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1

Emery-Dreifuss Muscular dystrophy. Laminopathies and other nuclear envelopathies Gisle Bonne1  

E-print Network

1 Emery-Dreifuss Muscular dystrophy. Laminopathies and other nuclear envelopathies Gisèle Bonne1-CMD is a severe congenital muscular dystrophy characterized either by the absence of motor acquisitions-Dreifuss muscular dystrophy (EDMD) has a later onset and typically shows the triad of slowly progressive scapulo

2

Emery-Dreifuss muscular dystrophy: linkage to markers in distal Xq28  

Microsoft Academic Search

Emery-Dreifuss muscular dystrophy (EMD) is characterised by (1) early contractures of the Achilles tendons, elbows, and postcervical muscles, (2) slowly progressive muscle wasting and weakness with a predominantly humeroperoneal distribution in the early stages, and (3) cardiomyopathy with conduction defects and risk of sudden death. Inheritance is usually X linked recessive but can be autosomal dominant. Family linkage studies have

J R Yates; J P Warner; J A Smith; F Deymeer; J P Azulay; I Hausmanowa-Petrusewicz; J Zaremba; J Borkowska; N A Affara; M A Ferguson-Smith

1993-01-01

3

Expression of Lamin A Mutated in the Carboxyl-Terminal Tail Generates an Aberrant Nuclear Phenotype Similar to That Observed in Cells from Patients with Dunnigan-Type Partial Lipodystrophy and Emery-Dreifuss Muscular Dystrophy  

Microsoft Academic Search

Autosomal dominantly inherited missense mutations in lamins A and C cause familialpartial lipodystrophy of the Dunnigan-type (FPLD), and myopathies including Emery-Dreifuss muscular dystrophy (EDMD). While mutations responsible for FPLD are restricted to the carboxyl-terminal tails, those responsible for EDMD are spread throughout the molecules. We observed here the same structural abnormalities in the nuclear envelope and chromatin of fibroblasts from

Catherine Favreau; Emmanuelle Dubosclard; Corinne Vigouroux; Jacqueline Capeau; Manfred Wehnert; Dominique Higuet; Howard J. Worman; Jean-Claude Courvalin; Brigitte Buendia

2003-01-01

4

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

PubMed Central

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

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

2015-01-01

5

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

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.

Wheeler, Matthew A. [Randall Division of Cell and Molecular Biophysics, King's College, New Hunts House, Guy's Campus, London, SE1 1UL (United Kingdom); Davies, John D. [Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 2QQ (United Kingdom); Zhang Qiuping [Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 2QQ (United Kingdom); Emerson, Lindsay J. [Randall Division of Cell and Molecular Biophysics, King's College, New Hunts House, Guy's Campus, London, SE1 1UL (United Kingdom); Hunt, James [Randall Division of Cell and Molecular Biophysics, King's College, New Hunts House, Guy's Campus, London, SE1 1UL (United Kingdom); Shanahan, Catherine M. [Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Rd, Cambridge, CB2 2QQ (United Kingdom); Ellis, Juliet A. [Randall Division of Cell and Molecular Biophysics, King's College, New Hunts House, Guy's Campus, London, SE1 1UL (United Kingdom) ]. E-mail: juliet.ellis@kcl.ac.uk

2007-08-01

6

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

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.

Favreau, Catherine [Institut Jacques Monod, UMR7592, CNRS et Universites Paris 6 et 7, 2 Place Jussieu, 75251 Paris Cedex 05 (France); Delbarre, Erwan [Institute of Basic Medical Sciences, Department of Biochemistry, Faculty of Medicine, University of Oslo, PO Box 1112 Blindern, 0317 Oslo (Norway); Courvalin, Jean-Claude [Institut Jacques Monod, UMR7592, CNRS et Universites Paris 6 et 7, 2 Place Jussieu, 75251 Paris Cedex 05 (France); Buendia, Brigitte [Institut Jacques Monod, UMR7592, CNRS et Universites Paris 6 et 7, 2 Place Jussieu, 75251 Paris Cedex 05 (France)], E-mail: buendia@ijm.jussieu.fr

2008-04-01

7

Dreifuss muscular dystrophy 1991. Neuromuscul Disord 1991; Dubowics V. Muscle biopsy: a practical approach. 2nd ed.  

E-print Network

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. IS. Dreifuss muscular dystrophy 1991. Neuromuscul Disord 1991 GG, Thomas NST, Stayton CL, et al. Assignment of Emery-Dreifuss muscular dystrophy to the distal al. Enierin deficiency at the nuclear membrane in patients with Emery-Dreifuss muscular dystrophy

Hayar, Abdallah

8

Congenital Muscular Dystrophy with Rigid Spine Syndrome: A Clinical, Pathological,  

E-print Network

Congenital Muscular Dystrophy with Rigid Spine Syndrome: A Clinical, Pathological, Radiological. While spinal rigidity is a nonspecific feature, found in Emery-Dreifuss muscular dystrophy and in some muscular dystrophy, where it is generally associated with stable or only slowly progressive weakness

Campbell, Kevin P.

9

The nuclear envelope, muscular dystrophy and gene expression  

Microsoft Academic Search

Lamins and other nuclear envelope proteins organize nuclear architecture through structural attachments that vary dynamically during the cell cycle and cell differentiation. Genetic studies have now shown that people with mutations in either lamins A\\/C or emerin, a nuclear membrane protein, develop Emery–Dreifuss muscular dystrophy. A mouse model for this rare disease has been created by knocking out the gene

Katherine L Wilson

2000-01-01

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

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

12

Muscular Dystrophy  

MedlinePLUS

... need a ventilator to breathe. Becker muscular dystrophy (BMD) , like DMD, affects boys. The disease is very ... start later and can be less severe. With BMD, symptoms like muscle breakdown and weakness sometimes don' ...

13

Muscular Dystrophy  

MedlinePLUS

... Much of the information comes from outside the United States. CDC scientists are working to estimate the number ... with each type of muscular dystrophy in the United States. The table below shows what is known about ...

14

Muscular Dystrophy  

MedlinePLUS

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

15

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. ...

16

Muscular Dystrophy Coordinating Committee  

MedlinePLUS

Muscular Dystrophy Coordinating Committee (MDCC) WE ARE NO LONGER ACCEPTING COMMENTS AND EDITS THROUGH THIS SITE. THIS COPY ... on the Draft 2015 Action Plan for the Muscular Dystrophies Draft 2015 Action Plan (PDF, 1.06MB) Request ...

17

Original article Duchenne muscular dystrophy  

E-print Network

Original article Duchenne muscular dystrophy: a model for studying the contribution of muscle muscular dystrophy (DMD) is associated with a dramatic muscle mass loss. We hypothesized that DMD would. © Inra/Elsevier, Paris Duchenne muscular dystrophy / resting energy expenditure / protein

Paris-Sud XI, Université de

18

Evaluation of Limb-Girdle Muscular Dystrophy  

ClinicalTrials.gov

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)

2014-03-06

19

Learning about Duchenne Muscular Dystrophy  

MedlinePLUS

... form of muscular dystrophy that occurs primarily in boys. It is caused by an alteration (mutation) in ... to date, which encodes the muscle protein, dystrophin. Boys with Duchenne muscular dystrophy do not make the ...

20

FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY  

PubMed Central

SUMMARY Facioscapulohumeral muscular dystrophy (FSHD), a dominantly inherited disorder, is the third most common dystrophy after Duchenne and myotonic muscular dystrophy. No known effective treatments exist for FSHD. The lack of an understanding of the underlying pathophysiology remains an obstacle in the development of targeted therapeutic interventions. The genetic defect is a loss of a critical number of a repetitive element (D4Z4) in the 4q subtelomeric region. The loss of the repeats results in specific changes in chromatin, structure, although neither the molecular nor the cellular consequences of this change are known. Nevertheless, these epigenetic changes in chromatic structure offer a potential therapeutic target. The following chapter discusses current management strategies in FSHD as well as potential therapeutic interventions to slow down or reverse the progressive muscle atrophy and weakness. PMID:19019312

Tawil, Rabi

2008-01-01

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

PubMed Central

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

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

2014-01-01

22

Halofuginone and muscular dystrophy.  

PubMed

Muscular dystrophies (MDs) include different inherited diseases that all result in progressive muscle degeneration, impaired locomotion and often premature death. The major focus of MD research has been on alleviating the primary genetic deficit - using gene therapy and myoblast-transfer approaches to promote expression of the deficient or mutated genes in the muscle fibers. Although promising, these approaches have not yet entered into clinical practice and unfortunately for MD patients, there is currently no cure. Thus, the development of complementary and supportive therapies that slow disease progression and improve patients' quality of life is critically important. The main features of MDs are sarcolemmal instability and increased myofiber vulnerability to mechanical stress, resulting in myofiber degeneration. Fibrosis, with progressive replacement of muscle tissue, is a prominent feature in some MDs, preventing complete regeneration and hampering muscle functions. TGF? is the leading candidate for activating fibroblasts and eliciting overproduction of extracellular matrix (ECM) proteins. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of TGF? signaling, inhibits the activation of fibroblasts and their ability to synthesize ECM, regardless of their origin or location. In animal models of MDs with prominent muscle fibrosis, halofuginone treatment has resulted in both prevention of collagen production in young animals and resolution of established fibrosis in older ones: the reduction in muscle collagen content was associated with improved muscle histopathology and major improvements in muscle function. Recently, these halofuginone-dependent improvements were also observed in MD with minor fibrosis involvement, probably due to a direct effect of halofuginone on muscle cells, resulting in myotube fusion that is dependent on Akt and MAPK pathway activation. In summary, halofuginone improves muscle histopathology and muscle functions in various MDs, via inhibition of muscle fibrosis on the one hand, and increased myotube fusion on the other. PMID:21117034

Pines, Mark; Halevy, Orna

2011-01-01

23

The Cardiomyopathy of Muscular Dystrophy  

PubMed Central

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

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

1964-01-01

24

Dysregulation of calcium homeostasis in muscular dystrophies.  

PubMed

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

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

2014-01-01

25

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 University of New York, New York, New York ABSTRACT. Duchenne muscular dystrophy (DMD) is a chronic, 2006. Index terms: Duchenne muscular dystrophy, behavior, behavioral phenotype, social problems

26

Genetics Home Reference: Duchenne and Becker muscular dystrophy  

MedlinePLUS

... OMIM Genetic disorder catalog Conditions > Duchenne and Becker muscular dystrophy On this page: Description Genetic changes Inheritance Diagnosis ... Reviewed February 2012 What is Duchenne and Becker muscular dystrophy? Muscular dystrophies are a group of genetic conditions ...

27

Duchenne and Becker muscular dystrophies.  

PubMed

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

Flanigan, Kevin M

2014-08-01

28

Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability  

E-print Network

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 dystrophy calponin homology domain Duchenne muscular dystrophy protein aggregation Muscular dystrophy (MD

Mallela, Krishna M. G.

29

Genetics Home Reference: Facioscapulohumeral muscular dystrophy  

MedlinePLUS

... number of methyl groups (consisting of one carbon atom and three hydrogen atoms) attached to the DNA. The addition of methyl ... glossary definitions help with understanding facioscapulohumeral muscular dystrophy? atom ; atrophy ; autosomal ; autosomal dominant ; cardiac ; cell ; chromatin ; chromosome ; ...

30

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

ClinicalTrials.gov

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

2014-10-15

31

Glycomic Analyses of Mouse Models of Congenital Muscular Dystrophy*S  

E-print Network

Glycomic Analyses of Mouse Models of Congenital Muscular Dystrophy*S Received for publication University, Syracuse, New York 13210 Dystroglycanopathies are a subset of congenital muscular dystrophies muscular dystrophy. In this study, we sought to perform glycomic anal- ysis on brain O-linked glycan

Campbell, Kevin P.

32

Researchers Measure Scope of Muscular Dystrophies That Strike Boys  

MedlinePLUS

... Researchers Measure Scope of Muscular Dystrophies That Strike Boys Hispanics more likely to develop muscle-weakening disorders, ... two types of muscular dystrophy that strike mostly boys. A team led by researchers from the University ...

33

If I Had - A Family History of Muscular Dystrophy  

MedlinePLUS Videos and Cool Tools

... Through Psychological Counseling If I Had - A Family History of Muscular Dystrophy - Eric Hoffman, PhD, Children's National ... to Home Page If I Had - A Family History of Muscular Dystrophy - Eric Hoffman, PhD, Children's National ...

34

Introduction Of nine diagnosed phenotypes of muscular dystrophy (MD),  

E-print Network

Introduction Of nine diagnosed phenotypes of muscular dystrophy (MD), most result from a disruption dystrophy, Limb-girdle muscular dystrophy, Differentiation Summary -Sarcoglycan deficiency increases cell into a key membrane complex with dystroglycan and its deficiency is one known cause of limb-girdle muscular

Discher, Dennis

35

Characterization of aquaporin-4 in muscle and muscular dystrophy  

E-print Network

Characterization of aquaporin-4 in muscle and muscular dystrophy RACHELLE H. CROSBIE,1 SHERRI A investigated aquaporin expression in various mouse models of muscular dystrophy and car- diomyopathy before in muscular dystrophies caused by primary mutations in the sarcoglycan genes. Taken together, our data

Campbell, Kevin P.

36

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

E-print Network

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

Campbell, Kevin P.

37

Dysferlin and the plasma membrane repair in muscular dystrophy  

E-print Network

Dysferlin and the plasma membrane repair in muscular dystrophy Dimple Bansal and Kevin P. Campbell of the skeletal muscles. Dysferlin was identified as a gene mutated in limb­girdle muscular dystrophy (type 2B of the skeletal muscle cells. Muscular dystrophy includes a diverse group of inherited myogenic disorders

Campbell, Kevin P.

38

Impact of Tracheostomy on Swallowing Performance in Duchenne Muscular Dystrophy  

E-print Network

Impact of Tracheostomy on Swallowing Performance in Duchenne Muscular Dystrophy Nicolas TERZI1 improved survival in patients with Duchenne muscular dystrophy (DMD). Over time, these patients experience muscular dystrophy (DMD) from about 15 years in the 1960s to more than 30 years now [1-4]. However

Paris-Sud XI, Université de

39

Cellular and molecular mechanisms underlying muscular dystrophy  

PubMed Central

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

2013-01-01

40

What Are the Treatments for Muscular Dystrophy?  

MedlinePLUS

... the treatments for muscular dystrophy? Skip sharing on social media links Share this: Page Content No treatment is ... show that the treatment may have the same positive results as prednisone, but without the side effects. 5 Anticonvulsants. Typically taken for epilepsy, these drugs ...

41

Mammalian animal models for Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease that affects boys and leads to early death. In the quest for new treatments that improve the quality of life and in the search for a possible definitive cure, the use of animal models plays undoubtedly an important role. Therefore, a number of different mammalian models for DMD have been described.

Raffaella Willmann; Stefanie Possekel; Judith Dubach-Powell; Thomas Meier; Markus A. Ruegg

2009-01-01

42

Visuospatial Attention Disturbance in Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2010-01-01

43

Duchenne and Becker Muscular Dystrophies  

MedlinePLUS

... dystrophy, we were devastated. Immediately, our hopes and dreams for Mike — playing sports, graduating high school, having ... you strength. Never give up your hopes and dreams. My son has graduated from high school, has ...

44

Distinctive Serum miRNA Profile in Mouse Models of Striated Muscular Pathologies  

PubMed Central

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

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

45

Distinctive serum miRNA profile in mouse models of striated muscular pathologies.  

PubMed

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

Vignier, Nicolas; Amor, Fatima; 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

46

Limb Girdle Muscular Dystrophy (LGMD): Case Report  

PubMed Central

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

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

2015-01-01

47

Oculopharyngeal muscular dystrophy: A polyalanine myopathy  

Microsoft Academic Search

It has been 10 years since the identification of the first PABPN1 gene (GCN)n\\/polyalanine mutations responsible for oculopharyngeal muscular dystrophy (OPMD). These mutations have been found in most\\u000a cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous\\u000a times in human history. Although PABPN1 was found early on to be a

Bernard Brais

2009-01-01

48

Of Mice and Men - Duchenne Muscular Dystrophy  

NSDL National Science Digital Library

Forty-seventh monthly installment of our "What A Year!" website project, introducing life science breakthroughs to middle and high school students and their teachers. Duchenne Muscular Dystrophy (DMD) is a severe, chronic muscle wasting disease caused by a mutation in a gene called the DMD gene located on the X chromosome. Mice and humans can both have this mutation, but mice don't get the disease. Sometimes the differences among animals are as informative as the similarities.

2011-04-04

49

[Myocardiopathy of progressive muscular dystrophy].  

PubMed

The authors have effected a clinical, radiological, electrocardiographic and apexocardiographic survey in 13 patients with progressive muscular distrophy (PMD) and in 6 healthy subjects belonging to families affected by the disease, in parallel with a group of 11 patients with severe myasthenia and 23 healthy subjects. Comparing the results with those found in the literature lead to the following results: 1) The ECG modifications and above all the abnormalities of the ventricular complex develop precociously in the PMD and express the pleiotropism of the myopathic gene. 2) The myocardial dyssynergia represents a link in the physiopathological chain of the cardiac distress. 3) The precociousness of electro and apexocardiographic modifications and their presence in healthy parents recommend these investigations in the genetic enquiry. 4) Clinical, histological and haemodynamic data individualize the myocardial distress as a true myocardiopathy. PMID:1005267

Ion, I C; Dumitriu, M; Nisipeanu, P; Cinteza, M

1976-01-01

50

Osteoprotegerin Protects against Muscular Dystrophy.  

PubMed

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

Dufresne, Sébastien S; Dumont, Nicolas A; Bouchard, Patrice; Lavergne, Éliane; Penninger, Josef M; Frenette, Jérôme

2015-04-01

51

Activating internal ribosome entry to treat Duchenne muscular dystrophy.  

PubMed

Mutations in the DMD gene, encoding dystrophin, cause the most common forms of muscular dystrophy. A new study shows that forcing translation of DMD from an internal ribosome entry site can alleviate Duchenne muscular dystrophy symptoms in a mouse model. PMID:25198047

Lamandé, Shireen R; North, Kathryn N

2014-09-01

52

Gene Therapy in Large Animal Models of Muscular Dystrophy  

Microsoft Academic Search

The muscular dystrophies are a group of genetically and phenotypically heterogeneously inherited diseases charac- terized 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 ab- sence of proteins that are critical components of the dystro- phin-glycoprotein complex, which links the cytoskeleton and

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

2009-01-01

53

Defective membrane repair in dysferlin-deficient muscular dystrophy  

Microsoft Academic Search

Muscular dystrophy includes a diverse group of inherited muscle diseases characterized by wasting and weakness of skeletal muscle. Mutations in dysferlin are linked to two clinically distinct muscle diseases, limb-girdle muscular dystrophy type 2B and Miyoshi myopathy, but the mechanism that leads to muscle degeneration is unknown. Dysferlin is a homologue of the Caenorhabditis elegans fer-1 gene, which mediates vesicle

Dimple Bansal; Katsuya Miyake; Steven S. Vogel; Séverine Groh; Chien-Chang Chen; Roger Williamson; Paul L. McNeil; Kevin P. Campbell

2003-01-01

54

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

PubMed

Lamins are the major components of nuclear envelope architecture, being required for both the structural and informational roles of the nuclei. Mutations of lamins cause a spectrum of diseases in humans, including muscular dystrophy. We report here that the loss of the A-type lamin gene, lamin C in Drosophila resulted in pupal metamorphic lethality caused by tendon defects, matching the characteristics of human A-type lamin revealed by Emery-Dreifuss muscular dystrophy (EDMD). In tendon cells lacking lamin C activity, overall cell morphology was affected and organization of the spectraplakin family cytoskeletal protein Shortstop which is prominently expressed in tendon cells gradually disintegrated, notably around the nucleus and in a manner correlating well with the degradation of musculature. Furthermore, lamin C null mutants were efficiently rescued by restoring lamin C expression to shortstop-expressing cells, which include tendon cells but exclude skeletal muscle cells. Thus the critical function of A-type lamin C proteins in Drosophila musculature is to maintain proper function and morphology of tendon cells. PMID:22982669

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

2013-01-01

55

Congenital Muscular Dystrophies: A Brief Review  

PubMed Central

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

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

2011-01-01

56

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

E-print Network

Review Dystrophin, its interactions with other proteins, and implications for muscular dystrophy dystrophy is the most prevalent and severe form of human muscular dystrophy. Investigations into the molecular basis for Duchenne muscular dystrophy were greatly facilitated by seminal studies in the 1980s

Ervasti, James M.

57

Steroid Therapy and Cardiac Function in Duchenne Muscular Dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy leads to progressive deterioration in skeletal and cardiac muscle function. Steroids prolong ambulation\\u000a and improve respiratory muscle strength. The authors hypothesized that steroid treatment would stabilize cardiac muscle function.\\u000a Echocardiograms performed from 1997 to 2004 for 111 subjects 21 years of age or younger with Duchenne muscular dystrophy were\\u000a restrospectively reviewed. The medical record was reviewed for

L. W. Markham; R. L. Spicer; P. R. Khoury; B. L. Wong; K. D. Mathews; L. H. Cripe

2005-01-01

58

Deletion of brain dystroglycan recapitulates aspects of congenital muscular dystrophy  

Microsoft Academic Search

Fukuyama congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and Walker-Warburg syndrome are congenital muscular dystrophies (CMDs) with associated developmental brain defects. Mutations reported in genes of FCMD and MEB patients suggest that the genes may be involved in protein glycosylation. Dystroglycan is a highly glycosylated component of the muscle dystrophin-glycoprotein complex that is also expressed in brain, where its function

Steven A. Moore; Fumiaki Saito; Jianguo Chen; Daniel E. Michele; Michael D. Henry; Albee Messing; Ronald D. Cohn; Susan E. Ross-Barta; Steve Westra; Roger A. Williamson; Toshinori Hoshi; Kevin P. Campbell

2002-01-01

59

Dysphagia in Duchenne Muscular Dystrophy Assessed by Validated Questionnaire  

ERIC Educational Resources Information Center

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…

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

2013-01-01

60

Satellite cells: regenerative mechanisms and applicability in muscular dystrophy.  

PubMed

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

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

2015-01-01

61

Satellite Cells: Regenerative Mechanisms and Applicability in Muscular Dystrophy  

PubMed Central

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

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

2015-01-01

62

Early neurodevelopmental assessment in Duchenne muscular dystrophy.  

PubMed

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7-47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity. PMID:23535446

Pane, Marika; Scalise, Roberta; Berardinelli, Angela; D'Angelo, Grazia; Ricotti, Valeria; Alfieri, Paolo; Moroni, Isabella; Hartley, Louise; Pera, Maria Carmela; Baranello, Giovanni; Catteruccia, Michela; Casalino, Tiziana; Romeo, Domenico M; Graziano, Alessandra; Gandioli, Claudia; Bianco, Flaviana; Mazzone, Elena Stacy; Lombardo, Maria Elena; Scoto, Mariacristina; Sivo, Serena; Palermo, Concetta; Gualandi, Francesca; Sormani, Maria Pia; Ferlini, Alessandra; Bertini, Enrico; Muntoni, Francesco; Mercuri, Eugenio

2013-06-01

63

Gene therapy in Duchenne muscular dystrophy.  

PubMed

Experiments in dystrophin gene transgenic mice have supported the concept of treating Duchenne muscular dystrophy (DMD) by demonstrating that regional expression of recombinant dystrophin in dystrophic muscle leads to regional restoration of normal muscle morphology and that dystrophin mini-genes driven by muscle specific regulatory elements are probably more effective than the full-length dystrophin gene. As a gene therapy trial for DMD, dystrophin cDNAs were introduced into skeletal muscle fibers of dystrophin-deficient mice (mdx) through direct DNA injection into plasmid expression vectors, and by replication-defective recombinant retrovirus or adenovirus vectors. With direct injection of dystrophin cDNA into a plasmid expression vector or retrovirus vectors, less than 10% of adult mdx fibers of the injected muscle expressed dystrophin. On the other hand, greater efficiency has been reported for recombinant adenovirus injection into young mdx muscle. However, it is necessary to develop vectors, viral or plasmid DNA, which can be injected intravenously and directed to muscle tissues. This will involve designing vectors possessing appropriate cell-type specific tropism and/or gene transcriptional activity for DMD treatment. This is anticipated to be a vital component in the second stage of experiments aimed at DMD treatment. PMID:8891229

Inui, K; Okada, S; Dickson, G

1996-01-01

64

Targeting Fibrosis in Duchenne Muscular Dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease affecting 1 in 3,500 live male births. It is an X-linked recessive disease caused by a defective dystrophin gene. The disease is characterized by progressive limb weakness, respiratory and cardiac failure and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. It directly causes muscle dysfunction and contributes to the lethal DMD phenotype. Although gene therapy and cell therapy may ultimately provide a cure for DMD, currently the disease is devastating, with no effective therapies. Recent studies have demonstrated that ameliorating muscle fibrosis may represent a viable therapeutic approach for DMD. By reducing scar formation, antifibrotic therapies may not only improve muscle function but also enhance muscle regeneration and promote gene and stem cell engraftment. Antifibrotic therapy may serve as a necessary addition to gene and cell therapies to treat DMD in the future. Therefore, understanding cellular and molecular mechanisms underlying muscle fibrogenesis associated with dystrophin deficiency is key to the development of effective antifibrotic therapies for DMD. PMID:20613637

Zhou, Lan; Lu, Haiyan

2010-01-01

65

Molecular analysis of facioscapulohumeral muscular dystrophy (FSHD)  

SciTech Connect

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

Upadhyaya, M.; Maynard, J.; Osborn, M. [Institute of Medical Genetics, Cardiff (United Kingdom)] [and others

1994-09-01

66

Serum Creatinine Level: A Supplemental Index to Distinguish Duchenne Muscular Dystrophy from Becker Muscular Dystrophy  

PubMed Central

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

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

2015-01-01

67

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.

68

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

E-print Network

Exon-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 of dystro- phin lead to Duchenne muscular dystrophy (DMD), while mutations--including exon deletions

Discher, Dennis

69

Dissecting muscle and neuronal disorders in a Drosophila model of muscular dystrophy  

E-print Network

Dissecting muscle and neuronal disorders in a Drosophila model of muscular dystrophy Halyna R Perturbation in the Dystroglycan (Dg)­Dystrophin (Dys) complex results in muscular dystrophies and brain abnor muscular dystrophies and neuronal abnormalities caused by defects in this complex. Using a fluorescence

Baker, David

70

Congenital muscular dystrophy with glycosylation defects of a-dystroglycan in Japan  

E-print Network

Congenital muscular dystrophy with glycosylation defects of a-dystroglycan in Japan Hiroshi-dystroglycan (a-DG) cause various muscular dystrophies. We performed clinical, pathological and genetic analyses of 62 Japanese patients with congenital muscular dystrophy, whose skeletal muscle showed deficiency

Campbell, Kevin P.

71

Basic Res Cardiol . Author manuscript Vascular endothelial dysfunction in Duchenne muscular dystrophy is  

E-print Network

muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS Hubert Dabiré 1 oxide synthases (eNOS and nNOS) in Duchenne muscular dystrophy (DMD). Bradykinin is involved oxide synthase ; bradykinin Introduction Duchenne muscular dystrophy (DMD) affects one in 3500 male

Paris-Sud XI, Université de

72

Genetic Therapy for Duchenne Muscular Dystrophy: Viral Vectors and Micro-Gene Therapy  

E-print Network

Genetic Therapy for Duchenne Muscular Dystrophy: Viral Vectors and Micro-Gene Therapy Taeyoung Koo, Royal Holloway-University of London, Egham, TW20 0EX What is Duchenne Muscular Dystrophy (DMD)? DMD is Duchenne Muscular Dystrophy (DMD)? DMD is a Neuromuscular disease caused by mutations in the dystrophin

Royal Holloway, University of London

73

Salaried Summer Internship The Muscular Dystrophy Association is seeking graduate students, graduating seniors or  

E-print Network

Salaried Summer Internship The Muscular Dystrophy Association is seeking graduate students muscular dystrophy, ALS and related diseases by funding worldwide research. The Association also provides:Contact:Contact:Contact: Kelli Park | Public Relations Coordinator | Muscular Dystrophy Association | 3300 E. Sunrise Drive

Cinabro, David

74

Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub-Phenotypes and Predictive  

E-print Network

Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub Background: To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major, Becane H-M, et al. (2009) Clinical Heterogeneity of Duchenne Muscular Dystrophy (DMD): Definition of Sub

Paris-Sud XI, Université de

75

The burden of Duchenne muscular dystrophy  

PubMed Central

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

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

2014-01-01

76

[A clinical trial of creatine monohydrate in muscular dystrophy patients].  

PubMed

To investigate the effects of creatine monohydrate on muscle performance and cognitive functions in muscular dystrophy patients, we made an open trial. Twenty-nine individuals, including 14 myotonic dystrophy (DM), seven facioscapurohumeral muscular dystrophy (FSHD), two limb-girdle muscular dystrophy and six healthy volunteers, were enrolled in this study and 27 participants completed it. All participants took creatine 20g/day for an initial week and 5g/day for successive eight weeks. Somatotonic measurements, global subjective assessment, muscle performance, cardiopulmonary function, cognitive function, laboratory studies and magnetic resonance spectroscopy (MRS) were evaluated at both pre and post examination. Subjective improvements were reported from twelve individuals. Contrary adverse effects were also complained from ten individuals, although all these problems were not serious. Quantitative muscle power was slightly but significantly increased in the patients and the number of the patients who failed to complete cycle ergometer test was decreased. Phosphocreatine concentrations of left calf muscle were not different between pre and post trial examination. No obvious changes were detected in cardiopulmonary assessment, cognitive function and laboratory date. Creatine has certain expectance for muscular dystrophy patients in motor performance. The effect may be achieved not only by increase of energy buffer, because clinical improvements were observed in our study nevertheless no increase was detected in phosphocreatine concentration. The usage of creatine should be managed under medical monitoring since ideal protocol has not yet been established and adverse effects can not be ignored. PMID:15568480

Matsumura, Tsuyoshi; Yokoe, Masaru; Nakamori, Masayuki; Hattori, Noriaki; Saito, Toshio; Nozaki, Sonoko; Fujimura, Harutoshi; Shinno, Susumu

2004-10-01

77

Feasibility of neonatal screening for Duchenne muscular dystrophy.  

PubMed Central

During the period November 1976 to September 1980, 2703 babies born in one Edinburgh hospital were screened in the neonatal period by estimation of their serum creatine kinase levels for Duchenne muscular dystrophy. Among the 2336 male babies tested, none proved to be affected and only 16 required second specimens to be obtained. Overall the false positive rate in the study was 0.78%. This study confirms that neonatal screening for Duchenne muscular dystrophy is feasible in a British hospital setting and is here most conveniently carried out on the 5th day of life along with routine testing for phenylketonuria. PMID:7069739

Skinner, R; Emery, A E; Scheuerbrandt, G; Syme, J

1982-01-01

78

New aspects on patients affected by dysferlin deficient muscular dystrophy  

Microsoft Academic Search

Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin

Lars Klinge; Ahmed Aboumousa; Michelle Eagle; Judith Hudson; Anna Sarkozy; Gianluca Vita; Richard Charlton; Mark Roberts; Volker Straub; Rita Barresi; Hanns Lochmüller; Kate Bushby

2009-01-01

79

Mutations in B3GALNT2 Cause Congenital Muscular Dystrophy  

E-print Network

glycosyltransferases cause glycosylation defects in a-dystroglycan (a-DG), an integral component of the dystrophin dystroglycan glycosyl- ation was reduced in the fibroblasts and muscle (when available) of these individuals, knockdown of b3galnt2 in zebrafish recapitulated the human congenital muscular dystrophy pheno- type

Campbell, Kevin P.

80

Therapies in Muscular Dystrophy: Current Concepts and Future Prospects  

Microsoft Academic Search

In the fast moving field of muscular dystrophy, therapeutic matters are now high on the agenda. Despite little progress made in the understanding of the exact pathogenesis, hopes have been raised with the advent of molecular medicine applied to such disorders. A constellation of techniques or therapeutic solutions are now available, but very few have reached the clinical stage. Gene

J. Andoni Urtizberea

2000-01-01

81

Swallow Characteristics in Patients with Oculopharyngeal Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2010-01-01

82

X Chromosome-Linked Muscular Dystrophy (mdx) in the Mouse  

Microsoft Academic Search

An X chromosome-linked mouse mutant (gene symbol, mdx) has been found that has elevated plasma levels of muscle creatine kinase and pyruvate kinase and exhibits histological lesions characteristic of muscular dystrophy. The mutants show mild clinical symptoms and are viable and fertile. Linkage analysis with four X chromosome loci indicates that mdx maps in the Hq Bpa region of the

Grahame Bulfield; W. G. Siller; P. A. L. Wight; Karen J. Moore

1984-01-01

83

Oculopharyngeal muscular dystrophy - an under-diagnosed disorder?  

