calpain 3 (also known as p94). However, the precise mechanism by which p94 functions in the pathogenesis of this disease remains unclear. Here, using p94 knockin mice (termed herein p94KI mice) in which endogenous p94 was replaced with a proteolytically inactive but structurally intact p94:C129S mutant protein, we have demonstrated that stretch-dependent p94 distribution in sarcomeres plays a crucial role in the pathogenesis of LGMD2A. The p94KI mice developed a progressive muscular dystrophy, which was exacerbated by exercise. The exercise-induced muscle degeneration in p94KI mice was associated with an inefficient redistribution of p94:C129S in stretched sarcomeres. Furthermore, the p94KI mice showed impaired adaptation to physical stress, which was accompanied by compromised upregulation of muscle ankyrin-repeat protein-2 and hsp upon exercise. These findings indicate that the stretch-induced dynamic redistribution of p94 is dependent on its protease activity and essential to protect muscle from degeneration, particularly under conditions of physical stress. Furthermore, our data provide direct evidence that loss of p94 protease activity can result in LGMD2A and molecular insight into how this could occur. PMID:20592470

  12. A slowly progressive form of limb-girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics

    PubMed Central

    Al-Zaidy, Samiah A; Malik, Vinod; Kneile, Kelley; Rosales, Xiomara Q; Gomez, Ana Maria; Lewis, Sarah; Hashimoto, Sayaka; Gastier-Foster, Julie; Kang, Peter; Darras, Basil; Kunkel, Louis; Carlo, Jose; Sahenk, Zarife; Moore, Steven A; Pyatt, Robert; Mendell, Jerry R

    2015-01-01

    Limb-girdle muscular dystrophy type 2C (LGMD2C) is considered one of the severe forms of childhood-onset muscular dystrophy. The geographical distribution of founder mutations in the SGCG gene has a prominent effect on the prevalence of LGMD2C in certain populations. The aim of this study was to confirm the hypothesis that the c.787G>A (p.E263K) mutation in the SGCG gene is a founder mutation among Puerto Rican Hispanics and to characterize the associated clinical and immunohistochemical phenotype. Genotyping of six polymorphic microsatellite markers internal to (D13S232) and flanking (D13S175, D13S292, D13S787, D13S1243, D13S283) the SGCG gene was performed on four unrelated Puerto Rican patients with LGMD2C. Preserved ambulation to the second decade of life was observed in at least two subjects. Immunostaining of skeletal muscle demonstrated absence of ?-sarcoglycan in all affected subjects. Two markers, D13S232 and D13S292, were highly informative and confirmed that all four families share the haplotype of the mutant allele. Our findings confirm that the E263K missense mutation in the SGCG gene is a founder mutation in Puerto Rican Hispanics. A slowly progressive disease course with prolonged preservation of ambulation can be seen in association with this mutation, providing evidence for phenotypic variability. PMID:25802879

  13. PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.

    PubMed

    Guicheney, P; Vignier, N; Zhang, X; He, Y; Cruaud, C; Frey, V; Helbling-Leclerc, A; Richard, P; Estournet, B; Merlini, L; Topaloglu, H; Mora, M; Harpey, J P; Haenggeli, C A; Barois, A; Hainque, B; Schwartz, K; Tomé, F M; Fardeau, M; Tryggvason, K

    1998-03-01

    Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy. PMID:9541105

  14. [Diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy: experience and recommendations for Mexico. Administración del Patrimonio de la Beneficencia Pública. Asociación de Distrofia Muscular de Occidente].

    PubMed

    Vázquez-Cárdenas, Norma A; Ibarra-Hernández, Francisco; López-Hernández, Luz B; Escobar-Cedillo, Rosa E; Ruano-Calderón, Luis A; Gómez-Díaz, Benjamín; García-Calderón, Noemí; Carriedo-Dávila, M Fernanda; Rojas-Hurtado, Liliana G; Luna-Padrón, Emilia; Coral-Vázquez, Ramón M

    2013-11-16

    Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The long-term steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy. PMID:24203668

  15. The L-arginine/NO pathway and homoarginine are altered in Duchenne muscular dystrophy and improved by glucocorticoids.

    PubMed

    Hörster, Irina; Weigt-Usinger, Katharina; Carmann, Christina; Chobanyan-Jürgens, Kristine; Köhler, Cornelia; Schara, Ulrike; Kayacelebi, Arslan Arinc; Beckmann, Bibiana; Tsikas, Dimitrios; Lücke, Thomas

    2015-09-01

    The L-arginine/nitric oxide (L-Arg/NO) pathway regulates endothelial function and may play an important role in the pathogenesis of Duchenne muscular dystrophy (DMD). Yet, this pathway is poorly investigated in children suffering from DMD. Endothelial dysfunction can affect the perfusion of contracting muscles, thus leading to ischemia and hypoxia. In the present study, we tested the hypothesis that reduced NO production due to elevated synthesis of N (G),N (G)-dimethyl-L-arginine (asymmetric dimethylarginine, ADMA), an endogenous inhibitor of NO synthesis, is a possible pathophysiological mechanism for progressive intramuscular muscle ischemia and disturbed endothelial function in children with DMD. Given the possible antagonistic action of homoarginine (hArg) on ADMA, we also analyzed this amino acid. We investigated 55 male patients with DMD and 54 healthy male controls (HC; aged 11.9 ± 4.8 vs. 11.1 ± 4.9 years, mean ± SD). Urinary creatinine and metabolites of the L-Arg/NO pathway were measured in plasma and urine by GC-MS or GC-MS/MS. Urine levels of ADMA and its major urinary metabolite dimethylamine (DMA), nitrite and nitrate (P < 0.001 for all) and hArg (P = 0.002) were significantly higher in DMD patients compared to HC, while the urinary DMA/ADMA molar ratio was lower (P = 0.002). In plasma, nitrate (P < 0.001), hArg (P = 0.002) and the hArg/ADMA ratio (P < 0.001) were lower in DMD than in HC. In plasma, ADMA (631 ± 119 vs. 595 ± 129 nM, P = 0.149), arginine and nitrite did not differ between DMD and HC. In DMD, positive correlations between ADMA, DMA or nitrate excretion and the stage of disease (according to Vignos and Thompson) were found. In DMD patients on steroid medication, lower concentrations of ADMA in plasma, and of DMA, ADMA, nitrate and hArg in urine were observed compared to non-treated patients. The L-Arg/NO pathway is impaired in DMD patients, with the disease progression being clinically negatively correlated with the extent of impairment. One of the underlying mechanisms in DMD may involve insufficient antagonism of ADMA by hArg. Steroids, but not creatine supplementation, seems to improve the L-Arg/NO pathway in DMD. PMID:26066683

  16. Myofibrillar disruption and RNA-binding protein aggregation in a mouse model of limb-girdle muscular dystrophy 1D.

    PubMed

    Bengoechea, Rocio; Pittman, Sara K; Tuck, Elizabeth P; True, Heather L; Weihl, Conrad C