Microsoft Academic Search

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant muscle disorder, usually of late onset. OPMD is among the few triplet re- peat diseases\\/ polyalanine (poly(A)) expansion dis- eases for which the function of the mutated gene is quite well established. The disease is charac- terised by slowly progressive bilateral ptosis, dys- phagia and proximal limb weakness, appearing after the age

Stephan Rüegg; Monique Lehky Hagen; Ursula Hohla; Ludwig Kappos; Peter Fuhr; Martina Plasilova; Hansjakob Müller; Karl Heinimann

84

Brain alterations in the classical form of congenital muscular dystrophy  

Microsoft Academic Search

In the classical form of congenital muscular dystrophy (CMD), subclinical brain involvement is frequent. In order to establish the natural evolution of CNS alterations in this type of CMD, the cerebral functions of 12 cases were examined longitudinally for a mean period of 8 years. There were 7 boys and 5 girls, with a mean age of 5 years at

Carlo P. Trevisan; Francesco Martinello; Emilia Ferruzza; Marina Fanin; Martine Chevallay; Fernando M. S. Tomé

1996-01-01

85

Expression of laminin subunits in congenital muscular dystrophy  

Microsoft Academic Search

The expression of laminin subunits M, A, B1 and B2 was studied immunocytochemically in 25 cases of classical congenital muscular dystrophy (CMD), 11 hypotonic infants, 20 cases of a variety of inherited and acquired neuromuscular disorders, and 11 controls. Merosin, as indicated by labelling for the M chain, was deficient in 12 (48%) of the cases of classical CMD. Seven

C. A. Sewry; J. Philpot; D. Mahony; L. A. Wilson; F. Muntoni; V. Dubowitz

1995-01-01

86

The Assessment of Intelligence in Boys with Duchenne Muscular Dystrophy.  

ERIC Educational Resources Information Center

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).…

Mearig, Judith S.

1979-01-01

87

The Child with Muscular Dystrophy in School. Revised.  

ERIC Educational Resources Information Center

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

Schock, Nancy C.

88

Phonological Awareness Skills in Young Boys with Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

Waring, Phoebe; Woodyatt, Gail

2011-01-01

89

Phosphorylation of intact erythrocytes in human muscular dystrophy  

SciTech Connect

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.

Johnson, R.M.; Nigro, M.

1986-04-01

90

Occupational Potential in a Population with Duchenne Muscular Dystrophy.  

ERIC Educational Resources Information Center

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…

Schkade, Janette K.; And Others

1987-01-01

91

Poor Facial Affect Recognition among Boys with Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2007-01-01

92

Stem cell transplantation for treating Duchenne muscular dystrophy  

PubMed Central

OBJECTIVE: To identify global research trends in stem cell transplantation for treating Duchenne muscular dystrophy using a bibliometric analysis of Web of Science. DATA RETRIEVAL: We performed a bibliometric analysis of studies on stem cell transplantation for treating Duchenne muscular dystrophy from 2002 to 2011 retrieved from Web of Science. SELECTION CRITERIA: Inclusion criteria: (a) peer-reviewed published articles on stem cell transplantation for treating Duchenne muscular dystrophy indexed in Web of Science; (b) original research articles, reviews, meeting abstracts, proceedings papers, book chapters, editorial material, and news items; and (c) publication between 2002 and 2011. Exclusion criteria: (a) articles that required manual searching or telephone access; (b) documents that were not published in the public domain; and (c) corrected papers. MAIN OUTCOME MEASURES: (1) Annual publication output; (2) distribution according to subject areas; (3) distribution according to journals; (4) distribution according to country; (5) distribution according to institution; (6) distribution according to institution in China; (7) distribution according to institution that cooperated with Chinese institutions; (8) top-cited articles from 2002 to 2006; (9) top-cited articles from 2007 to 2011. RESULTS: A total of 318 publications on stem cell transplantation for treating Duchenne muscular dystrophy were retrieved from Web of Science from 2002 to 2011, of which almost half derived from American authors and institutes. The number of publications has gradually increased over the past 10 years. Most papers appeared in journals with a focus on gene and molecular research, such as Molecular Therapy, Neuromuscular Disorders, and PLoS One. The 10 most-cited papers from 2002 to 2006 were mostly about different kinds of stem cell transplantation for muscle regeneration, while the 10 most-cited papers from 2007 to 2011 were mostly about new techniques of stem cell transplantation for treating Duchenne muscular dystrophy. CONCLUSION: The publications on stem cell transplantation for treating Duchenne muscular dystrophy were relatively few. It also needs more research to confirm that stem cell therapy is a reliable treatment for Duchenne muscular dystrophy. PMID:25624797

Yang, Xiaofeng

2012-01-01

93

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

E-print Network

Action Plan for the Muscular Dystrophies DEPARTMENT OF HEALTH AND HUMAN SERVICES Muscular Dystrophy Glycosylation 25 26 Development of Mutation Testing for Myotonic Dystrophy Type 2 27 Improved Diagnostic Testing of and Advances to Treat Sleep-Disordered Breathing 56 Improved Techniques for Diagnosis and Testing 56 Early

94

Origins and early descriptions of "Duchenne muscular dystrophy".  

PubMed

One of the seminal events in the history of neurology was the identification of primary diseases of muscle and their separation from diseases in which muscle weakness was secondary to injury involving the anterior horns of the spinal cord ("progressive muscular atrophy"). Not surprisingly, one of the first groups of primary muscle diseases to be satisfactorily characterized belonged to what would today be classified as muscular dystrophies. Pride of place in this group belongs to Duchenne muscular dystrophy (DMD). DMD's primacy as the first well-characterized muscular dystrophy was due both to the fact that it is relatively common, as well as to the clinically striking feature, apparent in many cases, of apparent paradoxical enlargement of severely weakened muscles ("pseudo-hypertrophy"). This review traces the historical roots of DMD in the 19th century, from the early papers by Conte, Bell, Partridge, and Meryon through the classic monographs by Duchenne and Gowers. In addition, the first American contributions to DMD are reviewed, including those by Pepper, Hammond, and S. Weir Mitchell. Many of the original papers describing this disease are now unavailable outside of major medical libraries, and several important contributions, excepting those of Duchenne, which are recognized eponymously, are now virtually forgotten. PMID:14506712

Tyler, Kenneth L

2003-10-01

95

Spinal motor neurones in murine muscular dystrophy and spinal muscular atrophy  

PubMed Central

Recent electrophysiological studies of human and mouse muscular dystrophy have prompted the hypothesis that both are of neurogenic rather than myogenic origin. A decreased number of spinal motor neurones might be expected if this hypothesis were correct. The total number of neurones in the anterior grey horns of seven normal mice, six Bar Harbor 129 strain dystrophic mice, and six mice suffering from genetically-determined spinal muscular atrophy have been counted. The number of neurones in the cell types believed to include the motor neurones was significantly reduced to 13 to 71% of normal in mice with spinal muscular atrophy. In mice with muscular dystrophy, the number of anterior horn neurones was higher rather than lower than normal. The significance of these findings is discussed. Images PMID:5026011

Papapetropoulos, T. A.; Bradley, W. G.

1972-01-01

96

Aberrant glycosylation of a-dystroglycan causes defective binding of laminin in the muscle of chicken muscular dystrophy  

E-print Network

of chicken muscular dystrophy Fumiaki Saitoa,*, Martina Blankb , Jo¨rn Schro¨derb , Hiroshi Manyac , Teruo as an animal model of human muscular dystrophy, the pathomechanism leading to muscular degeneration remains of muscular dystrophy. Ó 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All

Campbell, Kevin P.

97

GENE AND CELL-MEDIATED THERAPIES FOR MUSCULAR DYSTROPHY  

PubMed Central

Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, the most recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and non-viral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene. PMID:23553671

Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S.

2014-01-01

98

Gene and cell-mediated therapies for muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3,500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, more recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and nonviral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene. PMID:23553671

Konieczny, Patryk; Swiderski, Kristy; Chamberlain, Jeffrey S

2013-05-01

99

Succinylcholine-induced cardiac arrest in unsuspected Duchenne muscular dystrophy  

Microsoft Academic Search

A case history is presented of a three-year-old boy with unsuspected Duchenne muscular dystrophy, who suffered a cardiac arrest\\u000a following the administration of a single dose of succinylcholine during a halothane anaesthetic. The arrest was associated\\u000a with lack of fasciculations, muscle rigidity, hyperkalemia, myoglobinuria, and massive elevation of serum creatine phosphokinase.\\u000a Asystole was prolonged and refractory to treatment, although cardiac

W. A. V. Henderson

1984-01-01

100

Poor Facial Affect Recognition Among Boys with Duchenne Muscular Dystrophy  

Microsoft Academic Search

Children with Duchenne or Becker muscular dystrophy (MD) have delayed language and poor social skills and some meet criteria\\u000a for Pervasive Developmental Disorder, yet they are identified by molecular, rather than behavioral, characteristics. To determine\\u000a whether comprehension of facial affect is compromised in boys with MD, children were given a matching-to-sample test with\\u000a four types of visual recognition (Object, Face,

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

2007-01-01

101

Duchenne muscular dystrophy: Pathogenetic aspects and genetic prevention  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is the most common sex linked lethal disease in man (one case in about 4000 male live births). The patients are wheelchair bound around the age of 8–10 years and usually die before the age of 20 years. The mutation rate, estimated by different methods and from different population studies, is in the order of 7×10-5,

H. Moser

1984-01-01

102

Noncoding RNAs: Emerging Players in Muscular Dystrophies  

PubMed Central

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

2014-01-01

103

Therapeutic trials in muscular dystrophy. III. Studies of microbial proteinase inhibitors in murine dystrophy.  

PubMed

The microbial antiproteinases--antipain, leupeptin, and pepstatin--have been reported to inhibit the degeneration of chicken dystrophic muscle in tissue culture. Trials of antipain and pepstatin, and of leupeptin and pepstatin administered subcutaneously in murine muscular dystrophy, failed to produce evidence of benefit. It is suggested that these antiproteinases cannot pass through an intact sarcolemma into muscle fibers. Further studies with liposomes may allow these agents to enter muscle fibers. PMID:337944

Enomoto, A; Bradley, W G

1977-12-01

104

Identification of three distinguishable phenotypes in golden retriever muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is a human disease characterized by progressive and irreversible skeletal muscle degeneration caused by mutations in genes coding for important muscle proteins. Unfortunately, there is no efficient treatment for this disease; it causes progressive loss of motor and muscular ability until death. The canine model (golden retriever muscular dystrophy) is similar to DMD, showing similar clinical signs. Fifteen dogs were followed from birth and closely observed for clinical signs. Dogs had their disease status confirmed by polymerase chain reaction analysis and genotyping. Clinical observations of musculoskeletal, morphological, gastrointestinal, respiratory, cardiovascular, and renal features allowed us to identify three distinguishable phenotypes in dystrophic dogs: mild (grade I), moderate (grade II) and severe (grade III). These three groups showed no difference in dystrophic alterations of muscle morphology and creatine kinase levels. This information will be useful for therapeutic trials, because DMD also shows significant, inter- and intra-familiar clinical variability. Additionally, being aware of phenotypic differences in this animal model is essential for correct interpretation and understanding of results obtained in pre-clinical trials. PMID:19440974

Ambrósio, C E; Fadel, L; Gaiad, T P; Martins, D S; Araújo, K P C; Zucconi, E; Brolio, M P; Giglio, R F; Morini, A C; Jazedje, T; Froes, T R; Feitosa, M L T; Valadares, M C; Beltrão-Braga, P C B; Meirelles, F V; Miglino, M A

2009-01-01

105

What is muscular dystrophy?, 2D animationSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.

2008-10-06

106

What causes muscular dystrophy?, 2D animationSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.

2008-10-06

107

Duchenne muscular dystrophy, 2D animationSite: DNA Interactive (www.dnai.org)  

NSDL National Science Digital Library

The DMD gene codes for a large protein called dystrophin that is necessary for muscle cells to maintain their shape. When this protein is missing, muscle cells literally explode as material from outside the cell walls leaks in raising cell pressure. Mutations in the DMD gene can cause a muscle-wasting disorder, called Duchenne muscular dystrophy, or its milder form, Becker muscular dystrophy.

2008-10-06

108

Expression Profiling in the Muscular Dystrophies: Identification of Novel Aspects of Molecular Pathophysiology  

Microsoft Academic Search

We used expression profiling to define the pathophysiological cascades involved in the progres- sion of two muscular dystrophies with known primary biochemical defects, dystrophin deficiency (Duchenne muscular dystrophy) and a -sarcoglycan deficiency (a dystrophin-associated protein). We employed a novel protocol for expression profiling in human tissues using mixed samples of multiple patients and iterative com- parisons of duplicate datasets. We

Yi-Wen Chen; Po Zhao; Rehannah Borup; Eric P. Hoffman

2000-01-01

109

Meeting the Assistive Technology Needs of Students with Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2009-01-01

110

257. Ex Vivo Gene Therapy for Duchenne Muscular Dystrophy: Lentiviral and PhiC31 Integrase Approaches  

Microsoft Academic Search

Duchenne muscular dystrophy is the most severe muscular dystrophy. It is caused by the absence of dystrophin in muscle fibers. This absence lead to increased muscle damage, loss of muscle mass, loss of strength, respiratory and heart failure. This disease as currently no treatment. Myogenic cells transplantation is a possible cure for Duchenne muscular dystrophy. However, allogeneic graft success relies

Simon P. Quenneville; Pierre Chapdelaine; Joël Rousseau; Michele P. Calos; Jacques P. Tremblay

2005-01-01

111

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

ERIC Educational Resources Information Center

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

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

2008-01-01

112

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

E-print Network

-girdle muscular dystrophy Julien Couthouis a,1 , Alya R. Raphael a,1 , Carly Siskind b,1 , Andrew R. Findlay c,2 2014 Abstract Limb-girdle muscular dystrophy primarily affects the muscles of the hips and shoulders-girdle muscular dystrophy type 1D. Additional family members were Sanger sequenced and the mutation in DNAJB6

Straight, Aaron

113

Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving  

E-print Network

ARTICLE Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion online 19 January 2011 Keywords: congenital muscular dystrophy 1D; alpha-dystroglycan; DNA duplication pathogenic mechanism for a group of congenital muscular dystrophies (CMD), collectively called the `a

Campbell, Kevin P.

114

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

E-print Network

Cell, 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 of Duchenne muscular dystrophy (DMD) patients. In the last few years, the role of dystrophin in skeletal

Campbell, Kevin P.

115

Congenital disorder of glycosylation due to DPM1 mutations presenting with dystroglycanopathy-type congenital muscular dystrophy  

E-print Network

-type congenital muscular dystrophy Amy C. Yang a, ,1 , Bobby G. Ng b,1 , Steven A. Moore c , Jeffrey Rush d of glycosylation Dystroglycanopathy Congenital muscular dystrophy DPM1 DPM1-CDG CDG-Ie Congenital disorders kinase. Muscle biopsy showed muscular dystrophy and reduced -dystroglycan immu- nostaining

Campbell, Kevin P.

116

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

E-print Network

A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype in severity from Walker­Warburg 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

Campbell, Kevin P.

117

Creatine monohydrate in muscular dystrophies: A double-blind, placebo-controlled clinical study.  

PubMed

The authors assessed the safety and efficacy of creatine monohydrate (Cr) in various types of muscular dystrophies in a double-blind, crossover trial. Thirty-six patients (12 patients with facioscapulohumeral dystrophy, 10 patients with Becker dystrophy, 8 patients with Duchenne dystrophy, and 6 patients with sarcoglycan-deficient limb girdle muscular dystrophy) were randomized to receive Cr or placebo for 8 weeks. There was mild but significant improvement in muscle strength and daily-life activities by Medical Research Council scales and the Neuromuscular Symptom Score. Cr was well tolerated throughout the study period. PMID:10802796

Walter, M C; Lochmüller, H; Reilich, P; Klopstock, T; Huber, R; Hartard, M; Hennig, M; Pongratz, D; Müller-Felber, W

2000-05-01

118

NAD+ Biosynthesis Ameliorates a Zebrafish Model of Muscular Dystrophy  

PubMed Central

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

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

2012-01-01

119

New aspects on patients affected by dysferlin deficient muscular dystrophy  

PubMed Central

Mutations in the dysferlin gene lead to limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. A cohort of 36 patients affected by dysferlinopathy is described, in the first UK study of clinical, genetic, pathological and biochemical data. The diagnosis was established by reduction of dysferlin in the muscle biopsy and subsequent mutational analysis of the dysferlin gene. Seventeen mutations were novel; the majority of mutations were small deletions/insertions, and no mutational hotspots were identified. Sixty-one per cent of patients (22 patients) initially presented with limb girdle muscular dystrophy 2B, 31% (11 patients) with a Miyoshi phenotype, one patient with proximodistal mode of onset, one patient with muscle stiffness after exercise and one patient as a symptomatic carrier. A wider range of age of onset was noted than previously reported, with 25% of patients having first symptoms before the age of 13?years. Independent of the initial mode of presentation, in our cohort of patients the gastrocnemius muscle was the most severely affected muscle leading to an inability to stand on tiptoes, and lower limbs were affected more severely than upper limbs. As previous anecdotal evidence on patients affected by dysferlinopathy suggests good muscle prowess before onset of symptoms, we also investigated pre-symptomatic fitness levels of the patients. Fifty-three per cent of the patients were very active and sporty before the onset of symptoms which makes the clinical course of dysferlinopathy unusual within the different forms of muscular dystrophy and provides a challenge to understanding the underlying pathomechanisms in this disease. PMID:19528035

Klinge, Lars; Aboumousa, Ahmed; Eagle, Michelle; Hudson, Judith; Sarkozy, Anna; Vita, Gianluca; Charlton, Richard; Roberts, Mark; Straub, Volker; Barresi, Rita; Lochmüller, Hanns

2009-01-01

120

Halofuginone improves muscle-cell survival in muscular dystrophies.  

PubMed

Halofuginone has been shown to prevent fibrosis via the transforming growth factor-?/Smad3 pathway in muscular dystrophies. We hypothesized that halofuginone would reduce apoptosis--the presumed cause of satellite-cell depletion during muscle degradation-in the mdx mouse model of Duchenne muscular dystrophy. Six-week-old mdx mouse diaphragm exhibited fourfold higher numbers of apoptotic nuclei compared with wild-type mice as determined by a TUNEL assay. Apoptotic nuclei were found in macrophages and in Pax7-expressing cells; some were located in centrally-nucleated regenerating myofibers. Halofuginone treatment of mdx mice reduced the apoptotic nuclei number in the diaphragm, together with reduction in Bax and induction in Bcl2 levels in myofibers isolated from these mice. A similar effect was observed when halofuginone was added to cultured myofibers. No apparent effect of halofuginone was observed in wild-type mice. Inhibition of apoptosis or staurosporine-induced apoptosis by halofuginone in mdx primary myoblasts and C2 myogenic cell line, respectively, was reflected by less pyknotic/apoptotic cells and reduced Bax expression. This reduction was reversed by a phosphinositide-3-kinase and mitogen-activated protein kinase/extracellular signal-regulated protein kinase inhibitors, suggesting involvement of these pathways in mediating halofuginone's effects on apoptosis. Halofuginone increased apoptosis in ? smooth muscle actin- and prolyl 4-hydroxylase ?-expressing cells in mdx diaphragm and in myofibroblasts, the major source of extracellular matrix. The data suggest an additional mechanism by which halofuginone improves muscle pathology and function in muscular dystrophies. PMID:24703880

Bodanovsky, Anna; Guttman, Noga; Barzilai-Tutsch, Hila; Genin, Ola; Levy, Oshrat; Pines, Mark; Halevy, Orna

2014-07-01

121

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

PubMed Central

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

Liew, Wendy K. M.

2013-01-01

122

The Molecular Biology of Mutations and Muscular Dystrophy  

NSDL National Science Digital Library

In this mind-on analysis and discussion activity students explore the effects of different types of point mutations and deletion mutations and analyze the reasons why deletion mutations generally have more severe effects than point mutations. Students use their understanding of the molecular biology of mutations to analyze the genetic basis for the differences in severity of two types of muscular dystrophy. To maximize student participation and learning, I recommend that you have your students complete the questions individually or in pairs and then have a whole class discussion.

Ingrid Waldron

123

A two-amino-acid mutation encountered in a Duchenne muscular dystrophy decreases stability of the R23 spectrin-like repeat of dystrophin  

E-print Network

A two-amino-acid mutation encountered in a Duchenne muscular dystrophy decreases stability of the R severe Duchenne muscular dystrophy (DMD). While dystrophin's native function is still unknown, its in muscle cell. Dystrophin-associated muscular dystrophies range from the severe Duchenne muscular dystrophy

Paris-Sud XI, Université de

124

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

E-print Network

INVITED 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-deficient limb-girdle muscular dystrophy. Intri- guingly, two other forms of limb-girdle muscular dystrophy

Campbell, Kevin P.

125

Restoring Dystrophin Expression in Duchenne Muscular Dystrophy Muscle  

PubMed Central

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

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

2011-01-01

126

Oculopharyngeal muscular dystrophy as a rare cause of dysphagia  

PubMed Central

Oculopharyngeal muscular dystrophy (OPMD) is a rare cause for late-onset dysphagia. OPMD normally follows an autosomal dominant inheritance. Herein we describe a rare case of an autosomal recessive inheritance of OPMD. An 80-year-old male presented with progressive dysphagia, frequent aspiration and change of voice getting inarticulate and hoarse. Physical examination showed ptosis of the right eyelid. Endoscopic and manometric investigation revealed a nonspecific motility disorder with hypopharyngeal esophageal hypotension. The severity of dysphagia became apparent when significant aspiration occurred during a barium swallow. Magnetic resonance imaging of the head ruled out a malignant or cerebral ischemic process. Based on the neurological examination, neurogenic muscular dystrophy was suspected and DNA analysis was performed. The analysis confirmed the extremely rare diagnosis of an autosomal recessive inheritance pattern of OPMD with homozygous (GCN)6(GCN)4(GCN) expansion of the poly-(A) binding protein nuclear 1 gene. As OPMD normally follows an autosomal dominant inheritance, consanguinity of the patient’s parents was suspected.

Werling, Sarah; Schrank, Bertold; Eckardt, Alexander J.; Hauburger, Anja; Deschauer, Marcus; Müller, Michaela

2015-01-01

127

Arginine butyrate: a therapeutic candidate for Duchenne muscular dystrophy.  

PubMed

As a strategy to treat Duchenne muscular dystrophy, we used arginine butyrate, which combines two pharmacological activities: nitric oxide pathway activation, and histone deacetylase inhibition. Continuous intraperitoneal administration to dystrophin-deficient mdx mice resulted in a near 2-fold increase in utrophin (protein homologous to dystrophin) in skeletal muscle, heart, and brain, accompanied by an improvement of the dystrophic phenotype in both adult and newborn mice (45 and 70% decrease in creatine kinase level, respectively; 14% increase in tidal volume, 30% decrease in necrotic area in limb and 23% increase in isometric force). Intermittent administration, as performed in clinical trials, was then used to reduce the frequency of injections and to improve safety. This also enhanced utrophin level around 2-fold (EC50=284 mg/ml) and alleviated the dystrophic phenotype (inverted grid and grip test performance near to wild-type values, creatine kinase level decreased by 50%). Skin biopsies were used to monitor treatment efficacy, instead of invasive muscle biopsies, and this could be done a few days after the start of treatment. A 2-fold increase in utrophin expression was also shown in cultured human myotubes. In vivo and in vitro experiments demonstrated that the drug combination acts synergistically. Together, these data constitute a proof of principle of the beneficial effects of arginine butyrate on muscular dystrophy. PMID:23430975

Vianello, Sara; Yu, Hua; Voisin, Vincent; Haddad, Hafedh; He, Xun; Foutz, Arthur S; Sebrié, Catherine; Gillet, Brigitte; Roulot, Morgane; Fougerousse, Françoise; Perronnet, Caroline; Vaillend, Cyrille; Matecki, Stefan; Escolar, Diana; Bossi, Laura; Israël, Maurice; de la Porte, Sabine

2013-06-01

128

Dystrophin in frameshift deletion patients with Becker Muscular Dystrophy  

SciTech Connect

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.

Gangopadhyay, S.B.; Ray, P.N.; Worton, R.G.; Sherratt, T.G.; Heckmatt, J.Z.; Dubowitz, V.; Strong, P.N.; Miller, G. (Penn State College of Medicine, Hershey, PA (United States)); Shokeir, M. (Univ. Hospital, Saskatchewan (Canada))

1992-09-01

129

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

PubMed Central

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

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

130

Serum profiling identifies novel muscle miRNA and cardiomyopathy-related miRNA biomarkers in Golden Retriever muscular dystrophy dogs and Duchenne muscular dystrophy patients.  

PubMed

Duchenne muscular dystrophy (DMD) is a fatal, X-linked neuromuscular disease that affects 1 boy in 3500 to 5000 boys. The golden retriever muscular dystrophy dog is the best clinically relevant DMD animal model. Here, we used a high-thoughput miRNA sequencing screening for identification of candidate serum miRNA biomarkers in golden retriever muscular dystrophy dogs. We confirmed the dysregulation of the previously described muscle miRNAs, miR-1, miR-133, miR-206, and miR-378, and identified a new candidate muscle miRNA, miR-95. We identified two other classes of dysregulated serum miRNAs in muscular dystrophy: miRNAs belonging to the largest known miRNA cluster that resides in the imprinting DLK1-DIO3 genomic region and miRNAs associated with cardiac disease, including miR-208a, miR-208b, and miR-499. No simple correlation was identified between serum levels of cardiac miRNAs and cardiac functional parameters in golden retriever muscular dystrophy dogs. Finally, we confirmed a dysregulation of miR-95, miR-208a, miR-208b, miR-499, and miR-539 in a small cohort of DMD patients. Given the interspecies conservation of miRNAs and preliminary data in DMD patients, these newly identified dysregulated miRNAs are strong candidate biomarkers for DMD patients. PMID:25194663

Jeanson-Leh, Laurence; Lameth, Julie; Krimi, Soraya; Buisset, Julien; Amor, Fatima; Le Guiner, Caroline; Barthélémy, Inès; Servais, Laurent; Blot, Stéphane; Voit, Thomas; Israeli, David

2014-11-01

131

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

PubMed Central

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.

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

2014-01-01

132

Duchenne muscular dystrophy: Drug development and regulatory considerations.  

PubMed

Duchenne muscular dystrophy (DMD) is one of the most commonly recognized dystrophinopathies. There are no approved therapeutic options available for this disease but recent discoveries have led to hope that effective therapies might be forthcoming. With funding from patient advocacy groups, private investors, and governmental bodies such as the Food and Drug Administration Office of Orphan Product Development (FDA/OOPD), gene modification and other molecular therapies are being actively investigated. However, since DMD patients are few in number and disease manifestations vary considerably in early and late stages of disease, obtaining the data needed for full evaluation of putative therapies may prove challenging. Should ambulation remain the focus of Phase 2/3 studies or should consideration be given to the primary causes of late-stage morbidity and mortality, e.g., cardiac and respiratory dysfunction related to reduced or absent dystrophin production? It seems reasonable to argue that clinical trials planned for DMD should consider the entire population. PMID:20373504

McNeil, D Elizabeth; Davis, Carole; Jillapalli, Devanand; Targum, Shari; Durmowicz, Anthony; Coté, Timothy R

2010-06-01

133

Rimmed Vacuoles in Becker Muscular Dystrophy Have Similar Features with Inclusion Myopathies  

PubMed Central

Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45–48 in DMD gene. All patients having rimmed vacuoles showed milder clinical features compared to those without rimmed vacuoles. Interestingly, the rimmed vacuoles in Becker muscular dystrophy muscles seem to represent autophagic vacuoles and are also associated with polyubiquitinated protein aggregates. These findings support the notion that rimmed vacuoles can appear in Becker muscular dystrophy, and may be related to the chronic changes in muscle pathology induced by certain mutations in the DMD gene. PMID:23251671

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

2012-01-01

134

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

E-print Network

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

Campbell, Kevin P.

135

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.

136

Histological parameters for the quantitative assessment of muscular dystrophy in the mdx-mouse  

Microsoft Academic Search

Duchenne muscular dystrophy is a severe X-linked hereditary disease caused by the absence of functional dystrophin. The dystrophin-deficient mdx-mouse strain is a widely used animal model for dystrophin-deficiency. Several therapeutic approaches for muscular dystrophy have been proposed by different laboratories. In order to compare the efficacy of these therapies in the mdx-mouse, it is essential to implement standardized protocols for

Alexandre Briguet; Isabelle Courdier-Fruh; Mark Foster; Thomas Meier; Josef P. Magyar

2004-01-01

137

Posttranslational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies  

Microsoft Academic Search

Muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD) are congenital muscular dystrophies with associated, similar brain malformations. The FCMD gene, fukutin, shares some homology with fringe-like glycosyltransferases, and the MEB gene, POMGnT1, seems to be a new glycosyltransferase. Here we show, in both MEB and FCMD patients, that alpha-dystroglycan is expressed at the muscle membrane, but similar hypoglycosylation in

Daniel E. Michele; Rita Barresi; Motoi Kanagawa; Fumiaki Saito; Ronald D. Cohn; Jakob S. Satz; James Dollar; Ichizo Nishino; Richard I. Kelley; Hannu Somer; Volker Straub; Katherine D. Mathews; Steven A. Moore; Kevin P. Campbell

2002-01-01

138

Decreased Insulin Receptors but Normal Glucose Metabolism in Duchenne Muscular Dystrophy  

NASA Astrophysics Data System (ADS)

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.

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

1982-04-01

139

The Duchenne muscular dystrophy gene product is localized in sarcolemma of human skeletal muscle  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) and its milder form, Becker muscular dystrophy (BMD), are allelic X-linked muscle disorders in man1. The gene responsible for the disease has been cloned from knowledge of its map location at band Xp21 on the short arm of the X chromosome2-5. The product of the DMD gene, a protein of relative molecular mass 400,000 (Mr 400K)

Elizabeth E. Zubrzycka-Gaarn; Dennis E. Bulman; George Karpati; Arthur H. M. Burghes; Bonnie Belfall; Henry J. Klamut; Jim Talbot; Robert S. Hodges; Peter N. Ray; Ronald G. Worton

1988-01-01

140

The mdx mouse diaphragm reproduces the degenerative changes of Duchenne muscular dystrophy  

Microsoft Academic Search

ALTHOUGH murine X-linked muscular dystrophy (mdx) and Duchenne muscular dystrophy (DMD) are genetically homologous and both characterized by a complete absence of dystrophin1,2, the limb muscles of adult mdx mice suffer neither the detectable weakness nor the progressive degeneration that are features of DMD3-8. Here we show that the mdx mouse diaphragm exhibits a pattern of degeneration, fibrosis and severe

H. H. Stedman; H. L. Sweeney; J. B. Shrager; H. C. Maguire; R. A. Panettieri; B. Petrof; M. Narusawa; J. M. Leferovich; J. T. Sladky; A. M. Kelly

1991-01-01

141

Cloning of the breakpoint of an X;21 translocation associated with Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder which affects approximately 1 in 3,300 males, making it the most common of the neuromuscular dystrophies (see ref. 1 for review). The biochemical basis of the disease is unknown and as yet no effective treatment is available. A small number of females are also affected with the disease, and these have

Peter N. Ray; Bonnie Belfall; Catherine Duff; Cairine Logan; Vanora Kean; Margaret W. Thompson; James E. Sylvester; Jerome L. Gorski; Roy D. Schmickel; Ronald G. Worton

1985-01-01

142

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

PubMed Central

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

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

2014-01-01

143

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

PubMed

An X-linked muscular dystrophy, with deficiency of full-length dystrophin and expression of a low molecular weight dystrophin-related protein, has been described in Japanese Spitz dogs. The aim of this study was to identify the causative mutation and develop a specific test to identify affected cases and carrier animals. Gene expression studies in skeletal muscle of an affected animal indicated aberrant expression of the Duchenne muscular dystrophy (dystrophin) gene and an anomaly in intron 19 of the gene. Genome-walking experiments revealed an inversion that interrupts two genes on the X chromosome, the Duchenne muscular dystrophy gene and the retinitis pigmentosa GTPase regulator gene. All clinically affected dogs and obligate carriers that were tested had the mutant chromosome, and it is concluded that the inversion is the causative mutation for X-linked muscular dystrophy in the Japanese Spitz breed. A PCR assay that amplifies mutant and wild-type alleles was developed and proved capable of identifying affected and carrier individuals. Unexpectedly, a 7-year-old male animal, which had not previously come to clinical attention, was shown to possess the mutant allele and to have a relatively mild form of the disease. This observation indicates phenotypic heterogeneity in Japanese Spitz muscular dystrophy, a feature described previously in humans and Golden Retrievers. With the availability of a simple, fast and accurate test for Japanese Spitz muscular dystrophy, detection of carrier animals and selected breeding should help eliminate the mutation from the breed. PMID:25644216

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

2015-04-01

144

A novel form of recessive limb girdle muscular dystrophy with mental retardation and abnormal expression of alpha-dystroglycan.  