    2015-12-01

    Limb-girdle muscular dystrophy type 1D (LGMD1D) is caused by dominantly inherited missense mutations in DNAJB6, an Hsp40 co-chaperone. LGMD1D muscle has rimmed vacuoles and inclusion bodies containing DNAJB6, Z-disc proteins and TDP-43. DNAJB6 is expressed as two isoforms; DNAJB6a and DNAJB6b. Both isoforms contain LGMD1D mutant residues and are expressed in human muscle. To identify which mutant isoform confers disease pathogenesis and generate a mouse model of LGMD1D, we evaluated DNAJB6 expression and localization in skeletal muscle as well as generating DNAJB6 isoform specific expressing transgenic mice. DNAJB6a localized to myonuclei while DNAJB6b was sarcoplasmic. LGMD1D mutations in DNAJB6a or DNAJB6b did not alter this localization in mouse muscle. Transgenic mice expressing the LGMD1D mutant, F93L, in DNAJB6b under a muscle-specific promoter became weak, had early lethality and developed muscle pathology consistent with myopathy after 2 months; whereas mice expressing the same F93L mutation in DNAJB6a or overexpressing DNAJB6a or DNAJB6b wild-type transgenes remained unaffected after 1 year. DNAJB6b localized to the Z-disc and DNAJB6b-F93L expressing mouse muscle had myofibrillar disorganization and desmin inclusions. Consistent with DNAJB6 dysfunction, keratin 8/18, a DNAJB6 client also accumulated in DNAJB6b-F93L expressing mouse muscle. The RNA-binding proteins hnRNPA1 and hnRNPA2/B1 accumulated and co-localized with DNAJB6 at sarcoplasmic stress granules suggesting that these proteins maybe novel DNAJB6b clients. Similarly, hnRNPA1 and hnRNPA2/B1 formed sarcoplasmic aggregates in patients with LGMD1D. Our data support that LGMD1D mutations in DNAJB6 disrupt its sarcoplasmic function suggesting a role for DNAJB6b in Z-disc organization and stress granule kinetics. PMID:26362252

  17. "The Things That Are inside of You Are Horrible": Children and Young Men with Duchenne Muscular Dystrophy Talk about the Impact of Living with a Long-Term Condition

    ERIC Educational Resources Information Center

    Abbott, David; Carpenter, John

    2015-01-01

    Duchenne muscular dystrophy (DMD) is an inherited, progressive and life-limiting neuromuscular disease that affects boys. During their lives, they experience a series of medical and surgical interventions. Research reported in this paper took place in England with 37 young men living with DMD and their families and explored their experiences of…

  18. Myotonic Muscular Dystrophy

    MedlinePLUS

    ... the DNA expansion leads to expanded strands of RNA and that these RNA expansions have toxic effects on cells. In addition, ... chromosome 3 (or the expanded genetic material called RNA that’s made from this DNA) so that they ...

  19. Muscular Dystrophy (MD)

    MedlinePLUS

    ... form of MD. Treatment may include physical therapy, respiratory therapy, speech therapy, orthopedic appliances used for support, and ... to dying muscle cells, and antibiotics to fight respiratory infections. Some ... therapy and assistive technology. Some patients may need assisted ...

  20. Meaning of Muscular Dystrophy

    MedlinePLUS

    ... That Help Feelings Q&A Movies & More Quizzes Games Kids' Medical Dictionary En Español What Other Kids Are Reading Girls and Puberty Boys and Puberty Video: Am I Normal? (Girls and Puberty) Movie: Digestive ...

  1. Duchenne muscular dystrophy

    MedlinePLUS

    ... effects of these treatments have not been proven. Stem cells and gene therapy may be used in the future. Activity is encouraged. Inactivity (such as bedrest) can make the muscle disease worse. Physical therapy may help to maintain ...

  2. Alternative isoform regulation in myotonic dystrophy

    E-print Network

    Wang, Eric T. (Eric Tzy-shi)

    2012-01-01

    Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, affecting more than 1 in 8000 individuals globally. The symptoms of DM are multi-systemic and include myotonia, severe muscle wasting, ...

  3. Abnormal short-latency synaptic plasticity in the motor cortex of subjects with Becker muscular dystrophy: a rTMS study.

    PubMed

    Golaszewski, Stefan; Schwenker, Kerstin; Bergmann, Jürgen; Brigo, Francesco; Christova, Monica; Trinka, Eugen; Nardone, Raffaele

    2016-01-01

    We used repetitive transcranial magnetic stimulation (rTMS) to further investigate motor cortex excitability in 13 patients with Becker muscular dystrophy (BMD), six of them with slight mental retardation. RTMS delivered at 5Hz frequency and suprathreshold intensity progressively increases the size of motor evoked potentials (MEPs) in healthy subjects; the rTMS-induced facilitation of MEPs was significantly reduced in the BMD patients mentally retarded or classified as borderline when compared with age-matched control subjects and the BMD patients with normal intelligence. The increase in the duration of the cortical silent period was similar in both patient groups and controls. These findings suggest an altered cortical short-term synaptic plasticity in glutamate-dependent excitatory circuits within the motor cortex in BMD patients with intellectual disabilities. RTMS studies may shed new light on the physiological mechanisms of cortical involvement in dystrophinopathies. PMID:26562314

  4. Limb-Girdle Muscular Dystrophy Type 2A Resulting From c.C479G and c.G1818A Mutations in the Calpain-3 Gene.

    PubMed

    Ramos, Edwardo; Pardo, Sherly; Mas Rodríguez, Manuel F; Vélez, John

    2015-12-01

    Limb-Girdle Muscular Dystrophy type 2A (LGMD2A) is an autosomal recessive disorder characterized by progressive weakness of proximal muscles. Here, we describe a patient with clinical features consistent with LGMD2A who harbors 2 rare changes in the CAPN3 gene sequence of unknown clinical significance. Mechanisms by which these 2 mutations could affect the protein are discussed. The c.C479G mutation seems to affect the proteolytic domain of calpain-3. Whereas the novel mutation c.G1818A seems to affect mRNA translation of the protein region involved in titin binding. We strongly believe that these genomic variants in CAPN3 are indeed deleterious and thus are currently misclassified. Since LGMD2 is considered a disorder of autosomal recessive inheritance, further population studies involving the molecular characterization of symptomatic patients must be performed as well as in vitro studies to ascertain the functional effects of these specific variants. PMID:26583491

  5. Novel Use of Tolvaptan in a Pediatric Patient With Congestive Heart Failure Due to Duchenne Muscular Dystrophy and Congenital Adrenal Hyperplasia

    PubMed Central

    Sami, Sarah A.; Moffett, Brady S.; Karlsten, Melissa L.; Cabrera, Antonio G.; Price, Jack F.; Dreyer, William J.; Denfield, Susan W.

    2015-01-01

    Successful management of hyponatremia in heart failure patients requires a multifaceted approach in order to preserve end-organ function. We describe the novel use of a selective vasopressin receptor antagonist, tolvaptan, for management of hyponatremia in a 17-year-old Caucasian male with severe Duchenne muscular dystrophy, congestive heart failure (CHF), and congenital adrenal hyperplasia. The medical history was significant for recurrent admissions for hyponatremia secondary to adrenal crises, which was also exacerbated by his CHF. After initiation of tolvaptan and its extended administration, he had no further hyponatremia-related admissions and no adverse reactions. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed. PMID:26472954

  6. Revisiting the dystrophin-ATP connection: How half a century of research still implicates mitochondrial dysfunction in Duchenne Muscular Dystrophy aetiology.

    PubMed

    Timpani, Cara A; Hayes, Alan; Rybalka, Emma

    2015-12-01

    Duchenne Muscular Dystrophy (DMD) is a fatal neuromuscular disease that is characterised by dystrophin-deficiency and chronic Ca(2+)-induced skeletal muscle wasting, which currently has no cure. DMD was once considered predominantly as a metabolic disease due to the myriad of metabolic insufficiencies evident in the musculature, however this aspect of the disease has been extensively ignored since the discovery of dystrophin. The collective historical and contemporary literature documenting these metabolic nuances has culminated in a series of studies that importantly demonstrate that metabolic dysfunction exists independent of dystrophin expression and a mild disease phenotype can be expressed even in the complete absence of dystrophin expression. Targeting and supporting metabolic pathways with anaplerotic and other energy-enhancing supplements has also shown therapeutic value. We explore the hypothesis that DMD is characterised by a systemic mitochondrial impairment that is central to disease aetiology rather than a secondary pathophysiological consequence of dystrophin-deficiency. PMID:26365249

  7. The identification of point mutations in Duchenne muscular dystrophy patients by using reverse-transcription PCR and the protein truncation test

    SciTech Connect

    Gardner, R.J.; Bobrow, M.; Roberts, R.G.

    1995-08-01

    The protein truncation test (PTT) is a mutation-detection method that monitors the integrity of the open reading frame (ORF). More than 60% of cases of Duchenne muscular dystrophy (DMD) result from gross frameshifting deletions in the dystrophin gene that are detectable by multiplex PCR system. It has become apparent that virtually all of the remaining DMD mutations also disrupt the translational reading frame, making the PTT a logical next step toward a comprehensive strategy for the identification of all DMD mutations. We report here a pilot study involving 22 patients and describe the mutations characterized. These constitute 12 point mutations or small insertions/deletions and 4 gross rearrangements. We also have a remaining five patients in whom there does not appear to be mutation in the ORF. We believe that reverse-transcription-PCR/PTT is an efficient method by which to screen for small mutations in DMD patients with no deletion. 29 refs., 2 figs., 3 tabs.

  8. Novel Use of Tolvaptan in a Pediatric Patient With Congestive Heart Failure Due to Duchenne Muscular Dystrophy and Congenital Adrenal Hyperplasia.

    PubMed

    Sami, Sarah A; Moffett, Brady S; Karlsten, Melissa L; Cabrera, Antonio G; Price, Jack F; Dreyer, William J; Denfield, Susan W; Jeewa, Aamir

    2015-01-01

    Successful management of hyponatremia in heart failure patients requires a multifaceted approach in order to preserve end-organ function. We describe the novel use of a selective vasopressin receptor antagonist, tolvaptan, for management of hyponatremia in a 17-year-old Caucasian male with severe Duchenne muscular dystrophy, congestive heart failure (CHF), and congenital adrenal hyperplasia. The medical history was significant for recurrent admissions for hyponatremia secondary to adrenal crises, which was also exacerbated by his CHF. After initiation of tolvaptan and its extended administration, he had no further hyponatremia-related admissions and no adverse reactions. The complexity of this combination of conditions is presented, and the efficacy of the drug and the rationale behind the treatment approach is discussed. PMID:26472954

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

    PubMed

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

    2015-04-01

    The regeneration of muscle tissue has been achieved using multipotent mesenchymal stem cells in mouse models of injured skeletal muscle. In the present study, the utility of multipotent human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in the treatment of Becker muscular dystrophy (BMD), a genetic disease where muscle tissue fails to regenerate, was examined in members from a pedigree affected by BMD. The disease status was evaluated in 4 affected pedigree members (II1, II2, II3 and III2; aged 50, 46, 42 and 6 years, respectively). The transplantation of the hUC?MSCs (performed on 3 patients, I2, II3 and III2) was performed by infusion with an intravenous drip over a 30?min period, and the patients were evaluated at 1, 3, 4 and 12 weeks following the procedure. The evaluation was based on physical characteristics, as well as on molecular testing for serum creatine kinase (CK) and lactate dehydrogenase (LDH) levels and a histological examination of muscle biopsies. The patients suffered no adverse reactions in response to the transplantation of the hUC?MSCs. At 1 week following transplantation all 3 patients showed improvement in the muscle force of the limbs, muscle size and daily activity. The walking gait of patient III2 had improved by 1 week post-transplantation and reached a normal status by 12 weeks. Serum CK and LDH levels were decreased relative to the baseline levels. A histological examination of muscle biopsies displayed no obvious tissue regeneration. In conclusion, the treatment of patients with BMD using hUC-MSCs was safe and of therapeutic benefit that lasted for up to 12 weeks. hUC-MSCs are, therefore, a potential cell therapy-based treatment option for patients with muscular dystrophies. PMID:25647308

  10. A phase I trial of adeno-associated virus serotype 1-?-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C.

    PubMed

    Herson, Serge; Hentati, Faycal; Rigolet, Aude; Behin, Anthony; Romero, Norma B; Leturcq, France; Laforêt, Pascal; Maisonobe, Thierry; Amouri, Rim; Haddad, Hafedh; Audit, Muriel; Montus, Marie; Masurier, Carole; Gjata, Bernard; Georger, Christophe; Cheraï, Mustapha; Carlier, Pierre; Hogrel, Jean-Yves; Herson, Ariane; Allenbach, Yves; Lemoine, François M; Klatzmann, David; Sweeney, H Lee; Mulligan, Richard C; Eymard, Bruno; Caizergues, Didier; Voït, Thomas; Benveniste, Olivier

    2012-02-01

    ?-Sarcoglycanopathy or limb girdle muscular dystrophy type 2C is an untreatable disease caused by autosomal recessively inherited mutations of the ?-sarcoglycan gene. Nine non-ambulatory patients (two males, seven females, mean age 27?years; range 16-38?years) with del525T homozygous mutation of the ?-sarcoglycan gene and no ?-sarcoglycan immunostaining on muscle biopsy were divided into three equal groups to receive three escalating doses of an adeno-associated virus serotype 1 vector expressing the human ?-sarcoglycan gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3?×?10(9) viral genomes in 100?µl, the second group received a single injection of 1.5?×?10(10) viral genomes in 100?µl, and the third group received three simultaneous 100-µl injections at the same site, delivering a total dose of 4.5?×?10(10) viral genomes. No serious adverse effects occurred during 6?months of follow-up. All nine patients became adeno-associated virus serotype 1 seropositive and one developed a cytotoxic response to the adeno-associated virus serotype 1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed ?-sarcoglycan expression in all three patients who received the highest dose (4.7-10.5% positively stained fibres), while real-time polymerase chain reaction detected ?-sarcoglycan messenger RNA. In one patient, ?-sarcoglycan protein was detected by western blot. For two other patients who received the low and intermediate doses, discrete levels of ?-sarcoglycan expression (<1% positively stained fibres) were also detectable. Expression of ?-sarcoglycan protein can be induced in patients with limb girdle muscular dystrophy type 2C by adeno-associated virus serotype 1 gene transfer, with no serious adverse effects. PMID:22240777

  11. Early Detection of Myocardial Bioenergetic Deficits: A 9.4 Tesla Complete Non Invasive 31P MR Spectroscopy Study in Mice with Muscular Dystrophy

    PubMed Central

    Cui, Weina; Jang, Albert; Zhang, Pengyuan; Thompson, Brian; Townsend, DeWayne; Metzger, Joseph M.; Zhang, Jianyi

    2015-01-01

    Background Duchenne muscular dystrophy (DMD) is the most common fatal form of muscular dystrophy characterized by striated muscle wasting and dysfunction. Patients with DMD have a very high incidence of heart failure, which is increasingly the cause of death in DMD patients. We hypothesize that in the in vivo system, the dystrophic cardiac muscle displays bioenergetic deficits prior to any functional or structural deficits. To address this we developed a complete non invasive 31P magnetic resonance spectroscopy (31P MRS) approach to measure myocardial bioenergetics in the heart in vivo. Methods and Results Six control and nine mdx mice at 5 months of age were used for the study. A standard 3D -Image Selected In vivo Spectroscopy (3D-ISIS) sequence was used to provide complete gradient controlled three-dimensional localization for heart 31P MRS. These studies demonstrated dystrophic hearts have a significant reduction in PCr/ATP ratio compare to normal (1.59±0.13 vs 2.37±0.25, p<0.05). Conclusion Our present study provides the direct evidence of significant cardiac bioenergetic deficits in the in vivo dystrophic mouse. These data suggest that energetic defects precede the development of significant hemodynamic or structural changes. The methods provide a clinically relevant approach to use myocardial energetics as an early marker of disease in the dystrophic heart. The new method in detecting the in vivo bioenergetics abnormality as an early non-invasive marker of emerging dystrophic cardiomyopathy is critical in management of patients with DMD, and optimized therapies aimed at slowing or reversing the cardiomyopathy. PMID:26262993