PubMed

The limb girdle muscular dystrophies are a heterogeneous group of conditions characterized by proximal muscle weakness and disease onset ranging from infancy to adulthood. We report here eight patients from seven unrelated families affected by a novel and relatively mild form of autosomal recessive limb girdle muscular dystrophy (LGMD2) with onset in the first decade of life and characterized by severe mental retardation but normal brain imaging. Immunocytochemical studies revealed a significant selective reduction of alpha-dystroglycan expression in the muscle biopsies. Linkage analysis excluded known loci for both limb girdle muscular dystrophy and congenital muscular dystrophies in the consanguineous families. We consider that this represents a novel form of muscular dystrophy with associated brain involvement. The biochemical studies suggest that it may belong to the growing number of muscular dystrophies with abnormal expression of alpha-dystroglycan. PMID:14678799

Dinçer, Pervin; Balci, Burcu; Yuva, Yeliz; Talim, Beril; Brockington, Martin; Dinçel, Deniz; Torelli, Silvia; Brown, Sue; Kale, Gülsev; Haliloglu, Göknur; Gerçeker, Filiz Ozbas; Atalay, Rengül Cetin; Yakicier, Cengiz; Longman, Cheryl; Muntoni, Francesco; Topaloglu, Haluk

2003-12-01

145

Proteomics profiling of urine reveals specific titin fragments as biomarkers of Duchenne muscular dystrophy.  

PubMed

Diagnosis of muscular dystrophies is currently based on invasive methods requiring muscle biopsies or blood tests. The aim of the present study was to identify urinary biomarkers as a diagnostic tool for muscular dystrophies. Here, the urinary proteomes of Duchenne muscular dystrophy (DMD) patients and healthy donors were compared with a bottom-up proteomic approach. Label-free analysis of more than 1100 identified proteins revealed that 32 of them were differentially expressed between healthy controls and DMD patients. Among these 32 proteins, titin showed the highest fold change between healthy subjects and DMD patients. Interestingly, most of the sequenced peptides belong to the N-terminal and C-terminal parts of titin, and the presence of the corresponding fragments in the urine of DMD patients was confirmed by Western blot analysis. Analysis of a large cohort of DMD patients and age-matched controls (a total of 104 individuals aged from 3 to 20 years) confirmed presence of the N-ter fragment in all but two patients. In two DMD patients aged 16 and 20 years this fragment was undetectable and two healthy controls of 16 and 19 years with serum CK >800 IU/L demonstrated a low level of the fragment. N- and C-terminal titin fragments were also detected in urine from patients with other muscular dystrophies such as Becker muscular dystrophy and Limb-girdle muscular dystrophy (type 1D, 2D and 2J) but not in neurogenic spinal muscular atrophy. They were also present in urine of dystrophin-deficient animal models (GRMD dogs and mdx mice). Titin is the first urinary biomarker that offers the possibility to develop a simple, non-invasive and easy-to-use test for pre-screening of muscular dystrophies, and may also prove to be useful for the non-invasive follow up of DMD patients under treatment. PMID:24813925

Rouillon, Jeremy; Zocevic, Aleksandar; Leger, Thibaut; Garcia, Camille; Camadro, Jean-Michel; Udd, Bjarne; Wong, Brenda; Servais, Laurent; Voit, Thomas; Svinartchouk, Fedor

2014-07-01

146

Some Dynamics of Personality Development in Boys Suffering from Muscular Dystrophy  

ERIC Educational Resources Information Center

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)

Mearig, Judith S.

1973-01-01

147

Investigation of Poor Academic Achievement in Children with Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2004-01-01

148

Vascular-targeted therapies for Duchenne muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy-receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy. PMID:23618411

2013-01-01

149

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

PubMed

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 30years 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

Nigro, Vincenzo; Piluso, Giulio

2015-04-01

150

Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C  

Microsoft Academic Search

The limb girdle and congenital muscular dystrophies (LGMD and CMD) are characterized by skeletal muscle weakness and dystrophic muscle changes. The onset of symptoms in CMD is within the first few months of life, whereas in LGMD they can occur in late childhood, adolescence or adult life. We have recently demonstrated that the fukutin-related protein gene (FKRP) is mutated in

Martin Brockington; Yeliz Yuva; Paola Prandini; Susan C. Brown; Silvia Torelli; Matthew A. Benson; Ralf Herrmann; Louise V. B. Anderson; Rumaisa Bashir; Jean-Marc Burgunder; Shari Fallet; Norma Romero; Michel Fardeau; Volker Straub; Gillian Storey; Christine Pollitt; Isabelle Richard; Caroline A. Sewry; Kate Bushby; Thomas Voit; Derek J. Blake; Francesco Muntoni

2001-01-01

151

Predictive factors for masticatory performance in Duchenne muscular dystrophy.  

PubMed

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

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

2014-08-01

152

Cellular Transplantation Alters the Disease Progression in Becker's Muscular Dystrophy  

PubMed Central

Becker's Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council's Manual Muscle Testing (mMRC-MMT). Static sitting balance was poor. He was wheelchair dependent for ambulation and moderately independent in Activities of Daily Living (ADL). Functional Independence Measure (FIM) score was 93. Musculoskeletal Magnetic Resonance Imaging (MRI-MSK) showed moderate fatty infiltration in the muscles. Three cellular transplantations were carried out. Clinical assessment and the investigations were repeated. Progressive increase in the muscle strength was noted. Ambulation was independent using push-knee splints and minimal assistance when weary. Static and dynamic balance in sitting and standing improved. FIM score increased from 93 to 105. There was no increase in the degree of fatty infiltration, as seen on the MRI-MSK. The case study provides evidence for the putative benefits of cellular therapy in altering the disease progression in BMD. It also suggests augmented clinical benefits of combination of cellular therapy and rehabilitation. PMID:23841012

Sharma, Alok; Sane, Hemangi; Bhagawanani, Khushboo; Gokulchandran, Nandini; Badhe, Prerna

2013-01-01

153

Mouse fukutin deletion impairs dystroglycan processing and recapitulates muscular dystrophy  

PubMed Central

Dystroglycan is a transmembrane glycoprotein that links the extracellular basement membrane to cytoplasmic dystrophin. Disruption of the extensive carbohydrate structure normally present on ?-dystroglycan causes an array of congenital and limb girdle muscular dystrophies known as dystroglycanopathies. The essential role of dystroglycan in development has hampered elucidation of the mechanisms underlying dystroglycanopathies. Here, we developed a dystroglycanopathy mouse model using inducible or muscle-specific promoters to conditionally disrupt fukutin (Fktn), a gene required for dystroglycan processing. In conditional Fktn-KO mice, we observed a near absence of functionally glycosylated dystroglycan within 18 days of gene deletion. Twenty-week-old KO mice showed clear dystrophic histopathology and a defect in glycosylation near the dystroglycan O-mannose phosphate, whether onset of Fktn excision driven by muscle-specific promoters occurred at E8 or E17. However, the earlier gene deletion resulted in more severe phenotypes, with a faster onset of damage and weakness, reduced weight and viability, and regenerating fibers of smaller size. The dependence of phenotype severity on the developmental timing of muscle Fktn deletion supports a role for dystroglycan in muscle development or differentiation. Moreover, given that this conditional Fktn-KO mouse allows the generation of tissue- and timing-specific defects in dystroglycan glycosylation, avoids embryonic lethality, and produces a phenotype resembling patient pathology, it is a promising new model for the study of secondary dystroglycanopathy. PMID:22922256

Beedle, Aaron M.; Turner, Amy J.; Saito, Yoshiaki; Lueck, John D.; Foltz, Steven J.; Fortunato, Marisa J.; Nienaber, Patricia M.; Campbell, Kevin P.

2012-01-01

154

Muscular dystrophies related to the cytoskeleton/nuclear envelope.  

PubMed

Mutations in genes encoding proteins expressed in skeletal muscle cause a significant number of human diseases. Neuromuscular diseases are often severely debilitating for affected individuals, frequently leading to a shortened life span. Identifying the cause of these muscle diseases has provided insight not only into disease pathogenesis and muscle dysfunction, but also into the normal function of muscle. In 1987, dystrophin became the first disease-related human gene to be identified by positional cloning. Dystrophin is an integral component of the membrane-attached cytoskeleton of muscle fibres, with mutations in this gene causing Duchenne and Becker muscular dystrophy. One group of proteins known as the dystrophin-associated protein complex (DAPC), is believed to provide a molecular link between the actin cytoskeleton and the extracellular matrix in muscle cells, thereby sustaining sarcolemmal integrity during muscle contraction. Mutations in many members of the DAPC cause a variety of diseases, emphasising the importance of these genes. Another group of important proteins in skeletal muscle is the intermediate filament family, which provides mechanical strength and a supporting framework within the muscle cell. They anchor actin thin filaments through their expression at the Z-disk in sarcomeres, which in turn interact with myosin thick filaments to cause muscle contraction. This chapter will explore the protein components of the DAPC and the intermediate filament complex, highlighting a novel protein, which links the two, syncoilin. Human diseases and studies of existing animal models caused by mutations in these genes will also be described. PMID:15773750

Nowak, Kristen; McCullagh, Karl; Poon, Ellen; Davies, Kay E

2005-01-01

155

miRNAs as serum biomarkers for Duchenne muscular dystrophy  

PubMed Central

Dystrophin absence in Duchenne muscular dystrophy (DMD) causes severe muscle degeneration. We describe that, as consequence of fibre damage, specific muscle-miRNAs are released in to the bloodstream of DMD patients and their levels correlate with the severity of the disease. The same miRNAs are abundant also in the blood of mdx mice and recover to wild-type levels in animals ‘cured’ through exon skipping. Even though creatine kinase (CK) blood levels have been utilized as diagnostic markers of several neuromuscular diseases, including DMD, we demonstrate that they correlate less well with the disease severity. Although the analysis of a larger number of patients should allow to obtain more refined correlations with the different stages of disease progression, we propose that miR-1, miR-133, and miR-206 are new and valuable biomarkers for the diagnosis of DMD and possibly also for monitoring the outcomes of therapeutic interventions in humans. Despite many different DMD therapeutic approaches are now entering clinical trials, a unifying method for assessing the benefit of different treatments is still lacking. PMID:21425469

Cacchiarelli, Davide; Legnini, Ivano; Martone, Julie; Cazzella, Valentina; D'Amico, Adele; Bertini, Enrico; Bozzoni, Irene

2011-01-01

156

The Congenital Muscular Dystrophies: Recent Advances and Molecular Insights  

PubMed Central

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

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

2010-01-01

157

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's muscular dys- trophy. N Engl J Med 1989;320:1592­1597. 6. Fenichel GM, Griggs RC, Kissel J, et al

158

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

PubMed Central

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

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

2013-01-01

159

Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS  

E-print Network

Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin throughNOS and nNOS) in Duchenne muscular dystrophy (DMD). Bradykinin is involved in the regulation of e. Vascular function was examined in conscious golden retriever muscular dystrophy (GRMD) dogs with left

Paris-Sud XI, Université de

160

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

PubMed Central

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

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

2013-01-01

161

Complete allele information in the diagnosis of facioscapulohumeral muscular dystrophy by triple DNA analysis.  

PubMed

Facioscapulohumeral muscular dystrophy is caused by partial deletion of the D4Z4 repeat array on chromosome 4q35. Genetic diagnosis is based on sizing of this repeat array, which is complicated by cross-hybridization of a homologous polymorphic repeat array on chromosome 10 and by the frequent exchanges between these chromosomal regions. The restriction enzyme XapI optimizes the diagnosis of facioscapulohumeral muscular dystrophy by uniquely digesting 4-derived repeat units and leaving 10-derived repeat units undigested, thus complementing BlnI, which uniquely digests 10-derived repeat units. A triple analysis with EcoRI, EcoRI/BlnI, and XapI unequivocally allows characterization of each of the four alleles, whether homogeneous or hybrid. This is particularly useful in the case of identical sized 4-derived and 10-derived arrays, in situations of suspected facioscapulohumeral muscular dystrophy with nonstandard allele configurations, and for assignment of hybrid fragments to their original alleles. PMID:11761483

Lemmers RJL; de Kievit, P; van Geel, M; van der Wielen, M J; Bakker, E; Padberg, G W; Frants, R R; van der Maarel, S M

2001-12-01

162

Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)  

PubMed Central

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive primary disease of muscle which is usually inherited as an autosomal dominant disorder. FSHD has been localized to the long arm of chromosome 4, specifically to the 4q3.5-qter region. Initially published linkage studies showed no evidence for heterogeneity in FSHD. In the present study we have examined individuals in seven FSHD families. Two-point lod scores show significant evidence for linkage for D4S163 (lod score 3.04 at recombination fraction .21) and D4S139 (lod score 3.84 at recombination fraction .20). D4S171 also gave a positive score (lod score 2.56 at recombination fraction .24). Significant evidence for heterogeneity was found for each of the three markers. Multipoint linkage analysis in this region resulted in a peak multipoint lod score of 6.47. The multipoint analysis supported the two-point studies with odds of 20:1 showing linkage and heterogeneity over linkage and homogeneity. Five of the seven families gave a posterior probability of >95% of being of the linked type, while two families appeared unlinked to this region of 4q (P < .01%). Individuals in the two unlinked families met the clinical criteria for the diagnosis of FSHD, including facial weakness, clavicular flattening, scapula winging, proximal muscle weakness, and myopathic changes on muscle biopsies without inflammatory or mitochondrial pathology. This study demonstrates genetic heterogeneity in FSHD and has important implications for both genetic counseling and the elucidation of the etiology of FSHD. PMID:8328457

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

1993-01-01

163

Red-green color vision impairment in Duchenne muscular dystrophy.  

PubMed

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

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

2007-06-01

164

Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy  

PubMed Central

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

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

2015-01-01

165

Direct interplay between two candidate genes in FSHD muscular dystrophy  

PubMed Central

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

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

2015-01-01

166

Direct interplay between two candidate genes in FSHD muscular dystrophy.  

PubMed

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

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

2015-03-01

167

Oculopharyngeal Muscular Dystrophy as a Paradigm for Muscle Aging  

PubMed Central

Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging. PMID:25426070

Raz, Yotam; Raz, Vered

2014-01-01

168

Facioscapulohumeral Muscular Dystrophy: More Complex than it Appears  

PubMed Central

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.

G, Ricci; M, Zatz; R, Tupler

2014-01-01

169

Evidence for heterogeneity in facioscapulohumeral muscular dystrophy (FSHD)  

SciTech Connect

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

Gilbert, J.R.; Stajich, J.M.; Wall, S.; Carter, S.C.; Qiu, H.; Vance, J.M.; Stewart, C.S.; Speer, M.C.; Pufky, J.; Yamaoka, L.H.; Rozear, M.; Roses, A.D.; Pericak-Vance, M.A. (Duke Univ. Medical Center, Durham, NC (United States)); Samson, F.; Fardeau, M. (INSERM, Paris (France))

1993-08-01

170

Characterization of pulmonary function in Duchenne Muscular Dystrophy.  

PubMed

Decline in pulmonary function in Duchenne Muscular Dystrophy (DMD) contributes to significant morbidity and reduced longevity. Spirometry is a widely used and fairly easily performed technique to assess lung function, and in particular lung volume; however, the acceptability criteria from the American Thoracic Society (ATS) may be overly restrictive and inappropriate for patients with neuromuscular disease. We examined prospective spirometry data (Forced Vital Capacity [FVC] and peak expiratory flow [PEF]) from 60 DMD patients enrolled in a natural history cohort study (median age 10.3 years, range 5-24 years). Expiratory flow-volume curves were examined by a pulmonologist and the data were evaluated for acceptability using ATS criteria modified based on the capabilities of patients with neuromuscular disease. Data were then analyzed for change with age, ambulation status, and glucocorticoid use. At least one acceptable study was obtained in 44 subjects (73%), and 81 of the 131 studies (62%) were acceptable. The FVC and PEF showed similar relative changes in absolute values with increasing age, i.e., an increase through 10 years, relative stabilization from 10-18 years, and then a decrease at an older age. The percent predicted, FVC and PEF showed a near linear decline of approximately 5% points/year from ages 5 to 24. Surprisingly, no difference was observed in FVC or PEF by ambulation or steroid treatment. Acceptable spirometry can be performed on DMD patients over a broad range of ages. Using modified ATS criteria, curated spirometry data, excluding technically unacceptable data, may provide a more reliable means of determining change in lung function over time. Pediatr Pulmonol. 2015; 50:487-494. © 2015 Wiley Periodicals, Inc. PMID:25755201

Mayer, O H; Finkel, R S; Rummey, C; Benton, M J; Glanzman, A M; Flickinger, J; Lindström, B-M; Meier, T

2015-05-01

171

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

SciTech Connect

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.

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

1995-08-28

172

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

SciTech Connect

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.

Othmane, K.B.; Speer, M.C.; Stauffer, J. [Duke Univ. Medical Center, Durham, NC (United States)] [and others

1995-09-01

173

The first Italian family with tibial muscular dystrophy caused by a novel titin mutation  

Microsoft Academic Search

Tibial muscular dystrophy (TMD) or Udd myopathy is an autosomal dominant distal myopathy with late onset, at first described\\u000a in the Finnish population. We report here the first Italian cases of TTN mutated titinopathy. The proband, a 60 year-old female, had the first muscular signs at the age of 59 years, with difficulty\\u000a in walking and right foot drop. Muscle imaging showed

Tiina Suominen; Sini Penttilä; Alessandro Malandrini; Maria Alessandra Carluccio; Mauro Mondelli; Annabella Marozza; Antonio Federico; Alessandra Renieri; Peter Hackman; Maria Teresa Dotti; Bjarne Udd

2010-01-01

174

Renal function in children and adolescents with Duchenne muscular dystrophy.  

PubMed

Improved life expectancy and the need for robust tools to monitor renal safety of emerging new therapies have fueled the interest in renal function in Duchenne muscular dystrophy (DMD) patients. We aimed to establish a methodology to accurately assess their renal function. Twenty DMD patients (5-22 years) were included in this prospective study. After obtaining medical history, all patients underwent a clinical examination, 24-hour ambulatory blood pressure monitoring, ultrasound of the kidneys, direct GFR measurement ((51)Cr-EDTA, mGFR), complete blood and urine analysis. Seventeen of 20 patients were treated with corticosteroids and 5/20 with angiotensin converting enzyme inhibitor (lisinopril). No patient suffered from urinary tract infections or other renal diseases. Hypertension (systolic or diastolic blood pressure?>P95) was found in 9/20 patients (8/9 patients were on steroid treatment) and a non-dipping blood pressure profile in 13/20 subjects (10/13 patients were on steroid treatment). Urinary protein to creatinine ratio was elevated in 17/18 patients, whereas 24-hour urine protein excretion was normal in all subjects. Median interquartile range (IQR) mGFR was 130.4 (29.1) mL/min/1.73?m(2). Hyperfiltration (mGFR >150?mL/min/1.73?m(2)) was found in 5/20 patients. Inverse correlation between mGFR and age was observed (R(2)?=?0.45, p?=?0.001). Serum creatinine based estimated GFR (eGFR) equations overestimated mGFR up to 300%. eGFR based on cystatin C Filler equation was closest to the mGFR (median eGFR (IQR) of 129.5 (39.7) mL/min/1.73?m(2)). Our study demonstrates a high prevalence of hyperfiltration and hypertension in children and adolescents with DMD. Because the majority of hypertensive patients were under corticosteroid treatment, the iatrogenic cause of hypertension cannot be excluded. Serum or urine creatinine measurements are of no value to evaluate renal function in DMD patients due to the reduced skeletal muscle mass. PMID:25683700

Braat, Elke; Hoste, Liesbeth; De Waele, Liesbeth; Gheysens, Olivier; Vermeersch, Pieter; Goffin, Karolien; Pottel, Hans; Goemans, Nathalie; Levtchenko, Elena

2015-05-01

175

Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy  

Microsoft Academic Search

BACKGROUNDRespiratory failure is the commonest cause of death in patients with Duchenne muscular dystrophy (DMD). Life expectancy is less than one year once diurnal hypercapnia develops. This study examines the effects of nasal intermittent positive pressure ventilation (NIPPV) on survival in symptomatic Duchenne patients with established ventilatory failure.METHODSNocturnal NIPPV was applied in 23 consecutive patients with DMD of mean (SD)

A K Simonds; F Muntoni; S Heather; S Fielding

1998-01-01

176

DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies  

PubMed Central

Albeit genetically highly heterogeneous, muscular dystrophies (MDs) share a convergent pathology leading to muscle wasting accompanied by proliferation of fibrous and fatty tissue, suggesting a common MD–pathomechanism. Here we show that mutations in muscular dystrophy genes (Dmd, Dysf, Capn3, Large) lead to the spontaneous formation of skeletal muscle-derived malignant tumors in mice, presenting as mixed rhabdomyo-, fibro-, and liposarcomas. Primary MD–gene defects and strain background strongly influence sarcoma incidence, latency, localization, and gender prevalence. Combined loss of dystrophin and dysferlin, as well as dystrophin and calpain-3, leads to accelerated tumor formation. Irrespective of the primary gene defects, all MD sarcomas share non-random genomic alterations including frequent losses of tumor suppressors (Cdkn2a, Nf1), amplification of oncogenes (Met, Jun), recurrent duplications of whole chromosomes 8 and 15, and DNA damage. Remarkably, these sarcoma-specific genetic lesions are already regularly present in skeletal muscles in aged MD mice even prior to sarcoma development. Accordingly, we show also that skeletal muscle from human muscular dystrophy patients is affected by gross genomic instability, represented by DNA double-strand breaks and age-related accumulation of aneusomies. These novel aspects of molecular pathologies common to muscular dystrophies and tumor biology will potentially influence the strategies to combat these diseases. PMID:21533183

Schmidt, Wolfgang M.; Uddin, Mohammed H.; Dysek, Sandra; Moser-Thier, Karin; Pirker, Christine; Höger, Harald; Ambros, Inge M.; Ambros, Peter F.; Berger, Walter; Bittner, Reginald E.

2011-01-01

177

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

PubMed

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

Murphy, M E; Kehrer, J P

1986-01-29

178

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

PubMed Central

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

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

179

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

PubMed

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

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

180

Mesenchymal stem cells as anti-inflammatories: Implications for treatment of Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a lethal X-linked musculodegenerative condition consisting of an underlying genetic defect whose manifestation is augmented by inflammatory mechanisms. Previous treatment approaches using gene replacement, exon-skipping or allogeneic cell therapy have been relatively unsuccessful. The only intervention to mediate improvement in survival, albeit minor, is glucocorticoid treatment. Given this modality appears to function via suppression of

Thomas E. Ichim; Doru T. Alexandrescu; Fabio Solano; Fabian Lara; Rosalia De Necochea Campion; Eugenia Paris; Erik J. Woods; Michael P. Murphy; Constantin A. Dasanu; Amit N. Patel; Annette M. Marleau; Alejandro Leal; Neil H. Riordan

2010-01-01

181

Detection of duchenne muscular dystrophy carriers: quantitative echography and creatine kinasemia  

Microsoft Academic Search

Data obtained from simultaneous determinations of serum creatine-kinase levels and estimation of ultrasound attenuation values in muscles greatly improved the detection of obligate carriers of Duchenne muscular dystrophy than when only one of these methods was employed alone. Eleven carriers out of 19 had a high creatine-kinasemia level and nine carriers out of 19 had a high (abnormal) attenuation value.

Georges Schapira I; Pascal Laugier; Jacques Rochette; Geneviève Berger; Pierre Katz; Jean Perrin

1987-01-01

182

Infraspinatus muscle hypertrophy and wasting of axillary folds as the important signs in Duchenne muscular dystrophy  

Microsoft Academic Search

Eighty-four patients with Duchenne muscular dystrophy (DMD) were examined clinically for hypertrophy and wasting in different muscles, parts of the muscles or muscle groups. Some muscles were examined under mild contraction to bring out any subclinical pseudohypertrophy. Findings revealed infraspinatus muscle hypertrophy to be significantly frequent (88%) and closely second to well known calf hypertrophy (94%). Infraspinatus hypertrophy was noted

Sunil Pradhan; Balraj Mittal

1995-01-01

183

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

PubMed

Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix. PMID:23115202

Berger, Joachim; Currie, Peter D

2012-11-01

184

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

PubMed

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

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

2015-05-01

185

Dentofacial characteristics of growing patients with Duchenne muscular dystrophy: a morphological study  

Microsoft Academic Search

SUMMARY Occlusal traits and craniofacial morphology were studied in growing patients with Duchenne muscular dystrophy (DMD). Sixteen patients from 6 to 20 years of age were examined and compared with 16 healthy male individuals matched according to age. The dental arches and occlusal traits of both groups were analysed on dental casts and compared with the norms of healthy individuals

Catherine Morel; Sébastien Botteron; Stavros Kiliaridis

186

De novo LMNA mutations cause a new form of congenital muscular dystrophy  

Microsoft Academic Search

Objective: To describe a new entity of congenital muscular dystrophies caused by de novo LMNA mutations. Methods: Fifteen patients presenting with a myopathy of onset in the first year of life were subjected to neurological and genetic evaluation. Histopathological and immunohistochemical analyses were performed for all patients. Results: The 15 patients presented with muscle weakness in the first year of

Susana Quijano-Roy; Blaise Mbieleu; Carsten G. Bönnemann; Pierre-Yves Jeannet; Jaume Colomer; Nigel F. Clarke; Jean-Marie Cuisset; Helen Roper; Linda De Meirleir; Adele D'Amico; Rabah Ben Yaou; Andrés Nascimento; Annie Barois; Laurence Demay; Enrico Bertini; Ana Ferreiro; Caroline A. Sewry; Norma B. Romero; Monique Ryan; Francesco Muntoni; Pascale Guicheney; Pascale Richard; Gisèle Bonne; Brigitte Estournet

2008-01-01

187

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

PubMed

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

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

2014-12-20

188

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

PubMed

Facioscapulohumeral muscular dystrophy cases with facial weakness before the age of 5 and signs of shoulder weakness by the age of 10 are defined as early onset. Contraction of the D4Z4 repeat on chromosome 4q35 is causally related to facioscapulohumeral muscular dystrophy type 1, and the residual size of the D4Z4 repeat shows a roughly inverse correlation with the severity of the disease. Contraction of the D4Z4 repeat on chromosome 4q35 is believed to induce a local change in chromatin structure and consequent transcriptional deregulation of 4qter genes. We present early-onset cases in the Polish population that amounted to 21% of our total population with facioscapulohumeral muscular dystrophy. More than 27% of them presented with severe phenotypes (wheelchair dependency). The residual D4Z4 repeat sizes ranged from 1 to 4 units. In addition, even within early-onset facioscapulohumeral muscular dystrophy type 1 phenotypes, some cases had uncommon features (head drop, early disabling contractures, progressive ptosis, and respiratory insufficiency and cardiomyopathy). PMID:24717985

Dorobek, Ma?gorzata; van der Maarel, Silvère M; Lemmers, Richard J L F; Ryniewicz, Barbara; Kabzi?ska, Dagmara; Frants, Rune R; Gawel, Malgorzata; Walecki, Jerzy; Hausmanowa-Petrusewicz, Irena

2015-04-01

189

Skeletal and Cardiac Myopathies in Mice Lacking Utrophin and Dystrophin: A Model for Duchenne Muscular Dystrophy  

Microsoft Academic Search

Dystrophin is a cytoskeletal protein of muscle fibers; its loss in humans leads to Duchenne muscular dystrophy, an inevitably fatal wasting of skeletal and cardiac muscle. mdx mice also lack dystrophin, but are only mildly dystrophic. Utrophin, a homolog of dystrophin, is confined to the postsynaptic membrane at skeletal neuromuscular junctions and has been implicated in synaptic development. However, mice

R. Mark Grady; Haibing Teng; Mia C Nichol; Jeanette C Cunningham; Robert S Wilkinson; Joshua R Sanes

1997-01-01

190

Expression of full-length utrophin prevents muscular dystrophy in mdx mice  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a lethal, progressive muscle wasting disease caused by a loss of sarcolemmal bound dystrophin, which results in the death of the muscle fiber leading to the gradual depletion of skeletal muscle. The molecular structure of dystrophin is very similar to that of the related protein utrophin. Utrophin is found in all tissues and is confined

Jonathon Tinsley; Nicolas Deconinck; Rosie Fisher; David Kahn; Steve Phelps; Jean-Marie Gillis; Kay Davies

1998-01-01

191

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...

192

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

ERIC Educational Resources Information Center

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…

Webb, Carol L.

2005-01-01

193

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

ERIC Educational Resources Information Center

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…

Hoskin, Janet; Fawcett, Angela

2014-01-01

194

Evaluation of Narrative Abilities in Patients Suffering from Duchenne Muscular Dystrophy  

ERIC Educational Resources Information Center

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…

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

2007-01-01

195

Clinical phenotype in congenital muscular dystrophy: correlation with expression of merosin in skeletal  

Microsoft Academic Search

It has recently been shown that merosin, an extracellular matrix protein linked to the dystrophin-associated glycoproteins, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD). We have undertaken a detailed study of the clinical features and brain imaging in 24 cases of CMD in relation to the merosin status.Immunocytochemistry showed that merosin was present in 13

J. Philpot; C. Sewry; J. Pennock; V. Dubowitz

1995-01-01

196

Modular flexibility of dystrophin: Implications for gene therapy of Duchenne muscular dystrophy  

Microsoft Academic Search

Attempts to develop gene therapy for Duchenne muscular dystrophy (DMD) have been complicated by the enormous size of the dystrophin gene. We have performed a detailed functional analysis of dystrophin structural domains and show that multiple regions of the protein can be deleted in various combinations to generate highly functional mini- and micro-dystrophins. Studies in transgenic mdx mice, a model

Scott Q. Harper; Michael A. Hauser; Christiana DelloRusso; Dongsheng Duan; Robert W. Crawford; Stephanie F. Phelps; Hollie A. Harper; Ann S. Robinson; John F. Engelhardt; Susan V. Brooks; Jeffrey S. Chamberlain

2002-01-01

197

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

SciTech Connect

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.

McNally, E.M.; Boennemann, C.G.; Lidov, H.G.W. [Brigham and Women`s Hospital, Boston, MA (United States)] [and others

1996-11-01

198

Psycho-organic symptoms as early manifestation of adult onset POMT1-related limb girdle muscular dystrophy.  

PubMed

We report two siblings of Croatian consanguineous healthy parents with a novel homozygous missense mutation in the POMT1 gene, presenting with intellectual disability and psychotic, in particular hallucinatory symptoms and abnormal brain MRIs, preceding classical symptoms of limb-girdle muscular dystrophy by several years. Weakness became apparent in early adulthood and both siblings remained ambulant into the 3rd and 4th decade of life. The muscle biopsy showed reduced ?-dystroglycan compatible with the POMT1 defect. This case report extends the phenotypic spectrum of POMT1 associated muscular dystrophies to the adult onset limb girdle muscular dystrophies with psycho-organic deficits. PMID:25088310

Haberlova, J; Mitrovi?, Z; Zarkovi?, K; Lovri?, D; Bari?, V; Berlengi, L; Bili?, K; Fumi?, K; Kranz, K; Huebner, A; von der Hagen, M; Barresi, R; Bushby, K; Straub, V; Bari?, I; Lochmüller, H

2014-11-01

199

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

SciTech Connect

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.

Kao, L.; Krstenansky, J.; Mendell, J.; Rammohan, K.W.; Gruenstein, E. (Univ. of Cincinnati College of Medicine, OH (USA))

1988-06-01

200

[Erythrocyte membrane in Duchenne muscular dystrophy. III. Modifications of acetylcholinesterase].  