  12. AB032. Mutation spectrum in the dystrophin gene disclosed by multiplex ligation-dependent probe amplification in 181 Vietnamese Duchenne/Becker muscular dystrophy patients

    PubMed Central

    Tran, Van Khanh; Do, Ngoc Hai; Tran, Thinh Huy; Ta, Minh Hieu; Tuan-Pham, Le Anh; Chi, Dung Vu; Khanh, Nguyen Ngoc; Ta, Van Thanh; Matsuo, Masafumi

    2015-01-01

    Duchenne/Becker muscular dystrophy (DMD/BMD) the most common X-linked muscular dystrophy is caused by mutation in dystrophin gene. Deletion and duplication in the dystrophin gene account for 60-70% of mutation. Multiplex ligation-dependent probe amplification (MLPA) is the most powerful and convenient method to identify exon deletions or duplications in the dystrophin gene because of its overall gene coverage. The present investigation was designed to detect mutation in the dystrophin gene in 181 unrelated Vietnamese Becker/Duchenne patients using MLPA analysis. Among the 181 cases, deletions and duplications encompassing one or more exons were identified in 105 (58%) or 12 (6.6%) cases, respectively. Deletions were found to cluster in the proximal (14.3%) and central hotspot regions (72.4%); 14% were observed to have gross deletions and 1.2% had deletion out of hotspot regions (exon 61-67). The deletion patterns were categorized into 48 patterns. Deletion of exon 48-50 or 45-50 where the most common pattern was deletion of exon 48-50, which was found in 11 cases (10%). Single-exon deletion was found in 14 cases (13%) by MLPA. Further examination disclosed that one of them was not an exon deletion but a single-nucleotide change (c.2227C > T) leading to a nonsense mutation. Outliers from the reading frame rule were 11 DMD (10.4%). Remarkably, 25 and 14 cases were found treatable by exon 51 and 53 skipping, respectively. From these findings, the largest mutation database of Vietnam dystrophinopathy was established.

  13. Differential roles of MMP-9 in early and late stages of dystrophic muscles in a mouse model of Duchenne muscular dystrophy.

    PubMed

    Shiba, Naoko; Miyazaki, Daigo; Yoshizawa, Takahiro; Fukushima, Kazuhiro; Shiba, Yuji; Inaba, Yuji; Imamura, Michihiro; Takeda, Shin'ichi; Koike, Kenichi; Nakamura, Akinori

    2015-10-01

    Matrix metalloprotease (MMP)-9 is an endopeptidase associated with the pathogenesis of Duchenne muscular dystrophy (DMD). The precise function of MMP-9 in DMD has not been elucidated to date. We investigated the effect of genetic ablation of MMP-9 in the mdx mouse model (mdx/Mmp9(-/-)). At the early disease stage, the muscles of mdx/Mmp9(-/-) mice showed reduced necrosis and neutrophil invasion, accompanied by down-regulation of chemokine MIP-2. In addition, muscle regeneration was enhanced, which coincided with increased macrophage infiltration and upregulation of MCP-1, and resulted in increased muscle strength. The mdx/Mmp9(-/-) mice also displayed accelerated upregulation of osteopontin expression in skeletal muscle at the acute onset phase of dystrophy. However, at a later disease stage, the mice exhibited muscle growth impairment through altered expression of myogenic factors, and increased fibroadipose tissue. These results showed that MMP-9 might have multiple functions during disease progression. Therapy targeting MMP-9 may improve muscle pathology and function at the early disease stage, but continuous inhibition of this protein may result in the accumulation of fibroadipose tissues and reduced muscle strength at the late disease stage. PMID:26170062

  14. Physical map, marker order, and YAC contig of an 11 cM region of 5q31 involved in myeloid leukemia and limb girdle muscular dystrophy

    SciTech Connect

    Horrigan, S.K.; Ramesar, R.S.; Yamaoka, L.H.

    1994-09-01

    Chromosome band 5q31 contains a large number of disease genes including those for limb girdle muscular dystrophy 1 (LGM1), an autosomal dominant form of hereditary deafness, corneal dystrophies, as well as a putative tumor suppressor gene involved in myelodysplastic syndrome/acute myeloid leukemia. To facilitate the identification of these genes, we prepared a YAC contig spanning the region from IL9 to D5S434. This was done with reference to a composite map consisting of markers which had been ordered physically by FISH, which was integrated with CEPH and CHLC markers that had been ordered genetically. These markers were used to screen the CEPH megaYAC library, and also to extract YACs from the CEPH-genethon physical map data base. YAC overlaps were used to confirm marker order and localize additional markers to the region. This YAC contig spans approximately 11 cM and contains 24 polymorphic microsatellite markers, 12 non-polymorphic STS markers and 6 known genes (including IL9, CDC25, EGR1, CD14, FGF1, GRL). A total of 51 YACs were isolated using these markers. YAC overlaps were identified by STS content and Alu-PCR hybridization. Thirty nine YACs fall within the minimum deleted region involved in acute myeloid leukemia (IL9 to D5S166 interval); these YACs were further used to order 10 microsatellite and 8 STS markers that had been regionally localized. This map and the new markers will be used to facilitate the search for candidate genes for the myeloid leukemia tumor suppressor and for LGM1.

  15. Substitution of a conserved cysteine-996 in a cysteine-rich motif of the laminin {alpha}2-chain in congenital muscular dystrophy with partial deficiency of the protein

    SciTech Connect

    Nissinen, M.; Xu Zhang; Tryggvason, K.

    1996-06-01

    Congenital muscular dystrophies (CMDs) are autosomal recessive muscle disorders of early onset. Approximately half of CMD patients present laminin {alpha}2-chain (merosin) deficiency in muscle biopsies, and the disease locus has been mapped to the region of the LAMA2 gene (6q22-23) in several families. Recently, two nonsense mutations in the laminin {alpha}2-chain gene were identified in CMD patients exhibiting complete deficiency of the laminin {alpha}2-chain in muscle biopsies. However, a subset of CMD patients with linkage to LAMA2 show only partial absence of the laminin {alpha}2-chain around muscle fibers, by immunocytochemical analysis. In the present study we have identified a homozygous missense mutation in the {alpha}2-chain gene of a consanguineous Turkish family with partial laminin {alpha}2-chain deficiency. The T{r_arrow}C transition at position 3035 in the cDNA sequence results in a Cys996{r_arrow}Arg substitution. The mutation that affects one of the conserved cysteine-rich repeats in the short arm of the laminin {alpha}2-chain should result in normal synthesis of the chain and in formation and secretion of a heterotrimeric laminin molecule. Muscular dysfunction is possibly caused either by abnormal disulfide cross-links and folding of the laminin repeat, leading to the disturbance of an as yet unknown binding function of the laminin {alpha}2-chain and to shorter half-life of the muscle-specific laminin-2 and laminin-4 isoforms, or by increased proteolytic sensitivity, leading to truncation of the short arm. 42 refs., 7 figs.