PubMed

Membrane-bound acetylcholinesterase was assayed in erythrocyte ghosts from patients with Duchenne Muscular Distrophy and from the members of their family. Modifications was observed both in Km and Vmax, indicating changes in conformations of the enzyme. PMID:7470283

Campagnoli, P; Leporoni, B; Bravi, S; Lenaz, G

1980-12-15

201

Muscular dystrophy in an X; 1 translocation female suggests that Duchenne locus is on X chromosome short arm  

Microsoft Academic Search

A unique combination of a Duchenne-like muscular dystrophy in a girl with a translocation-inversion rearrangement involving an X chromosome and a no 1 chromosome appeared as a result of both gene mutation and chromosome mutation in the mother. The X-autosome rearrangement would permit full expression of an X-linked recessive gene, such as that for Duchenne muscular dystrophy, in a female,

R H Lindenbaum; G Clarke; C Patel; M Moncrieff; J T Hughes

1979-01-01

202

Quantitation of argyrophilic nucleolar organizer regions in regenerating muscle fibers in Duchenne and Becker muscular dystrophies and polymyositis  

Microsoft Academic Search

We have investigated the quantity of argyrophilic nucleolar organizer region (AgNOR) proteins in vastus lateralis muscle\\u000a samples from 13 patients with Duchenne muscular dystrophy (DMD) (6 months–12 years), 9 with Becker muscular dystrophy (BMD)\\u000a (13 months– 36 years), 9 with polymyositis (PM) (8–77 years) and 10 normal subjects (5 months–32 years). AgNORs were visualized\\u000a on 4-?m-thick cryostat sections and quantified

Giovanni Tuccari; Giuseppe Giuffrè; Costantino Crisafulli; Maria C. Monici; Antonio Toscano; Giuseppe Vita

1999-01-01

203

Challenges in the management of the child with Duchenne muscular dystrophy in a resource poor setting:a case report  

PubMed Central

Duchenne muscular dystrophy is a progressive genetic disease with no cure at present. Children suffering from this disease eventually become wheelchair bound and die in their late teens. Paediatricians caring for the child with Duchenne Muscular Dystrophy in resource poor settings face a lot challenges. These challenges include: poverty, inadequate multidisciplinary care, emotional burn-out of parents and lack of facilities for dystrophin assay or genetic testing.

Odinaka, Kelechi Kenneth; Nwolisa, Emeka Charles

2014-01-01

204

1. Dubowitz V, Fardeau M (1995) Proceedings of the 27th ENMC sponsored workshop on congenital muscular dystrophy, 2224 April 1994, The Netherlands. Neuromuscul Disord  

E-print Network

dystrophy, mental retardation and cerebellar cysts. Neurology 60:988­992. 14. Kawazaki ES (1990) Sample (2003) Merosin-deficient congenital muscular dystrophy with mental retardation and cerebellar cysts

205

Muscle MRI findings in limb girdle muscular dystrophy type 2L.  

PubMed

Limb girdle muscular dystrophy type 2L (LGMD2L) is an adult-onset slowly progressive muscular dystrophy associated with recessive mutations in the ANO5 gene. We analysed the muscle MRI pattern in a cohort of 25 LGMD2L patients in order to understand the extent and progression of muscle pathology in LGM2L and assess if muscle MRI might help in the diagnostic work-up of these patients. Our results showed a homogeneous pattern of muscle pathology on muscle MRI, with a predominant involvement of the posterior compartment muscles in both the thighs and calves. The muscles of the anterior compartments in the leg together with the sartorius and gracilis muscles were best preserved, which partially overlaps with patterns observed for other recessive LGMDs. Muscle MRI therefore does not appear to be as useful in the diagnostic work up of LGMD2L as for other neuromuscular diseases, such as Bethlem myopathy or myofibrillar myopathy. PMID:22980763

Sarkozy, Anna; Deschauer, Marcus; Carlier, Robert-Yves; Schrank, Bertold; Seeger, Jürgen; Walter, Maggie C; Schoser, Benedikt; Reilich, Peter; Leturq, France; Radunovic, Aleksandar; Behin, Anthony; Laforet, Pascal; Eymard, Bruno; Schreiber, Herbert; Hicks, Debbie; Vaidya, Sujit S; Gläser, Dieter; Carlier, Pierre G; Bushby, Kate; Lochmüller, Hanns; Straub, Volker

2012-10-01

206

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

PubMed

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

Whitmore, Charlotte; Morgan, Jennifer

2014-12-01

207

Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model  

PubMed Central

Duchenne muscular dystrophy is an X-linked muscle disease characterized by mutations in the dystrophin gene. Many of these can be corrected at the posttranscriptional level by skipping the mutated exon. We have obtained persistent exon skipping in mdx mice by tail vein injection with an adeno-associated viral (AAV) vector expressing antisense sequences as part of the stable cellular U1 small nuclear RNA. Systemic delivery of the AAV construct resulted in effective body-wide colonization, significant recovery of the functional properties in vivo, and lower creatine kinase serum levels, suggesting an overall decrease in muscle wasting. The transduced muscles rescued dystrophin expression and displayed a significant recovery of function toward the normal values at single muscle fiber level. This approach provides solid bases for a systemic use of AAV-mediated antisense-U1 small nuclear RNA expression for the therapeutic treatment of Duchenne muscular dystrophy. PMID:16501048

Denti, Michela Alessandra; Rosa, Alessandro; D’Antona, Giuseppe; Sthandier, Olga; De Angelis, Fernanda Gabriella; Nicoletti, Carmine; Allocca, Mariacarmela; Pansarasa, Orietta; Parente, Valeria; Musarò, Antonio; Auricchio, Alberto; Bottinelli, Roberto; Bozzoni, Irene

2006-01-01

208

Body-wide gene therapy of Duchenne muscular dystrophy in the mdx mouse model.  

PubMed

Duchenne muscular dystrophy is an X-linked muscle disease characterized by mutations in the dystrophin gene. Many of these can be corrected at the posttranscriptional level by skipping the mutated exon. We have obtained persistent exon skipping in mdx mice by tail vein injection with an adeno-associated viral (AAV) vector expressing antisense sequences as part of the stable cellular U1 small nuclear RNA. Systemic delivery of the AAV construct resulted in effective body-wide colonization, significant recovery of the functional properties in vivo, and lower creatine kinase serum levels, suggesting an overall decrease in muscle wasting. The transduced muscles rescued dystrophin expression and displayed a significant recovery of function toward the normal values at single muscle fiber level. This approach provides solid bases for a systemic use of AAV-mediated antisense-U1 small nuclear RNA expression for the therapeutic treatment of Duchenne muscular dystrophy. PMID:16501048

Denti, Michela Alessandra; Rosa, Alessandro; D'Antona, Giuseppe; Sthandier, Olga; De Angelis, Fernanda Gabriella; Nicoletti, Carmine; Allocca, Mariacarmela; Pansarasa, Orietta; Parente, Valeria; Musarò, Antonio; Auricchio, Alberto; Bottinelli, Roberto; Bozzoni, Irene

2006-03-01

209

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

NASA Astrophysics Data System (ADS)

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.

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

210

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

PubMed

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

Zeidman, Lawrence A; Kondziella, Daniel

2014-04-01

211

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

NASA Astrophysics Data System (ADS)

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.

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

1988-03-01

212

Progress in muscular dystrophy research with special emphasis on gene therapy  

PubMed Central

Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle-wasting disease caused by mutations in the DMD gene. Since the disease was described by physicians in the 19th century, information about the subject has been accumulated. One author (Sugita) was one of the coworkers who first reported that the serum creatine kinase (CK) level is elevated in progressive muscular dystrophy patients. Even 50 years after that first report, an elevated serum CK level is still the most useful marker in the diagnosis of DMD, a sensitive index of the state of skeletal muscle, and useful to evaluate therapeutic effects. In the latter half of this article, we describe recent progress in the therapy of DMD, with an emphasis on gene therapies, particularly exon skipping. PMID:20689232

SUGITA, Hideo; TAKEDA, Shin’ichi

2010-01-01

213

Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine.  

PubMed

Variants in ACTA1, which encodes ?-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal ?-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal ?-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression.European Journal of Human Genetics advance online publication, 3 September 2014; doi:10.1038/ejhg.2014.169. PMID:25182138

O'Grady, Gina L; Best, Heather A; Oates, Emily C; Kaur, Simranpreet; Charlton, Amanda; Brammah, Susan; Punetha, Jaya; Kesari, Akanchha; North, Kathryn N; Ilkovski, Biljana; Hoffman, Eric P; Clarke, Nigel F

2014-09-01

214

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

SciTech Connect

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.

Shomrat, R.; Gluck, E.; Legum, C.; Shiloh, Y. [Tel Aviv Univ. (Israel)

1994-02-15

215

Adult life with Duchenne muscular dystrophy: Observations among an emerging and unforeseen patient population  

Microsoft Academic Search

The knowledge of adult life with Duchenne muscular dystrophy (DMD) is sparse. The purpose of this study was to review existing information and describe body functional, social participatory and quality of life profiles of the ordinary adult Danish DMD patient. Sixty-five study subjects aged 18-42 years were included in a cross-sectional survey based on data from a semi-structured questionnaire comprising

JES RAHBEK; BIRGIT WERGE; ANNY MADSEN; JOHN MARQUARDT; BIRGIT FYNBO STEFFENSEN; JOERGEN JEPPESEN

216

A founder mutation in Anoctamin 5 is a major cause of limb girdle muscular dystrophy  

PubMed Central

The limb girdle muscular dystrophies (LGMDs) are a group of disorders with wide genetic and clinical heterogeneity. Recently, mutations in the ANO5 gene, which encodes a putative calcium-activated chloride channel belonging to the Anoctamin family of proteins, were identified in five families with one of two previously identified disorders, LGMD2L and non-dysferlin Miyoshi muscular dystrophy (MMD3). We screened a candidate group of 64 patients from 59 British and German kindreds and found the truncating mutation, c.191dupA in exon 5 of ANO5 in 20 patients, homozygously in 15 and in compound heterozygosity with other ANO5 variants in the rest. An intragenic SNP and an extragenic microsatellite marker are in linkage disequilibrium with the mutation, suggesting a founder effect in the Northern European population. We have further defined the clinical phenotype of ANO5-associated muscular dystrophy. Patients show adult onset proximal lower limb weakness with highly raised creatinine kinase (CK) values (average 4500 IU/l) and frequent muscle atrophy and asymmetry of muscle involvement. Onset varies from the early 20s to 50s and the weakness is generally slowly progressive, with most patients remaining ambulant for several decades. Distal presentation is much less common but a milder degree of distal lower limb weakness is often observed. Upper limb strength is only mildly affected and cardiac and respiratory function is normal. Females appear less frequently affected. In the North of England population we have identified eight patients with ANO5 mutations, suggesting a minimum prevalence of 0.27/100 000, twice as common as dysferlinopathy. We suggest that mutations in ANO5 represent a relatively common cause of adult onset muscular dystrophy with high CK and that mutation screening, particularly of the common mutation c.191dupA, should be an early step in the diagnostic algorithm of adult LGMD patients. PMID:21186264

Muelas, Nuria; Köehler, Katrin; Huebner, Angela; Hudson, Gavin; Chinnery, Patrick F.; Barresi, Rita; Eagle, Michelle; Polvikoski, Tuomo; Bailey, Geraldine; Miller, James; Radunovic, Aleksander; Hughes, Paul J.; Roberts, Richard; Krause, Sabine; Walter, Maggie C.; Laval, Steven H.; Straub, Volker; Lochmüller, Hanns; Bushby, Kate

2014-01-01

217

Quantifiable diagnosis of muscular dystrophies and neurogenic atrophies through network analysis  

PubMed Central

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

2013-01-01

218

Muscular Dystrophy and Neuronal Migration Disorder Caused by Mutations in a Glycosyltransferase, POMGnT1  

Microsoft Academic Search

Muscle-eye-brain disease (MEB) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and lissencephaly. Mammalian O-mannosyl glycosylation is a rare type of protein modification that is observed in a limited number of glycoproteins of brain, nerve, and skeletal muscle. Here we isolated a human cDNA for protein O-mannose ?-1,2-N-acetylglucosaminyltransferase (POMGnT1), which participates in O-mannosyl glycan synthesis. We

Aruto Yoshida; Kazuhiro Kobayashi; Hiroshi Manya; Kiyomi Taniguchi; Hiroki Kano; Mamoru Mizuno; Toshiyuki Inazu; Hideyo Mitsuhashi; Seiichiro Takahashi; Makoto Takeuchi; Ralf Herrmann; Volker Straub; Beril Talim; Thomas Voit; Haluk Topaloglu; Tatsushi Toda; Tamao Endo

2001-01-01

219

Combined Effects of Muscular Dystrophy, Ecological Stress, and Selenium on Blood Antioxidant Status in Broiler Chickens  

Microsoft Academic Search

The results obtained in this study demonstrated that experimentally induced alimentary muscular dystrophy (MD) in Cobb 500\\u000a broiler chickens resulted in increased plasma concentrations of malondialdehyde (MDA), deviations in activities of erythrocyte\\u000a antioxidant enzymes Cu,Zn-SOD (decrease), and CAT (increase) as well as reduction in plasma concentrations of trace elements\\u000a Cu, Zn, and Se in affected birds. These data evidenced the

Nedyalka V. Georgieva; Krasimir Stoyanchev; Nadia Bozakova; Ivanka Jotova

220

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

PubMed Central

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

Sitzia, Clementina; Erratico, Silvia; Torrente, Yvan

2014-01-01

221

Skeletal muscle pathology in X chromosome-linked muscular dystrophy ( mdx ) mouse  

Microsoft Academic Search

Histological, histochemical, and morphometric analyses were performed chronologically on muscles from mutant mice with X chromosome-linked muscular dystrophy (mdx), and the findings were compared with those in nondystrophic control animals (C57BL\\/10ScSn). Massive grouped muscle fiber destruction, followed by complete regeneration, occurred abruptly at 20 days of age. There were no preceding changes in body weight, the number and mean diameter

Y. Tanabe; K. Esaki; T. Nomura

1986-01-01

222

Postoperative complications in patients with oculopharyngeal muscular dystrophy: A retrospective study  

Microsoft Academic Search

Purpose  Oculopharyngeal muscular dystrophy (OPMD) is a genetic disease with autosomal dominant transmission particularly common in\\u000a Quebec where its prevalence is about 1: 1000. The main features are bilateral ptosis of the eyelids and dysphagia. These symptoms\\u000a are frequently treated surgically by levator palpebrae resection (LPR) and cricopharyngeal myotomy (CPM). The objectives of\\u000a this retrospective chart review were to describe the

Hélène G. Pellerin; Pierre C. Nicole; Claude A. Trépanier; Martin R. Lessard

2007-01-01

223

Co-occurring Duchenne muscular dystrophy and hypertrophic cardiomyopathy in an adult with atypical cardiac phenotype.  

PubMed

We present the case of a 29-year-old man with mutation-positive Duchenne muscular dystrophy and mutation-positive hypertrophic cardiomyopathy. His cardiac phenotype has characteristics of both disorders; he manifests sub-epicardial left ventricular free wall late gadolinium enhancement that is consistent with Duchenne cardiomyopathy, as well as asymmetric ventricular septal hypertrophy, hyperdynamic left ventricular systolic function, and septal mid-myocardial late gadolinium enhancement, which are characteristic of hypertrophic cardiomyopathy. PMID:24472441

Tandon, Animesh; Taylor, Michael D; Cripe, Linda H

2015-02-01

224

Cognitive profile and MRI findings in limb-girdle muscular dystrophy 2I  

Microsoft Academic Search

Limb-girdle muscular dystrophy 2I (LGMD2I) is a neuromuscular disorder with a heterogeneous phenotype. It is caused by mutations\\u000a in the Fukutin Related Protein (FKRP) gene, which is ubiquitously expressed in human tissues. FKRP functions in CNS are largely unknown. To investigate possible\\u000a cognitive impairment in LGMD2I and to describe brain MRI features. Ten LGMD2I patients (four males and six females,

A. Palmieri; R. Manara; L. Bello; G. Mento; L. Lazzarini; C. Borsato; L. Bortolussi; C. Angelini; E. Pegoraro

225

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

PubMed

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

Chambers, Henry G

2014-01-01

226

Diagnostic, predictive, and prenatal testing for facioscapulohumeral muscular dystrophy: diagnostic approach for sporadic and familial cases  

Microsoft Academic Search

Facioscapulohumeral muscular dystrophy (FSHD) is one of the common inherited neuromuscular disorders. The major gene involved, FSHD1, has been localised to chromosome 4q35. This 4q35 locus, detected by pE13-11 (D4F104S1), shows a mutation frequency of about 10% of the incidence. New mutants are characterised by de novo deletions of tens to hundreds of kilobases of DNA. Although these deletion fragments

E. Bakker; M. J. R. van der Wielen; E. Voorhoeve; P. F. Ippel; G. W. A. M. Padberg; R. R. Frants; C. Wijmenga

1996-01-01

227

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

Microsoft Academic Search

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

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

2011-01-01

228

Analysis of deletions in DNA from patients with Becker and Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder for which the biochemical defect is as yet unknown. Recently, two cloned segments of human X-chromosome DNA have been described which detect structural alterations within or near the genetic locus responsible for the disorder1,2. Both of these cloned segments were described as tightly linked to the locus and were capable

Louis M. Kunkel

1986-01-01

229

Duchenne Muscular Dystrophy Gene Expression in Normal and Diseased Human Muscle  

NASA Astrophysics Data System (ADS)

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.

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

230

Nitric oxide synthase complexed with dystrophin and absent from skeletal muscle sarcolemma in Duchenne muscular dystrophy  

Microsoft Academic Search

Nitric oxide (NO) is synthesized in skeletal muscle by neuronal-type NO synthase (nNOS), which is localized to sarcolemma of fast-twitch fibers. Synthesis of NO in active muscle opposes contractile force. We show that nNOS partitions with skeletal muscle membranes owing to association of nNOS with dystrophin, the protein mutated in Duchenne muscular dystrophy (DMD). The dystrophin complex interacts with an

Jay E Brenman; Daniel S Chao; Houhui Xia; Ken Aldape; David S Bredt

1995-01-01

231

Detection of deletions spanning the Duchenne muscular dystrophy locus using a tightly linked DNA segment  

Microsoft Academic Search

The Duchenne muscular dystrophy (DMD) locus has been localized to the short arm of the human X chromosome (Xp21) by detection of structural abnormalities1-5 and by genetic linkage studies6-8. A library highly enriched for human DNA from Xp21 was constructed9 using DNA isolated from a male patient who had a visible deletion and three X-linked disorders (DMD, retinitis pigmentosa and

Anthony P. Monaco; Corlee J. Bertelson; William Middlesworth; Chris-Anne Colletti; John Aldridge; Kenneth H. Fischbeck; Richard Bartlett; Margaret A. Pericak-Vance; Allen D. Roses; Louis M. Kunkel

1985-01-01

232

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

Microsoft Academic Search

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

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

1994-01-01

233

Deficiency of the 50K dystrophin-associated glycoprotein in severe childhood autosomal recessive muscular dystrophy  

Microsoft Academic Search

X-LINKED recessive Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin, a membrane cytoskeletal protein1,2. Dystrophin is associated with a large oligomeric com-plex of sarcolemmal glycoproteins3-10. The dystrophin-glycoprotein complex has been proposed to span the sarcolemma to provide a link fyetween the subsarcolemmal cytoskeleton and the extracellular matrix component, laminin7,9. In DMD, the absence of dystrophin leads to

Kiichiro Matsumura; Fernando M. S. Tomé; Huguette Collin; Kemal Azibi; Malika Chaouch; Jean-Claude Kaplan; Michel Fardeau; Kevin P. Campbell

1992-01-01

234

Utrophin-Dystrophin-Deficient Mice as a Model for Duchenne Muscular Dystrophy  

Microsoft Academic Search

The absence of dystrophin at the muscle membrane leads to Duchenne muscular dystrophy (DMD), a severe muscle-wasting disease that is inevitably fatal in early adulthood. In contrast, dystrophin-deficient mdx mice appear physically normal despite their underlying muscle pathology. We describe mice deficient for both dystrophin and the dystrophin-related protein utrophin. These mice show many signs typical of DMD in humans:

Anne E Deconinck; Jill A Rafael; Judith A Skinner; Susan C Brown; Allyson C Potter; Laurent Metzinger; Diana J Watt; J. George Dickson; Jonathon M Tinsley; Kay E Davies

1997-01-01

235

Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A  

Microsoft Academic Search

Limb-girdle muscular dystrophies (LGMDs) are a group of inherited diseases whose genetic etiology has yet to be elucidated. The autosomal recessive forms (LGMD2) constitute a genetically heterogeneous group with LGMD2A mapping to chromosome 15815.1–821.1. The gene encoding the muscle-specific calcium-activated neutral protease 3 (CANP3) large subunit is located in this region. This cysteine protease belongs to the family of intracellular

Isabelle Richard; Odile Broux; Valéerie Allamand; Françoise Fougerousse; Nuchanard Chiannilkulchai; Nathalie Bourg; Lydie Brenguier; Catherine Devaud; Patricia Pasturaud; Carinne Roudaut; Dominique Hillaire; Maria-Rita Passos-Bueno; Mayana Zatz; Jay A Tischfield; Michel Fardeau; Charles E Jackson; Daniel Cohen; Jacques S Beckmann

1995-01-01

236

Immunostaining of skeletal and cardiac muscle surface membrane with antibody against Duchenne muscular dystrophy peptide  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a debilitating X-linked muscle disease. We have used sequence information from complementary DNA clones, derived from the gene that is deleted in DMD patients1-3, to generate an antiserum that stains the surface membrane of intact human and mouse skeletal muscle, but not that of DMD patients and mdx mice4. Here we identify the protein reacting

Kiichi Arahata; Shoichi Ishiura; Tsuneo Ishiguro; Toshifumi Tsukahara; Yoshihiro Suhara; Chikahiko Eguchi; Tadayuki Ishiharat; Ikuya Nonaka; Eijiro Ozawa; Hideo Sugita

1988-01-01

237

[Staircase phenomenon in children with progressive muscular dystrophy and dermatomyositis].  

PubMed

The electrical and mechanical activity of the isometric twitch of flexor carpi ulnaris muscle during two per second indirect supramaximal stimulation for 90 sec was examined in 14 children with muscular distrophy and 8 children with dermatomyositis. The muscle electrical responses show no significant changes in the amplitude of its first negative phase. The first derivative of the dinamogram shows some of the following abnormalities in 8 of the examined children with muscular distrophy and in 2 of these with dermatomyositis: 1. Prolonged and increased negative staircase; 2. Insufficient or absent positive staircase potentiation. These abnormalities of the staircase phenomenon disclose disorders of the contractile function of the examined muscle. PMID:213914

Uzunova, M; Gatev, V; Stomatova, L

1978-01-01

238

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

PubMed Central

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

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

2008-01-01

239

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

PubMed

Sulforaphane (SFN), one of the most important isothiocyanates in the human diet, is known to have chemo-preventive and antioxidant activities in different tissues via activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated induction of antioxidant/phase II enzymes, such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. However, its effects on muscular dystrophy remain unknown. This work was undertaken to evaluate the effects of SFN on Duchenne muscular dystrophy. Four-week-old mdx mice were treated with SFN by gavage (2 mg·kg body wt(-1)·day(-1) for 8 wk), and our results demonstrated that SFN treatment increased the expression and activity of muscle phase II enzymes NAD(P)H quinone oxidoreductase 1 and heme oxygenase-1 with a Nrf2-dependent manner. SFN significantly increased skeletal muscle mass, muscle force (?30%), running distance (?20%), and GSH-to-GSSG ratio (?3.2-fold) of mdx mice and decreased the activities of plasma creatine phosphokinase (?45%) and lactate dehydrogenase (?40%), gastrocnemius hypertrophy (?25%), myocardial hypertrophy (?20%), and malondialdehyde levels (?60%). Furthermore, SFN treatment also reduced the central nucleation (?40%), fiber size variability, and inflammation and improved the sarcolemmal integrity of mdx mice. Collectively, these results show that SFN can improve muscle function and pathology and protect dystrophic muscle from oxidative damage in mdx mice associated with Nrf2 signaling pathway, which indicate Nrf2 may have clinical implications for the treatment of patients with muscular dystrophy. PMID:25593219

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

2015-01-15

240

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

PubMed Central

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

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

241

Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation  

PubMed Central

The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of ?-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced ?-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of ?-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of ?-dystroglycan hypoglycosylation in skeletal muscle. PMID:19342235

Puckett, Rebecca L.; Moore, Steven A.; Winder, Thomas L.; Willer, Tobias; Romansky, Stephen G.; Covault, Kelly King; Campbell, Kevin P.; Abdenur, Jose E.

2009-01-01

242

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

PubMed Central

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

Aristizabal, Juan Fernando; Smit, Rosana Martínez

2014-01-01

243

[Critical evaluation of changes of serum CK after exertion in the identification of carriers of Duchenne's muscular dystrophy].  

PubMed

Serum creatine kinase activity is the most useful test for Duchenne muscular dystrophy carrier detection, but only in 50-80% the carriers do have increased serum creatine kinase activity. To evaluate the diagnostic accuracy of post-exercise serum creatine kinase activity in identifying Duchenne muscular dystrophy carriers we did determine it in normal and possible Duchenne muscular distrophy carrier women. Creatine kinase activity was determined in basal conditions and at predetermined time intervals up to 10 hours after a constant exercise on a cycloergometer. Statistical analysis included: Fisher test on basal values; percent increase, difference between maximum and minimum values, absolute value after 8 hours and b coefficient of linear regression. Accuracy and sensitivity were evaluated for some of the data. Our results suggest that the activity of serum creatine kinase 8 hours after a quantified exercise can be useful to detect Duchenne muscular dystrophy carriers when basal activity is normal. PMID:6545595

Cordone, G; Venzano, V; Rossi, G; Cavallero, G; Minetti, C

1984-01-01

244

Muscle research needs you today! The information contained within this document is privileged and private between Paul and Sheila Wellstone Muscular Dystrophy Center (to be identified further as MD Center) and the Applicant mentioned above.  

E-print Network

and private between Paul and Sheila Wellstone Muscular Dystrophy Center (to be identified further as MD Center Muscular Dystrophy Center (MD Center), and have filled out this application completely and accurately. I

Thomas, David D.

245

The Zebrafish runzel Muscular Dystrophy is Linked to the Titin Gene  

PubMed Central

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

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

2007-01-01

246

Preliminary diffusion tensor imaging studies in limb-girdle muscular dystrophies  

NASA Astrophysics Data System (ADS)

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.

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

247

Mutations in GDP-Mannose Pyrophosphorylase B Cause Congenital and Limb-Girdle Muscular Dystrophies Associated with Hypoglycosylation of ?-Dystroglycan  

PubMed Central

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

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

2013-01-01

248

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

PubMed

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

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

249

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

PubMed Central

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

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

250

Presence of emerinopathy in cases of rigid spine syndrome  

Microsoft Academic Search

Rigid spine syndrome (RSS) shows clinical similarities to Emery–Dreifuss muscular dystrophy (EDMD). Differential diagnosis between EDMD and RSS is essential because EDMD is often associated with life-threatening cardiomyopathy that can be cured by an implantation of a cardiac pacemaker. To determine if any of the patients with RSS had mutations of the emerin gene (responsible gene for X-linked EDMD or

Shinichiro Kubo; Toshifumi Tsukahara; Masakazu Takemitsu; Kim Bong Yoon; Hiroya Utsumi; Ikuya Nonaka; Kiichi Arahata

1998-01-01

251

Expression of the myodystrophic R453W mutation of lamin A in C2C12 myoblasts causes promoter-specific and global epigenetic defects  

Microsoft Academic Search

Autosomal dominant Emery–Dreifuss muscular dystrophy (EDMD) is characterized by muscle wasting and is caused by mutations in the LMNA gene encoding A-type lamins. Overexpression of the EDMD lamin A R453W mutation in C2C12 myoblasts impairs myogenic differentiation. We show here the influence of stable expression of the R453W and of the Dunnigan-type partial lipodystrophy R482W mutation of lamin A in

Anne-Mari Håkelien; Erwan Delbarre; Kristine G. Gaustad; Brigitte Buendia; Philippe Collas

2008-01-01

252

Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: Local or systemic?  

Microsoft Academic Search

BACKGROUND: The golden retriever muscular dystrophy (GRMD) dogs represent the best available animal model for therapeutic trials aiming at the future treatment of human Duchenne muscular dystrophy (DMD). We have obtained a rare litter of six GRMD dogs (3 males and 3 females) born from an affected male and a carrier female which were submitted to a therapeutic trial with

Irina Kerkis; Carlos E Ambrosio; Alexandre Kerkis; Daniele S Martins; Eder Zucconi; Simone AS Fonseca; Rosa M Cabral; Carlos MC Maranduba; Thais P Gaiad; Adriana C Morini; Natassia M Vieira; Marina P Brolio; Osvaldo A Sant'Anna; Maria A Miglino; Mayana Zatz

2008-01-01

253

Learning about Myotonic Dystrophy  

MedlinePLUS

... FAQ Top of page Additional Resources on Myotonic Muscular Dystrophy Myotonic dystrophy [ghr.nlm.gov] From Genetics Home ... the CNBP gene. From Genetics Home Reference NINDS Muscular Dystrophy Information Page [ninds.nih.gov] From the National ...

254

Congenital muscular dystrophy phenotype with neuromuscular spindles excess in a 5-year-old girl caused by HRAS mutation.  

PubMed

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders. PMID:25070542

Bolocan, Anamaria; Quijano-Roy, Susana; Seferian, Andreea M; Baumann, Clarisse; Allamand, Valérie; Richard, Pascale; Estournet, Brigitte; Carlier, Robert; Cavé, Hélène; Gartioux, Corine; Blin, Nathalie; Le Moing, Anne-Gaëlle; Gidaro, Teresa; Germain, Dominique P; Fardeau, Michel; Voit, Thomas; Servais, Laurent; Romero, Norma Beatriz

2014-11-01

255

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

PubMed

Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1? in Fnip1 null skeletal muscle. Genetic disruption of PGC1? rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. PMID:25548157

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

2015-01-13

256

Echocardiographic evaluation of fibrous replacement in the myocardium of patients with Duchenne muscular dystrophy.  

PubMed Central

OBJECTIVES--To study myocardial echo amplitude in Duchenne muscular dystrophy and to examine the implications of increased echo amplitude. DESIGN--Regional echo amplitude, wall motion, and uptake of thallium-201 were examined in the left ventricular wall and the relation between these variables was investigated. SETTING--Hara National Sanatorium, Japan. PATIENTS--Seven healthy controls aged 10-28 years and 14 patients with Duchenne muscular dystrophy aged 12 to 30 years. INTERVENTIONS--Echocardiography with a sector scanner (Hitachi EUB-150, Japan) and a 3.5 MHz transducer (Hitachi EUP-S21, Japan); thallium-201 myocardial single photon emission computed tomography at rest with a rotating gamma camera system (Hitachi RC-135DT, Japan). MAIN OUTCOME MEASURES--Echo amplitude of the myocardium, thickness and wall motion of the posterior wall and ventricular septum, and myocardial uptake of thallium-201. RESULTS--Areas of increased echo amplitude were detected along the outer half of or throughout the posterior wall of left ventricle in nine of the 14 patients. Their posterior walls showed significantly decreased maximal systolic and diastolic endocardial velocities (mean (SE) 31.4 (16.0) and 55.6 (53.5) mm/s) compared with normal subjects (57.7(19.4) and 113.0 (27.5) mm/s), and decreased uptake of thallium-201. Their ventricular septa, however, showed normal echo amplitude and wall motion and normal uptake of thallium-201. CONCLUSION--Areas of increased echo amplitude were detected in the posterior walls of left ventricles of patients with Duchenne muscular dystrophy. These areas were suspected to be the sites of myocardial fibrosis. Images PMID:1772712

Miyoshi, K

1991-01-01

257

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

PubMed

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

Tedesco, Francesco Saverio

2015-02-01

258

[Rigid spine congenital muscular dystrophy produced by SEPN1 mutations (RSMD1)].  

PubMed

RSMD1 is a rare autosomal recessive disorder. Unlike most congenital muscular dystrophies, early motor improvement and normal CPK are typical, while in contrast to structural myopathies there is no specific muscle morphology. Rigid spine, early scoliosis and joint contractures are characteristic. We diagnosed RSMD1 in a 27-year-old Russian female with previous diagnosis of unspecified myopathy. DNA test detected compound heterozygosity for two SEPN1 mutations: already known missence-mutation c.1397G>A (p.Arg466Gln) and novel frame-shift mutation c.683_689dup7 leading to preterm stop-codon. PMID:24988964

Rudenskaia, G E; Kadnikova, V A; Poliakov, A V

2014-01-01

259

Rapid carrier and prenatal diagnosis of Duchenne and Becker muscular dystrophy  

SciTech Connect

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.

Roberts, R.G.; Cole, C.G.; Hart, K.A.; Bobrow, M.; Bentley, D.R. (Guy's Hospital, London (England))

1989-01-25

260

Conservation of the Duchenne muscular dystrophy gene in mice and humans  

SciTech Connect

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.

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

1987-10-16

261

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

SciTech Connect

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.

Mostacciuolo, M.L.; Miorin, M.; Vitiello, L.; Rampazzo, A.; Fanin, M.; Angelini, C.; Danieli, G.A. [Univ. of Padua (Italy)

1994-03-01

262

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

NASA Astrophysics Data System (ADS)

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.

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

1989-06-01

263

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

PubMed Central

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

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

264

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

PubMed

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

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

2015-01-01

265

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

PubMed Central

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

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

2014-01-01

266

Impaired primary hemostasis with normal platelet function in Duchenne muscular dystrophy during highly-invasive spinal surgery  

Microsoft Academic Search

A defective, normal or enhanced hemostasis has been reported in Duchenne muscular dystrophy (DMD). A retrospective analysis of intra-and postoperative (up to 36h) estimated blood losses was performed in 156 patients undergoing spinal surgery for: DMD (n=31), idiopathic scoliosis (IS) (n=70), poliomyelitis (n=10), cerebral palsy (CP) (n=28), spinal muscular atrophy (SMA) (n=17). Platelet aggregation and bleeding times were also investigated

Francesco Turturro; Bianca Rocca; Stefano Gumina; Raimondo De Cristofaro; Fortunato Mangiola; Nicola Maggiano; Antonella Evangelista; Vittorio Salsano; Antonello Montanaro

2005-01-01

267

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

NASA Astrophysics Data System (ADS)

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.

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

2013-04-01

268

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

PubMed Central

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

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

269

Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades?  

PubMed

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks. PMID:22428906

McGowan, Ruth; Challoner, Benjamin R; Ross, Sarah; Holloway, Susan; Joss, Shelagh; Wilcox, Douglas; Holden, Simon T; Tolmie, John; Longman, Cheryl

2013-02-01

270

Linker molecules between laminins and dystroglycan ameliorate laminin-?2–deficient muscular dystrophy at all disease stages  

PubMed Central

Mutations in laminin-?2 cause a severe congenital muscular dystrophy, called MDC1A. The two main receptors that interact with laminin-?2 are dystroglycan and ?7?1 integrin. We have previously shown in mouse models for MDC1A that muscle-specific overexpression of a miniaturized form of agrin (mini-agrin), which binds to dystroglycan but not to ?7?1 integrin, substantially ameliorates the disease (Moll, J., P. Barzaghi, S. Lin, G. Bezakova, H. Lochmuller, E. Engvall, U. Muller, and M.A. Ruegg. 2001. Nature. 413:302–307; Bentzinger, C.F., P. Barzaghi, S. Lin, and M.A. Ruegg. 2005. Matrix Biol. 24:326–332.). Now we show that late-onset expression of mini-agrin still prolongs life span and improves overall health, although not to the same extent as early expression. Furthermore, a chimeric protein containing the dystroglycan-binding domain of perlecan has the same activities as mini-agrin in ameliorating the disease. Finally, expression of full-length agrin also slows down the disease. These experiments are conceptual proof that linking the basement membrane to dystroglycan by specifically designed molecules or by endogenous ligands, could be a means to counteract MDC1A at a progressed stage of the disease, and thus opens new possibilities for the development of treatment options for this muscular dystrophy. PMID:17389231

Meinen, Sarina; Barzaghi, Patrizia; Lin, Shuo; Lochmüller, Hanns; Ruegg, Markus A.

2007-01-01

271

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

PubMed

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. © 2014 Wiley Periodicals, Inc. PMID:25297835

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

2014-10-01

272

Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy.  

PubMed

The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores ?33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids. PMID:25454732

De Sanctis, Roberto; Pane, Marika; Sivo, Serena; Ricotti, Valeria; Baranello, Giovanni; Frosini, Silvia; Mazzone, Elena; Bianco, Flaviana; Fanelli, Lavinia; Main, Marion; Corlatti, Alice; D'Amico, Adele; Colia, Giulia; Scalise, Roberta; Palermo, Concetta; Alfonsi, Chiara; Tritto, Giovanna; Romeo, Domenico M; Graziano, Alessandra; Battini, Roberta; Morandi, Lucia; Bertini, Enrico; Muntoni, Francesco; Mercuri, Eugenio

2015-01-01

273

Glycosaminoglycan modifications in Duchenne muscular dystrophy: specific remodeling of chondroitin sulfate/dermatan sulfate.  

PubMed

Widespread skeletal muscle degeneration and impaired regeneration lead to progressive muscle weakness and premature death in patients with Duchenne muscular dystrophy (DMD). Dystrophic muscles are progressively replaced by nonfunctional tissue because of exhaustion of muscle precursor cells and excessive accumulation of extracellular matrix (ECM). Sulfated glycosaminoglycans (GAGs) are components of the ECM and are increasingly implicated in the regulation of biologic processes, but their possible role in the progression of DMD pathology is not understood. In the present study, we performed immunohistochemical and biochemical analyses of endogenous GAGs in skeletal muscle biopsies of 10 DMD patients and 11 healthy individuals (controls). Immunostaining targeted to specific GAG species showed greater deposition of chondroitin sulfate (CS)/dermatan (DS) sulfate in DMD patient biopsies versus control biopsies. The selective accumulation of CS/DS in DMD biopsies was confirmed by biochemical quantification assay. In addition, high-performance liquid chromatography analysis demonstrated a modification of the sulfation pattern of CS/DS disaccharide units in DMD muscles. In conclusion, our data open up a new path of investigation and suggest that GAGs could represent a new and original therapeutic target for improving the success of gene or cell therapy for the treatment of muscular dystrophies. PMID:25003237

Negroni, Elisa; Henault, Emilie; Chevalier, Fabien; Gilbert-Sirieix, Marie; Van Kuppevelt, Toin H; Papy-Garcia, Dulce; Uzan, Georges; Albanese, Patricia

2014-08-01

274

NBD delivery improves the disease phenotype of the golden retriever model of Duchenne muscular dystrophy  

PubMed Central

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.

2014-01-01

275

Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data?  

PubMed Central

Objective: To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care. Methods: We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery. Results: Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival. Conclusions: CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD. PMID:23382369

Cwik, Valerie A.; Marshall, Bruce C.; Ciafaloni, Emma; Wolff, Jodi M.; Getchius, Thomas S.; Griggs, Robert C.

2013-01-01

276

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

PubMed Central

Abstract Duchenne muscular dystrophy (DMD) is the most devastating type of muscular dystrophy, leading to progressive weakness of respiratory (e.g. diaphragm) and locomotor muscles (e.g. gastrocnemius). DMD is caused by X-linked defects in the gene that encodes for dystrophin, a key scaffolding protein of the dystroglycan complex (DCG) within the sarcolemmal cytoskeleton. As a result of a compromised dystroglycan complex, mechanical integrity is impaired and important signalling proteins (e.g. nNOS, caveolin-3) and pathways are disrupted. Disruption of the dystroglycan complex leads to high susceptibility to injury with repeated, eccentric contractions as well as inflammation, resulting in significant damage and necrosis. Chronic damage and repair cycling leads to fibrosis and weakness. While the link between inflammation with damage and weakness in the DMD diaphragm is unresolved, elevated oxidative stress may contribute to damage, weakness and possibly fibrosis. While utilization of non-specific antioxidant interventions has yielded inconsistent results, recent data suggest that NAD(P)H oxidase could play a pivotal role in elevating oxidative stress via integrated changes in caveolin-3 and stretch-activated channels (SACs). Oxidative stress may act as an amplifier, exacerbating disruption of the dystroglycan complex, upregulation of the inflammatory transcription factor NF-?B, and thus functional impairment of force-generating capacity. PMID:21486793

Lawler, John M

2011-01-01

277

[Challenge toward gene-therapy using iPS cells for Duchenne muscular dystrophy].  

PubMed

Human artificial chromosomes (HACs) are stable episomal gene vectors that can carry large gene inserts. We have reported complete correction of a genetic deficiency following the transfer of a HAC carrying the genomic dystrophin sequence (DYS-HAC) into induced pluripotent stem (iPS) cells derived from either a Duchenne muscular dystrophy (DMD) model mouse or a human DMD patient. The engineered iPS cells could differentiate in immunodeficient nude mice, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice generated from the engineered cells showed tissue-specific expression of dystrophin. Recently, Giulio's group has isolated and characterized a population of blood vessel-associated stem cells, called mesoangioblasts, that can differentiate into multiple mesoderm cell types, including skeletal muscle. The DYS-HAC was transferred to mesoangioblasts from the DMD-model mouse. Thus, when delivered in the arterial circulation, mesoangioblasts crossed the blood vessel wall and participated in skeletal muscle regeneration, ameliorating signs of muscular dystrophy in the DMD model mice. Most recently, the iPS cells from a DMD patient corrected with the DYS-HAC, were successfully differentiated to mesoangioblasts. Therefore, autologous transfer of genetically corrected iPS cells and muscle progenitor cells will be desirable therapeutic cells because immune suppression would not be required. PMID:23196542

Oshimura, Mitsuo; Kazuki, Yasuhiro; Uno, Narumi

2012-01-01

278

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

SciTech Connect

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.

Schwartz, L.S.; Hoffman, E.P. (Univ. of Pittsburgh Schoool of Medicine, Pittsburgh, PA (United States)); Tarleton, J. (Self Memorial Hospital, Greenwood, SC (United States)); Popovich, B. (Children's Hosptial and Health Center, San Diego, CA (United States)); Seltzer, W.K. (Univ. of Colorado Health Sciences Center, Denver, CO (United States))

1992-10-01

279

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

SciTech Connect

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.

Sunada, Y.; Campbell, K.P. [Univ. of Iowa, Iowa City, IA (United States); Bernier, S.M. [and others

1994-09-01

280

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

SciTech Connect

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.

Roberds, S.L.; Anderson, R.D.; Lim, L.E. [Univ. of Iowa, Iowa City, IA (United States)] [and others

1994-09-01

281

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

PubMed Central

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

2014-01-01

282

Sleep-related respiratory disturbances in patients with Duchenne muscular dystrophy.  

PubMed

Sleep-related respiratory disturbances (SRD) in patients with muscle diseases may have significant clinical implications, because the patients frequently die at night. The aims of the study were to :1) assess the presence and severity of sleep-related respiratory disturbances in patients with Duchenne muscular distrophy (DMD); and 2) investigate the relationship of sleep-related respiratory disturbances to daytime symptoms and pulmonary function. We studied six clinically stable patients with Duchenne muscular dystrophy, mean age (+/- SD) 18 +/- 2 yrs. Vital capacity was 27 +/- 19% of predicted and daytime arterial oxygen tension (PaO2) was 10.9 +/- 1 kPa (range 8.9-12.4 kPa). The presence of daytime somnolence, insomnia, headache, nightmares and/or snoring was recorded. Four patients (67%) showed symptoms that suggest sleep-related respiratory disturbances. At night, the apnoea-hypopnoea index (AHI) was 11 +/- 6. The patients with more symptoms during the daytime had the highest AHI scores. Most of the apnoeas (85%) were central, particularly during rapid eye movement (REM) sleep. Sleep architecture was well-preserved. Arterial desaturation (> 5% below baseline) occurred during 25 +/- 23% of total time. AHI correlated with daytime PaO2, and AHI in REM sleep correlated with age. A stepwise multivariate analysis showed that PaO2 and, to some extent, the degree of airflow obstruction were significantly correlated with AHI. We conclude that sleep-related respiratory disturbance are frequently present in patients with Duchenne muscular dystrophy. Therefore, physicians should look for symptoms related to sleep-related respiratory disturbances in these patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7957826

Barbé, F; Quera-Salva, M A; McCann, C; Gajdos, P; Raphael, J C; de Lattre, J; Agustí, A G

1994-08-01

283

Hypersensitivity to DNA-damaging agents in cultured cells from patients with Usher's syndrome and Duchenne muscular dystrophy  

Microsoft Academic Search

Lymphoblastoid lines from nine Usher's syndrome (recessively inherited retinitis pigmentosa and congenital sensorineural deafness) patients (representing eight kindreds) and from ten Duchenne muscular dystrophy patients (representing seven kindreds) showed a small but statistically significant hypersensitivity to the lethal effects of X-rays, as measured by the cellular ability to exclude the vital dye trypan blue, when compared with lines from 26

J H Robbins; D A Scudiero; F Otsuka; R E Tarone; R A Brumback; J D Wirtschafter; R J Polinsky; S F Barrett; A N Moshell; R G Scarpinato

1984-01-01

284

Sarcospan integration into laminin-binding adhesion complexes that ameliorate muscular dystrophy requires utrophin and ?7 integrin.  

PubMed

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene that result in loss of the dystrophin-glycoprotein complex, a laminin receptor that connects the myofiber to its surrounding extracellular matrix. Utrophin, a dystrophin ortholog that is normally localized to the neuromuscular junction, is naturally upregulated in DMD muscle, which partially compensates for the loss of dystrophin. Transgenic overexpression of utrophin causes broad sarcolemma localization of utrophin, restoration of laminin binding and amelioration of disease in the mdx mouse model of DMD. We previously demonstrated that overexpression of sarcospan, a dystrophin- and utrophin-binding protein, ameliorates mdx muscular dystrophy. Sarcospan boosts levels of utrophin to therapeutic levels at the sarcolemma, where attachment to laminin is restored. However, understanding the compensatory mechanism is complicated by concomitant upregulation of ?7?1 integrin, which also binds laminin. Similar to the effects of utrophin, transgenic overexpression of ?7 integrin prevents DMD disease in mice and is accompanied by increased abundance of utrophin around the extra-synaptic sarcolemma. In order to investigate the mechanisms underlying sarcospan 'rescue' of muscular dystrophy, we created double-knockout mice to test the contributions of utrophin or ?7 integrin. We show that sarcospan-mediated amelioration of muscular dystrophy in DMD mice is dependent on the presence of both utrophin and ?7?1 integrin, even when they are individually expressed at therapeutic levels. Furthermore, we found that association of sarcospan into laminin-binding complexes is dependent on utrophin and ?7?1 integrin. PMID:25504048

Marshall, Jamie L; Oh, Jennifer; Chou, Eric; Lee, Joy A; Holmberg, Johan; Burkin, Dean J; Crosbie-Watson, Rachelle H

2015-04-01

285

Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation  

Microsoft Academic Search

We reviewed the notes of 197 patients with Duchenne muscular dystrophy whose treatment was managed at the Newcastle muscle centre from 1967 to 2002, to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation altered the pattern of survival. Patients were grouped according to the decade of death and whether or not they were

Michelle Eagle; Simon V Baudouin; Colin Chandler; David R Giddings; Robert Bullock; Kate Bushby

2002-01-01

286

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

Microsoft Academic Search

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,

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

2011-01-01

287

North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy  

Microsoft Academic Search

The North Star Ambulatory Assessment is a functional scale specifically designed for ambulant boys affected by Duchenne muscular dystrophy (DMD). Recently the 6-minute walk test has also been used as an outcome measure in trials in DMD.The aim of our study was to assess a large cohort of ambulant boys affected by DMD using both North Star Assessment and 6-minute

Elena Mazzone; Diego Martinelli; Angela Berardinelli; Sonia Messina; Adele D’Amico; Gessica Vasco; Marion Main; Luca Doglio; Luisa Politano; Filippo Cavallaro; Silvia Frosini; Luca Bello; Adelina Carlesi; Anna Maria Bonetti; Elisabetta Zucchini; Roberto De Sanctis; Marianna Scutifero; Flaviana Bianco; Francesca Rossi; Maria Chiara Motta; Annalisa Sacco; Maria Alice Donati; Tiziana Mongini; Antonella Pini; Roberta Battini; Elena Pegoraro; Marika Pane; Elisabetta Pasquini; Claudio Bruno; Giuseppe Vita; Chiara de Waure; Enrico Bertini; Eugenio Mercuri

2010-01-01

288

Fatty liver disease and hypertransaminasemia hiding the association of clinically silent Duchenne muscular dystrophy and hereditary fructose intolerance  

PubMed Central

We report a case with the association of well self-compensated hereditary fructose intolerance and still poorly symptomatic Duchenne type muscular dystrophy. This case illustrates the problems of a correct diagnosis in sub-clinical patients presenting with “cryptogenic” hypertransaminasemia. PMID:23114028

2012-01-01

289

Gender-specific differences in the psychosocial adjustment of parents of a child with duchenne muscular dystrophy (DMD)  

Microsoft Academic Search

Research was conducted on parents' experience of caring for a child living with Duchenne muscular dystrophy (DMD). The focus of this research was on the key psychological aspects of the process of adjustment to the illness of their child (family and spousal relationship, daily life, emotions, career, spirituality, and coping strategies). There was evidence throughout the study of gender-specific differences

Eva M. Tomiak; Andre Samson; Sarah A. Miles; Mireille C. Choquette; Pranesh K. Chakraborty

290

Accurate diagnosis of carriers of deletions and duplications in Duchenne\\/Becker muscular dystrophy by fluorescent dosage analysis  

Microsoft Academic Search

We have developed a semiautomated approach to amplify 25 exons of the dystrophin gene using two fluorescent multiplex PCR assays which detect over 98% of reported deletions and 90% of duplications causing Duchenne\\/Becker muscular dystrophy. The 5' multiplex detects 11 exons from the proximal deletion hotspot of the gene while the 3' multiplex detects 14 exons from the central deletion

S C Yau; M Bobrow; C G Mathew; S J Abbs

1996-01-01

291

Tl-201 myocardial SPECT in patients with Duchenne's muscular dystrophy: A long-term follow-up  

SciTech Connect

Tl-201 SPECT was used to evaluate myocardial involvement in 13 patients with Duchenne's muscular dystrophy. Serial studies of 9 patients were done at two-year intervals. The hypoperfused areas of the left ventricle became more prominent with age and severity.

Nagamachi, S.; Jinnouchi, S.; Ono, S.; Hoshi, H.; Inoue, K.; Watanabe, K. (Miyazaki Medical College (Japan))

1989-11-01

292

Functional Behavioral Assessment for a Boy with Duchenne Muscular Dystrophy and Problem Behavior: A Case Study from Greece  

ERIC Educational Resources Information Center

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…

Theodoridou, Zoe; Koutsoklenis, Athanasios

2013-01-01

293

Motor and Cognitive Assessment of Infants and Young Boys with Duchenne Muscular Dystrophy; Results from the Muscular Dystrophy Association DMD Clinical Research Network  

PubMed Central

Therapeutic trials in Duchenne Muscular dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley-III Scales of Infant and Toddler Development (Bayley-III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n=24; 1.9±0.7 years) were assessed. The mean Bayley-III motor composite score was low (82.8 ± 8; p=<.0001)(normal=100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p=<.0001). The mean cognitive comprehensive (p=.0002), receptive language (p=<.0001), and expressive language (p=.0001) were also low compared to normal children. Age was negatively associated with Bayley-III gross motor (r=?0.44 p=.02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n =18 boys; 2.2 ± 0.4years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley-III. PMID:23726376

Connolly, Anne M.; Florence, Julaine M.; Cradock, Mary M.; Malkus, Elizabeth C.; Schierbecker, Jeanine R.; Siener, Catherine A.; Wulf, Charlie O.; Anand, Pallavi; Golumbek, Paul T.; Zaidman, Craig M; Miller, J Philip; Lowes, Linda P; Alfano, Lindsay N.; Viollet-Callendret, Laurence; Flanigan, Kevin M.; Mendell, Jerry R.; McDonald, Craig M.; Goude, Erica; Johnson, Linda; Nicorici, Alina; Karachunski, Peter I.; Day, John W.; Dalton, Joline C.; Farber, Janey M.; Buser, Karen K.; Darras, Basil T.; Kang, Peter B.; Riley, Susan O.; Shriber, Elizabeth; Parad, Rebecca; Bushby, Kate; Eagle, Michelle

2013-01-01

294

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network.  

PubMed

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ? .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ? .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ? .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III. PMID:23726376

Connolly, Anne M; Florence, Julaine M; Cradock, Mary M; Malkus, Elizabeth C; Schierbecker, Jeanine R; Siener, Catherine A; Wulf, Charlie O; Anand, Pallavi; Golumbek, Paul T; Zaidman, Craig M; Philip Miller, J; Lowes, Linda P; Alfano, Lindsay N; Viollet-Callendret, Laurence; Flanigan, Kevin M; Mendell, Jerry R; McDonald, Craig M; Goude, Erica; Johnson, Linda; Nicorici, Alina; Karachunski, Peter I; Day, John W; Dalton, Joline C; Farber, Janey M; Buser, Karen K; Darras, Basil T; Kang, Peter B; Riley, Susan O; Shriber, Elizabeth; Parad, Rebecca; Bushby, Kate; Eagle, Michelle

2013-07-01

295

Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis  

SciTech Connect

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.

Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K., E-mail: mcloo001@tc.umn.edu

2011-04-01

296

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

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

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

2011-01-01

297

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency  

PubMed Central

The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (?-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function. PMID:22727687

Pane, M.; Messina, S.; Vasco, G.; Foley, A.R.; Morandi, L.; Pegoraro, E.; Mongini, T.; D’Amico, A.; Bianco, F.; Lombardo, M.E.; Scalise, R.; Bruno, C.; Berardinelli, A.; Pini, A.; Moroni, I.; Mora, M.; Toscano, A.; Moggio, M.; Comi, G.; Santorelli, F.M.; Bertini, E.; Muntoni, F.; Mercuri, E.

2012-01-01

298

Respiratory and cardiac function in congenital muscular dystrophies with alpha dystroglycan deficiency.  

PubMed

The aim of this retrospective study was to assess respiratory and cardiac function in a large cohort of patients with congenital muscular dystrophies (CMD) with reduced glycosylation of alphadystroglycan (?-DG). Thirteen of the 115 patients included in the study died between the age of 1 month and 20 years. The age at last follow up of the surviving 102 ranged between 1 year and 68 years (median: 9.3 years). Cardiac involvement was found in 7 of the 115 (6%), 5 with dilated cardiomyopathy, 1 cardiac conductions defects and 1 mitral regurgitation. Respiratory function was impaired in 14 (12%). Ten of the 14 required non invasive nocturnal respiratory support, while the other four required invasive ventilation. Cardiac or respiratory involvement was found in patients with mutations in FKRP, POMT1, POMT2. All of the patients in whom mutation in POMGnT1 were identified had normal cardiac and respiratory function. PMID:22727687

Pane, M; Messina, S; Vasco, G; Foley, A R; Morandi, L; Pegoraro, E; Mongini, T; D'Amico, A; Bianco, F; Lombardo, M E; Scalise, R; Bruno, C; Berardinelli, A; Pini, A; Moroni, I; Mora, M; Toscano, A; Moggio, M; Comi, G; Santorelli, F M; Bertini, E; Muntoni, F; Mercuri, E

2012-08-01

299

Adult onset limb-girdle muscular dystrophy - A recessive titinopathy masquerading as myositis.  

PubMed

Rarely, inflammation can be present in genetic myopathies, such as dysferlinopathies, facioscapulohumeral muscular dystrophy and GNE-myopathy (hereditary inclusion body myopathy). This may lead to erroneous initial diagnosis and unnecessary therapy which bear serious side effects. We report on an unusual case of mutations in the TTN gene presenting with inflammatory infiltrates in the muscle biopsy. Only after intensive immune-modulating therapies failed, a genetic myopathy was considered. Exome sequencing and search for mutated muscle protein-encoding genes disclosed compound heterozygous mutations in TTN: K26320T and A6135G. The parents carry one each of the mutations. Titinopathy could be considered also in patients presenting with inflammatory infiltrates resistant to therapy. PMID:25772186

Dabby, Ron; Sadeh, Menachem; Hilton-Jones, David; Plotz, Paul; Hackman, Peter; Vihola, Anna; Udd, Bjarne; Leshinsky-Silver, Esther

2015-04-15

300

Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy  

PubMed Central

The genetic basis of oculopharyngeal muscular dystrophy (OPMD) is a short expansion of a polyalanine tract (normal allele: 10 alanines, mutant allele: 11–17 alanines) in the nuclear polyadenylate binding protein PABPN1 which is essential for controlling poly(A) tail length in messenger RNA. Mutant PABPN1 forms nuclear inclusions in OPMD muscle. To investigate the pathogenic role of mutant PABPN1 in vivo, we generated a ligand-inducible transgenic mouse model by using the mifepristone-inducible gene expression system. Induction of ubiquitous expression of mutant PABPN1 resulted in skeletal and cardiac myopathy. Histological changes of degenerative myopathy were preceded by nuclear inclusions of insoluble PABPN1. Downregulation of mutant PABPN1 expression attenuated the myopathy and reduced the nuclear burden of insoluble PABPN1. These results support association between mutant PABPN1 accumulation and degenerative myopathy in mice. Resolution of myopathy in mice suggests that the disease process in OPMD patients may be treatable. PMID:21964252

Mankodi, Ami; Wheeler, Thurman M.; Shetty, Reena; Salceies, Kelly M.; Becher, Mark W.; Thornton, Charles A.

2011-01-01

301

Coexistence of gene mutations causing Fabry disease and Duchenne muscular dystrophy in a Japanese boy.  

PubMed

Both Fabry disease and Duchenne muscular dystrophy were confirmed by gene analysis in a Japanese boy. He developed muscle weakness at 4 years of age. A muscle biopsy revealed lamellar inclusion bodies in vascular endothelial cells in addition to myopathic changes with negative dystrophin staining. The myopathic symptoms progressed, and he died of pneumonia at 24 years of age. No clinical manifestations of Fabry disease were observed except for hypohidrosis and angiokeratoma. However, glycolipid accumulation was found in biopsied renal tissue. Molecular analysis demonstrated two gene mutations; a novel single-base deletion in exon 3 of the alpha-galactosidase gene, and a dystrophin gene deletion extending from exon 46 to exon 50. His mother was confirmed to be heterozygous for both gene deletions. PMID:8832134

Takenaka, T; Sakuraba, H; Hashimoto, K; Fujino, O; Fujita, T; Tanaka, H; Suzuki, Y

1996-05-01

302

Intermittent Pre-Excitation-Syndrome in Facio-Scapulo-Humeral Muscular Dystrophy  

PubMed Central

Pre-excitation-syndrome has not been reported as a phenotypic feature of facio-scapulo-humeral muscular dystrophy (FSH-MD). In a 39-year-old male with FSH-MD due to a reduced tandem repeat size in the D4Z4-locus on chromosome 4q35, cardiac involvement, manifesting as an incomplete right bundle-branch-block, tall T-waves in V 3-5, ST-elevation in V 2-4, and mild thickening of the left ventricular myocardium, was first recognised 10 years earlier. Follow-up at age 39 years revealed mild myocardial thickening, two intra-ventricular aberrant bands, and, surprisingly, intermittent pre-excitation on a routine electrocardiography. Cardiac involvement in FSH-MD may manifest as hypertrophic cardiomyopathy or various arrhythmias, of which one may be pre-excitation-syndrome. PMID:25278989

Stöllberger, Claudia; Gatterer, Edmund; Jakubiczka, Sibylle

2014-01-01

303

Psychological Aspects in Children Affected by Duchenne De Boulogne Muscular Dystrophy  

PubMed Central

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

Parisi, Lucia; Roccella, Michele

2014-01-01

304

Mesenchymal stem cells as anti-inflammatories: implications for treatment of Duchenne muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is a lethal X-linked musculodegenerative condition consisting of an underlying genetic defect whose manifestation is augmented by inflammatory mechanisms. Previous treatment approaches using gene replacement, exon-skipping or allogeneic cell therapy have been relatively unsuccessful. The only intervention to mediate improvement in survival, albeit minor, is glucocorticoid treatment. Given this modality appears to function via suppression of underlying inflammation; we focus this review on the inflammatory response as a target for mesenchymal stem cell (MSC) therapy. In contrast to other cell based therapies attempted in DMD, MSC have the advantages of (a) ability to fuse with and genetically complement dystrophic muscle; (b) possess anti-inflammatory activities; and (c) produce trophic factors that may augment activity of endogenous repair cells. We conclude by describing one practical scenario of stem cell therapy for DMD. PMID:19917503

Ichim, Thomas E; Alexandrescu, Doru T; Solano, Fabio; Lara, Fabian; Campion, Rosalia De Necochea; Paris, Eugenia; Woods, Erik J; Murphy, Michael P; Dasanu, Constantin A; Patel, Amit N; Marleau, Annette M; Leal, Alejandro; Riordan, Neil H

2010-01-01

305

Initial Pulmonary Respiration Causes Massive Diaphragm Damage and Hyper-CKemia in Duchenne Muscular Dystrophy Dog  

PubMed Central

The molecular mechanism of muscle degeneration in a lethal muscle disorder Duchene muscular dystrophy (DMD) has not been fully elucidated. The dystrophic dog, a model of DMD, shows a high mortality rate with a marked increase in serum creatine kinase (CK) levels in the neonatal period. By measuring serum CK levels in cord and venous blood, we found initial pulmonary respiration resulted in massive diaphragm damage in the neonates and thereby lead to the high serum CK levels. Furthermore, molecular biological techniques revealed that osteopontin was prominently upregulated in the dystrophic diaphragm prior to the respiration, and that immediate-early genes (c-fos and egr-1) and inflammation/immune response genes (IL-6, IL-8, COX-2, and selectin E) were distinctly overexpressed after the damage by the respiration. Hence, we segregated dystrophic phases at the molecular level before and after mechanical damage. These molecules could be biomarkers of muscle damage and potential targets in pharmaceutical therapies. PMID:23851606

Nakamura, Akinori; Kobayashi, Masanori; Kuraoka, Mutsuki; Yuasa, Katsutoshi; Yugeta, Naoko; Okada, Takashi; Takeda, Shin'ichi

2013-01-01

306

Psychological aspects in children affected by duchenne de boulogne muscular dystrophy.  

PubMed

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

Filippo, Teresa Di; Parisi, Lucia; Roccella, Michele

2012-07-26

307

Novel compounds for the treatment of Duchenne muscular dystrophy: emerging therapeutic agents  

PubMed Central

The identification of dystrophin and the causative role of mutations in this gene in Duchenne and Becker muscular dystrophies (D/BMD) was expected to lead to timely development of effective therapies. Despite over 20 years of research, corticosteroids remain the only available pharmacological treatment for DMD, although significant benefits and extended life have resulted from advances in the clinical care and management of DMD individuals. Effective treatment of DMD will require dystrophin restitution in skeletal, cardiac, and smooth muscles and nonmuscle tissues; however, modulation of muscle loss and regeneration has the potential to play an important role in altering the natural history of DMD, particularly in combination with other treatments. Emerging biological, molecular, and small molecule therapeutics are showing promise in ameliorating this devastating disease, and it is anticipated that regulatory environments will need to display some flexibility in order to accommodate the new treatment paradigms. PMID:23776365

Wilton, Steve D; Fletcher, Sue

2011-01-01

308

Cardioembolic stroke related to limb-girdle muscular dystrophy 1B  

PubMed Central

Background Cardioembolic stroke is an under-recognized complication in patients with limb-girdle muscular dystrophy 1B. Here we present a young stroke patient who had a novel lamin A/C gene (LMNA) mutation. Case presentation This is a 39-year-old man who had slowly progressive proximal muscle weakness and cardiac arrhythmia since adolescent and a family history of similar manifestation. He sustained acute ischemic stroke in the left middle cerebral artery territory. Intravenous recombinant tissue plasminogen activator therapy was given with significant neurological improvement. Additionally, genetic sequencing of the LMNA gene of the patient identified a mutation in c.513+1 G>A that resulted in a splicing aberration. Conclusion We suggested that LMNA gene related myopathies should be considered in young stroke patients with long-standing myopathic features. PMID:23360689

2013-01-01

309

miR-31 modulates dystrophin expression: new implications for Duchenne muscular dystrophy therapy  

PubMed Central

Duchenne muscular dystrophy (DMD)—which is caused by mutations in the dystrophin gene—is one of the most severe myopathies. Among therapeutic strategies, exon skipping allows the rescue of dystrophin synthesis through the production of a shorter but functional messenger RNA. Here, we report the identification of a microRNA—miR-31—that represses dystrophin expression by targeting its 3? untranslated region. In human DMD myoblasts treated with exon skipping, we demonstrate that miR-31 inhibition increases dystrophin rescue. These results indicate that interfering with miR-31 activity can provide an ameliorating strategy for those DMD therapies that are aimed at efficiently recovering dystrophin synthesis. PMID:21212803

Cacchiarelli, Davide; Incitti, Tania; Martone, Julie; Cesana, Marcella; Cazzella, Valentina; Santini, Tiziana; Sthandier, Olga; Bozzoni, Irene

2011-01-01

310

Evidence for locus heterogeneity in autosomal dominant limb-girdle muscular dystrophy  

SciTech Connect

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.

Speer, M.C.; Stajich, J.M.; Gaskell, P.C. [Duke Univ. Medical School, Durham, NC (United States)] [and others

1995-12-01

311

Molecular analysis of the Duchenne muscular dystrophy gene in Spanish individuals: Deletion detection and familial diagnosis  

SciTech Connect

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.

Patino, A.; Garcia-Delgado, M.; Narbona, J. [Univ. of Navarra, Pamplona (Spain)

1995-11-06

312

Dystrophin, utrophin and {beta}-dystroglycan expression in skeletal muscle from patients with Becker muscular dystrophy  

SciTech Connect

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.

Kawajiri, Masakazu; Mitsui, Takao; Kawai, Hisaomi [Univ. of Tokushima (Japan)] [and others

1996-08-01

313

Restoration of half the normal dystrophin sequence in a double-deletion Duchenne muscular dystrophy family  

SciTech Connect

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.

Hoop, R.C.; Schwartz, L.S.; Hoffman, E.P. [Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States); Russo, L.S. [Univ. of Florida, Jacksonville, FL (United States); Riconda, D.L. [Orlando Regional Medical Center, Orlando, FL (United States)

1994-02-01

314

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

NASA Astrophysics Data System (ADS)

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.

Rodemann, H. Peter; Bayreuther, Klaus

1984-08-01

315

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family  

SciTech Connect

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.

Frydman, M.; Straussberg, R.; Shomrat, R.; Legum, C. [Tel Aviv Univ. (Israel)] [and others

1995-09-11

316

Delayed Developmental Language Milestones in Children with Duchenne’s Muscular Dystrophy  

PubMed Central

Objectives To document the attainment of developmental milestones in children with Duchenne’s muscular dystrophy (DMD) and to determine whether early delays are associated with later performance on measures of cognition. Study design Retrospective parental report was utilized to document the acquisition of 10 common developmental milestones in children with DMD (n = 130) and their unaffected siblings (n = 59). Children completed tests of cognitive functioning. Results Parents rated children with DMD as delayed on achieving both language and motor milestones more frequently than their unaffected siblings. Furthermore, those children with DMD who were rated as late talkers or late walkers performed more poorly on tests of cognitive function than their on-time peers. Conclusions In addition to the commonly reported delays in motor milestones, the current study documents delays in the acquisition of language milestones as well. These early delays are associated with significant impairments in later cognitive functioning. PMID:17452219

Cyrulnik, Shana E.; Fee, Robert J.; De Vivo, Darryl C.; Goldstein, Edward; Hinton, Veronica J.

2007-01-01

317

Further evidence of Fukutin mutations as a cause of childhood onset limb-girdle muscular dystrophy without mental retardation.  

PubMed

The dystroglycanopathies comprise a clinically and genetically heterogeneous group of muscular dystrophies characterized by deficient glycosylation of alpha-dystroglycan. Mutations in the fukutin (FKTN) gene have primarily been identified among patients with classic Fukuyama congenital muscular dystrophy (FCMD), a severe form of dystroglycanopathy characterized by CMD, cobblestone lissencephaly and ocular defects. We describe two brothers of Caucasian and Japanese ancestry with normal intelligence and limb-girdle muscular dystrophy (LGMD) due to compound heterozygous FKTN mutations. Muscle biopsy showed a dystrophy with selectively reduced alpha-dystroglycan glycoepitope immunostaining. Immunoblots revealed hypoglycosylation of alpha-dystroglycan and loss of laminin binding. FKTN gene sequencing identified two variants: c.340G>A and c.527T>C, predicting missense mutations p.A114T and p.F176S, respectively. Our results provide further evidence for ethnic and allelic heterogeneity and the presence of milder phenotypes in FKTN-dystroglycanopathy despite a substantial degree of alpha-dystroglycan hypoglycosylation in skeletal muscle. PMID:19342235

Puckett, Rebecca L; Moore, Steven A; Winder, Thomas L; Willer, Tobias; Romansky, Stephen G; Covault, Kelly King; Campbell, Kevin P; Abdenur, Jose E

2009-05-01

318

Long Term Natural History Data in Ambulant Boys with Duchenne Muscular Dystrophy: 36-Month Changes  

PubMed Central

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of ?15.8 (SD 77.3) m at 12 months, of ?58.9 (SD 125.7) m at 24 months and ?104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p?=?0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available. PMID:25271887

Sormani, Maria Pia; Messina, Sonia; D?Amico, Adele; Carlesi, Adelina; Vita, Gianluca; Fanelli, Lavinia; Berardinelli, Angela; Torrente, Yvan; Lanzillotta, Valentina; Viggiano, Emanuela; D?Ambrosio, Paola; Cavallaro, Filippo; Frosini, Silvia; Barp, Andrea; Bonfiglio, Serena; Scalise, Roberta; De Sanctis, Roberto; Rolle, Enrica; Graziano, Alessandra; Magri, Francesca; Palermo, Concetta; Rossi, Francesca; Donati, Maria Alice; Sacchini, Michele; Arnoldi, Maria Teresa; Baranello, Giovanni; Mongini, Tiziana; Pini, Antonella; Battini, Roberta; Pegoraro, Elena; Previtali, Stefano; Bruno, Claudio; Politano, Luisa; Comi, Giacomo P.; Bertini, Enrico; Mercuri, Eugenio

2014-01-01

319

Mutations in B3GALNT2 cause congenital muscular dystrophy and hypoglycosylation of ?-dystroglycan.  

PubMed

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

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

2013-03-01

320

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

PubMed Central

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

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

321

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

PubMed

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

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

322

The role of proteases in excitation-contraction coupling failure in muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is one of the most frequent types of muscular dystrophy. Alterations in intracellular calcium (Ca(2+)) handling are thought to contribute to the disease severity in DMD, possibly due to the activation of Ca(2+)-activated proteases. The purpose of this study was twofold: 1) to determine whether prolonged excitation-contraction (E-C) coupling disruption following repeated contractions is greater in animals lacking both dystrophin and utrophin (mdx/Utr(-/-)) compared with mice lacking only dystrophin (mdx); and 2) to assess whether protease inhibition can prevent E-C coupling failure following repeated tetani in these dystrophic mouse models. Excitation-contraction coupling was assessed using Fura-2 ratio, as an index of intracellular free Ca(2+) concentration, in response to electrical stimulation of single muscle fibers from the flexor digitorum brevis muscle. Resting Fura-2 ratio was higher in dystrophic compared with control (Con) fibers, but peak Fura-2 ratios during stimulation were similar in dystrophic and Con fibers. One hour after a series of repeated tetani, peak Fura-2 ratios were reduced by 30 ± 5.6%, 23 ± 2%, and 36 ± 3.1% in mdx, mdx/Utr(+/-), and mdx/Utr(-/-), respectively, with the greatest reduction in mdx/Utr(-/-) fibers (P < 0.05). Protease inhibition attenuated this decrease in peak Fura-2 ratio. These data indicate that E-C coupling impairment after repeated contractions is greatest in fibers lacking both dystrophin and utrophin and that prevention of protease activation can mitigate the prolonged E-C coupling impairment. These data further suggest that acute protease inhibition may be useful in reducing muscle weakness in DMD. PMID:25298424

Mázala, Davi A G; Grange, Robert W; Chin, Eva R

2015-01-01

323

Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23.  

PubMed Central

Inherited cardiomyopathies may arise from mutations in genes that are normally expressed in both heart and skeletal muscle and therefore may be accompanied by skeletal muscle weakness. Phenotypically, patients with familial dilated cardiomyopathy (FDC) show enlargement of all four chambers of the heart and develop symptoms of congestive heart failure. Inherited cardiomyopathies may also be accompanied by cardiac conduction-system defects that affect the atrioventricular node, resulting in bradycardia. Several different chromosomal regions have been linked with the development of autosomal dominant FDC, but the gene defects in these disorders remain unknown. We now characterize an autosomal dominant disorder involving dilated cardiomyopathy, cardiac conduction-system disease, and adult-onset limb-girdle muscular dystrophy (FDC, conduction disease, and myopathy [FDC-CDM]). Genetic linkage was used to exclude regions of the genome known to be linked to dilated cardiomyopathy and muscular dystrophy phenotypes and to confirm genetic heterogeneity of these disorders. A genomewide scan identified a region on the long arm of chromosome 6 that is significantly associated with the presence of myopathy (D6S262; maximum LOD score [Z(max)] 4.99 at maximum recombination fraction [theta(max)] .00), identifying FDC-CDM as a genetically distinct disease. Haplotype analysis refined the interval containing the genetic defect, to a 3-cM interval between D6S1705 and D6S1656. This haplotype analysis excludes a number of striated muscle-expressed genes present in this region, including laminin alpha2, laminin alpha4, triadin, and phospholamban. Images Figure 2 PMID:9382102

Messina, D N; Speer, M C; Pericak-Vance, M A; McNally, E M

1997-01-01

324

Pharmacologic Management of Duchenne Muscular Dystrophy: Target Identification and Preclinical Trials  

PubMed Central

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

Kornegay, Joe N.; Spurney, Christopher F.; Nghiem, Peter P.; Brinkmeyer-Langford, Candice L.; Hoffman, Eric P.; Nagaraju, Kanneboyina

2014-01-01

325

Emerging gene editing strategies for Duchenne muscular dystrophy targeting stem cells  

PubMed Central

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

Bertoni, Carmen

2014-01-01

326

Myogenic Differentiation of Muscular Dystrophy-Specific Induced Pluripotent Stem Cells for Use in Drug Discovery  

PubMed Central

Human induced pluripotent stem cells (iPSCs) represent a scalable source of potentially any cell type for disease modeling and therapeutic screening. We have a particular interest in modeling skeletal muscle from various genetic backgrounds; however, efficient and reproducible methods for the myogenic differentiation of iPSCs have not previously been demonstrated. Ectopic myogenic differentiation 1 (MyoD) expression has been shown to induce myogenesis in primary cell types, but the same effect has been unexpectedly challenging to reproduce in human iPSCs. In this study, we report that optimization of culture conditions enabled direct MyoD-mediated differentiation of iPSCs into myoblasts without the need for an intermediate step or cell sorting. MyoD induction mediated efficient cell fusion of mature myocytes yielding multinucleated myosin heavy chain-positive myotubes. We applied the same approach to dystrophic iPSCs, generating 16 iPSC lines from fibroblasts of four patients with Duchenne and Becker muscular dystrophies. As seen with iPSCs from healthy donors, within 36 hours from MyoD induction there was a clear commitment toward the myogenic identity by the majority of iPSCs in culture (50%–70%). The patient iPSC-derived myotubes successfully adopted the skeletal muscle program, as determined by global gene expression profiling, and were functionally responsive to treatment with hypertrophic proteins insulin-like growth factor 1 (IGF-1) and wingless-type MMTV integration site family, member 7A (Wnt7a), which are being investigated as potential treatments for muscular dystrophy in clinical and preclinical studies, respectively. Our results demonstrate that iPSCs have no intrinsic barriers preventing MyoD from inducing efficient and rapid myogenesis and thus providing a scalable source of normal and dystrophic myoblasts for use in disease modeling and drug discovery. PMID:24396035

Abujarour, Ramzey; Bennett, Monica; Valamehr, Bahram; Lee, Tom Tong; Robinson, Megan; Robbins, David; Le, Thuy; Lai, Kevin

2014-01-01

327

Long term natural history data in ambulant boys with Duchenne muscular dystrophy: 36-month changes.  

PubMed

The 6 minute walk test has been recently chosen as the primary outcome measure in international multicenter clinical trials in Duchenne muscular dystrophy ambulant patients. The aim of the study was to assess the spectrum of changes at 3 years in the individual measures, their correlation with steroid treatment, age and 6 minute walk test values at baseline. Ninety-six patients from 11 centers were assessed at baseline and 12, 24 and 36 months after baseline using the 6 minute walk test and the North Star Ambulatory Assessment. Three boys (3%) lost the ability to perform the 6 minute walk test within 12 months, another 13 between 12 and 24 months (14%) and 11 between 24 and 36 months (12%). The 6 minute walk test showed an average overall decline of -15.8 (SD 77.3) m at 12 months, of -58.9 (SD 125.7) m at 24 months and -104.22 (SD 146.2) m at 36 months. The changes were significantly different in the two baseline age groups and according to the baseline 6 minute walk test values (below and above 350 m) (p<0.001). The changes were also significantly different according to steroid treatment (p = 0.01). Similar findings were found for the North Star Ambulatory Assessment. These are the first 36 month longitudinal data using the 6 minute walk test and North Star Ambulatory Assessment in Duchenne muscular dystrophy. Our findings will help not only to have a better idea of the progression of the disorder but also provide reference data that can be used to compare with the results of the long term extension studies that are becoming available. PMID:25271887

Pane, Marika; Mazzone, Elena Stacy; Sivo, Serena; Sormani, Maria Pia; Messina, Sonia; D Amico, Adele; Carlesi, Adelina; Vita, Gianluca; Fanelli, Lavinia; Berardinelli, Angela; Torrente, Yvan; Lanzillotta, Valentina; Viggiano, Emanuela; D Ambrosio, Paola; Cavallaro, Filippo; Frosini, Silvia; Barp, Andrea; Bonfiglio, Serena; Scalise, Roberta; De Sanctis, Roberto; Rolle, Enrica; Graziano, Alessandra; Magri, Francesca; Palermo, Concetta; Rossi, Francesca; Donati, Maria Alice; Sacchini, Michele; Arnoldi, Maria Teresa; Baranello, Giovanni; Mongini, Tiziana; Pini, Antonella; Battini, Roberta; Pegoraro, Elena; Previtali, Stefano; Bruno, Claudio; Politano, Luisa; Comi, Giacomo P; Bertini, Enrico; Mercuri, Eugenio

2014-01-01

328

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

PubMed Central

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

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

329

MRI-based quantification of Duchenne muscular dystrophy in a canine model  

NASA Astrophysics Data System (ADS)

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.

Wang, Jiahui; Fan, Zheng; Kornegay, Joe N.; Styner, Martin A.

2011-03-01

330

Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy  

PubMed Central

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

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

331

Asynchronous remodeling is a driver of failed regeneration in Duchenne muscular dystrophy.  

PubMed

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

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; Hoffman, Eric P

2014-10-13

332

The involvement of collagen triple helix repeat containing 1 in muscular dystrophies.  

PubMed

Fibrosis is the main complication of muscular dystrophies. We identified collagen triple helix repeat containing 1 (Cthrc1) in skeletal and cardiac muscles of mice, representing Duchenne and congenital muscle dystrophies (DMD and CMD, respectively), and dysferlinopathy. In all of the mice, Cthrc1 was associated with high collagen type I levels; no Cthrc1 or collagen was observed in muscles of control mice. High levels of Cthrc1 were also observed in biopsy specimens from patients with DMD, in whom they were reversibly correlated with that of ?-dystroglycan, whereas collagen type I levels were elevated in all patients with DMD. At the muscle sites where collagen and Cthrc1 were adjacent, collagen fibers appeared smaller, suggesting involvement of Cthrc1 in collagen turnover. Halofuginone, an inhibitor of Smad3 phosphorylation downstream of the transforming growth factor-? signaling, reduced Cthrc1 levels in skeletal and cardiac muscles of mice, representing DMD, CMD, and dysferlinopathy. The myofibroblasts infiltrating the dystrophic muscles of the murine models of DMD, CMD, and dysferlinopathy were the source of Cthrc1. Transforming growth factor-? did not affect Cthrc1 levels in the mdx fibroblasts but decreased them in the control fibroblasts, in association with increased migration of mdx fibroblasts and dystrophic muscle invasion by myofibroblasts. To our knowledge, this is the first demonstration of Cthrc1 as a marker of the severity of the disease progression in the dystrophic muscles, and as a possible target for therapy. PMID:23274062

Spector, Itai; Zilberstein, Yael; Lavy, Adi; Genin, Olga; Barzilai-Tutsch, Hila; Bodanovsky, Ana; Halevy, Orna; Pines, Mark

2013-03-01

333

SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy  

PubMed Central

Objective: Duchenne muscular dystrophy (DMD) is the most common single-gene lethal disorder. Substantial patient–patient variability in disease onset and progression and response to glucocorticoids is seen, suggesting genetic or environmental modifiers. Methods: Two DMD cohorts were used as test and validation groups to define genetic modifiers: a Padova longitudinal cohort (n = 106) and the Cooperative International Neuromuscular Research Group (CINRG) cross-sectional natural history cohort (n = 156). Single nucleotide polymorphisms to be genotyped were selected from mRNA profiling in patients with severe vs mild DMD, and genome-wide association studies in metabolism and polymorphisms influencing muscle phenotypes in normal volunteers were studied. Results: Effects on both disease progression and response to glucocorticoids were observed with polymorphism rs28357094 in the gene promoter of SPP1 (osteopontin). The G allele (dominant model; 35% of subjects) was associated with more rapid progression (Padova cohort log rank p = 0.003), and 12%–19% less grip strength (CINRG cohort p = 0.0003). Conclusions: Osteopontin genotype is a genetic modifier of disease severity in Duchenne dystrophy. Inclusion of genotype data as a covariate or in inclusion criteria in DMD clinical trials would reduce intersubject variance, and increase sensitivity of the trials, particularly in older subjects. PMID:21178099

Pegoraro, E.; Hoffman, E.P.; Piva, L.; Gavassini, B.F.; Cagnin, S.; Ermani, M.; Bello, L.; Soraru, G.; Pacchioni, B.; Bonifati, M.D.; Lanfranchi, G.; Angelini, C.; Kesari, A.; Lee, I.; Gordish-Dressman, H.; Devaney, J.M.; McDonald, C.M.

2011-01-01

334

Myocardial metabolism, perfusion, wall motion and electrical activity in Duchenne muscular dystrophy  

SciTech Connect

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.

Perloff, J.K.; Henze, E.; Schelbert, H.R.

1982-01-01

335

Evaluation of myocardial involvement in muscular dystrophy with Thallium-201 emission computed tomography  

SciTech Connect

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.

Yamamoto, S.; Kawai, N.; Matsushima, H.; Okada, M.; Yamauchi, K.; Yokota, M.; Hayashi, H.; Sotobata, I.; Sakuma, S.

1985-05-01

336

Specific profiles of neurocognitive and reading functions in a sample of 42 Italian boys with Duchenne Muscular Dystrophy.  

PubMed

A group of 42 Italian boys with Duchenne Muscular Dystrophy was compared with a control group of 10 boys with Spinal Muscular Atrophy and Osteogenesis Imperfecta on tests assessing general intellectual ability, language, neuropsychological functions, and reading skills with the aim of describing a comprehensive profile of the various functions and investigating their interrelationships. The influence of general intellectual level on performance was analyzed. Further, correlations between various neuropsychological measures and language performances were computed for the group with Duchenne Muscular Dystrophy, as well as the correlations between reading scores and other cognitive and linguistic measures. A general lowering in VIQ, PIQ, and FSIQ scores was found to characterize the group with Duchenne Muscular Dystrophy. Expressive language skills were within the normal range, while syntactic and grammatical comprehension were significantly impaired. The presence of below-average reading performances was further confirmed. However, unlike previous studies on irregular orthographies, the present results show that (a) the mild reading difficulties found in the sample essentially concern speed rather than accuracy; (b) they concern word rather than nonword reading; (c) lower reading performances are related to lower scores in general IQ; (d) no correlations emerge with phonological abilities, verbal short-term memory, or working memory, but rather with long-term memory and lexical skills. This may suggest that language-specific effects modulate the cognitive expressions of Duchenne Muscular Dystrophy and raises the possibility that the dysfunctions underlying the reading difficulties observed in affected readers of regular orthographies involve different neurocognitive systems than the cortico-cerebellar circuits usually invoked. PMID:22385039

Lorusso, Maria Luisa; Civati, Federica; Molteni, Massimo; Turconi, Anna Carla; Bresolin, Nereo; D'Angelo, Maria Grazia

2013-01-01

337

Dysregulation of matricellular proteins is an early signature of pathology in laminin-deficient muscular dystrophy  

PubMed Central

Background MDC1A is a congenital neuromuscular disorder with developmentally complex and progressive pathologies that results from a deficiency in the protein laminin ?2. MDC1A is associated with a multitude of pathologies, including increased apoptosis, inflammation and fibrosis. In order to assess and treat a complicated disease such as MDC1A, we must understand the natural history of the disease so that we can identify early disease drivers and pinpoint critical time periods for implementing potential therapies. Results We found that DyW mice show significantly impaired myogenesis and high levels of apoptosis as early as postnatal week 1. We also saw a surge of inflammatory response at the first week, marked by high levels of infiltrating macrophages, nuclear factor ?B activation, osteopontin expression and overexpression of inflammatory cytokines. Fibrosis markers and related pathways were also observed to be elevated throughout early postnatal development in these mice, including periostin, collagen and fibronectin gene expression, as well as transforming growth factor ? signaling. Interestingly, fibronectin was found to be the predominant fibrous protein of the extracellular matrix in early postnatal development. Lastly, we observed upregulation in various genes related to angiotensin signaling. Methods We sought out to examine the dysregulation of various pathways throughout early development (postnatal weeks 1-4) in the DyW mouse, the most commonly used mouse model of laminin-deficient muscular dystrophy. Muscle function tests (stand-ups and retractions) as well as gene (qRT-PCR) and protein levels (western blot, ELISA), histology (H&E, picrosirius red staining) and immunohistochemistry (fibronectin, TUNEL assay) were used to assess dysregulation of matricelluar protieins. Conclusions Our results implicate the involvement of multiple signaling pathways in driving the earliest stages of pathology in DyW mice. As opposed to classical dystrophies, such as Duchenne muscular dystrophy, the dysregulation of various matricellular proteins appears to be a distinct feature of the early progression of DyW pathology. On the basis of our results, we believe that therapies that may reduce apoptosis and stabilize the homeostasis of extracellular matrix proteins may have increased efficacy if started at a very early age. PMID:25075272

2014-01-01

338

Age and origin of the FCMD 3?-untranslated-region retrotransposal insertion mutation causing Fukuyama-type congenital muscular dystrophy in the Japanese population  

Microsoft Academic Search

Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disorder with a high prevalence in the Japanese\\u000a population, is characterised by severe muscular dystrophy associated with brain malformation (cortical dysgenesis) and mental\\u000a retardation. In Japan, 87% of FCMD-bearing chromosomes carry a 3-kb retrotransposal insertion of tandemly repeated sequences\\u000a within the disease gene recently identified on chromosome 9q31, and most of them

Roberto Colombo; Angelo A. Bignamini; Anna Carobene; Junko Sasaki; Masashi Tachikawa; Kazuhiro Kobayashi; Tatsushi Toda

2000-01-01

339

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

PubMed Central

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

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

340

Identification of muscle necrosis in the mdx mouse model of Duchenne muscular dystrophy using three-dimensional optical coherence tomography  

NASA Astrophysics Data System (ADS)

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.

Klyen, Blake R.; Shavlakadze, Thea; Radley-Crabb, Hannah G.; Grounds, Miranda D.; Sampson, David D.

2011-07-01

341

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

PubMed

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

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

2014-08-01

342

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

PubMed Central

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.

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

2015-01-01

343

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

PubMed

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

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

2015-01-01

344

Selective deficits in verbal working memory associated with a known genetic etiology: The neuropsychological profile of Duchenne muscular dystrophy  

Microsoft Academic Search

Forty-one boys diagnosed with Duchenne muscular dystrophy (DMD) were each compared to an unaffected sibling on a battery of neuropsychological tests. Verbal, visuospatial, attention 0memory, abstract thinking, and academic achievement skills were tested. Results indicated the boys with DMD performed similarly to their siblings on the majority of measures, indicating intact verbal, visuospatial, long-term memory, and abstract skills. However, the

VERONICA J. HINTON; DARRYL C. DE VIVO; NANCY E. NEREO; EDWARD GOLDSTEIN; YAAKOV STERN

2001-01-01

345

Chronic oral administration of Ang-(1-7) improves skeletal muscle, autonomic and locomotor phenotypes in muscular dystrophy.  

PubMed

Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying aetiologies but they all have a common hallmark of myofibre degeneration, atrophy and decreased mobility. Mutation in Sgcd (sarcoglycan-?), a subunit of dystrophin glycoprotein complex, causes LGMD2F (limb girdle muscular dystrophy 2F). Previously, we have reported that Sgcd-deficient (Sgcd-/-) mice exhibit AngII (angiotensin II)-induced autonomic and skeletal muscle dysfunction at a young age, which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory RAS (renin-angiotensin system) pathways have been identified: deleterious actions of AngII acting on the AT1R (AngII type 1 receptor) compared with the protective actions of Ang-(1-7) [angiotensin-(1-7)] acting on the receptor Mas. We propose that the balance between the AngII/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd-/- mice. Control C57BL/6J and Sgcd-/- mice were treated with Ang-(1-7) included in hydroxypropyl ?-cyclodextrin (in drinking water) for 8-9 weeks beginning at 3 weeks of age. Ang-(1-7) treatment restored the AngII/AT1R compared with Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd-/- mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang-(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy. PMID:24502705

Sabharwal, Rasna; Cicha, Michael Z; Sinisterra, Ruben D M; De Sousa, Frederico B; Santos, Robson A; Chapleau, Mark W

2014-07-01

346

Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy  

Microsoft Academic Search

Myocardial involvement is a common finding in patients with Duchenne-type muscular dystrophy (DMD). Nevertheless, the prognostic values of standard electrocardiogram (ECG), ventricular arrhythmias, ventricular late potentials (LPs), and left ventricular (LV) systolic dysfunction have not been extensively investigated. Eighty-four patients with DMD (aged 18.6 ± 4.8 years) underwent standard and signal-averaged electrocardiography, 24-hour Holter monitoring, and echocardiography. The prevalence of

Giovanni Corrado; Alberto Lissoni; Sandro Beretta; Laura Terenghi; Giorgio Tadeo; Giovanni Foglia-Manzillo; Luca M Tagliagambe; Manuela Spata; Mauro Santarone

2002-01-01

347

The natural history of Duchenne muscular dystrophy. Analysis of data from a Dutch survey and review of age related events  

Microsoft Academic Search

We collected data on 473 Dutch Duchenne muscular dystrophy patients born and diagnosed during 1961-1982. Life-time events were analysed for birth years 1961-1974 to avoid possible effects of downward bias of age at diagnosis resulting from inclusion of birth years 1975-1982. Mean and median in certain DMD patients were calculated for, age at onset: 2.4 and 2.0 years (range 0.5-7

Anthonie J. van Essen; Joke B. G. M. Verheij; Jennita Reefhuis; Vaclav Fidler; Jacobus H. Begeer; Marianne de Visser

348

Orthodontic treatment of a patient with Duchenne muscular dystrophy and macroglossia: how informed consent was critical to success.  

PubMed

This article describes the complex orthodontic treatment of a 22-year-old patient with Duchenne muscular dystrophy and macroglossia. His orthodontic treatment hinged on providing proper informed consent and management of the malocclusion with glossectomy, extractions, fixed appliances, and elastics. Challenges to traditional treatment are outlined, and compromises to both process and outcome are discussed from an informed consent point of view because of the serious risks involved. The treatment objectives were met, and the outcome was considered a success. PMID:24286912

Miller, James R

2013-12-01

349

Genetic and physical mapping at the limb-girdle muscular dystrophy locus (LGMD2B) on chromosome 2p  

SciTech Connect

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.

Bashir, R.; Keers, S.; Strachan, T. [Univ. of Newcastle upon Tyne (United Kingdom)] [and others] [Univ. of Newcastle upon Tyne (United Kingdom); and others

1996-04-01

350

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

SciTech Connect

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

Toda, Tatsushi; Ikegawa, Shiro; Okui, Keiko; Nakamura, Yusuke; Kanazawa, Ichiro [Univ. of Tokyo (Japan); Kondo, Eri; Saito, Kayoko; Fukuyama, Yukio [Tokyo Women`s Medical College (Japan); Yoshioka, Mieko [Kobe General Hospital (Japan); Kumagai, Toshiyuki [Aichi Welfare Center for Persons with Developmental Disabilities, Kasugai (Japan)] [and others

1994-11-01

351

Progression and variation of fatty infiltration of the thigh muscles in Duchenne muscular dystrophy, a muscle magnetic resonance imaging study.  

PubMed

The purpose of this study was to assess the progression and variation of fatty infiltration of the thigh muscles of Duchenne muscular dystrophy patients. Muscle magnetic resonance imaging was used to measure the degree of fatty infiltration of the thigh muscles of 171 boys with Duchenne muscular dystrophy (mean age, 6.09?±?2.30 years). Fatty infiltration was assigned using a modified Mercuri's scale 0-5 (normal-severe). The gluteus maximus and adductor magnus were affected in patients less than two years old, followed by the biceps femoris. Quadriceps and semimembranosus were first affected at the age of five to six years; the sartorius, gracilis and adductor longus remained apparently unaffected until seven years of age. Fatty infiltration of all the thigh muscles developed rapidly after seven years of age. The standard deviation of the fatty infiltration scores ranged from 2.41 to 4.87 before five years old, and from 6.84 to 11.66 between six and ten years old. This study provides evidence of highly variable degrees of fatty infiltration in children of different ages with Duchenne muscular dystrophy, and indicates that fatty infiltration progresses more quickly after seven years of age. These findings may be beneficial for the selection of therapeutic regimens and the analysis of future clinical trials. PMID:25701397

Li, Wenzhu; Zheng, Yiming; Zhang, Wei; Wang, Zhaoxia; Xiao, Jiangxi; Yuan, Yun

2015-05-01

352

Nuclear entrapment and extracellular depletion of PCOLCE is associated with muscle degeneration in oculopharyngeal muscular dystrophy  

PubMed Central

Background Muscle fibrosis characterizes degenerated muscles in muscular dystrophies and in late onset myopathies. Fibrotic muscles often exhibit thickening of the extracellular matrix (ECM). The molecular regulation of this process is not fully understood. In oculopharyngeal muscular dystrophy (OPMD), an expansion of an alanine tract at the N-terminus of poly(A)-binding protein nuclear 1 (PABPN1) causes muscle symptoms. OPMD patient muscle degeneration initiates after midlife, while at an earlier age carriers of alanine expansion mutant PABPN1 (expPABPN1) are clinically pre-symptomatic. OPMD is characterized by fibrosis in skeletal muscles but the causative molecular mechanisms are not fully understood. Methods We studied the molecular processes that are involved in OPMD pathology using cross-species mRNA expression profiles in muscles from patients and model systems. We identified significant dysregulation of the ECM functional group, among which the procollagen C-endopeptidase enhancer 1 gene (PCOLCE) was consistently down-regulated across species. We investigated PCOLCE subcellular localization in OPMD muscle samples and OPMD model systems to investigate any functional relevance of PCOLCE down-regulation in this disease. Results We found that muscle degeneration in OPMD is associated with PCOLCE down-regulation. In addition to its known presence at the ECM, we also found PCOLCE within the nucleus of muscle cells. PCOLCE sub-cellular localization changes during myoblast cell fusion and is disrupted in cells expressing mutant expPABPN1. Our results show that PCOLCE binds to soluble PABPN1 and co-localizes with aggregated PABPN1 with a preference for the mutant protein. In muscle biopsies from OPMD patients we find that extracellular PCOLCE is depleted with its concomitant enrichment within the nuclear compartment. Conclusions PCOLCE regulates collagen processing at the ECM. Depletion of extracellular PCOLCE is associated with the expression of expPABPN1 in OPMD patient muscles. PCOLCE is also localized within the nucleus where it binds to PABPN1, suggesting that PCOLCE shuttles between the ECM and the nucleus. PCOLCE preferentially binds to expPABPN1. Nuclear-localized PCOLCE is enriched in muscle cells expressing expPABPN1. We suggest that nuclear entrapment of PCOLCE and its extracellular depletion represents a novel molecular mechanism in late-onset muscle fibrosis. PMID:23815790

2013-01-01

353

Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction.  

PubMed

Facioscapulohumeral muscular dystrophy (FSHD), the most frequent muscular dystrophy, is an autosomal dominant disease. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is genetically linked to contractions of the D4Z4 repeat array causing activation of several genes. One of these maps in the repeat itself and expresses the DUX4 (the double homeobox 4) transcription factor causing a gene deregulation cascade. In addition, analyses of the RNA or protein expression profiles in muscle have indicated deregulations in the oxidative stress response. Since oxidative stress affects peripheral muscle function, we investigated mitochondrial function and oxidative stress in skeletal muscle biopsies and blood samples from patients with FSHD and age-matched healthy controls, and evaluated their association with physical performances. We show that specifically, oxidative stress (lipid peroxidation and protein carbonylation), oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase, copper-zinc-dependent superoxide dismutase, and glutathione reductase) were higher in FSHD than in control muscles. FSHD muscles also presented abnormal mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP synthesis). In addition, the ratio between reduced (GSH) and oxidized glutathione (GSSG) was strongly decreased in all FSHD blood samples as a consequence of GSSG accumulation. Patients with FSHD also had reduced systemic antioxidative response molecules, such as low levels of zinc (a SOD cofactor), selenium (a GPx cofactor involved in the elimination of lipid peroxides), and vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher ferritin concentrations. Both systemic oxidative stress and mitochondrial dysfunction were correlated with functional muscle impairment. Mitochondrial ATP production was significantly correlated with both quadriceps endurance (T(LimQ)) and maximal voluntary contraction (MVC(Q)) values (rho=0.79, P=0.003; rho=0.62, P=0.05, respectively). The plasma concentration of oxidized glutathione was negatively correlated with the T(LimQ), MVC(Q) values, and the 2-min walk distance (MWT) values (rho=-0.60, P=0.03; rho=-0.56, P=0.04; rho=-0.93, P<0.0001, respectively). Our data characterized oxidative stress in patients with FSHD and demonstrated a correlation with their peripheral skeletal muscle dysfunction. They suggest that antioxidants that might modulate or delay oxidative insult may be useful in maintaining FSHD muscle functions. PMID:22796148

Turki, Ahmed; Hayot, Maurice; Carnac, Gilles; Pillard, Fabien; Passerieux, Emilie; Bommart, Sébastien; Raynaud de Mauverger, Eric; Hugon, Gérald; Pincemail, Joel; Pietri, Sylvia; Lambert, Karen; Belayew, Alexandra; Vassetzky, Yegor; Juntas Morales, Raul; Mercier, Jacques; Laoudj-Chenivesse, Dalila

2012-09-01

354

Automated DNA mutation detection using universal conditions direct sequencing: application to ten muscular dystrophy genes  

PubMed Central

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

2009-01-01

355

Large scale genotype–phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy  

PubMed Central

Facioscapulohumeral muscular dystrophy has been genetically linked to reduced numbers (?8) of D4Z4 repeats at 4q35 combined with 4A(159/161/168) DUX4 polyadenylation signal haplotype. However, we have recently reported that 1.3% of healthy individuals carry this molecular signature and 19% of subjects affected by facioscapulohumeral muscular dystrophy do not carry alleles with eight or fewer D4Z4 repeats. Therefore, prognosis for subjects carrying or at risk of carrying D4Z4 reduced alleles has become more complicated. To test for additional prognostic factors, we measured the degree of motor impairment in a large group of patients affected by facioscapulohumeral muscular dystrophy and their relatives who are carrying D4Z4 reduced alleles. The clinical expression of motor impairment was assessed in 530 subjects, 163 probands and 367 relatives, from 176 unrelated families according to a standardized clinical score. The associations between clinical severity and size of D4Z4 allele, degree of kinship, gender, age and 4q haplotype were evaluated. Overall, 32.2% of relatives did not display any muscle functional impairment. This phenotype was influenced by the degree of relation with proband, because 47.1% of second- through fifth-degree relatives were unaffected, whereas only 27.5% of first-degree family members did not show motor impairment. The estimated risk of developing motor impairment by age 50 for relatives carrying a D4Z4 reduced allele with 1–3 repeats or 4–8 repeats was 88.7% and 55%, respectively. Male relatives had a mean score significantly higher than females (5.4 versus 4.0, P = 0.003). No 4q haplotype was exclusively associated with the presence of disease. In 13% of families in which D4Z4 alleles with 4–8 repeats segregate, the diagnosis of facioscapulohumeral muscular dystrophy was reported only in one generation. In conclusion, this large-scale analysis provides further information that should be taken into account when counselling families in which a reduced allele with 4–8 D4Z4 repeats segregates. In addition, the reduced expression of disease observed in distant relatives suggests that a family’s genetic background plays a role in the occurrence of facioscapulohumeral muscular dystrophy. These results indicate that the identification of new susceptibility factors for this disease will require an accurate classification of families. PMID:24030947

Scionti, Isabella; Sera, Francesco; Govi, Monica; D’Amico, Roberto; Frambolli, Ilaria; Mele, Fabiano; Filosto, Massimiliano; Vercelli, Liliana; Ruggiero, Lucia; Berardinelli, Angela; Angelini, Corrado; Antonini, Giovanni; Bucci, Elisabetta; Cao, Michelangelo; Daolio, Jessica; Di Muzio, Antonio; Di Leo, Rita; Galluzzi, Giuliana; Iannaccone, Elisabetta; Maggi, Lorenzo; Maruotti, Valerio; Moggio, Maurizio; Mongini, Tiziana; Morandi, Lucia; Nikolic, Ana; Pastorello, Ebe; Ricci, Enzo; Rodolico, Carmelo; Santoro, Lucio; Servida, Maura; Siciliano, Gabriele; Tomelleri, Giuliano

2013-01-01

356

The 6 Minute Walk Test and Performance of Upper Limb in Ambulant Duchenne Muscular Dystrophy Boys  

PubMed Central

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

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

357

Complete Genetic Correction of iPS Cells From Duchenne Muscular Dystrophy  

PubMed Central

Human artificial chromosome (HAC) has several advantages as a gene therapy vector, including stable episomal maintenance that avoids insertional mutations and the ability to carry large gene inserts including the regulatory elements. Induced pluripotent stem (iPS) cells have great potential for gene therapy, as such cells can be generated from the individual's own tissues, and when reintroduced can contribute to the specialized function of any tissue. As a proof of concept, we show herein the complete correction of a genetic deficiency in iPS cells derived from Duchenne muscular dystrophy (DMD) model (mdx) mice and a human DMD patient using a HAC with a complete genomic dystrophin sequence (DYS-HAC). Deletion or mutation of dystrophin in iPS cells was corrected by transferring the DYS-HAC via microcell-mediated chromosome transfer (MMCT). DMD patient- and mdx-specific iPS cells with the DYS-HAC gave rise to differentiation of three germ layers in the teratoma, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice from mdx-iPS (DYS-HAC) cells were produced and DYS-HAC was detected in all tissues examined, with tissue-specific expression of dystrophin. Therefore, the combination of patient-specific iPS cells and HAC-containing defective genes represents a powerful tool for gene and cell therapies. PMID:19997091

Kazuki, Yasuhiro; Hiratsuka, Masaharu; Takiguchi, Masato; Osaki, Mitsuhiko; Kajitani, Naoyo; Hoshiya, Hidetoshi; Hiramatsu, Kei; Yoshino, Toko; Kazuki, Kanako; Ishihara, Chie; Takehara, Shoko; Higaki, Katsumi; Nakagawa, Masato; Takahashi, Kazutoshi; Yamanaka, Shinya; Oshimura, Mitsuo

2009-01-01

358

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

PubMed Central

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

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

2014-01-01

359

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.  

PubMed

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials. PMID:24440357

Pane, Marika; Mazzone, Elena S; Fanelli, Lavinia; De Sanctis, Roberto; Bianco, Flaviana; Sivo, Serena; D'Amico, Adele; Messina, Sonia; Battini, Roberta; Scutifero, Marianna; Petillo, Roberta; Frosini, Silvia; Scalise, Roberta; Vita, Gianluca; 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; Bonfiglio, Serena; Rolle, Enrica; Colia, Giulia; Catteruccia, Michela; Palermo, Concetta; D'Angelo, Grazia; Pini, Antonella; Iotti, Elena; Gorni, Ksenija; Baranello, Giovanni; Morandi, Lucia; Bertini, Enrico; Politano, Luisa; Sormani, MariaPia; Mercuri, Eugenio

2014-03-01

360

Burden, professional support, and social network in families of children and young adults with muscular dystrophies.  

PubMed

Introduction This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy. Methods The study was carried out on 502 key relatives of 4-25 year-old patients, suffering from Duchenne, Becker, or Limb-Girdle MD who were living with at least 1 adult relative. Results 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts. Discussion Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patient's disability increases. © 2014 Wiley Periodicals, Inc. PMID:25363165

Magliano, Lorenza; Patalano, Melania; Sagliocchi, Alessandra; Scutifero, Marianna; Zaccaro, Antonella; Grazia D'Angelo, Maria; Civati, Federica; Brighina, Erika; Vita, Giuseppe; Vita, Gian Luca; Messina, Sonia; Sframeli, Maria; Pane, Marika; Lombardo, Maria Elena; Scalise, Roberta; D'Amico, Adele; Colia, Giulia; Catteruccia, Michela; Balottin, Umberto; Berardinelli, Angela; Motta, Maria Chiara; Angelini, Corrado; Gaiani, Alessandra; Semplicini, Claudio; Bello, Luca; Battini, Roberta; Astrea, Guja; Politano, Luisa

2014-10-31

361

Use of a Lower Dosage Liver-Detargeted AAV Vector to Prevent Hamster Muscular Dystrophy  

PubMed Central

Abstract The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting. PMID:23427808

Rotundo, Ida Luisa; Lancioni, Alessio; Savarese, Marco; D'Orsi, Luca; Iacomino, Michele; Nigro, Gerardo; Piluso, Giulio; Auricchio, Alberto

2013-01-01

362

Use of a lower dosage liver-detargeted AAV vector to prevent hamster muscular dystrophy.  

PubMed

The BIO14.6 hamster carries a mutation in the delta sarcoglycan gene causing muscular dystrophy and cardiomyopathy. The disease can be prevented by systemic delivery of delta sarcoglycan cDNA using adeno-associated viruses (AAVs). However, all AAVs also target the liver, raising concerns about their therapeutic efficacy in human applications. We compared the AAV2/8 with the chimeric AAV2/2i8, in which the 585-QQNTAP-590 motif of the AAV8 serotype was added to the heparan sulfate receptor footprint of the AAV2 strain. Both vectors carrying the human delta sarcoglycan cDNA were delivered into 24 14-day-old BIO14.6 hamsters. We followed transgene expression in muscle and liver for 7 months. We detected a sustained ectopic expression of delta sarcoglycan in the liver when using AAV2/8 but not AAV2/2i8. Genomic copies of AAV2/2i8 were not detectable in the liver, while at least 100-fold more copies of AAV2/8 were counted. In contrast, the hamster skeletal muscle expressed more delta sarcoglycan using AAV2/2i8 and were still healthy after 7 months at the lower dosage. We conclude that this chimeric vector is a robust option for safer and longer-term diseased muscle targeting. PMID:23427808

Rotundo, Ida Luisa; Lancioni, Alessio; Savarese, Marco; D'Orsi, Luca; Iacomino, Michele; Nigro, Gerardo; Piluso, Giulio; Auricchio, Alberto; Nigro, Vincenzo

2013-04-01

363

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

PubMed Central

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

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

2015-01-01

364

The heart in Duchenne muscular dystrophy: early detection of contractile performance alteration  

PubMed Central

Progressive cardiomyopathy is a major cause of death in Duchenne muscular dystrophy (DMD) patients. Coupling between Ca2+ handling and contractile properties in dystrophic hearts is poorly understood. It is also not clear whether developing cardiac failure is dominated by alterations in Ca2+ pathways or more related to the contractile apparatus. We simultaneously recorded force and Ca2+ transients in field-stimulated papillary muscles from young (10–14 weeks) wild-type (wt) and dystrophic mdx mice. Force amplitudes were fivefold reduced in mdx muscles despite only 30 % reduction in fura-2 ratio amplitudes. This indicated mechanisms other than systolic Ca2+ to additionally account for force decrements in mdx muscles. pCa-force relations revealed decreased mdx myofibrillar Ca2+ sensitivity. ‘In vitro’ motility assays, studied in mdx hearts here for the first time, showed significantly slower sliding velocities. mdx MLC/MHC isoforms were not grossly altered. Dystrophic hearts showed echocardiography signs of early ventricular wall hypertrophy with a significantly enlarged end-diastolic diameter ‘in vivo’. However, fractional shortening was still comparable to wt mice. Changes in the contractile apparatus satisfactorily explained force drop in mdx hearts. We give first evidence of early hypertrophy in mdx mice and possible mechanisms for already functional impairment of cardiac muscle in DMD. PMID:22970922

Wagner, Sören; Knipp, Stephan; Weber, Cornelia; Hein, Selina; Schinkel, Stefanie; Walther, Andreas; Bekeredjian, Raffi; Müller, Oliver J; Friedrich, Oliver

2012-01-01

365

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

PubMed Central

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

Noviello, Maddalena

2014-01-01

366

Cyclosporine A in Ullrich Congenital Muscular Dystrophy: Long-Term Results  

PubMed Central

Six individuals with Ullrich congenital muscular dystrophy (UCMD) and mutations in the genes-encoding collagen VI, aging 5–9, received 3–5?mg/kg of cyclosporine A (CsA) daily for 1 to 3.2 years. The primary outcome measure was the muscle strength evaluated with a myometer and expressed as megalimbs. The megalimbs score showed significant improvement (P = 0.01) in 5 of the 6 patients. Motor function did not change. Respiratory function deteriorated in all. CsA treatment corrected mitochondrial dysfunction, increased muscle regeneration, and decreased the number of apoptotic nuclei. Results from this study demonstrate that long-term treatment with CsA ameliorates performance in the limbs, but not in the respiratory muscles of UCMD patients, and that it is well tolerated. These results suggest considering a trial of CsA or nonimmunosuppressive cyclosporins, that retains the PTP-desensitizing properties of CsA, as early as possible in UCMD patients when diaphragm is less compromised. PMID:22028947

Merlini, Luciano; Sabatelli, Patrizia; Armaroli, Annarita; Gnudi, Saverio; Angelin, Alessia; Grumati, Paolo; Michelini, Maria Elena; Franchella, Andrea; Gualandi, Francesca; Bertini, Enrico; Maraldi, Nadir Mario; Ferlini, Alessandra; Bonaldo, Paolo; Bernardi, Paolo

2011-01-01

367

Clinical outcome measures for trials in Duchenne muscular dystrophy: report from International Working Group meetings  

PubMed Central

In June 2010, 25 representatives from Europe and the US met in Washington, DC, USA, to discuss clinical outcome measures in Duchenne muscular dystrophy (DMD) in the context of clinical trial design and analysis. The workshop was organized in response to a September 2009 European Medicines Agency meeting where a clear directive was given that an international consensus needs to be developed that provides a foundation for age-appropriate clinical outcome measures for use in clinical trials of emerging therapeutics for DMD. Data were presented from eight multicenter longitudinal datasets, representing nearly 1900 patients over a 20-year time period. This experience confirmed the feasibility of repeated evaluations performed at multiple sites and addressed several core issues in drug development for DMD, such as the ‘new’ natural history in the steroidera, reliability and sensitivity of specific outcome measures, as well as disease staging and patient selection. These data form a valuable asset for academic investigators, pharmaceutical sponsors and regulatory agencies involved in DMD therapeutics. The group remains committed working together on a number of collaborative goals to support the therapeutics development effort in this orphan disease and to make these data available to stakeholders working in the field. PMID:22639722

Bushby, Kate; Connor, Edward

2012-01-01

368

Functional correction in mouse models of muscular dystrophy using exon-skipping tricyclo-DNA oligomers.  

PubMed

Antisense oligonucleotides (AONs) hold promise for therapeutic correction of many genetic diseases via exon skipping, and the first AON-based drugs have entered clinical trials for neuromuscular disorders. However, despite advances in AON chemistry and design, systemic use of AONs is limited because of poor tissue uptake, and recent clinical reports confirm that sufficient therapeutic efficacy has not yet been achieved. Here we present a new class of AONs made of tricyclo-DNA (tcDNA), which displays unique pharmacological properties and unprecedented uptake by many tissues after systemic administration. We demonstrate these properties in two mouse models of Duchenne muscular dystrophy (DMD), a neurogenetic disease typically caused by frame-shifting deletions or nonsense mutations in the gene encoding dystrophin and characterized by progressive muscle weakness, cardiomyopathy, respiratory failure and neurocognitive impairment. Although current naked AONs do not enter the heart or cross the blood-brain barrier to any substantial extent, we show that systemic delivery of tcDNA-AONs promotes a high degree of rescue of dystrophin expression in skeletal muscles, the heart and, to a lesser extent, the brain. Our results demonstrate for the first time a physiological improvement of cardio-respiratory functions and a correction of behavioral features in DMD model mice. This makes tcDNA-AON chemistry particularly attractive as a potential future therapy for patients with DMD and other neuromuscular disorders or with other diseases that are eligible for exon-skipping approaches requiring whole-body treatment. PMID:25642938

Goyenvalle, Aurélie; Griffith, Graziella; Babbs, Arran; Andaloussi, Samir El; Ezzat, Kariem; Avril, Aurélie; Dugovic, Branislav; Chaussenot, Rémi; Ferry, Arnaud; Voit, Thomas; Amthor, Helge; Bühr, Claudia; Schürch, Stefan; Wood, Matthew J A; Davies, Kay E; Vaillend, Cyrille; Leumann, Christian; Garcia, Luis

2015-03-01

369

Patient-tailored application for Duchene muscular dystrophy on mdx mice based induced mesenchymal stem cells.  

PubMed

Mesenchymal stem cells (MSCs) may be used as powerful tools for the repair and regeneration of damaged tissues. However, isolating tissue specific-derived MSCs may cause pain and increased infection rates in patients, and repetitive isolations may be required. To overcome these difficulties, we have examined alternative methods for MSC production. Here, we show that induced pluripotent stem cells (iPSCs) may be differentiated into mesenchymal stem cells (iMSCs) following exposure to SB431542. Purified iMSCs were administered to mdx mice to study skeletal muscle regeneration in a murine model of muscular dystrophy. Purified iMSCs displayed fibroblast-like morphology, formed three-dimensional spheroid structures, and expressed characteristic mesenchymal stem cell surface markers such as CD29, CD33, CD73, CD90, and CD105. Moreover, iMSCs were capable of differentiating into adipogenic, osteogenic, and chondrogenic lineages. Transplanting iMSC cells to tibialis anterior skeletal muscle tissue in mdx mice lowered oxidative damage as evidenced by a reduction in nitrotyrosine levels, and normal dystrophin expression levels were restored. This study demonstrates the therapeutic potential of purified iMSCs in skeletal muscle regeneration in mdx mice, and suggests that iPSCs are a viable alternate source for deriving MSCs as needed. PMID:25102299

Jeong, Jaemin; Shin, Kyungshin; Lee, Seung Bum; Lee, Dong Ryul; Kwon, Heechung

2014-10-01

370

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

PubMed

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

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

2014-08-01

371

Nitric Oxide Signaling Pathway in Duchenne Muscular Dystrophy Mice: Upregulation of L-arginine Transporters  

PubMed Central

SYNOPSIS Duchenne muscular dystrophy (DMD) is an incurable, rapidly-worsening neuromuscular degenerative disease caused by the absence of dystrophin. In skeletal muscle, lack of dystrophin disrupts the recruitment of neuronal nitric oxide synthase (nNOS) to the sarcolemma thus affecting nitric oxide (NO) production. Utrophin is a dystrophin homolog which expression is greatly upregulated in the sarcolemma of dystrophin-negative fibers from mdx mice, a mouse model of DMD. Although cardiomyopathy is an important cause of death, little is known about the NO signaling pathway in cardiac muscle of DMD patients. Thus, we used cardiomyocytes and hearts from two month-old mdx and mdx:utrophin (?/?) double knockout mice (mdx:utr) to study key steps in NO signaling: L-arginine transporters, NOS, and soluble guanylyl cyclase (sGC). nNOS did not co-localize with dystrophin or utrophin to the cardiomyocyte membrane. Despite this, nNOS activity was markedly decreased in both mdx and mdx:utr mice while nNOS expression was only decreased in mdx:utr hearts, suggesting that utrophin upregulation in cardiomyocytes maintains nNOS levels but not function. sGC protein levels and activity remained at control levels. Unexpectedly, L-arginine transporter expression and function were significantly increased, suggesting a novel biochemical compensatory mechanism of the NO pathway and a potential entry site for therapeutics. PMID:23009292

Ramachandran, Jayalakshmi; Schneider, Joel S.; Crassous, Pierre-Antoine; Zheng, Ruifang; Gonzalez, James P.; Xie, Lai-Hua; Beuve, Annie; Fraidenraich, Diego; Peluffo, R. Daniel

2015-01-01

372

Laminin-111 improves muscle repair in a mouse model of merosin-deficient congenital muscular dystrophy  

PubMed Central

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a severe and fatal muscle-wasting disease with no cure. MDC1A patients and the dyW?/? mouse model exhibit severe muscle weakness, demyelinating neuropathy, failed muscle regeneration and premature death. We have recently shown that laminin-111, a form of laminin found in embryonic skeletal muscle, can substitute for the loss of laminin-211/221 and prevent muscle disease progression in the dyW?/? mouse model. What is unclear from these studies is whether laminin-111 can restore failed regeneration to laminin-?2-deficient muscle. To investigate the potential of laminin-111 protein therapy to improve muscle regeneration, laminin-111 or phosphate-buffered saline-treated laminin-?2-deficient muscle was damaged with cardiotoxin and muscle regeneration quantified. Our results show laminin-111 treatment promoted an increase in myofiber size and number, and an increased expression of ?7?1 integrin, Pax7, myogenin and embryonic myosin heavy chain, indicating a restoration of the muscle regenerative program. Together, our results show laminin-111 restores muscle regeneration to laminin-?2-deficient muscle and further supports laminin-111 protein as a therapy for the treatment of MDC1A. PMID:24009313

Van Ry, Pam M.; Minogue, Priscilla; Hodges, Bradley L.; Burkin, Dean J.

2014-01-01

373

A novel splice site mutation in a Becker muscular dystrophy patient.  

PubMed Central

A Becker muscular dystrophy patient was found to have a single base substitution at the 5' end of intron 54. This single base substitution disrupts the invariant GT dinucleotide within the 5' donor splice site and was shown to cause an out of frame deletion of exon 54 during mRNA processing. This is predicted to produce a truncated dystrophin protein which is more consistent with a DMD phenotype. However, small quantities of normal mRNA are also transcribed and these are sufficient to produce a reduced amount of normal molecular weight dystrophin and give rise to a milder BMD phenotype. This indicates that a single base substitution at an invariant dinucleotide of the splice site consensus sequence may still allow read through of the message and allow the production of some normal protein. This shows that there are a greater number of possible intronic mutations that can lead to a mild phenotype and it also underlines the importance of performing cDNA analysis when screening for small gene alterations in the BMD patient population. Images PMID:8730289

Bartolo, C; Papp, A C; Snyder, P J; Sedra, M S; Burghes, A H; Hall, C D; Mendell, J R; Prior, T W

1996-01-01

374

Evaluation of plantar flexion contracture contribution during the gait of children with Duchenne muscular dystrophy.  

PubMed

Because of extensor weakness, children with Duchenne muscular dystrophy (DMD) maintain internal flexion moments at the joints of the lower extremities when they walk. We believe that at the ankle, the plantar flexion moments caused by contractures may contribute significantly to the production of the net ankle flexion moment during the gait in these children. The goal of the present study is to quantify ankle plantar flexion passive moments that may be associated with the presence of flexion contractures and to estimate their contribution to the net moment during the gait of children with DMD. Kinematic and kinetic parameters were collected during gait of eleven subjects with DMD. Ankle plantar flexion passive moments were also measured experimentally during the same session. Fourteen control children participated in the study in order to have normal reference values. The presence of ankle plantar flexion contractures in children with DMD was reflected by a rigidity coefficient obtained at a common moment of -7 Nm that was higher for these children (0.75 Nm/degrees vs. 0.48 Nm/degrees; p<0.05). The relative passive moment contribution to the net plantar flexion moments was higher for the children with DMD at the end of the lengthening phase of the plantar flexors (25% vs. 18%; p<0.05). We believe that the passive moments can compensate for the presence of progressive muscle weakness in the children with DMD and help these children with gait. PMID:17977021

Gaudreault, Nathaly; Gravel, Denis; Nadeau, Sylvie

2009-06-01

375

Dimeric gold nanoparticle assembly for detection and discrimination of single nucleotide mutation in Duchenne muscular dystrophy.  

PubMed

Nanoparticles are increasingly being used for applications in clinical diagnostics due to their unique physical and chemical properties. Gold nanoparticles, in particular, have unique optical properties allowing simplicity of detection methods. In this study, an assay based on dimeric assembly of gold nanoparticles was developed for discriminating single nucleotide mismatches. Only gel electrophoresis is needed for assay readout. No other sophisticated or expensive equipment is required. In addition, no false-positive was observed in the readout. We used this assay for genotyping mutations in the Duchenne muscular dystrophy (DMD) gene, the largest known in the human genome. Our results show that conjugating the gold nanoparticles with short DNA probes of 18 bases and 70 bases complimentary to target sequences allows specific discrimination between wild-type and mutant sequences for c.4150G > T (NM.004006.1) mutation in exon 30 of the DMD gene using a simple colorimetric detection. This method allows identification of both the patients as well as the carriers of the mutation who are at risk of transmitting the disease. PMID:20219341

Qin, Wei Jie; Yim, Onn Siong; Lai, Poh San; Yung, Lin-Yue Lanry

2010-05-15

376

Prevention of muscular dystrophy in mice by CRISPR/Cas9–mediated editing of germline DNA  

PubMed Central

Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. DMD is characterized by progressive muscle weakness and a shortened life span, and there is no effective treatment. We used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)–mediated genome editing to correct the dystrophin gene (Dmd) mutation in the germ line of mdx mice, a model for DMD, and then monitored muscle structure and function. Genome editing produced genetically mosaic animals containing 2 to 100% correction of the Dmd gene. The degree of muscle phenotypic rescue in mosaic mice exceeded the efficiency of gene correction, likely reflecting an advantage of the corrected cells and their contribution to regenerating muscle. With the anticipated technological advances that will facilitate genome editing of postnatal somatic cells, this strategy may one day allow correction of disease-causing mutations in the muscle tissue of patients with DMD. PMID:25123483

Shelton, John M.; Mireault, Alex A.; Bassel-Duby, Rhonda; Olson, Eric N.

2015-01-01

377

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

PubMed

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

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

2015-04-01

378

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

PubMed

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

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

379

High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms  

PubMed Central

Summary The exact prevalence and nature of cardiac involvement in facioscapulohumeral muscular dystrophy (FSHD) is unknown. Nevertheless, the current opinion is that symptomatic cardiac disease is rare. We performed a cardiac screening [electrocardiogram (ECG) and echocardiography in the event of ECG abnormalities] in 75 genetically confirmed, ambulant FSHD patients without cardiac symptoms, with an eight-year follow-up of 57 patients, and compared the findings with results of previously performed cardiac screenings in the normal population. Baseline ECG demonstrated incomplete right bundle branch block (RBBB) in 33%, complete RBBB in 4%, and other minor abnormalities in 16%. Echocardiography showed no abnormalities. No significant changes were found after eight years of follow-up. Comparison with ECG abnormalities in the normal population showed a higher prevalence of incomplete RBBB (9.7 times higher) and of complete RBBB (4.8 times higher) in FSHD patients. This study in cardiac asymptomatic FSHD patients shows i) increased prevalence of incomplete RBBB in the absence of cardiomyopathy; ii) no progression of these abnormalities during eight years of follow-up. We conclude that FSHD patients without cardiac complaints do not need specific cardiac screening or surveillance. Furthermore, the increased prevalence of incomplete RBBB in the absence of cardiomyopathy suggests a selective involvement of the His-Purkinje system in FSHD. PMID:25473735

van Dijk, Gaby Pons; van der Kooi, Elly; Behin, Anthony; Smeets, Joep; Timmermans, Janneke; van der Maarel, Silvère; Padberg, George; Voermans, Nicol; van Engelen, Baziel

2014-01-01

380

Current Challenges and Future Directions in Recombinant AAV-Mediated Gene Therapy of Duchenne Muscular Dystrophy  

PubMed Central

Various characteristics of adeno-associated virus (AAV)-based vectors with long-term safe expression have made it an exciting transduction tool for clinical gene therapy of Duchenne muscular dystrophy (DMD). Although host immune reactions against the vector as well as transgene products were detected in some instances of the clinical studies, there have been promising observations. Methods of producing AAV vectors for considerable in vivo experimentation and clinical investigations have been developed and a number of studies with AAV vector-mediated muscle transduction were attempted. Notably, an intravenous limb perfusion transduction technique enables extensive transgene expression in the skeletal muscles without noticeable adverse events. Furthermore, cardiac transduction by the rAAV9-microdystrophin would be promising to prevent development of cardiac dysfunction. Recent achievements in transduction technology suggest that long-term transgene expression with therapeutic benefits in DMD treatment would be achieved by the rAAV-mediated transduction strategy with an adequate regimen to regulate host immune response. PMID:24276316

Okada, Takashi; Takeda, Shin'ichi

2013-01-01

381

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

PubMed Central

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

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

382

Modeling oculopharyngeal muscular dystrophy in myotube cultures reveals reduced accumulation of soluble mutant PABPN1 protein.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease caused by an alanine tract expansion mutation in poly(A) binding protein nuclear 1 (expPABPN1). To model OPMD in a myogenic and physiological context, we generated mouse myoblast cell clones stably expressing either human wild type (WT) or expPABPN1 at low levels. Transgene expression is induced on myotube differentiation and results in formation of insoluble nuclear PABPN1 aggregates that are similar to those observed in patients with OPMD. Quantitative analysis of PABPN1 in myotube cultures revealed that expPABPN1 accumulation and aggregation is greater than that of the WT protein. We found that aggregation of expPABPN1 is more affected than WT PABPN1 by inhibition of proteasome activity. Consistent with this, in myotube cultures expressing expPABPN1, deregulation of the proteasome was identified as the most significantly perturbed pathway. Differences in the accumulation of soluble WT and expPABPN1 were consistent with differences in ubiquitination and rate of protein turnover. This study demonstrates, for the first time to our knowledge, that, in myotubes, the ratio of soluble/insoluble expPABPN1 is significantly lower compared with that of the WT protein. We suggest that this difference can contribute to muscle weakness in OPMD. PMID:21854744

Raz, Vered; Routledge, Samantha; Venema, Andrea; Buijze, Hellen; van der Wal, Erik; Anvar, Seyedyahya; Straasheijm, Kirsten R; Klooster, Rinse; Antoniou, Michael; van der Maarel, Silvère M

2011-10-01

383

Modeling Oculopharyngeal Muscular Dystrophy in Myotube Cultures Reveals Reduced Accumulation of Soluble Mutant PABPN1 Protein  

PubMed Central

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disease caused by an alanine tract expansion mutation in poly(A) binding protein nuclear 1 (expPABPN1). To model OPMD in a myogenic and physiological context, we generated mouse myoblast cell clones stably expressing either human wild type (WT) or expPABPN1 at low levels. Transgene expression is induced on myotube differentiation and results in formation of insoluble nuclear PABPN1 aggregates that are similar to those observed in patients with OPMD. Quantitative analysis of PABPN1 in myotube cultures revealed that expPABPN1 accumulation and aggregation is greater than that of the WT protein. We found that aggregation of expPABPN1 is more affected than WT PABPN1 by inhibition of proteasome activity. Consistent with this, in myotube cultures expressing expPABPN1, deregulation of the proteasome was identified as the most significantly perturbed pathway. Differences in the accumulation of soluble WT and expPABPN1 were consistent with differences in ubiquitination and rate of protein turnover. This study demonstrates, for the first time to our knowledge, that, in myotubes, the ratio of soluble/insoluble expPABPN1 is significantly lower compared with that of the WT protein. We suggest that this difference can contribute to muscle weakness in OPMD. PMID:21854744

Raz, Vered; Routledge, Samantha; Venema, Andrea; Buijze, Hellen; van der Wal, Erik; Anvar, SeyedYahya; Straasheijm, Kirsten R.; Klooster, Rinse; Antoniou, Michael; van der Maarel, Silvère M.

2011-01-01

384

The genetic status of mothers of isolated cases of Duchenne muscular dystrophy.  

PubMed Central

Classical genetic theory, based on assumed equal mutation rates in males and females, predicts that one-third of all cases of Duchenne muscular dystrophy (DMD) in a generation are born as new mutants to non-carrier mothers. Furthermore, less than half the mothers of apparently isolated cases appear to be carriers on the basis of raised serum creatine kinase levels. We have analysed the pedigrees of 61 families of DMD boys seen in the Duke Neuromuscular Research Clinic and 45 DMD families followed at the University of Virginia. The frequency of affected boys among the next born male sibs of 37 initially isolated DMD cases in two clinic populations was significantly greater than predicted by Haldane's theory (p = 0.029) and the estimated proportion of new mutant cases in the combined clinic population of 106 families was 0.127 (SE 0.111). The absence of affected males in earlier generations in families of isolated cases may be explained in part by a high ratio of male to female stillbirths and infant deaths, which was more than three times that of the normal population in this study. These data suggest that new mutant cases are less common than expected and current predictions may underestimate genetic risks in mothers of isolated cases. PMID:6842530

Lane, R J; Robinow, M; Roses, A D

1983-01-01

385

Combined effects of muscular dystrophy, ecological stress, and selenium on blood antioxidant status in broiler chickens.  

PubMed

The results obtained in this study demonstrated that experimentally induced alimentary muscular dystrophy (MD) in Cobb 500 broiler chickens resulted in increased plasma concentrations of malondialdehyde (MDA), deviations in activities of erythrocyte antioxidant enzymes Cu,Zn-SOD (decrease), and CAT (increase) as well as reduction in plasma concentrations of trace elements Cu, Zn, and Se in affected birds. These data evidenced the presence of oxidative stress in birds with MD, reared both under conditions of ecological comfort and ecological stress. The increased MDA and ??? levels and the reduced Cu,Zn-SOD, Cu, Zn, and Se concentrations in healthy chickens reared under unfavorable microclimatic conditions such as higher air temperature and humidity, higher ammonia concentrations, and lower light intensity were indicative about an induced ecological stress. After the 10-day oral treatment with a selenium-containing preparation, the levels of MDA, Cu,Zn-SOD, CAT, Cu, Zn, and Se attained their normal values in chickens with MD, reared under ecologically comfortable conditions. According to our results, ecological stress was shown to exert independently a significant adverse effect upon the levels of the studied parameters and possibly to be a cause for their slower and not complete normalization despite the selenium therapy in experimental broiler chickens. PMID:20668960

Georgieva, Nedyalka V; Stoyanchev, Krasimir; Bozakova, Nadia; Jotova, Ivanka

2011-09-01

386

Dual exon skipping in myostatin and dystrophin for Duchenne muscular dystrophy  

PubMed Central

Background Myostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-? (TGF-?) family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD) is characterized by a loss of muscle fibers and impaired regeneration. In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients. Methods We targeted myostatin exon 2 using antisense oligonucleotides (AON) in healthy and DMD-derived myotubes cultures. We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. These AONs were also applied in the mdx mice models via intramuscular injections. Results Myostatin AON induced exon 2 skipping in cell cultures and to a lower extent in the mdx mice. It was accompanied by decrease in myostatin mRNA and enhanced MYOG and MYF5 expression. Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes. Conclusions We conclude that two AONs can be used to target two different genes, MSTN and DMD, in a straightforward manner. Targeting multiple ligands of TGF-beta family will be more promising as adjuvant therapies for DMD. PMID:21507246

2011-01-01

387

The value of respiratory muscle testing in a child with congenital muscular dystrophy.  

PubMed

Respiratory muscle testing is often limited to noninvasive volitional tests such as vital capacity and maximal static pressures. We report the case of a 12-year-old boy with congenital muscular dystrophy (CMD) in whom invasive and non-volitional respiratory muscle tests showed an elective diaphragmatic dysfunction with the preservation of expiratory muscle strength. This finding, coupled with a clinical phenotype associating diffuse muscle atrophy with finger hyperlaxity and proximal contractures, strengthened the suspicion of Ullrich CMD. Skin-cultured fibroblasts showed intracellular retention of collagen 6 (COL6), muscle magnetic resonance imaging was typical of COL6 myopathy, and molecular studies identified a COL6 gene mutation (COL6A2 c.954+2T>C). The diagnosis of a diaphragmatic dysfunction led to a sleep study that evidenced periods of hypoxemia which justified nocturnal noninvasive ventilation. This case report highlights the benefit of assessing respiratory muscles, through invasive procedure, to assist in clinical diagnosis and to guide clinical management. PMID:25473580

Khirani, Sonia; Dabaj, Ivana; Amaddeo, Alessandro; Ramirez, Adriana; Quijano-Roy, Susana; Fauroux, Brigitte

2014-09-01

388

Exon Deletion Pattern in Duchene Muscular Dystrophy in North West of Iran  

PubMed Central

Objective Duchene and Becker Muscular Dystrophy (DMD/ BMD) are x-linked disorders that both are the result of heterogeneous mutations in the dystrophin gene. The frequency and distribution of dystrophin gene deletions in DMD/ BMD patients show different patterns among different populations. This study investigates the deletion rate, type, and distribution of this gene in the Azeri Turk population of North West Iran. Materials &Methods In this study, 110 patients with DMD/ BMD were studied for intragenic deletions in 24 exons and promoter regions of dystrophin genes by using multiplex PCR. Results Deletions were detected in 63 (57.3%) patients, and around 83% localized in the mid-distal hotspot of the gene (on exons 44–52), 21 cases (33.3 %) with single-exon deletions, and 42 cases (66.6%) with multi-exonic deletions. The most frequent deleted exons were exon 50 (15 %) and exon 49 (14%). No deletion was detected in exon 3. Conclusion This study suggests that the frequency and pattern of dystrophin gene deletions in DMD/ BMD in the Azeri Turk population of North West Iran occur in the same pattern when compared with other ethnic groups. PMID:25767538

BARZEGAR, Mohammad; HABIBI, Parinaz; BONYADY, Mortaza; TOPCHIZADEH, Vahideh; SHIVA, Shadi

2015-01-01

389

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

PubMed Central

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

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

390

MRI/MRS Evaluation of a Female Carrier of Duchenne Muscular Dystrophy  

PubMed Central

The purpose of this study was to evaluate skeletal muscle composition of lower extremity muscles in a manifesting female carrier of Duchenne muscular dystrophy (MFCDMD) using magnetic resonance imaging (MRI) and spectroscopy (MRS). MRI/MRS was performed on the lower extremities and heart of a MFCDMD (47yr, 51kg) on four occasions within 21 months and in a control subject. Heterogeneity and asymmetry among muscles in the MFCDMD was observed in lipid fraction and mean transverse relaxation time (T2) of lower extremity muscles with some muscles presenting as unaffected (e.g., rectus femoris) and others showing substantial deterioration and lipid infiltration (e.g., vasti muscles). There was an association of abnormal MRI findings and strength and motor function. Over the 21 months a small decrease in CSAmax and increase in lipid fraction and T2 was observed in the MFCDMD in some muscles. In summary, this MFCDMD revealed significant imaging evidence of pathologic heterogeneity among muscles. Furthermore, this study shows the feasibility of combining various quantitative MRI and MRS approaches to monitor skeletal muscle involvement. PMID:22980762

Forbes, Sean C.; Lott, Donovan J.; Finkel, Richard S.; Senesac, Claudia; Byrne, Barry J.; Sweeney, H. L.; Walter, Glenn A.; Vandenborne, Krista

2012-01-01

391

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

PubMed Central

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

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

392

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy  

PubMed Central

Objective: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). Methods: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. Results: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD—producing functional muscle ischemia—despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. Conclusions: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. Classification of evidence: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis. PMID:24808022

Nelson, Michael D.; Rader, Florian; Tang, Xiu; Tavyev, Jane; Nelson, Stanley F.; Miceli, M. Carrie; Elashoff, Robert M.; Sweeney, H. Lee

2014-01-01

393

The 6 minute walk test and performance of upper limb in ambulant duchenne muscular dystrophy boys.  

PubMed

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

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

394

Quantitative Phenotyping of Duchenne Muscular Dystrophy Dogs by Comprehensive Gait Analysis and Overnight Activity Monitoring  

PubMed Central

The dystrophin-deficient dog is excellent large animal model for testing novel therapeutic modalities for Duchenne muscular dystrophy (DMD). Despite well-documented descriptions of dystrophic symptoms in these dogs, very few quantitative studies have been performed. Here, we developed a comprehensive set of non-invasive assays to quantify dog gait (stride length and speed), joint angle and limb mobility (for both forelimb and hind limb), and spontaneous activity at night. To validate these assays, we examined three 8-m-old mix-breed dystrophic dogs. We also included three age-matched siblings as the normal control. High-resolution video recorders were used to digitize dog walking and spontaneous movement at night. Stride speed and length were significantly decreased in affected dogs. The mobility of the limb segments (forearm, front foot, lower thigh, rear foot) and the carpus and hock joints was significantly reduced in dystrophic dogs. There was also a significant reduction of the movement in affected dogs during overnight monitoring. In summary, we have established a comprehensive set of outcome measures for clinical phenotyping of DMD dogs. These non-invasive end points would be valuable in monitoring disease progression and therapeutic efficacy in translational studies in the DMD dog model. PMID:23544107

Shin, Jin-Hong; Greer, Brian; Hakim, Chady H.; Zhou, Zhongna; Chung, Yu-chia; Duan, Ye; He, Zhihai; Duan, Dongsheng

2013-01-01

395

A human skeletal muscle interactome centered on proteins involved in muscular dystrophies: LGMD interactome  

PubMed Central

Background The complexity of the skeletal muscle and the identification of numerous human disease-causing mutations in its constitutive proteins make it an interesting tissue for proteomic studies aimed at understanding functional relationships of interacting proteins in both health and diseases. Method We undertook a large-scale study using two-hybrid screens and a human skeletal-muscle cDNA library to establish a proteome-scale map of protein-protein interactions centered on proteins involved in limb-girdle muscular dystrophies (LGMD). LGMD is a group of more than 20 different neuromuscular disorders that principally affect the proximal pelvic and shoulder girdle muscles. Results and conclusion The interaction network we unraveled incorporates 1018 proteins connected by 1492 direct binary interactions and includes 1420 novel protein-protein interactions. Computational, experimental and literature-based analyses were performed to assess the overall quality of this network. Interestingly, LGMD proteins were shown to be highly interconnected, in particular indirectly through sarcomeric proteins. In-depth mining of the LGMD-centered interactome identified new candidate genes for orphan LGMDs and other neuromuscular disorders. The data also suggest the existence of functional links between LGMD2B/dysferlin and gene regulation, between LGMD2C/?-sarcoglycan and energy control and between LGMD2G/telethonin and maintenance of genome integrity. This dataset represents a valuable resource for future functional investigations. PMID:23414517

2013-01-01

396

X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts.  

PubMed

As part of an international consortium, case-parent trios were collected for a genome-wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family-based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple-comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e., both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding-window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene. PMID:23489894

Patel, Poorav J; Beaty, Terri H; Ruczinski, Ingo; Murray, Jeffrey C; Marazita, Mary L; Munger, Ronald G; Hetmanski, Jacqueline B; Wu, Tao; Murray, Tanda; Rose, Margaret; Redett, Richard J; Jin, Sheng C; Lie, Rolv T; Wu-Chou, Yah-Huei; Wang, Hong; Ye, Xiaoqian; Yeow, Vincent; Chong, Samuel; Jee, Sun H; Shi, Bing; Scott, Alan F

2013-04-01

397

A case of Becker muscular dystrophy with early manifestation of cardiomyopathy.  

PubMed

An 18-year-old boy was admitted with chest discomfort, nausea, and dyspnea at rest. At the age of 3 years, he underwent muscle biopsy and dystrophin gene analysis owing to an enlarged calf muscle and elevated serum kinase level (6,378 U/L) without overt weakness; based on the results, Becker muscular dystrophy (BMD) was diagnosed. The dystrophin gene showed deletion of exons 45 to 49. He remained ambulant and could step upstairs without significant difficulties. A chest roentgenogram showed cardiomegaly (cardiothoracic ratio, 54%), and his electrocardiogram (ECG) showed abnormal ST-T wave, biatrial enlargement, and left ventricular hypertrophy. The 2-dimensional and M-mode ECGs showed a severely dilated left ventricular cavity with diffuse hypokinesis. The systolic indices were reduced, including fractional shortening (9%) and ejection fraction (19%). Despite receiving intensive medical treatment, he died from congestive heart failure 5 months after the initial cardiac symptoms. We report a case of BMD with early-onset dilated cardiomyopathy associated with deletion of exons 45 to 49. Early cardiomyopathy can occur in BMD patients with certain genotypes; therefore, careful follow-up is required even in patients with mild phenotypes of BMD. PMID:23049593

Doo, Ki Hyun; Ryu, Hye Won; Kim, Seung Soo; Lim, Byung Chan; Hwang, Hui; Kim, Ki Joong; Hwang, Yong Seung; Chae, Jong-Hee

2012-09-01

398

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

PubMed Central

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

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

2010-01-01

399

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

PubMed Central

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

MAHMOOD, OMAR A.; JIANG, XIN MEI

2014-01-01

400

Genetic heterogeneity of limb-girdle muscular dystrophy in Amish populations  

SciTech Connect

The autosomal recessive form of limb-girdle muscular dystrophy (LGMD2) is characterized by onset in childhood, progressive weakness predominantly of shoulder, pelvic and trunk muscles with sparing of facial muscles. A gene for LGMD2 was localized to chromosome 15q by Beckmann et al. in 1991 in Isle La Reunion families, subsequently confirmed in Amish families and in Brazilian families where genetic heterogeneity has been demonstrated. Analysis of LGM2 families for recombination events permitted the gene region to be restricted to an interval of about 7 cM defined by flanking markers D15S129 and D15S143. Extended haplotypes were established in the families on the basis of the segregation of multiple markers within this interval. Although the nine northern Indiana Amish families showed linkage of the gene to chromosome 15 markers (maximum lod score of 7.58 at {theta}=0.06 for D15S129 and 12.57 at {theta}=0.046 for D15S143), six large southern Indiana families with LGMD2, clinically indistinguishable from the LGMD2 in northern Indiana, were found to have a disease neither linked to chromosome 15 nor to chromosome 2 where a second localization has been reported. Although these two Indiana Amish LGMD2 kindreds contain some common ancestors and are clinically similar, the LGMD2 appears to be genetically heterogeneous.

Beckmann, J.S.; Allamand, V.; Broux, O. [CEPH, Paris (France)] [and others

1994-09-01

401

Ullrich congenital muscular dystrophy: clinicopathological features, natural history and pathomechanism(s).  

PubMed

Collagen VI is widely distributed throughout extracellular matrices (ECMs) in various tissues. In skeletal muscle, collagen VI is particularly concentrated in and adjacent to basement membranes of myofibers. Ullrich congenital muscular dystrophy (UCMD) is caused by mutations in either COL6A1, COL6A2 or COL6A3 gene, thereby leading to collagen VI deficiency in the ECM. It is known to occur through either recessive or dominant genetic mechanism, the latter most typically by de novo mutations. UCMD is well defined by the clinicopathological hallmarks including distal hyperlaxity, proximal joint contractures, protruding calcanei, scoliosis and respiratory insufficiency. Recent reports have depicted the robust natural history of UCMD; that is, loss of ambulation by early teenage years, rapid decline in respiratory function by 10?years of age and early-onset, rapidly progressive scoliosis. Muscle pathology is characterised by prominent interstitial fibrosis disproportionate to the relative paucity of necrotic and regenerating fibres. To date, treatment for patients is supportive for symptoms such as joint contractures, respiratory failure and scoliosis. There have been clinical trials based on the theory of mitochondrion-mediated myofiber apoptosis or impaired autophagy. Furthermore, the fact that collagen VI producing cells in skeletal muscle are interstitial mesenchymal cells can support proof of concept for stem cell-based therapy. PMID:24938411

Yonekawa, Takahiro; Nishino, Ichizo

2015-03-01

402

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

PubMed Central

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

Falzarano, Maria Sofia; Passarelli, Chiara

2014-01-01

403

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

PubMed Central

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

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

404

Autonomic dysfunction: a driving force for myocardial fibrosis in young duchenne muscular dystrophy patients?  

PubMed

Cardiac manifestations of Duchenne muscular dystrophy (DMD) include progressive cardiac dysfunction and an elevated resting heart rate (HR). We hypothesized this elevated HR reflects autonomic dysfunction that can be identified by heart rate variability (HRV) analyses which will be associated with myocardial fibrosis by cardiac magnetic resonance imaging (cMR). DMD patients (N = 74) and controls (N = 17) had time and frequency domain HRV analyses calculated via Holter monitoring. Cardiac magnetic resonance imaging was performed on DMD cases only. ? (2) test, T test, ANOVA, and logistic regression were used to perform comparisons between groups. A p value of <0.05 was used for statistical significance. DMD cases had higher resting average HR than controls (99.4 ± 8.9, 85.4 + 6.2, p < 0.001). Among HRV variables, decreases were seen in the following: standard deviation of R to R intervals, the percent RR intervals differing by >50 ms from previous RR interval, the root-meansquare of successive differences of RR intervals, the standard deviation of the mean R to R segment (SDANN), low frequency, and high frequency domain, all p values 0.001. Maximum HR and SDANN most significantly associated with positive LGE on cMR (p = 0.008, p = 0.016). DMD cases on beta blocker had an average HR lower than those not on beta blocker (p = 0.009), but with no difference in HRV analysis. DMD patients have reduced HRV and therefore autonomic dysfunction prior to the onset of heart failure which is associated with myocardial fibrosis. PMID:25399404

Thomas, Tamara O; Jefferies, John L; Lorts, Angela; Anderson, Jeffrey B; Gao, Zhiqian; Woodrow Benson, D; Hor, Kan N; Cripe, Linda H; Urbina, Elaine M

2015-03-01

405

Evidence for impaired neurovascular transmission in a murine model of Duchenne muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is a muscle-wasting disease caused by mutations in the dystrophin gene. Little is known about how blood flow control is affected in arteriolar networks supplying dystrophic muscle. We tested the hypothesis that mdx mice, a murine model for DMD, exhibit defects in arteriolar vasomotor control. The cremaster muscle was prepared for intravital microscopy in pentobarbital sodium-anesthetized mdx and C57BL/10 control mice (n ? 5 per group). Spontaneous vasomotor tone increased similarly with arteriolar branch order in both mdx and C57BL/10 mice [pooled values: first order (1A), 6%; second order (2A), 56%; and third order (3A), 61%] with no difference in maximal diameters between groups measured during equilibration with topical 10 ?M sodium nitroprusside (pooled values: 1A, 70 ± 3 ?m; 2A, 31 ± 3 ?m; and 3A, 19 ± 3 ?m). Concentration-response curves to acetylcholine (ACh) and norepinephrine added to the superfusion solution did not differ between mdx and C57BL/10 mice, nor did constriction to elevated (21%) oxygen. In response to local stimulation from a micropipette, conducted vasodilation to ACh and conducted vasoconstriction to KCl were also not different between groups; however, constriction decayed with distance (P < 0.05) whereas dilation did not. Remarkably, arteriolar constriction to perivascular nerve stimulation (PNS) at 2, 4, and 8 Hz was reduced by ?25–30% in mdx mice compared with C57BL/10 mice (P < 0.05). With intact arteriolar reactivity to agonists, attenuated constriction to perivascular nerve stimulation indicates impaired neurovascular transmission in arterioles controlling blood flow in mdx mice. PMID:21109597

Bagher, Pooneh; Duan, Dongsheng

2011-01-01

406

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

PubMed Central

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

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

2014-01-01

407

24 Month Longitudinal Data in Ambulant Boys with Duchenne Muscular Dystrophy  

PubMed Central

Objectives The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation. Methods One hundred and thirteen patients (age range 4.1–17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test. Results On the 6MWT there was an average overall decline of ?22.7 (SD 81.0) in the first year and of ?64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of ?1.86 (SD 4.21) in the first year and of ?2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years. Conclusions These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial. PMID:23326337

Sormani, Maria Pia; Scalise, Roberta; Berardinelli, Angela; Messina, Sonia; Torrente, Yvan; D’Amico, Adele; Doglio, Luca; Viggiano, Emanuela; D’Ambrosio, Paola; Cavallaro, Filippo; Frosini, Silvia; Bello, Luca; Bonfiglio, Serena; De Sanctis, Roberto; Rolle, Enrica; Bianco, Flaviana; Magri, Francesca; Rossi, Francesca; Vasco, Gessica; Vita, GianLuca; Motta, Maria Chiara; Donati, Maria Alice; Sacchini, Michele; Mongini, Tiziana; Pini, Antonella; Battini, Roberta; Pegoraro, Elena; Previtali, Stefano; Napolitano, Sara; Bruno, Claudio; Politano, Luisa; Comi, Giacomo Pietro; Bertini, Enrico; Mercuri, Eugenio

2013-01-01

408

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

PubMed Central

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

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

2014-01-01

409

Mechanisms Inducing Low Bone Density in Duchenne Muscular Dystrophy in Mice and Humans  

PubMed Central

Patients affected by Duchenne muscular dystrophy (DMD) and dystrophic MDX mice were investigated in this study for their bone phenotype and systemic regulators of bone turnover. Micro–computed tomographic (µCT) and histomorphometric analyses showed reduced bone mass and higher osteoclast and bone resorption parameters in MDX mice compared with wild-type mice, whereas osteoblast parameters and mineral apposition rate were lower. In a panel of circulating pro-osteoclastogenic cytokines evaluated in the MDX sera, interleukin 6 (IL-6) was increased compared with wild-type mice. Likewise, DMD patients showed low bone mineral density (BMD) Z-scores and high bone-resorption marker and serum IL-6. Human primary osteoblasts from healthy donors incubated with 10% sera from DMD patients showed decreased nodule mineralization. Many osteogenic genes were downregulated in these cultures, including osterix and osteocalcin, by a mechanism blunted by an IL-6-neutralizing antibody. In contrast, the mRNAs of osteoclastogenic cytokines IL6, IL11, inhibin-?A, and TGF?2 were increased, although only IL-6 was found to be high in the circulation. Consistently, enhancement of osteoclastogenesis was noted in cultures of circulating mononuclear precursors from DMD patients or from healthy donors cultured in the presence of DMD sera or IL-6. Circulating IL-6 also played a dominant role in osteoclast formation because ex vivo wild-type calvarial bones cultured with 10% sera of MDX mice showed increase osteoclast and bone-resorption parameters that were dampen by treatment with an IL-6 antibody. These results point to IL-6 as an important mediator of bone loss in DMD and suggest that targeted anti-IL-6 therapy may have a positive impact on the bone phenotype in these patients. © 2011 American Society for Bone and Mineral Research PMID:21509823

Rufo, Anna; Del Fattore, Andrea; Capulli, Mattia; Carvello, Francesco; De Pasquale, Loredana; Ferrari, Serge; Pierroz, Dominique; Morandi, Lucia; De Simone, Michele; Rucci, Nadia; Bertini, Enrico; Bianchi, Maria Luisa; De Benedetti, Fabrizio; Teti, Anna

2011-01-01

410

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

PubMed

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

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

2014-01-01

411

New insights on contraction efficiency in patients with Duchenne muscular dystrophy.  

PubMed

The decrease in muscle strength in patients with Duchenne muscular dystrophy (DMD) is mainly explained by a decrease in the number of active contractile elements. Nevertheless, it is possible that other electrochemical and force transmission processes may contribute. The present study aimed to quantify the effect of DMD on the relative contribution of electrochemical and force transmission components of the electromechanical delay (i.e., time lag between the onset of muscle activation and force production) in humans using very high frame rate ultrasound. Fourteen patients with DMD and thirteen control subjects underwent two electrically evoked contractions of the biceps brachii with the ultrasound probe over the muscle belly. The electromechanical delay was significantly longer in DMD patients compared with controls (18.5 ± 3.9 vs. 12.5 ± 1.4 ms, P < 0.0001). More precisely, DMD patients exhibited a longer delay between the onset of muscle fascicles motion and force production (13.6 ± 3.1 vs. 7.9 ± 2.0 ms, P < 0.0001). This delay was correlated to the chronological age of the DMD patients (r = 0.66; P = 0.01), but not of the controls (r = -0.45; P = 0.10). No significant difference was found for the delay between the onset of muscle stimulation and the onset of muscle fascicle motion. These results highlight the role of the alteration of muscle force transmission (delay between the onset of fascicle motion and force production) in the impairments of the contraction efficiency in patients with DMD. PMID:25103971

Lacourpaille, Lilian; Hug, François; Guével, Arnaud; Péréon, Yann; Magot, Armelle; Hogrel, Jean-Yves; Nordez, Antoine

2014-09-15

412

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is a lethal muscle-wasting disease. Studies in Drosophila showed that genetic increase of the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P) or delivery of 2-acetyl-5-tetrahydroxybutyl imidazole (THI), an S1P lyase inhibitor, suppresses dystrophic muscle degeneration. In the dystrophic mouse (mdx), upregulation of S1P by THI increases regeneration and muscle force. S1P can act as a ligand for S1P receptors and as a histone deacetylase (HDAC) inhibitor. Because Drosophila has no identified S1P receptors and DMD correlates with increased HDAC2 levels, we tested whether S1P action in muscle involves HDAC inhibition. Here we show that beneficial effects of THI treatment in mdx mice correlate with significantly increased nuclear S1P, decreased HDAC activity and increased acetylation of specific histone residues. Importantly, the HDAC2 target microRNA genes miR-29 and miR-1 are significantly upregulated, correlating with the downregulation of the miR-29 target Col1a1 in the diaphragm of THI-treated mdx mice. Further gene expression analysis revealed a significant THI-dependent decrease in inflammatory genes and increase in metabolic genes. Accordingly, S1P levels and functional mitochondrial activity are increased after THI treatment of differentiating C2C12 cells. S1P increases the capacity of the muscle cell to use fatty acids as an energy source, suggesting that THI treatment could be beneficial for the maintenance of energy metabolism in mdx muscles. PMID:24077965

Nguyen-Tran, Diem-Hang; Hait, Nitai C; Sperber, Henrik; Qi, Junlin; Fischer, Karin; Ieronimakis, Nick; Pantoja, Mario; Hays, Aislinn; Allegood, Jeremy; Reyes, Morayma; Spiegel, Sarah; Ruohola-Baker, Hannele

2014-01-01

413

Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness.  

PubMed

Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in 10 patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R(2)=80%) and maximum (R(2)=86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD. PMID:25687333

Rijken, N H M; van Engelen, B G M; de Rooy, J W J; Weerdesteyn, V; Geurts, A C H

2015-02-01

414

Effective Classification and Gene Expression Profiling for the Facioscapulohumeral Muscular Dystrophy  

PubMed Central

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

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

2013-01-01

415

High Throughput Screening in Duchenne Muscular Dystrophy: From Drug Discovery to Functional Genomics  

PubMed Central

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

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

2014-01-01

416

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

PubMed Central

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

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

2014-01-01

417

DNA Methylation Analysis of the Macrosatellite Repeat Associated with FSHD Muscular Dystrophy at Single Nucleotide Level  

PubMed Central

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited diseases of the skeletal muscle. It is characterized by asymmetric muscle weakness and variable penetrance. FSHD is linked to a reduction in copy number of the D4Z4 3.3 kb macrosatellite repeat, located in 4q35. This causes the epigenetic de-repression of FSHD candidate genes leading to disease. Nevertheless, the molecular mechanism responsible for silencing of FSHD candidate genes in healthy subjects is not fully understood. While a role for DNA methylation has been suggested, so far there is limited information regarding the methylation status of the 325 CpGs contained in each D4Z4 unit. Using a human/rodent monochromosomal hybrid cell line containing a single human chromosome 4, we performed an in depth analysis of DNA methylation for the majority of the CpGs inside D4Z4 at single nucleotide level. We found that D4Z4 is not uniformly methylated and that the level of DNA methylation does not correlate with the density of CpG dinucleotides. Moreover, in several D4Z4 regions characterized by near complete methylation, we found specific unmethylated CpGs. These elements are enriched in transcription factor binding sites that could be involved in muscle-specific D4Z4 activity. Our approach also detected differential methylation among different D4Z4 units, suggesting that the D4Z4 array is a mosaic of euchromatic and heterochromatic domains. Finally, we found that DNA methylation and histone de-acetylation are required to maintain FSHD candidate genes repressed. Taken together, our data underscore new players involved in the epigenetic regulation of the FSHD locus that could be targeted for therapeutic purposes. PMID:25545674

Huichalaf, Claudia; Micheloni, Stefano; Ferri, Giulia; Caccia, Roberta; Gabellini, Davide

2014-01-01

418

Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy  

PubMed Central

Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3. PMID:22876130

Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

2012-01-01

419

Postural alignment in children with Duchenne muscular dystrophy and its relationship with balance  

PubMed Central

Background In Duchenne muscular dystrophy, functional deficits seem to arise from body misalignment, deconditioning, and obesity secondary to weakness and immobility. The question remains about the effects of postural deviations on the functional balance of these children. Objectives To identify and quantify postural deviations in children with DMD in comparison to non-affected children (eutrophic and overweight/obese), exploring relationships between posture and function. Method This case-control study evaluated 29 participants aged 6 to 11 years: 10 DMD (DG), 10 eutrophic (EG), and 9 overweight/obese (OG). Digital photogrammetry and SAPo program were used to measure postural alignment and the Pediatric Balance Scale (PBS) was used to measure balance. The Kruskall-Wallis and Dunn post-hoc tests were used for inter-group comparison of posture and balance. Spearman's coefficient tested the correlation between postural and balance variables. Results The horizontal pelvic alignment data indicated that the anteversion of the DG was similar to that of the OG and twice that of the EG (p<0.05). Compared to the EG, the DG and OG showed an increased forward position of the center of mass (p<0.05). There was a moderate and weak correlation between the PBS score and horizontal pelvic alignment (0.58 and 0.47-left/right). The PBS showed a weak correlation with asymmetries in the sagittal plane (-0.39). The PBS scores for the OG and EG suggest that obesity did not have a deleterious effect on balance. Conclusions The balance deficit in children with DMD was accompanied by an increased forward position of the center of mass and significant pelvic anteversion that constitutes a compensatory strategy to guarantee similar performance to the children not affected by the disease. PMID:24838810

Baptista, Cyntia R. J. A.; Costa, Andreia A.; Pizzato, Tatiana M.; Souza, Francine B.; Mattiello-Sverzut, Ana C.

2014-01-01

420

Dystrophin Gene Mutation Location and the Risk of Cognitive Impairment in Duchenne Muscular Dystrophy  

PubMed Central

Background A significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms. Methods and Results Sixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r?=?0.83, p?=?0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented. Significance These data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk. PMID:20098710

Maroulis, Sarah; Gilissen, Christian; Pedersen, Robyn L.; Mowat, David R.; Johnston, Heather M.; Buckley, Michael F.

2010-01-01

421

Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic  

PubMed Central

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

2014-01-01

422

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

SciTech Connect

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.

Greenberg, C.R.; Nylen, E.G.; Halliday, W. [Univ. of Manitoba, Winnipeg (Canada)] [and others

1994-09-01

423

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

SciTech Connect

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.

Hewitt, J.E.; Clark, L.N.; Wienberg, J. [and others

1994-09-01

424

YAC contigs for 4q35 in the region of the facioscapulohumeral muscular dystrophy (FSHD) gene  

SciTech Connect

The authors report here the construction of a genetic linkage map and an overlapping set of clones containing DNA markers linked to the causative locus for facioscapulohumeral muscular dystrophy (FSHD) on 4q35. Multi-point linkage analysis placed eight loci in the following order with odds greater than 1000:1: cen-D4S171-FXI-D4S426-D4S187-D4S130-D4S163-D4S139-D4F35S1-qter. The most likely position of D4S809 was distal to D4F35S1. Thirty-four yeast artificial chromosomes (YACs) were isolated by PCR-based assays for STSs derived from DNA markers with known genetic and physical order. Walking from the insert ends of 2 YACs identified 7 additional YACs, bridging the gaps between three of the markers. Two new YACs were found by hybridization of a cosmid inter-Alu PCR product to dot blots of inter-Alu PCR products of YAC DNA pools. All YAC clones were positioned using the genetic and physical order of the STSs and inter-Alu PCR fingerprint data. Eleven of the YAC-, and two cosmids were mapped by fluorescence in situ hybridization to confirm the location of the clones and to detect chimerism.