  16. How the magnitude of clinical severity and recurrence risk affects reproductive decisions in adult males with different forms of progressive muscular dystrophy.

    PubMed Central

    Eggers, S; Zatz, M

    1998-01-01

    The reproductive history of 177 male patients affected with Becker (BMD) (n=69), limb-girdle (LGMD) (n=54), and facioscapulohumeral (FSHMD) (n=54) muscular dystrophy (MD) was analysed according to severity of the disease (BMD>LGMD>FSHMD) and magnitude of recurrence risk (RR) (high for FSHMD, intermediate for BMD, and low for LGMD). Additionally, 62 male patients were interviewed on psychosocial issues, in order to disentangle the factors influencing reproductive decisions among patients affected with MD. Among male adults, significantly more FSHMD than LGMD or BMD patients were married and had children. Age specific reproductive outcome was 0.31-0.32 for BMD, 0.51-0.62 for LGMD, and 0.58-1.02 for FSHMD, reflecting the influence of the disease's severity. High RRs did not significantly diminish reproduction after genetic counselling or correlate with less prospective desire for children. Instead, early onset, severity of the disease, and past reproductive history were found to diminish reproductive outcome after genetic counselling, and prospective family planning was also found to be influenced by past reproductive history as well as by emotional/sexual dysfunction with the opposite sex. PMID:9541101

  17. Identical de novo mutation at the D4F104S1 locus in monozygotic male twins affected by facioscapulohumeral muscular dystrophy (FSHD) with different clinical expression.

    PubMed Central

    Tupler, R; Barbierato, L; Memmi, M; Sewry, C A; De Grandis, D; Maraschio, P; Tiepolo, L; Ferlini, A

    1998-01-01

    Facioscapulohumeral muscular dystrophy (FSHD) is a progressive hereditary neuromuscular disorder, transmitted in an autosomal dominant fashion. Its clinical expression is highly variable, ranging from almost asymptomatic subjects to wheelchair dependent patients. The molecular defect has been linked to chromosome 4q35 markers and has been related to deletions of tandemly repeated sequences located in the subtelomeric region detected by probe p13E-11 (D4F104S1). We describe a pair of monozygotic male twins affected by FSHD, carrying an identical de novo p13E-11 EcoRI fragment of paternal origin and showing great variability in the clinical expression of the disease, one being almost asymptomatic and the other severely affected. Their medical history was the same, with the exception of an anti-rabies vaccination performed at the age of 5 in the more severely affected twin. We hypothesise that the vaccination might have triggered an inflammatory immune reaction contributing to the more severe phenotype. Images PMID:9733041

  18. Magnetic Resonance Assessment of Hypertrophic and Pseudo-Hypertrophic Changes in Lower Leg Muscles of Boys with Duchenne Muscular Dystrophy and Their Relationship to Functional Measurements

    PubMed Central

    Vohra, Ravneet S.; Lott, Donovan; Mathur, Sunita; Senesac, Claudia; Deol, Jasjit; Germain, Sean; Bendixen, Roxanna; Forbes, Sean C.; Sweeney, H. Lee; Walter, Glenn A.; Vandenborne, Krista

    2015-01-01

    Introduction The primary objectives of this study were to evaluate contractile and non-contractile content of lower leg muscles of boys with Duchenne muscular dystrophy (DMD) and determine the relationships between non-contractile content and functional abilities. Methods Lower leg muscles of thirty-two boys with DMD and sixteen age matched unaffected controls were imaged. Non-contractile content, contractile cross sectional area and non-contractile cross sectional area of lower leg muscles (tibialis anterior, extensor digitorum longus, peroneal, medial gastrocnemius and soleus) were assessed by magnetic resonance imaging (MRI). Muscle strength, timed functional tests and the Brooke lower extremity score were also assessed. Results Non-contractile content of lower leg muscles (peroneal, medial gastrocnemius, and soleus) was significantly greater than control group (p<0.05). Non-contractile content of lower leg muscles correlated with Brooke score (rs = 0.64-0.84) and 30 feet walk (rs = 0.66-0.80). Dorsiflexor (DF) and plantarflexor (PF) specific torque was significantly different between the groups. Discussion Overall, non-contractile content of the lower leg muscles was greater in DMD than controls. Furthermore, there was an age dependent increase in contractile content in the medial gastrocnemius of boys with DMD. The findings of this study suggest that T1 weighted MR images can be used to monitor disease progression and provide a quantitative estimate of contractile and non-contractile content of tissue in children with DMD. PMID:26103164

  19. Bi-specific splice-switching PMO oligonucleotides conjugated via a single peptide active in a mouse model of Duchenne muscular dystrophy

    PubMed Central

    Shabanpoor, Fazel; McClorey, Graham; Saleh, Amer F.; Järver, Peter; Wood, Matthew J.A.; Gait, Michael J.

    2015-01-01

    The potential for therapeutic application of splice-switching oligonucleotides (SSOs) to modulate pre-mRNA splicing is increasingly evident in a number of diseases. However, the primary drawback of this approach is poor cell and in vivo oligonucleotide uptake efficacy. Biological activities can be significantly enhanced through the use of synthetically conjugated cationic cell penetrating peptides (CPPs). Studies to date have focused on the delivery of a single SSO conjugated to a CPP, but here we describe the conjugation of two phosphorodiamidate morpholino oligonucleotide (PMO) SSOs to a single CPP for simultaneous delivery and pre-mRNA targeting of two separate genes, exon 23 of the Dmd gene and exon 5 of the Acvr2b gene, in a mouse model of Duchenne muscular dystrophy. Conjugations of PMOs to a single CPP were carried out through an amide bond in one case and through a triazole linkage (‘click chemistry’) in the other. The most active bi-specific CPP–PMOs demonstrated comparable exon skipping levels for both pre-mRNA targets when compared to individual CPP–PMO conjugates both in cell culture and in vivo in the mdx mouse model. Thus, two SSOs with different target sequences conjugated to a single CPP are biologically effective and potentially suitable for future therapeutic exploitation. PMID:25468897

  20. Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics.

    PubMed

    Coenen-Stass, Anna M L; McClorey, Graham; Manzano, Raquel; Betts, Corinne A; Blain, Alison; Saleh, Amer F; Gait, Michael J; Lochmüller, Hanns; Wood, Matthew J A; Roberts, Thomas C

    2015-01-01

    There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and mdx (dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (P?

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

    PubMed

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

    2015-09-15

    Duchenne Muscular Dystrophy is characterized by: near absence of dystrophin in skeletal muscles; low percentage of revertant myofibers; up-regulation of utrophin synthesis; and a high degree of muscle fibrosis. In patient quadriceps femoris biopsies (n = 6, ages between 3-9 years) an inverse correlation was observed between the levels of collagen type I - representing fibrosis - and the levels of utrophin. This correlation was independent of the patient's age and was observed in the entire muscle biopsy sections. In the mdx mice diaphragm (n = 6/group), inhibition of fibrosis by halofuginone resulted in increases in the levels of utrophin. The utrophin/fibrosis relationships were not limited to collagen type I, but also applied to other constituents of the fibrosis machinery. The inverse correlation was found also in old mdx mice with established fibrosis. In addition, inhibition of collagen type I levels was associated with increases in the numbers of revertant myofibers, both as single myofibers and in clusters in the diaphragm and the gastrocnemius. In summary, our results demonstrate an inverse correlation between the level of muscle fibrosis and the level of utrophin and that of the number of revertant myofibers. These findings may reveal common links between the fibrotic and utrophin-synthesis pathways and offer new insights into the regulation of utrophin synthesis. PMID:26015394

  2. Magnetic Resonance Imaging Is Sensitive to Pathological Amelioration in a Model for Laminin-Deficient Congenital Muscular Dystrophy (MDC1A)

    PubMed Central

    Vohra, Ravneet; Accorsi, Anthony; Kumar, Ajay; Walter, Glenn; Girgenrath, Mahasweta

    2015-01-01

    Purpose To elucidate the reliability of MRI as a non-invasive tool for assessing in vivo muscle health and pathological amelioration in response to Losartan (Angiotensin II Type 1 receptor blocker) in DyW mice (mouse model for Laminin-deficient Congenital Muscular Dystrophy Type 1A). Methods Multiparametric MR quantifications along with histological/biochemical analyses were utilized to measure muscle volume and composition in untreated and Losartan-treated 7-week old DyW mice. Results MRI shows that DyW mice have significantly less hind limb muscle volume and areas of hyperintensity that are absent in WT muscle. DyW mice also have significantly elevated muscle levels (suggestive of inflammation and edema). Muscle T2 returned to WT levels in response to Losartan treatment. When considering only muscle pixels without T2 elevation, DyW T2 levels are significantly lower than WT (suggestive of fibrosis) whereas Losartan-treated animals do not demonstrate this decrease in muscle T2. MRI measurements suggestive of elevated inflammation and fibrosis corroborate with increased Mac-1 positive cells as well as increased Picrosirius red staining/COL1a gene expression that is returned to WT levels in response to Losartan. Conclusions MRI is sensitive to and tightly corresponds with pathological changes in DyW mice and thus is a viable and effective non-invasive tool for assessing pathological changes. PMID:26379183

  3. Generation of skeletal muscle cells from embryonic and induced pluripotent stem cells as an in vitro model and for therapy of muscular dystrophies

    PubMed Central

    Salani, Sabrina; Donadoni, Chiara; Rizzo, Federica; Bresolin, Nereo; Comi, Giacomo P; Corti, Stefania

    2012-01-01

    Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness likely associated with exhaustion of muscle regeneration potential. At present, no cures or efficacious treatments are available for these diseases, but cell transplantation could be a potential therapeutic strategy. Transplantation of myoblasts using satellite cells or other myogenic cell populations has been attempted to promote muscle regeneration, based on the hypothesis that the donor cells repopulate the muscle and contribute to its regeneration. Embryonic stem cells (ESCs) and more recently induced pluripotent stem cells (iPSCs) could generate an unlimited source of differentiated cell types, including myogenic cells. Here we review the literature regarding the generation of myogenic cells considering the main techniques employed to date to elicit efficient differentiation of human and murine ESCs or iPSCs into skeletal muscle. We also critically analyse the possibility of using these cellular populations as an alternative source of myogenic cells for cell therapy of MDs. PMID:22129481

  4. Successful Regional Delivery and Long-term Expression of a Dystrophin Gene in Canine Muscular Dystrophy: A Preclinical Model for Human Therapies

    PubMed Central

    Wang, Zejing; Storb, Rainer; Halbert, Christine L; Banks, Glen B.; Butts, Tiffany M.; Finn, Eric E.; Allen, James M.; Miller, A. Dusty; Chamberlain, Jeffrey S.; Tapscott, Stephen J.

    2012-01-01

    Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials. PMID:22692496

  5. Successful regional delivery and long-term expression of a dystrophin gene in canine muscular dystrophy: a preclinical model for human therapies.

    PubMed

    Wang, Zejing; Storb, Rainer; Halbert, Christine L; Banks, Glen B; Butts, Tiffany M; Finn, Eric E; Allen, James M; Miller, A Dusty; Chamberlain, Jeffrey S; Tapscott, Stephen J

    2012-08-01

    Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle disease caused by mutations in the dystrophin gene. Adeno-associated viral (AAV) vector-mediated gene replacement strategies hold promise as a treatment. Studies in animal models and human trials suggested that immune responses to AAV capsid proteins and transgene products prevented efficient gene therapy. In this study, we used widespread intramuscular (i.m.) injection to deliver AAV6-canine micro-dystrophin (c-µdys) throughout a group of skeletal muscles in dystrophic dogs given a brief course of commonly used immunosuppressants. Robust c-µdys expression was obtained for at least two years and was associated with molecular reconstitution of the dystrophin-glycoprotein complex (DGC) at the muscle membrane. Importantly, c-µdys expression was maintained for at least 18 months after discontinuing immunosuppression. The results obtained in a relevant preclinical model of DMD demonstrate feasibility of widespread AAV-mediated muscle transduction and transgene expression in the presence of transient immunosuppression to achieve molecular reconstitution that can be directly translated to human trials. PMID:22692496

  6. Muscle and Heart Function Restoration in a Limb Girdle Muscular Dystrophy 2I (LGMD2I) Mouse Model by Systemic FKRP Gene Delivery

    PubMed Central

    Qiao, Chunping; Wang, Chi-Hsien; Zhao, Chunxia; Lu, Peijuan; Awano, Hiroyuki; Xiao, Bin; Li, Jianbin; Yuan, Zhenhua; Dai, Yi; Martin, Carrie Bette; Li, Juan; Lu, Qilong; Xiao, Xiao

    2014-01-01

    Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in ?-dystroglycan (?-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of ?-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective. PMID:25048216

  7. Maternal uniparental disomy of chromosome 4 in a patient with limb-girdle muscular dystrophy 2E confirmed by SNP array technology.

    PubMed

    Cottrell, C E; Mendell, J; Hart-Kothari, M; Ell, D; Thrush, D L; Astbury, C; Pastore, M; Gastier-Foster, J M; Pyatt, R E

    2012-06-01

    The limb-girdle muscular dystrophies (LGMDs) are a heterogenous group of diseases characterized by shoulder-girdle and pelvic muscle weakness and wasting. LGMD 2E is an autosomal recessively inherited form of the disease caused by mutations in the ?-sarcoglycan (SGCB) gene located at 4q12. In this report, we describe a patient who demonstrates non-Mendelian inheritance of a homozygous missense mutation in SGCB resulting in disease expression. A combination of single-nucleotide polymorphism (SNP) array technology and microsatellite analysis revealed the occurrence of maternal uniparental disomy (UPD) for chromosome 4 in the patient. As a consequence of segmental isodisomy at 4q12, the patient inherited two identical SGCB alleles carrying a missense mutation predicted to result in abnormal protein function. SNP array technology proved to be an elegant means to determine the most probable mechanism of UPD formation in this case, and enabled us to determine the location of recombination events along chromosome 4. In our patient, UPD likely arose from a trisomy rescue event due to maternal meiotic non-disjunction that we speculate may have been caused by abnormal recombination at the pericentromeric region. Maternal UPD 4 is a rare finding, and to our knowledge this is the first reported case of UPD in association with LGMD. PMID:21480868

  8. Targeted screening for the detection of Pompe disease in patients with unclassified limb-girdle muscular dystrophy or asymptomatic hyperCKemia using dried blood: A Spanish cohort.

    PubMed

    Gutiérrez-Rivas, E; Bautista, J; Vílchez, J J; Muelas, N; Díaz-Manera, J; Illa, I; Martínez-Arroyo, A; Olivé, M; Sanz, I; Arpa, J; Fernández-Torrón, R; López de Munáin, A; Jiménez, L; Solera, J; Lukacs, Z

    2015-07-01

    We aimed to screen for Pompe disease in patients with unclassified limb-girdle muscular dystrophy (LGMD) or asymptomatic hyperCKemia using dried blood spot (DBS) assays. Subsequently, we aimed to calculate the diagnostic delay between initial symptom presentation and the diagnosis. A prospective, multicenter, observational study was conducted in 348 patients: 146 with unclassified LGMD and 202 with asymptomatic or paucisymptomatic hyperCKemia. We quantified levels of acid alpha-glucosidase (GAA) from dried blood spots analyzed fluorometrically. The test was positive in 20 patients, and Pompe disease was confirmed by genetic testing in 16. Undiagnosed Pompe disease was detected in 7.5% of patients with LGMD and in 2.5% of patients with persistent, idiopathic elevation of serum creatine kinase. The c.-32-13 T?>?G mutation was found most commonly. The diagnostic delay was 15 years on average. In conclusion, DBS tests are useful and reliable screening tools for Pompe disease. We recommend the dried blood spot test to be included in the diagnostic work-up of patients with unclassified myopathies with proximal weakness and/or hyperCKemia of unknown cause and, when positive, to define the diagnosis, it will have to be confirmed by biochemical and/or molecular genetic analysis. PMID:25998610

  9. Identification of novel, therapy-responsive protein biomarkers in a mouse model of Duchenne muscular dystrophy by aptamer-based serum proteomics

    PubMed Central

    Coenen-Stass, Anna M. L.; McClorey, Graham; Manzano, Raquel; Betts, Corinne A.; Blain, Alison; Saleh, Amer F.; Gait, Michael J.; Lochmüller, Hanns; Wood, Matthew J. A.; Roberts, Thomas C.

    2015-01-01

    There is currently an urgent need for biomarkers that can be used to monitor the efficacy of experimental therapies for Duchenne Muscular Dystrophy (DMD) in clinical trials. Identification of novel protein biomarkers has been limited due to the massive complexity of the serum proteome and the presence of a small number of very highly abundant proteins. Here we have utilised an aptamer-based proteomics approach to profile 1,129 proteins in the serum of wild-type and mdx (dystrophin deficient) mice. The serum levels of 96 proteins were found to be significantly altered (P?

  10. Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

    PubMed Central

    Flanigan, Kevin M.; Voit, Thomas; Rosales, Xiomara Q.; Servais, Laurent; Kraus, John E.; Wardell, Claire; Morgan, Allison; Dorricott, Susie; Nakielny, Joanna; Quarcoo, Naashika; Liefaard, Lia; Drury, Tom; Campion, Giles; Wright, Padraig

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2?-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ?9 years, in wheelchairs for ?1 to ?4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. PMID:24321374

  11. A new human gene (DXS1357E) with ubiquitous expression, located in Xq28 adjacent to the adrenoleukodystrophy gene

    SciTech Connect

    Mosser, J.; Sarde, C.O.; Vicaire, S.

    1994-07-15

    The authors have isolated a new human gene (DXS1357E; laboratory name: CDM) localized in Xq28. This gene is transcribed from the same CpG island as the adrenoleukodystrophy gene (ALD) and is oriented in the opposite direction. It encodes a 1.5-kb transcript that exhibits ubiquitous expression and contains a single open reading frame. The 246 deduced amino acid sequence suggests the presence of membrane-associated segments and a weak similarity with the rod-like tail portion of heavy chain myosins from different species. The DXS1357E gene may be a candidate for one of the many diseases mapping to this region. A preliminary analysis did not show rearrangements of the gene in 19 independent patients with Emery-Dreifuss muscular dystrophy. 21 refs., 2 figs.

  12. Change in brain activity through virtual reality-based brain-machine communication in a chronic tetraplegic subject with muscular dystrophy

    PubMed Central

    2010-01-01

    Background For severely paralyzed people, a brain-computer interface (BCI) provides a way of re-establishing communication. Although subjects with muscular dystrophy (MD) appear to be potential BCI users, the actual long-term effects of BCI use on brain activities in MD subjects have yet to be clarified. To investigate these effects, we followed BCI use by a chronic tetraplegic subject with MD over 5 months. The topographic changes in an electroencephalogram (EEG) after long-term use of the virtual reality (VR)-based BCI were also assessed. Our originally developed BCI system was used to classify an EEG recorded over the sensorimotor cortex in real time and estimate the user's motor intention (MI) in 3 different limb movements: feet, left hand, and right hand. An avatar in the internet-based VR was controlled in accordance with the results of the EEG classification by the BCI. The subject was trained to control his avatar via the BCI by strolling in the VR for 1 hour a day and then continued the same training twice a month at his home. Results After the training, the error rate of the EEG classification decreased from 40% to 28%. The subject successfully walked around in the VR using only his MI and chatted with other users through a voice-chat function embedded in the internet-based VR. With this improvement in BCI control, event-related desynchronization (ERD) following MI was significantly enhanced (p < 0.01) for feet MI (from -29% to -55%), left-hand MI (from -23% to -42%), and right-hand MI (from -22% to -51%). Conclusions These results show that our subject with severe MD was able to learn to control his EEG signal and communicate with other users through use of VR navigation and suggest that an internet-based VR has the potential to provide paralyzed people with the opportunity for easy communication. PMID:20846418

  13. Psychological and practical difficulties among parents and healthy siblings of children with Duchenne vs. Becker muscular dystrophy: an Italian comparative study.

    PubMed

    Magliano, Lorenza; D'Angelo, Maria Grazia; Vita, Giuseppe; Pane, Marika; D'Amico, Adele; Balottin, Umberto; Angelini, Corrado; Battini, Roberta; Politano, Luisa; Patalano, Melania; Sagliocchi, Alessandra; Civati, Federica; Brighina, Erika; Vita, Gian Luca; Messina, Sonia; Sframeli, Maria; Lombardo, Maria Elena; Scalise, Roberta; Colia, Giulia; Catteruccia, Maria; Berardinelli, Angela; Motta, Maria Chiara; Gaiani, Alessandra; Semplicini, Claudio; Bello, Luca; Astrea, Guja; Zaccaro, Antonella; Scutifero, Marianna

    2014-12-01

    This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease. PMID:25873782

  14. Recessive TRAPPC11 Mutations Cause a Disease Spectrum of Limb Girdle Muscular Dystrophy and Myopathy with Movement Disorder and Intellectual Disability

    PubMed Central

    Bögershausen, Nina; Shahrzad, Nassim; Chong, Jessica X.; von Kleist-Retzow, Jürgen-Christoph; Stanga, Daniela; Li, Yun; Bernier, Francois P.; Loucks, Catrina M.; Wirth, Radu; Puffenberger, Eric G.; Hegele, Robert A.; Schreml, Julia; Lapointe, Gabriel; Keupp, Katharina; Brett, Christopher L.; Anderson, Rebecca; Hahn, Andreas; Innes, A. Micheil; Suchowersky, Oksana; Mets, Marilyn B.; Nürnberg, Gudrun; McLeod, D. Ross; Thiele, Holger; Waggoner, Darrel; Altmüller, Janine; Boycott, Kym M.; Schoser, Benedikt; Nürnberg, Peter; Ober, Carole; Heller, Raoul; Parboosingh, Jillian S.; Wollnik, Bernd; Sacher, Michael; Lamont, Ryan E.

    2013-01-01

    Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism. PMID:23830518

  15. Confirmation of a third locus, at 2p, for autosomal recessive limb-girdle muscular dystrophy indicates that at least 4 genes are responsible for this condition

    SciTech Connect

    Passos-Bueno, M.R.; Moreira, E.S.; Vasques, L.R.

    1994-09-01

    Autosomal recessive limb-girdle muscular dystrophies (AR LGMD) represent a heterogeneous group of diseases with a wide spectrum of clinical signs, varying from very severe to mild ones. One gene for a mild form was mapped at 15q while another gene for a severe form was mapped at 13p. In both cases, evidence of genetic heterogeneity were demonstrated following analysis of Brazilian families. More recently, a third gene was identified at 2p based on linkage analysis in 2 LGMD families with the markers D2S166, D2S136 and D2S134. The relative proportion of each genetic form among affected families is unknown. Therefore, the closest available markers for each of the LGMD genes have been tested in 12 Brazilian families with at least 3 affected patients. The following results have been observed: 3 were 15q-linked families, 1 was 13p-linked, at least 2 were linked to 2p and 2 were excluded for any of these 3 loci. In relation to the 2p locus, we have tested a total of 12 markers in the 2 linked Brazilian families. The maximum lod score for the marker which was informative for the two families (D2S291) was 8.35 at {theta}=0.01. Therefore, these results suggest the existence of at least 4 different genes causing the LGMD phenotype and confirm linkage to the 2p locus. In addition, our data refine the localization of the third locus since the marker D2S291 is at least 9 cM closer to this gene (FAPESP, CNPq, MDA, PADCT).

  16. Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: Case control study of dogs with Duchenne muscular dystrophy

    PubMed Central

    Kerwin, William S.; Naumova, Anna; Storb, Rainer; Tapscott, Stephen J.; Wang, Zejing

    2012-01-01

    Purpose Myocardial perfusion studies using dynamic contrast-enhanced cardiac magnetic resonance imaging (CMRI) could provide valuable, quantitative information regarding heart physiology in diseases such as Duchenne muscular dystrophy (DMD), that lead to diffuse myocardial damage. The goal of this effort was to develop an intuitive but physiologically meaningful method for quantifying myocardial perfusion by CMRI and to test its ability to detect global myocardial differences in a dog model of DMD. Methods A discrete-time model was developed that parameterizes contrast agent kinetics in terms of an uptake coefficient that describes the forward flux of contrast agent into the tissue, and a retention coefficient that describes the rate of decay in tissue concentration due to contrast agent efflux. This model was tested in 5 dogs with DMD and 6 healthy controls which were imaged using a perfusion sequence on a 3T clinical scanner. CINE and delayed-enhancement CMRI acquisitions were also used to assess cardiac function and the presence of myocardial scar. Results Among functional parameters measured by CMRI, no significant differences were observed. No myocardial scar was observed. Increased perfusion in DMD was observed with an uptake coefficient of 6.76% ± 2.41% compared to 2.98% ± 1.46% in controls (p=0.03). Additionally, the retention coefficient appeared lower at 82.2% ± 5.8% in dogs with DMD compared to 90.5% ± 6.6% in controls (p=0.12). Conclusions A discrete-time kinetic model of uptake and retention of contrast agent in perfusion CMRI shows potential for the study of DMD. PMID:23070737

  17. Mapping contrast agent uptake and retention in MRI studies of myocardial perfusion: case control study of dogs with Duchenne muscular dystrophy.

    PubMed

    Kerwin, William S; Naumova, Anna; Storb, Rainer; Tapscott, Stephen J; Wang, Zejing

    2013-04-01

    Myocardial perfusion studies using dynamic contrast-enhanced cardiac magnetic resonance imaging (CMRI) could provide valuable, quantitative information regarding heart physiology in diseases such as Duchenne muscular dystrophy (DMD), that lead to diffuse myocardial damage. The goal of this effort was to develop an intuitive but physiologically meaningful method for quantifying myocardial perfusion by CMRI and to test its ability to detect global myocardial differences in a dog model of DMD. A discrete-time model was developed that parameterizes contrast agent kinetics in terms of an uptake coefficient that describes the forward flux of contrast agent into the tissue, and a retention coefficient that describes the rate of decay in tissue concentration due to contrast agent efflux. This model was tested in 5 dogs with DMD and 6 healthy controls which were imaged using a perfusion sequence on a 3T clinical scanner. CINE and delayed-enhancement CMRI acquisitions were also used to assess cardiac function and the presence of myocardial scar. Among functional parameters measured by CMRI, no significant differences were observed. No myocardial scar was observed. Increased perfusion in DMD was observed with an uptake coefficient of 6.76 ± 2.41 % compared to 2.98 ± 1.46 % in controls (p = 0.03). Additionally, the retention coefficient appeared lower at 82.2 ± 5.8 % in dogs with DMD compared to 90.5 ± 6.6 % in controls (p = 0.12). A discrete-time kinetic model of uptake and retention of contrast agent in perfusion CMRI shows potential for the study of DMD. PMID:23070737

  18. Aberrant Location of Inhibitory Synaptic Marker Proteins in the Hippocampus of Dystrophin-Deficient Mice: Implications for Cognitive Impairment in Duchenne Muscular Dystrophy

    PubMed Central

    Krasowska, El?bieta; Zab?ocki, Krzysztof; Górecki, Dariusz C.; Swinny, Jerome D.

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a neuromuscular disease that arises from mutations in the dystrophin-encoding gene. Apart from muscle pathology, cognitive impairment, primarily of developmental origin, is also a significant component of the disorder. Convergent lines of evidence point to an important role for dystrophin in regulating the molecular machinery of central synapses. The clustering of neurotransmitter receptors at inhibitory synapses, thus impacting on synaptic transmission, is of particular significance. However, less is known about the role of dystrophin in influencing the precise expression patterns of proteins located within the pre- and postsynaptic elements of inhibitory synapses. To this end, we exploited molecular markers of inhibitory synapses, interneurons and dystrophin-deficient mouse models to explore the role of dystrophin in determining the stereotypical patterning of inhibitory connectivity within the cellular networks of the hippocampus CA1 region. In tissue from wild-type (WT) mice, immunoreactivity of neuroligin2 (NL2), an adhesion molecule expressed exclusively in postsynaptic elements of inhibitory synapses, and the vesicular GABA transporter (VGAT), a marker of GABAergic presynaptic elements, were predictably enriched in strata pyramidale and lacunosum moleculare. In acute contrast, NL2 and VGAT immunoreactivity was relatively evenly distributed across all CA1 layers in dystrophin-deficient mice. Similar changes were evident with the cannabinoid receptor 1, vesicular glutamate transporter 3, parvalbumin, somatostatin and the GABAA receptor alpha1 subunit. The data show that in the absence of dystrophin, there is a rearrangement of the molecular machinery, which underlies the precise spatio-temporal pattern of GABAergic synaptic transmission within the CA1 sub-field of the hippocampus. PMID:25260053

  19. Recessive TRAPPC11 mutations cause a disease spectrum of limb girdle muscular dystrophy and myopathy with movement disorder and intellectual disability.

    PubMed

    Bögershausen, Nina; Shahrzad, Nassim; Chong, Jessica X; von Kleist-Retzow, Jürgen-Christoph; Stanga, Daniela; Li, Yun; Bernier, Francois P; Loucks, Catrina M; Wirth, Radu; Puffenberger, Eric G; Hegele, Robert A; Schreml, Julia; Lapointe, Gabriel; Keupp, Katharina; Brett, Christopher L; Anderson, Rebecca; Hahn, Andreas; Innes, A Micheil; Suchowersky, Oksana; Mets, Marilyn B; Nürnberg, Gudrun; McLeod, D Ross; Thiele, Holger; Waggoner, Darrel; Altmüller, Janine; Boycott, Kym M; Schoser, Benedikt; Nürnberg, Peter; Ober, Carole; Heller, Raoul; Parboosingh, Jillian S; Wollnik, Bernd; Sacher, Michael; Lamont, Ryan E

    2013-07-11

    Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramaticall