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1

Atypical motor unit potentials in Emery–Dreifuss muscular dystrophy (EDMD)  

Microsoft Academic Search

ObjectiveThe aim of the study was to analyse electromyographic changes in Emery–Dreifuss muscular dystrophy (EDMD) that are atypical for myopathy. Our special interest was focused on high amplitude polyphasic motor unit potentials (MUPs), also termed irregular MUPs.

K. Rowi?ska-Marci?ska; E. Szmidt-Sa?kowska; A. Fidzia?ska; E. Zalewska; M. Dorobek; A. Karwa?ska; I. Hausmanowa-Petrusewicz

2005-01-01

2

Uncoordinated Transcription and Compromised Muscle Function in the Lmna-Null Mouse Model of Emery-Dreifuss Muscular Dystrophy  

Microsoft Academic Search

LMNA encodes both lamin A and C: major components of the nuclear lamina. Mutations in LMNA underlie a range of tissue-specific degenerative diseases, including those that affect skeletal muscle, such as autosomal-Emery-Dreifuss muscular dystrophy (A-EDMD) and limb girdle muscular dystrophy 1B. Here, we examine the morphology and transcriptional activity of myonuclei, the structure of the myotendinous junction and the muscle

Viola F. Gnocchi; Juergen Scharner; Zhe Huang; Ken Brady; Jaclyn S. Lee; Robert B. White; Jennifer E. Morgan; Yin-Biao Sun; Juliet A. Ellis; Peter S. Zammit; Sean Lee

2011-01-01

3

Increased solubility of lamins and redistribution of lamin C in X-linked Emery–Dreifuss muscular dystrophy fibroblasts  

Microsoft Academic Search

Emery–Dreifuss muscular dystrophy (EDMD) is caused by mutations in the gene encoding the nuclear membrane protein emerin (X-linked EDMD) or in the gene encoding lamins A\\/C (autosomal dominant EDMD). One hypothesis explaining the disease suggests that the mutations lead to weakness of the nuclear lamina. To test this hypothesis we investigated lamin solubility and distribution in skin fibroblasts from X-EDMD

Ewa Markiewicz; Rachel Venables; Mauricio-Alvarez-Reyes; Roy Quinlan; Margareth Dorobek; Irena Hausmanowa-Petrucewicz; Christopher Hutchison

2002-01-01

4

Disruption of nesprin-1 produces an Emery Dreifuss muscular dystrophy-like phenotype in mice  

PubMed Central

Mutations in the gene encoding the inner nuclear membrane proteins lamins A and C produce cardiac and skeletal muscle dysfunction referred to as Emery Dreifuss muscular dystrophy. Lamins A and C participate in the LINC complex that, along with the nesprin and SUN proteins, LInk the Nucleoskeleton with the Cytoskeleton. Nesprins 1 and 2 are giant spectrin-repeat containing proteins that have large and small forms. The nesprins contain a transmembrane anchor that tethers to the nuclear membrane followed by a short domain that resides within the lumen between the inner and outer nuclear membrane. Nesprin’s luminal domain binds directly to SUN proteins. We generated mice where the C-terminus of nesprin-1 was deleted. This strategy produced a protein lacking the transmembrane and luminal domains that together are referred to as the KASH domain. Mice homozygous for this mutation exhibit lethality with approximately half dying at or near birth from respiratory failure. Surviving mice display hindlimb weakness and an abnormal gait. With increasing age, kyphoscoliosis, muscle pathology and cardiac conduction defects develop. The protein components of the LINC complex, including mutant nesprin-1?, lamin A/C and SUN2, are localized at the nuclear membrane in this model. However, the LINC components do not normally associate since coimmunoprecipitation experiments with SUN2 and nesprin reveal that mutant nesprin-1 protein no longer interacts with SUN2. These findings demonstrate the role of the LINC complex, and nesprin-1, in neuromuscular and cardiac disease. PMID:19008300

Puckelwartz, Megan J.; Kessler, Eric; Zhang, Yuan; Hodzic, Didier; Randles, K. Natalie; Morris, Glenn; Earley, Judy U.; Hadhazy, Michele; Holaska, James M.; Mewborn, Stephanie K.; Pytel, Peter; McNally, Elizabeth M.

2009-01-01

5

Lamin A/C-mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy  

PubMed Central

The LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity–dependent genes and altered epigenetic chromatin modifications. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C–mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD. PMID:19124654

Mejat, Alexandre; Decostre, Valerie; Li, Juan; Renou, Laure; Kesari, Akanchha; Hantai, Daniel; Stewart, Colin L.; Xiao, Xiao; Hoffman, Eric; Bonne, Gisele; Misteli, Tom

2009-01-01

6

Lamin A N-terminal phosphorylation is associated with myoblast activation: impairment in Emery–Dreifuss muscular dystrophy  

PubMed Central

Background: Skeletal muscle disorders associated with mutations of lamin A/C gene include autosomal Emery–Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. The pathogenic mechanism underlying these diseases is unknown. Recent data suggest an impairment of signalling mechanisms as a possible cause of muscle malfunction. A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified. The stability of this protein complex appears to be related to phosphorylation mechanisms. Objective: To analyse lamin A/C phosphorylation in control and laminopathic muscle cells. Methods: Lamin A/C N-terminal phosphorylation was determined in cultured mouse myoblasts using a specific antibody. Insulin treatment of serum starved myoblast cultures was carried out to evaluate involvement of insulin signalling in the phosphorylation pathway. Screening of four Emery–Dreifuss and one limb girdle muscular dystrophy 1B cases was undertaken to investigate lamin A/C phosphorylation in both cultured myoblasts and mature muscle fibres. Results: Phosphorylation of lamin A was observed during myoblast differentiation or proliferation, along with reduced lamin A/C phosphorylation in quiescent myoblasts. Lamin A N-terminus phosphorylation was induced by an insulin stimulus, which conversely did not affect lamin C phosphorylation. Lamin A/C was also hyperphosphorylated in mature muscle, mostly in regenerating fibres. Lamin A/C phosphorylation was strikingly reduced in laminopathic myoblasts and muscle fibres, while it was preserved in interstitial fibroblasts. Conclusions: Altered lamin A/C interplay with a muscle specific phosphorylation partner might be involved in the pathogenic mechanism of Emery–Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. PMID:15744034

Cenni, V; Sabatelli, P; Mattioli, E; Marmiroli, S; Capanni, C; Ognibene, A; Squarzoni, S; Maraldi, N; Bonne, G; Columbaro, M; Merlini, L; Lattanzi, G

2005-01-01

7

Homozygous lamin A/C familial lipodystrophy R482Q mutation in autosomal recessive Emery Dreifuss muscular dystrophy.  

PubMed

Autosomal recessive Emery Dreifuss muscular dystrophy (AR-EDMD) is rare, with few reports in the medical literature. We describe the first cases of AR-EDMD and autosomal dominant familial partial lipodystrophy (FPLD) in the Hutterite population resulting from homozygous or heterozygous R482Q mutations in the lamin A/C gene (LMNA). Heterozygosity for LMNA R482Q mutation causes FPLD, which is associated with increased risk of hyperlipidemia and hypertension. The overall carrier frequency of the R482Q mutation in Dariusleut and Leherleut Hutterites in Alberta was found to be 1.45%. Homozygosity for this mutation has not been previously reported and here resulted in a combination of generalized lipodystrophy and EDMD. Knowledge that the LMNA R482Q mutation is present in this population is important for genetic counseling, surveillance, and management of the associated disorders. PMID:23313286

Wiltshire, Katie M; Hegele, Robert A; Innes, A Micheil; Brownell, A Keith W

2013-03-01

8

Oral exfoliative cytology for the non-invasive diagnosis in X-linked Emery–Dreifuss muscular dystrophy patients and carriers  

Microsoft Academic Search

Emery–Dreifuss muscular dystrophy (EMD) is an inherited myopathy characterised by muscle contractures, progressive muscle wasting and weakness, with humeroperoneal distribution. Cardiac arrhythmia and heart conduction block are also important characteristics of this disease. The X-linked form of EMD is caused by the absence of emerin, encoded by the STA gene (Xq28). Emerin is normally localised in muscle and other tissues

P Sabatelli; S Squarzoni; S Petrini; C Capanni; A Ognibene; L Cartegni; F Cobianchi; L Merlini; D Toniolo; N. M Maraldi

1998-01-01

9

Dysregulation of FHL1 spliceforms due to an indel mutation produces an Emery-Dreifuss muscular dystrophy plus phenotype.  

PubMed

Emery-Dreifuss muscular dystrophy (EDMD) is characterised by early-onset joint contractures, progressive muscular weakness and wasting and late-onset cardiac disease. The more common X-linked recessive form of EDMD is caused by mutations in either EMD (encoding emerin) or FHL1 (encoding four and a half LIM domains 1), while mutations in LMNA (encoding lamin A/C), SYNE1 (encoding nesprin-1) and SYNE2 (encoding nesprin-2) lead to autosomal dominant forms of the condition. Here, we identify a three-generation family with an extended EDMD phenotype due to a novel indel mutation in FHL1 that differentially affects the relative expression of the three known transcript isoforms produced from this locus. The additional phenotypic manifestations in this family-proportionate short stature, facial dysmorphism, pulmonary valvular stenosis, thoracic scoliosis, brachydactyly, pectus deformities and genital abnormalities-are reminiscent of phenotypes seen with dysregulated Ras-mitogen-activated protein kinase (RAS-MAPK) signalling [Noonan syndrome (NS) and related disorders]. The misexpression of FHL1 transcripts precipitated by this mutation, together with the role of FHL1 in the regulation of RAS-MAPK signalling, suggests that this mutation confers a complex phenotype through both gain- and loss-of-function mechanisms. This indel mutation in FHL1 broadens the spectrum of FHL1-related disorders and implicates it in the pathogenesis of NS spectrum disorders. PMID:23456229

Tiffin, Heather R; Jenkins, Zandra A; Gray, Mary J; Cameron-Christie, Sophia R; Eaton, Jennifer; Aftimos, Salim; Markie, David; Robertson, Stephen P

2013-05-01

10

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

11

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

12

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

MedlinePLUS

... ranging from noninvasive nighttime ventilation to a tracheostomy. Learning disabilities Some children with CMD may have significant ... the calf muscles of the legs. Another prominent aspect of this disease is the appearance of contractures ( ...

13

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

E-print Network

, in an axonal neuropathy and, more surprisingly, in lipodystrophy and a wide spectrum of premature aging and emerin. Concerning skeletal muscle, there is a spectrum of phenotypes of onset from birth to adult age. L

14

Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies  

Microsoft Academic Search

Laminopathies are a group of disorders caused by mutations in the LMNA gene encoding A-type lamins, components of the nuclear lamina. Three of these disorders affect specifically the skeletal and\\/or cardiac muscles, and their pathogenic mechanisms are still unknown. We chose the LMNA H222P missense mutation identified in a family with autosomal dominant Emery-Dreifuss muscular dystrophy, one of the striated

Takuro Arimura; Anne Helbling-Leclerc; Catherine Massart; Shaida Varnous; Florence Niel; Emmanuelle Lacene; Yves Fromes; Marcel Toussaint; Anne-Marie Mura; Dagmar I. Keller; Helge Amthor; Richard Isnard; Marie Malissen; Ketty Schwartz; Gisele Bonne

2004-01-01

15

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

Microsoft Academic Search

Mutations of lamin A\\/C (LMNA) cause a wide range of human disorders, including progeria, lipodystrophy, neuropathies and autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD). EDMD is also caused by X-linked recessive loss-of-function mutations of emerin, another component of the inner nuclear lamina that directly interacts with LMNA. One model for disease pathogenesis of LMNA and emerin mutations is cell- specific perturbations

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

2006-01-01

16

Becker muscular dystrophy  

MedlinePLUS

... provider will do a nervous system (neurological) and muscle examination. A careful medical history is also important, because symptoms are similar to those of Duchenne muscular dystrophy. However, Becker muscular dystrophy gets worse much more ...

17

Muscular Dystrophy Association  

MedlinePLUS

... Illinois 60606 (800) 572-1717 Privacy Policy | Terms of Use The Muscular Dystrophy Association (MDA) is a qualified 501(c)(3) tax-exempt organization. ©2014, Muscular Dystrophy Association Inc. All ...

18

Fatigue in muscular dystrophies  

PubMed Central

Fatigue is a frequent complaint in muscular dystrophies but it is yet not well defined or studied. We have examined the issue of muscle fatigue in a series of molecularly defined muscular dystrophies. A greater fatigability is seen in muscular dystrophy patients and can be an acute or chronic status. In Duchenne Muscular Dystrophy and beta-sarcoglycanopathy besides the alteration of dystrophin and/or sarcoglycan complex, a neuronal nitric oxide synthase depletion is frequently found and might correlate with post-exercise fatigability as well as with cardiac involvement. Therefore, it might be an important modulating factor of the severity of myopathy. In myotonic dystrophy, fatigue is a common complaint: muscle is involved and type 1 atrophy is a frequent feature; brain involvement and depressed mood might likely explain the extent of fatigue and daytime sleepiness commonly observed in these patients. Furthermore, in our observation in a series of 24 cases, muscle and brain can be independently involved in DM1 patients. These observations have profound impact on the type of physical therapy to be prescribed in such patients. PMID:23182642

Angelini, Corrado; Tasca, Elisabetta

2012-01-01

19

Meaning of Muscular Dystrophy  

MedlinePLUS

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

20

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

21

Wasting Mechanisms in Muscular Dystrophy  

PubMed Central

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

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

2013-01-01

22

Diagnosis and new treatments in muscular dystrophies  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD) and limb girdle muscular dystrophies (LGMD) represent a significant proportion of paediatric and adult neuromuscular neurology practice. The proactive symptom-based multidisciplinary team (MDT) management and access to non-invasive ventilation have enabled improved survival into adulthood. Nevertheless the severe disability imposed by conditions such as DMD poses a challenge for successful transition of

A Y Manzur; F Muntoni

2009-01-01

23

Modifying muscular dystrophy through TGF?  

PubMed Central

Muscular dystrophy arises from ongoing muscle degeneration and insufficient regeneration. This imbalance leads to loss of muscle with replacement by scar or fibrosis resulting in muscle weakness and, eventually, loss of muscle function. Human muscular dystrophy is characterized by a wide range of disease severity, even when the same genetic mutation is present. This variability implies that other factors, both genetic and environmental, modify the disease outcome. There has been an ongoing effort to define the genetic and molecular bases that influence muscular dystrophy onset and progression. Modifier genes for muscle disease have been identified through candidate gene approaches as well as genomewide surveys. Multiple lines of experimental evidence have now converged on the TGF? pathway as a modifier for muscular dystrophy. TGF? signaling is upregulated in dystrophic muscle as a result of a destabilized plasma membrane and/or altered extracellular matrix. Given the important biological role of the TGF? pathway, and its role beyond muscle homeostasis, we review modifier genes that alter the TGF? pathway and approaches to modulate TGF? activity to ameliorate muscle disease. PMID:23551962

Ceco, Ermelinda; McNally, Elizabeth M.

2013-01-01

24

Original article Duchenne muscular dystrophy  

E-print Network

muscular dystrophy (DMD) is associated with a dramatic muscle mass loss. We hypothesized that DMD would and protein metabolism in children. The qualitative impact of muscle mass loss on amino acid metabolism impact on muscle mass and function. However, the way muscle mass loss may affect whole body energy

Paris-Sud XI, Université de

25

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

26

Duchenne Muscular Dystrophy  

MedlinePLUS

... cardiacos. Se presenta, con más frecuencia, en los niños varones y ocurre en personas de cualquier raza ... signos de la distrofia muscular de Duchenne? Un niño con DMD no alcanza algunos indicadores del desarrollo ...

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

Genetics Home Reference: Facioscapulohumeral muscular dystrophy  

MedlinePLUS

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

29

Facioscapulohumeral muscular dystrophy  

Microsoft Academic Search

.  Facioscapulohumeral\\u000amuscular dystrophy (FSHD) is associated\\u000awith a decreased number\\u000aof D4Z4 repeats on chromosome\\u000a4q35. Diagnostic difficulties arise\\u000afrom atypical clinical presentations\\u000aand from an overlap in D4Z4 numbers\\u000abetween controls and FSHD\\u000aindividuals. Thus, a molecular genetic\\u000atest result with a borderline\\u000aD4Z4 number has its limitations\\u000afor the clinician wanting to differentiate\\u000abetween the diagnosis of\\u000aFSHD

Miriam Butz; Manuela C. Koch; W. Muller-Felber; Richard J. L. F. Lemmers; Silvère M. van der Maarel; Herbert Schreiber

2003-01-01

30

Myoglobin in Primary Muscular Disease: I. Duchenne Muscular Dystrophy: and: II. Muscular Dystrophy of Distal Type  

PubMed Central

Skeletal myoglobin from two cases of muscular dystrophy, one of Duchenne muscular dystrophy, and one of muscular dystrophy of distal type, have been examined and no differences from normal human myoglobin were found. The opportunity has been taken to discuss the nature of minor fractions of myoglobin-like material which are found when human skeletal myoglobin is isolated. Those which have been observed in the present study have been artefacts and it was possible to demonstrate that they were due to deamidation of certain glutamine and asparagine residues. Images PMID:4590363

Romero-Herrera, A. E.; Lehmann, H.; Tomlinson, B. E.; Walton, J. N.

1973-01-01

31

Ullrich's congenital atonic sclerotic muscular dystrophy  

Microsoft Academic Search

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

L. De Paillette; J. Aicardi; F. Goutières

1989-01-01

32

What Are the Treatments for Muscular Dystrophy?  

MedlinePLUS

... No treatment is currently available to stop or reverse any form of muscular dystrophy (MD). Instead, certain ... Technology NICHD News and Spotlights Encouraging Healthy Child Development with Birth to 5: Watch Me Thrive! Men’s ...

33

Targeting latent TGF? release in muscular dystrophy.  

PubMed

Latent transforming growth factor-? (TGF?) binding proteins (LTBPs) bind to inactive TGF? in the extracellular matrix. In mice, muscular dystrophy symptoms are intensified by a genetic polymorphism that changes the hinge region of LTBP, leading to increased proteolytic susceptibility and TGF? release. We have found that the hinge region of human LTBP4 was also readily proteolysed and that proteolysis could be blocked by an antibody to the hinge region. Transgenic mice were generated to carry a bacterial artificial chromosome encoding the human LTBP4 gene. These transgenic mice displayed larger myofibers, increased damage after muscle injury, and enhanced TGF? signaling. In the mdx mouse model of Duchenne muscular dystrophy, the human LTBP4 transgene exacerbated muscular dystrophy symptoms and resulted in weaker muscles with an increased inflammatory infiltrate and greater LTBP4 cleavage in vivo. Blocking LTBP4 cleavage may be a therapeutic strategy to reduce TGF? release and activity and decrease inflammation and muscle damage in muscular dystrophy. PMID:25338755

Ceco, Ermelinda; Bogdanovich, Sasha; Gardner, Brandon; Miller, Tamari; DeJesus, Adam; Earley, Judy U; Hadhazy, Michele; Smith, Lucas R; Barton, Elisabeth R; Molkentin, Jeffery D; McNally, Elizabeth M

2014-10-22

34

Radiographic features of Golden Retriever muscular dystrophy.  

PubMed

Golden Retriever muscular dystrophy is an inherited, degenerative myopathy due to the absence of dystrophin and is used as a model of Duchenne muscular dystrophy of young boys. This report describes the radiographic abnormalities of Golden Retriever muscular dystrophy in 26 dogs. The thoracic abnormalities included diaphragmatic asymmetry (18/26), diaphragmatic undulation (18/26), and gastro-esophageal hiatal hernia (6/26). Pelvic abnormalities included narrowing of the body of the ilia (14/19), ventral deviation and curvature of the tuber ischii (14/19), elongation of the obturator foramen with a decrease in opacity of the surrounding bone (12/19), and lateral flaring of the wings of the ilia (12/19). Abdominal abnormalities consisted of hepatomegaly (14/22) and poor serosal detail (12/22). The unique thoracic abnormalities were a consistent finding in affected Golden Retriever muscular dystrophy dogs. The diagnosis of muscular dystrophy should be included in the differential list if the combination of diaphragm undulation and asymmetry, and gastro-esophageal hiatal hernia are identified. These diaphragmatic abnormalities are related to hypertrophy and hyperplasia of the diaphragm. Additionally, the skeletal changes of pelvic tilt, elongation of the pelvis, widening of the obturator foramina and thinning of the ischiatic tables appear to be specific to Golden Retriever muscular dystrophy in dogs. These pelvic abnormalities are most likely secondary to bone remodeling associated with the progressive skeletal myopathy and subsequent contracture/fibrosis. PMID:17153067

Brumitt, Jason W; Essman, Stephanie C; Kornegay, Joe N; Graham, John P; Weber, William J; Berry, Clifford R

2006-01-01

35

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

36

If I Had - A Family History of Muscular Dystrophy  

MedlinePLUS Videos and Cool Tools

... Family History of Muscular Dystrophy - Eric Hoffman, PhD, Children's National Medical Center, George Washington University If I ... Family History of Muscular Dystrophy - Eric Hoffman, PhD, Children's National Medical Center, George Washington University (January 15, ...

37

788. Antisense Therapy for Duchenne Muscular Dystrophy: A Realistic Possibility  

Microsoft Academic Search

Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy affecting 1 in every 3500 live male births. The disease is characterized by severe muscle wasting and weakness, which becomes clinically evident between the ages of 3 to 5 years. The milder form of the disease is Becker muscular dystrophy (BMD) with a spectrum of phenotypes ranging from

Qi L. Lu; Adam Rabinowitz; HaiFang Yin; Julia Alter; George Bou-Gharios; Terrence Partridge

2005-01-01

38

Cognitive and Psychological Profile of Males With Becker Muscular Dystrophy  

Microsoft Academic Search

Duchenne and Becker muscular dystrophy are allelic X-linked disorders causing progressive muscle weakness in males. Duchenne muscular dystrophy is caused by absence of dystrophin in muscle and brain; boys with Duchenne muscular dystrophy have a static cognitive impairment with mean Full Scale IQ approximately 1 standard deviation below the mean. Less is known of the cognitive profile of males with

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

2008-01-01

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

Cardiopulmonary Support in Duchenne Muscular Dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is an X-linked, rapidly progressive myopathy affecting the limb muscles, the respiratory\\u000a muscles, the heart, the intestines, and the brain. Since about 90% of DMD patients die from muscular respiratory failure or\\u000a cardiomyopathy, early and adequate therapy is essential. Ventilatory failure from muscle weakness requires mechanical support\\u000a for ventilation and coughing as soon as there is

Josef Finsterer

2006-01-01

41

The management of Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a severe genetic disease with loss of walking at a mean age of 9.5 years and death in late teens or twenties. Despite major advances in understanding of the underlying molecular genetics and pathogenesis, curative treatment is not available. Physical therapy for prevention of contractures and promotion of ambulation is the mainstay of treatment. The

Adnan Y. Manzur; Francesco Muntoni

2002-01-01

42

Central nervous system involvement in progressive muscular dystrophy  

Microsoft Academic Search

Several abnormalities in the central nervous system were shown in patients with progressive muscular dystrophy using computerised tomography (CT) scans, electroencephalograms, psychometry, and ophthalmological methods. In congenital muscular dystrophy, the most characteristic finding in the CT scan was a low density area in the white matter, seen in 14 (56%) out of 25 cases. In Duchenne dystrophy, slight cerebral atrophy

M Yoshioka; T Okuno; Y Honda; Y Nakano

1980-01-01

43

Congenital Muscular Dystrophy with Central Nervous System Involvement: Case Report  

Microsoft Academic Search

A case of a mediterranean boy with congenital muscular dystrophy (CMD) and central nervous system (CNS) involvement with mild intellectual impairment and seizures is reported. Muscular dystrophy involved both skeletal and mimic muscles, and histological findings were consistent with a congenital dystrophy. EEG recordings showed generalized and localized paroxysmal activities. CT scan demonstrated low-density periventricular areas. Ophthalmoplegia was also observed.

P. Martinelli; A. S. Gabellini; G. Ciucci; E. Govoni; S. Vitali; M. R. Gullì

1987-01-01

44

Genetics Home Reference: Duchenne and Becker muscular dystrophy  

MedlinePLUS

... dystrophy are associated with a heart condition called cardiomyopathy. This form of heart disease weakens the cardiac ... efficiently. In both Duchenne and Becker muscular dystrophy, cardiomyopathy typically begins in adolescence. Later, the heart muscle ...

45

Early prednisone treatment in Duchenne muscular dystrophy  

Microsoft Academic Search

The purpose of this long-term, open parallel-group, double- consent study of alternate-day, low-dose prednisone in 2- 4-year-old pa- tients with Duchenne muscular dystrophy (DMD) was to determine whether prednisone produces a beneficial effect when given earlier than usual. Muscle function was evaluated by timed tests, and muscle strength with a hand-held myometer. After 55 months of treatment, the five patients

Luciano Merlini; Alessandro Cicognani; Elisabetta Malaspina; Monia Gennari; Saverio Gnudi; Beril Talim; Emilio Franzoni

2003-01-01

46

Oculopharyngeal Muscular Dystrophy in an Irish Family  

Microsoft Academic Search

Summary  Victor1 and his associates coined the term oculopharyngeal muscular dystrophy to describe a clinical syndrome characterised by dysphagia\\u000a and ptosis. Subsequent authors have traced a large series in French Canadians to a single Quebec isolate and have emphasized\\u000a that the condition is usually inherited as a dominant trait2,3. In 1974 Fried4 reported two isolated cases in an Ashkenazi Jewish family

S. Eustace; C. Gleeson; M. Joyce; P. Sullivan

1989-01-01

47

Congenital Muscular Dystrophies: Toward Molecular Therapeutic Interventions  

Microsoft Academic Search

Congenital muscular dystrophies (CMDs) are a clinically and genetically heterogeneous group of neuromuscular disorders that\\u000a typically present at birth or in early infancy with hypotonia, weakness, and histologic evidence of a dystrophic myopathy.\\u000a CMD biochemical types include various abnormalities of ?-dystroglycan O-mannosyl glycosylation as well as defects in integrin matrix receptors, the extracellular matrix proteins laminin-?2 and collagen VI, nuclear

James Collins; Carsten G. Bönnemann

2010-01-01

48

Cardiac Assessment in Duchenne and Becker Muscular Dystrophies  

Microsoft Academic Search

Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophies. In addition to muscle disease, there nearly\\u000a always is an associated cardiomyopathy in Duchenne or Becker muscular dystrophy. In these muscular dystrophies, the severity\\u000a of cardiomyopathy and congestive heart failure may not parallel the severity of skeletal muscle disease. Loss of normal dystrophin\\u000a function in the heart produces four-chamber

Anitra Romfh; Elizabeth M. McNally

2010-01-01

49

Creatine kinase, cell membrane and Duchenne muscular dystrophy  

Microsoft Academic Search

In 1958 Professor Setsuro Ebashi found that serum creatine kinase activity is increased in patients suffering from various muscular dystrophies, especially Duchenne muscular dystrophy (DMD). He and others proposed that creatine kinase passes through the cell membrane as it is released from DMD muscle fibers.

Eijiro Ozawa; Yasuko Hagiwara; Mikiharu Yoshida

1999-01-01

50

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

E-print Network

). Both DMD and the more benign Becker muscular dystrophy (BMD) are caused by mutations in the geneINTRODUCTION Duchenne muscular dystrophy (DMD) is a progressive, X- linked disease is emphasised by the finding that mutations in various components of the DGC, other than dystrophin, also result

Campbell, Kevin P.

51

Cardiac Assessment in Duchenne and Becker Muscular Dystrophies  

Microsoft Academic Search

Background: Cardiac problems are common and are a major cause of death in both Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Early diagnosis and proper management are very important for prolonging life expectancy, improving mobility and the quality of life in dystrophinopathic patients. The object of this study was to assess the cardiac dysfunction in dystrophinopathic patients. Methods:

Tae-Jin Song; Young-Chul Choi

52

Characterization of aquaporin-4 in muscle and muscular dystrophy  

E-print Network

demonstrate that AQP4 loss in skeletal muscle correlates with muscular dystrophy and is a common featureCharacterization of aquaporin-4 in muscle and muscular dystrophy RACHELLE H. CROSBIE,1 SHERRI A. Aquaporin-4 (AQP4) is enriched at the sarco- lemma of skeletal muscle and may play a role in accommodating

Campbell, Kevin P.

53

Oculopharyngeal muscular dystrophy associated with dementia.  

PubMed

We report genetically confirmed heterozygote oculopharyngeal muscular dystrophy (OPMD) accompanied by dementia, suggesting a possible causal association between OPMD and dementia. The proband first noticed bilateral ptosis, dysphagia, and proximal dominant muscle weakness in the lower extremities at age 53. Ten years later, she was found to have dementia with a score of 10/30 on the mini-mental state examination (MMSE). On PABPN1 gene analysis, the GCN repeat was expanded 17 times in one allele. In addition, the proband's younger brother exhibited myopathy and dementia. To our knowledge, this is the first report of genetically confirmed heterozygote OPMD associated with dementia. PMID:22001477

Mizoi, Yoshikazu; Yamamoto, Toshimasa; Minami, Narihiro; Ohkuma, Aya; Nonaka, Ikuya; Nishino, Ichizo; Tamura, Naotoshi; Amano, Takahiro; Araki, Nobuo

2011-01-01

54

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

E-print Network

limb-girdle muscular dystrophy SCARMD severe childhood autosomal recessive muscular dystrophy is genetically and clinically heterogeneous; it may be inherited in an autosomal domi- nant or recessive manner included Duchenne- like muscular dystrophy and severe childhood autosomal recessive muscular dystrophy

Campbell, Kevin P.

55

The superhealing MRL background improves muscular dystrophy  

PubMed Central

Background Mice from the MRL or “superhealing” strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking ?-sarcoglycan (Sgcg), a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis. Methods MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains. Results Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis. Conclusions These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease. PMID:23216833

2012-01-01

56

Oculopharyngeal muscular dystrophy: a polyalanine myopathy.  

PubMed

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 cases of OPMD diagnosed in more than 35 countries. Sequence analyses have shown that such mutations have occurred numerous times in human history. Although PABPN1 was found early on to be a component of the classic filamentous intranuclear inclusions (INIs), mRNA and other proteins also have been found to coaggregate in the INIs. It is still unclear if the INIs play a pathologic or a protective role. The generation of numerous cell and animal models of OPMD has led to greater insight into its complex molecular pathophysiology and identified the first candidate therapeutic molecules. This paper reviews basic and clinical research on OPMD, with special emphasis on recent developments in the understanding of its pathophysiology. PMID:19080757

Brais, Bernard

2009-01-01

57

Altered biomechanical properties of large arteries in muscular dystrophy  

E-print Network

the proteins dystrophin and sarcoglycan-delta. The absence of these proteins results in severe muscular dystrophies in humans, and thus knockout mice lacking the genes encoding for dystrophin (mdx mice) and sarcoglycan-delta (sgcd-/- mice) were studied...

Dye, Wendy Watson

2006-10-30

58

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

E-print Network

Congenital Muscular Dystrophy with Rigid Spine Syndrome: A Clinical, Pathological, Radiological weakness in infancy, early spinal rigidity, and early scoliosis. After initial improvement, muscle strength biopsy in an affected child at age 9 months revealed minimal, nonspecific myopathic changes, leading

Campbell, Kevin P.

59

Proteomic profiling of x-linked muscular dystrophy  

Microsoft Academic Search

Progressive x-linked muscular dystrophy represents the most commonly inherited neuromuscular disorder in humans. Although\\u000a the disintegration of the dystrophin-associated glycoprotein complex triggers the initial pathogenesis of Duchenne muscular\\u000a dystrophy, secondary alterations in metabolic pathways, cellular signaling and the regulation of ion homeostasis are probably\\u000a crucial factors that cause end-stage fibre degeneration. The application of mass spectrometry-based proteomics for the global

Caroline Lewis; Steven Carberry; Kay Ohlendieck

2009-01-01

60

Common pathological mechanisms in mouse models for muscular dystrophies  

Microsoft Academic Search

Duchenne\\/Becker and limb-girdle muscular dystrophies share clinical symptoms like muscle weakness and wasting but differ in clinical presentation and severity. To get a closer view on the differentiating molecular events responsible for the muscular dystrophies, we have carried out a comparative gene expression profiling of hindlimb muscles of the following mouse models: dystrophin-deficient (mdx, mdx3cv), sarcoglycan-deficient (Sgca null, Sgcb null,

R. Turk; E. Sterrenburg; E. J. de Meijer; R. X. de Menezes

2005-01-01

61

Unraveling the mysteries of Duchenne and Becker muscular dystrophy  

Microsoft Academic Search

Through a process that has come to be known as reverse genetics, the gene and gene product involved in Duchenne muscular dystrophy\\u000a (DMD) and Becker muscular dystrophy (BMD) have been identified. The DMD\\/BMD gene is over 2 million base pairs in size and\\u000a over 50% of DMD\\/BMD patients harbor submicroscopic deletions for portions of the gene. The gene product, named

Craig L. Hyser

1989-01-01

62

Muscular Dystrophy Gene Therapy in Small Animal Models  

Microsoft Academic Search

\\u000a Muscular dystrophies are inherited neuromuscular disorders characterized by progressive muscle loss and weakness. The morbidity\\u000a and fatality associated with the diseases and a lack of effective treatment have prompted urgent search for novel therapeutics.\\u000a Gene therapy is one of the frontiers. Currently, adeno-associated viral (AAV) vector-mediated gene transfer offers a powerful\\u000a tool for muscular dystrophy gene therapy for both skeletal

Chunping Qiao; Xiao Xiao

63

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

64

Muscular Dystrophies at Different Ages: Metabolic and Endocrine Alterations  

PubMed Central

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

Cruz Guzman, Oriana del Rocio; Chavez Garcia, Ana Laura; Rodriguez-Cruz, Maricela

2012-01-01

65

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

66

Early prednisone treatment in Duchenne muscular dystrophy.  

PubMed

The purpose of this long-term, open parallel-group, double-consent study of alternate-day, low-dose prednisone in 2-4-year-old patients with Duchenne muscular dystrophy (DMD) was to determine whether prednisone produces a beneficial effect when given earlier than usual. Muscle function was evaluated by timed tests, and muscle strength with a hand-held myometer. After 55 months of treatment, the five patients (mean age 8.3 years) in the prednisone group were still able to get up from the floor, whereas two of the three in the control group had lost this ability. Side effects included a decline in growth rate in the prednisone-treated patients and excessive weight gain in one control and three treated patients. Because steroids are effective in prolonging function, but not in recovering lost function, we propose that treatment be started with low-dose prednisone in DMD patients as soon as the diagnosis is definite. PMID:12548530

Merlini, Luciano; Cicognani, Alessandro; Malaspina, Elisabetta; Gennari, Monia; Gnudi, Saverio; Talim, Beril; Franzoni, Emilio

2003-02-01

67

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

68

Molecular diagnosis of duchenne muscular dystrophy.  

PubMed

Duchenne Muscular Dystrophy (DMD) is an X-linked inherited neuromuscular disorder caused by mutations in the dystrophin gene (DMD; locus Xp21.2). The mutation spectrum of DMD is unique in that 65% of causative mutations are intragenic deletions, with intragenic duplications and point mutations (along with other sequence variants) accounting for 6% to 10% and 30% to 35%, respectively. The strategy for molecular diagnostic testing for DMD involves initial screening for deletions/duplications using microarray-based comparative genomic hybridization (array-CGH) followed by full-sequence analysis of DMD for sequence variants. Recently, next-generation sequencing (NGS)-based targeted gene analysis has become clinically available for detection of point mutations and other sequence variants (small insertions, deletions, and indels). This unit initially discusses the strategic algorithm for establishing a molecular diagnosis of DMD and later provides detailed protocols of current molecular diagnostic methods for DMD, including array-CGH, PCR-based Sanger sequencing, and NGS-based sequencing assay. Curr. Protoc. Hum. Genet. 83:9.25.1-9.25.29 © 2014 by John Wiley & Sons, Inc. PMID:25271841

Nallamilli, Babi Ramesh Reddy; Ankala, Arunkanth; Hegde, Madhuri

2014-01-01

69

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

70

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

E-print Network

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

Discher, Dennis

71

Molecular deletion patterns in Duchenne and Becker muscular dystrophy patients from KwaZulu Natal  

Microsoft Academic Search

There exists much phenotypic heterogeneity in Duchenne muscular dystrophy and its allelic variant, Becker muscular dystrophy. The molecular findings on 53 patients with Duchenne and 15 patients with Becker type muscular dystrophy in KwaZulu Natal, South Africa are reported. Multiplex PCR was performed using primers targeting 18 hot-spot exons throughout the dystrophin gene. Analysis of the multiplex PCR data revealed

K. D. Hallwirth Pillay; P. L. A. Bill; S. Madurai; L. Mubaiwa; P. Rapiti

2007-01-01

72

Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair.  

PubMed

Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury. PMID:24717843

Swaggart, Kayleigh A; Demonbreun, Alexis R; Vo, Andy H; Swanson, Kaitlin E; Kim, Ellis Y; Fahrenbach, John P; Holley-Cuthrell, Jenan; Eskin, Ascia; Chen, Zugen; Squire, Kevin; Heydemann, Ahlke; Palmer, Abraham A; Nelson, Stanley F; McNally, Elizabeth M

2014-04-22

73

Annexin A6 modifies muscular dystrophy by mediating sarcolemmal repair  

PubMed Central

Many monogenic disorders, including the muscular dystrophies, display phenotypic variability despite the same disease-causing mutation. To identify genetic modifiers of muscular dystrophy and its associated cardiomyopathy, we used quantitative trait locus mapping and whole genome sequencing in a mouse model. This approach uncovered a modifier locus on chromosome 11 associated with sarcolemmal membrane damage and heart mass. Whole genome and RNA sequencing identified Anxa6, encoding annexin A6, as a modifier gene. A synonymous variant in exon 11 creates a cryptic splice donor, resulting in a truncated annexin A6 protein called ANXA6N32. Live cell imaging showed that annexin A6 orchestrates a repair zone and cap at the site of membrane disruption. In contrast, ANXA6N32 dramatically disrupted the annexin A6-rich cap and the associated repair zone, permitting membrane leak. Anxa6 is a modifier of muscular dystrophy and membrane repair after injury. PMID:24717843

Swaggart, Kayleigh A.; Demonbreun, Alexis R.; Vo, Andy H.; Swanson, Kaitlin E.; Kim, Ellis Y.; Fahrenbach, John P.; Holley-Cuthrell, Jenan; Eskin, Ascia; Chen, Zugen; Squire, Kevin; Heydemann, Ahlke; Palmer, Abraham A.; Nelson, Stanley F.; McNally, Elizabeth M.

2014-01-01

74

Gastrointestinal manifestations in myotonic muscular dystrophy.  

PubMed

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

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

2006-03-28

75

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

PubMed Central

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

2011-01-01

76

Torn apart: membrane rupture in muscular dystrophies and associated cardiomyopathies  

PubMed Central

Muscular dystrophies are often caused by mutations in cytoskeletal proteins that render cells more susceptible to strain-induced injury in mechanically active tissues such as skeletal or cardiac muscle. In this issue of the JCI, Han et al. report that dysferlin participates in membrane resealing in cardiomyocytes and that exercise results in increased membrane damage and disturbed cardiac function in dysferlin-deficient mice (see the related article beginning on page 1805). Thus, in addition to repetitive membrane damage, inadequate membrane repair may participate in the pathogenesis of muscular dystrophies and cardiomyopathies. PMID:17607350

Lammerding, Jan; Lee, Richard T.

2007-01-01

77

Concise Review: Stem Cell Therapy for Muscular Dystrophies  

PubMed Central

Muscular dystrophy comprises a group of genetic diseases that cause progressive weakness and degeneration of skeletal muscle resulting from defective proteins critical to muscle structure and function. This leads to premature exhaustion of the muscle stem cell pool that maintains muscle integrity during normal use and exercise. Stem cell therapy holds promise as a treatment for muscular dystrophy by providing cells that can both deliver functional muscle proteins and replenish the stem cell pool. Here, we review the current state of research on myogenic stem cells and identify the important challenges that must be addressed as stem cell therapy is brought to the clinic. PMID:23197695

Wilschut, Karlijn J.; Ling, Vivian B.

2012-01-01

78

Gene therapy progress and prospects: Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disorder affecting 1\\/3500 male births. There is currently no effective treatment, but gene therapy approaches are offering viable avenues for treatment development. The last 10 years have seen the development of a number of strategies and tools for muscle gene therapy. However, the major hurdle has been the inability to deliver

K Foster; H Foster; J G Dickson

2006-01-01

79

Preferential deletion of exons in Duchenne and Becker muscular dystrophies  

Microsoft Academic Search

Duchenne and Becker muscular dystrophy (DMD and BMD) genes are located in Xp21 on the short arm of the X chromosome. DMD patients display a much more severe clinical course than BMD patients, and yet about 10% of cases of each have been reported to have deletions for parts of the gene. Using a complementary DNA subclone of the DMD

S. M. Forrest; G. S. Cross; A. Speer; D. Gardner-Medwin; J. Burn; K. E. Davies

1987-01-01

80

Partial gene duplication in Duchenne and Becker muscular dystrophies  

Microsoft Academic Search

Duchenne and Becker muscular dystrophies (DMD and BMD) are progressive muscle wasting disorders with an X linked recessive mode of inheritance. We have surveyed 120 unrelated patients with DMD or BMD for gene duplications using a series of genomic probes from within the DMD\\/BMD gene locus. In three patients, two with DMD and one with BMD, a duplicated region within

X Y Hu; A H Burghes; P N Ray; M W Thompson; E G Murphy; R G Worton

1988-01-01

81

Readthrough strategies for stop codons in Duchenne muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy is due to mutations of the dystrophin gene. These are large deletions or duplications in 80% of cases, while premature stop codons (nonsense point mutations) account for 7% of cases. This subgroup of patients may take advantage of the properties of the antibi- otic gentamicin to suppress stop codons (readthrough). The efficiency of the readthrough varies inversely

S. AURINO; V. N IGRO

82

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

83

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

84

Distinct genetic regions modify specific muscle groups in muscular dystrophy.  

PubMed

Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein ?-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders. PMID:20959497

Swaggart, Kayleigh A; Heydemann, Ahlke; Palmer, Abraham A; McNally, Elizabeth M

2011-01-01

85

Distinct genetic regions modify specific muscle groups in muscular dystrophy  

PubMed Central

Phenotypic expression in the muscular dystrophies is variable, even with the identical mutation, providing strong evidence that genetic modifiers influence outcome. To identify genetic modifier loci, we used quantitative trait locus mapping in two differentially affected mouse strains with muscular dystrophy. Using the Sgcg model of limb girdle muscular dystrophy that lacks the dystrophin-associated protein ?-sarcoglycan, we evaluated chromosomal regions that segregated with two distinct quantifiable characteristics of muscular dystrophy, membrane permeability and fibrosis. We previously identified a single major locus on murine chromosome 7 that influences both traits of membrane permeability and fibrosis in the quadriceps muscle. Using a larger cohort, we now found that this same interval strongly associated with both traits in all limb skeletal muscle groups studied, including the gastrocnemius/soleus, gluteus/hamstring, and triceps muscles. In contrast, the muscles of the trunk were modified by distinct genetic loci, possibly reflecting the embryological origins and physiological stressors unique to these muscle groups. A locus on chromosome 18 was identified that modified membrane permeability of the abdominal muscles, and a locus on chromosome 3 was found that regulated diaphragm and abdominal muscle fibrosis. Fibrosis in the heart associated with a region on chromosome 9 and likely reflects differential function between cardiac and skeletal muscle. These data underscore the complexity of inheritance and penetrance of single-gene disorders. PMID:20959497

Swaggart, Kayleigh A.; Heydemann, Ahlke; Palmer, Abraham A.

2011-01-01

86

[Psychological characteristics of children suffering from Duchenne muscular dystrophy].  

PubMed

The authors examined intellectual and socio-emotional functioning of 39 subjects suffering from Duchenne muscular dystrophy. Their school situation, access to rehabilitation and a quality of familial upbringing attitude were characterized, as well. No significant differences concerning I.Q. between sick children and healthy population were found. PMID:12632918

Dubiel, Justyna; Rokicki, W?adys?aw; Skierska, Agnieszka

2002-01-01

87

Molecular bases of autosomal recessive limb-girdle muscular dystrophies  

Microsoft Academic Search

Limb-girdle muscular dystrophies (LGMD) are a hetero- geneous group of genetically determined disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is char- acterized by great variability, ranging from severe forms with rapid onset and progression to very mild forms allowing affected people to have fairly normal life spans and activity levels.

V. N IGRO

2003-01-01

88

Esophageal smooth muscle dysfunction in oculopharyngeal muscular dystrophy  

Microsoft Academic Search

Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic disorder with late-onset progressive myopathy affecting mainly head and neck striated muscles. It is more common in certain ethnic communities. Dysphagia was usually attributed to the malfunction of striated pharyngeal muscles. We studied a group of Bukharan immigrants affected by this disorder (N=13). Esophageal studies, including endoscopy, manometry, and scintigraphic emptying were

E. Timony; O. Khilkevic; A. D. Korczyn; R. Kimmel; A. Hallak; J. Baron; S. Blumen; A. Asherov; T. Gilat

1996-01-01

89

Congenital nutritional muscular dystrophy in a beef calf  

PubMed Central

A 13-hour-old Aberdeen-Angus was involuntarily recumbent since birth. Congenital nutritional muscular dystrophy was suspected based on clinical findings, increased serum creatine kinase, and decreased serum vitamin E and selenium levels. Recovery followed after supportive therapy and parenteral vitamin E and selenium. Reports of this disease in newborn calves are unusual. PMID:14524629

Abutarbush, Sameeh M.; Radostits, Otto M.

2003-01-01

90

The allure of stem cell therapy for muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a lethal muscle disease for which an effective treatment is urgently needed. The use of stem cells to produce normal muscle cells to replace the missing dystrophin protein has attracted much attention. Claims of success using stem cell treatment in animal models of human muscle diseases require careful evaluation and are not necessarily easily extrapolated

Miranda D. Grounds; Kay E. Davies

2007-01-01

91

Feeding problems in merosin deficient congenital muscular dystrophy  

Microsoft Academic Search

Feeding difficulties were assessed in 14 children (age range 2–14 years) with merosin deficient congenital muscular dystrophy, a disease characterised by severe muscle weakness and inability to achieve independent ambulation. Twelve of the 14 children were below the 3rd centile for weight. On questioning, all parents thought their child had difficulty chewing, 12 families modified the diet, and 13 children

J Philpot; A Bagnall; C King; V Dubowitz; F Muntoni

1999-01-01

92

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

93

TRIM Proteins in Therapeutic Membrane Repair of Muscular Dystrophy  

PubMed Central

Muscular dystrophy represents a major unmet medical need as only palliative treatments exist for these debilitating diseases. Since multiple forms of muscular dystrophy arise from compromised sarcolemmal membrane integrity a therapeutic approach that can target this loss of membrane barrier function could be applicable to a number of these distinct genetic diseases. One pathway that presents an excellent opportunity to affect compromised membrane integrity is the process that the cell uses to repair injuries to the plasma membrane. Membrane repair is a conserved pathway where disruptions in the plasma membrane of many different cell types are resealed by trafficking of intracellular vesicles to the injury site where these vesicles can fuse and patch the membrane disruption. Recent discoveries of multiple genes associated with this process in skeletal muscle provide opportunities to target this mechanism to increase membrane repair as a therapy to treat muscular dystrophy. One such gene is a member of the tripartite motif (TRIM) family of proteins, mitsugumin 53 (MG53) or TRIM72, that is an essential component of the membrane repair pathway in striated muscles. Recent results indicate that MG53/TRIM72 protein can be directly applied as a therapeutic agent to increase membrane repair capacity of many cell types and treat some aspects of the pathology in mouse models of muscular dystrophy. There is great potential for the use of recombinant human (rhMG53) in the treatment of muscular dystrophy and other diseases where compromised membrane integrity contributes to the progression of the disease. Other TRIM family proteins may provide additional targets for therapeutic intervention in similar disease states. PMID:23699904

Alloush, Jenna; Weisleder, Noah

2013-01-01

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

The link between stress disorders and autonomic dysfunction in muscular dystrophy  

PubMed Central

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

Sabharwal, Rasna

2014-01-01

96

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

97

Antisense-Mediated Exon Skipping for Duchenne Muscular Dystrophy  

Microsoft Academic Search

\\u000a Duchenne muscular dystrophy (DMD) is a severe, progressive neuromuscular disease for which there is currently no cure available.\\u000a The disease is caused by mutations in the dystrophin-encoding DMD gene that disrupt the open reading frame and completely abolish dystrophin function. Antisense-mediated exon skipping is\\u000a a promising approach that is close to clinical application. It aims to modulate pre-mRNA splicing such

Annemieke Aartsma-Rus; Gert-Jan B van Ommen

98

Disturbed Sleep in a Patient with Duchenne Muscular Dystrophy  

Microsoft Academic Search

17-year-old white male with Duchenne muscular dystrophy presented to the pediatric pulmonary clinic for a follow-up evaluation after being hospitalized for pneumonia. During the hospital stay he was noted to have nocturnal desaturation inter- mittently during sleep. The patient has been wheelchair bound since age 12 years. His father's two current concerns include the patient's difficulty swallowing and difficulty breathing

Mary H. Wagner; Richard B. Berry

99

Feeding problems and weight gain in Duchenne muscular dystrophy  

Microsoft Academic Search

The aim of the study was to conduct a survey using a dedicated questionnaire to estimate feeding difficulties, gastrointestinal involvement and weight gain in a population of 118 Duchenne muscular dystrophy (DMD) patients (age range 13.80–35.8 years). All the answers were entered in a database and the data analysed subdividing the cohort into age groups (3–9, 9–13, 13–18, 18–24, 24–30,

Marika Pane; Isabella Vasta; Sonia Messina; Domenica Sorleti; Annie Aloysius; Federico Sciarra; Fortunato Mangiola; Maria Kinali; Enzo Ricci; Eugenio Mercuri

2006-01-01

100

Duchenne\\/Becker muscular dystrophy: From molecular diagnosis to gene therapy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked muscular dystrophies. The recent isolation of the defective gene in DMD\\/BMD and the identification of its protein product, dystrophin, have revolutionized our ability to diagnose DMD\\/BMD and promoted speculation regarding the application of gene therapy. The purpose of this review is to present progress made in this area of

Masafumi Matsuo

1996-01-01

101

A small deletion in the Duchenne\\/Becker muscular dystrophy locus —a functionally important region?  

Microsoft Academic Search

A DNA deletion in a patient with Becker muscular dystrophy (BMD) has been delineated by restriction endonuclease mapping. The deletion is unusually small, removing six kilobases (kb) of DNA distal to pERT 87-1 (DXS164). This region has previously been shown to contain an exon of a candidate gene which, when defective, causes Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy.

K. A. Hart; A. P. Monaco; L. M. Kunkel; M. Bobrow

1987-01-01

102

Muscular involvement assessed by MRI correlates to motor function measurement values in oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a progressive skeletal muscle dystrophy characterized by ptosis, dysphagia, and upper and lower extremity weakness. We examined eight genetically confirmed OPMD patients to detect a MRI pattern and correlate muscle involvement, with validated clinical evaluation methods. Physical assessment was performed using the Motor Function Measurement (MFM) scale. We imaged the lower extremities on a 1.5 T scanner. Fatty replacement was graded on a 4-point visual scale. We found prominent affection of the adductor and hamstring muscles in the thigh, and soleus and gastrocnemius muscles in the lower leg. The MFM assessment showed relative mild clinical impairment, mostly affecting standing and transfers, while distal motor capacity was hardly affected. We observed a high (negative) correlation between the validated clinical scores and our visual imaging scores suggesting that quantitative and more objective muscle MRI might serve as outcome measure for clinical trials in muscular dystrophies. PMID:21340522

Fischmann, Arne; Gloor, Monika; Fasler, Susanne; Haas, Tanja; Rodoni Wetzel, Rachele; Bieri, Oliver; Wetzel, Stephan; Heinimann, Karl; Scheffler, Klaus; Fischer, Dirk

2011-07-01

103

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

104

Quantitative MRI can detect subclinical disease progression in muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant muscular dystrophy with late onset and slow progression. The aim of this study was to compare different methods of quantitative MRI in the follow-up of OPMD to semiquantitative evaluation of MRI images and to functional parameters. We examined 8 patients with genetically confirmed OPMD and 5 healthy volunteers twice at an interval of 13 months. Motor function measurements (MFM) were assessed. Imaging at 1.5 T (Siemens Magnetom Avanto) comprised two axial slice groups at the largest diameter of thigh and calf and included T1w TSE, 2-point Dixon for muscular fat fraction (MFF) and a multi-contrast TSE sequence to calculate quantitative T2 values. T1 images were analyzed using Fischer's semiquantitative 5-point (0–4) scale. MFM and visual scores showed no significant difference over the study period. Overall T2 values increased in patients over the study period from 49.4 to 51.6 ms, MFF increased from 19.2 to 20.7%. Neither T2 values nor MFF increased in controls. Changes in T2 correlated with the time interval between examinations (r 2 = 0.42). In this small pilot trial, it was shown that quantitative muscle MRI can detect subclinical changes in patients with OPMD. Quantitative MRI might, therefore, be a useful tool for monitoring disease progression in future therapeutic trials. PMID:22297459

Fischmann, Arne; Hafner, Patricia; Fasler, Susanne; Gloor, Monika; Bieri, Oliver; Studler, Ueli; Fischer, Dirk

2012-08-01

105

Somatic mosaicism for a deletion of the dystrophin gene in a carrier of Becker muscular dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) and the allelic milder form of Becker muscular dystrophy (BMD) are caused by mutations of the dystrophin gene on the short arm of the X chromosome. One third of affected indviduals are expected to result from de novo mutations. Genetic counselling of families with sporadic cases is complicated by the potential meiotic origin of the mutation

T. Voit; E. Neuen-Jacob; V. Mahler; A. Jauch; M. Cremer

1992-01-01

106

Identification of female carriers for Duchenne and Becker muscular dystrophies using a FISH-based approach  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive neuromuscular diseases caused by dystrophin gene mutations. Deletions, or more rarely duplications, of single or multiple exons within the dystrophin gene can be detected by current molecular methods in approximately 65% of DMD patients. Mothers of affected males have a two-thirds chance of carrying a dystrophin mutation, whilst

Azra H Ligon; Catherine D Kashork; C Sue Richards; Lisa G Shaffer

2000-01-01

107

Mutation analysis in Saudi Duchenne and Becker muscular dystrophy patients using multiplex PCR  

Microsoft Academic Search

IInnttrroodduuccttiioonn:: In Saudi Arabia, only limited work has been reported on the mutation patterns of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). This study looks at the spectrum of deletions in the 'hot spot' regions of the DMD gene in Saudi DMD\\/BMD patients using an enhanced multiplex PCR technique. M Maatteerriiaall aanndd mmeetthhooddss:: Twenty-six exons of the DMD

Adeel G. Chaudhary; Mohammed H. Alqahtani; Adel Abuzenadah; Mamdooh Gari; Abeer A. Al-Sofyani; Jumana Y. Al-Aama; Sahira A. Lary; Aisha H. Elaimi

2008-01-01

108

Altered aquaporin-4 expression in human muscular dystrophies: a common feature?  

Microsoft Academic Search

Duchenne Muscular Dystrophy (DMD) is a progressive lethal muscle disease that affects young boys. Dystrophin, absent in DMD and reduced in the milder form Becker Muscular Dystrophy (BMD), binds to several membrane-associated proteins known as dystrophin-associated proteins (DAPs). Once this critical structural link is disrupted, muscle fibers become more vulnerable to mechanical and osmotic stress. Recently, we have reported that

Antonio Frigeri; Grazia Paola Nicchia; Silvia Repetto; Massimo Bado; Carlo Minetti; Maria Svelto

2002-01-01

109

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

Microsoft Academic Search

Detection of large rearrangements in the dystrophin gene in Duchenne and Becker muscular dystrophy is possible in about 65-70% of patients by Southern blotting or multiplex PCR. Subsequently, carrier detection is possible by assessing the intensity of relevant bands, but preferably by a non-quantitative test method. Detection of microlesions in Duchenne and Becker muscular dystrophy is currently under way. Single

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

1997-01-01

110

Molecular deletion patterns in Turkish Duchenne and Becker muscular dystrophy patients  

Microsoft Academic Search

The dystrophin gene deletion patterns of Duchenne \\/ Becker muscular dystrophy were investigated in 57 DMD, 7 BMD and 1 DMD-BMD intermediate muscular dystrophy patients. Deletions, analyzed by multiplex amplification of selected exons, were observed in 58% (38 cases) of the patients. It was found that exon 48 was the most frequently affected, while exon 44 was the least frequently

Pervin Dinçer; ?ükrüye Ayter; Meral Özgüç; Yavuz Renda

1996-01-01

111

Molecular genetic analysis of 67 patients with duchenne\\/becker muscular dystrophy  

Microsoft Academic Search

A total of 56 Duchenne muscular dystrophy (DMD) patients and 11 Becker muscular dystrophy (BMD) patients was analyzed by extended “multiplex” amplification of the DMD\\/BMD gene; deletions were found in 60% of these patients. The data obtained were used to test the frameshift hypothesis and to compare the distribution of familial versus isolated cases. A significant correlation was found between

Susanne Niemann-Seyde; Ryszard Slomski; Frauke Rininsland; Ute Ellermeyer; Jolanta Kwiatkowska; Jochen Reiss

1992-01-01

112

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

113

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

114

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

E-print Network

Gene Replacement Therapy 39 Gene Correction/Gene-Based Therapy 40 Alternative Pathways (Indirect and Anti-Inflammatory Drugs 43 Growth Factor Modulation 44 Cell-Based Therapy 44 Viral Vector Gene Therapy Mechanisms of Muscular Dystrophy Subgroup 6 Diagnosis and Screening of Muscular Dystrophy Subgroup 6 Therapy

115

The zebrafish runzel muscular dystrophy is linked to the titin gene  

Microsoft Academic Search

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

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

2007-01-01

116

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

117

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

118

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

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; Lochmuller, Hanns

2009-01-01

120

Dysferlin protein analysis in limb-girdle muscular dystrophies  

Microsoft Academic Search

Dysferlin is the protein product of the DYSF gene mapped at 2p31, which mutations cause limb-girdle muscular dystrophy type\\u000a 2B (LGMD2B) and Miyoshi myopathy. To date, nine autosomal recessive forms (AR-LGMD) have been identified: four genes, which\\u000a code for the sarcoglycan glycoproteins, are associated with both mild and severe forms, the sarcoglycanopathies (LGMD2C, 2D,\\u000a 2E and 2F). The other five

Mariz Vainzof; Louise V. B. Anderson; Elizabeth M. McNally; Dawn B. Davis; Georgine Faulkner; Giorgio Valle; Eloisa S. Moreira; Rita C. M. Pavanello; Maria Rita Passos-Bueno; Mayana Zatz

2001-01-01

121

Cricopharyngeal myotomy in the treatment of oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathic disease which provokes oropharyngeal dysphagia, palpabral ptosis and proximal limb weakness. It is the abnormal expression of the GCG triplet in the PABPN1 gene on chromosome 14 that causes this disease. The study of the oropharyngeal dysphagia that these patients suffer from should include upper gastrointestinal endoscopy, barium video-radiology and oesophageal manometry. Genetic study confirms the diagnosis. We report 6 patients (3 of whom were siblings) referred to our department with a confirmed diagnosis of OPMD, who underwent cricopharyngeal myotomy to achieve normal swallowing. PMID:22898142

Gómez-Torres, Antonio; Abrante Jiménez, Antonio; Rivas Infante, Eloy; Menoyo Bueno, Alicia; Tirado Zamora, Isabel; Esteban Ortega, Francisco

2012-01-01

122

Animal models in therapeutic drug discovery for oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a late onset disease which affects specific muscles. No pharmacological treatments are currently available for OPMD. In recent years, genetically tractable models of OPMD – Drosophila and Caenorhabditis elegans – have been generated. Although these models have not yet been used for large-scale primary drug screening, they have been very useful in candidate approaches for the identification of potential therapeutic compounds for OPMD. In this brief review, we summarize the data that validated active molecules for OPMD in animal models including Drosophila, C. elegans and mouse. PMID:24050237

Chartier, Aymeric; Simonelig, Martine

2013-01-01

123

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.

Waldron, Ingrid

124

Lumbar extension in Duchenne muscular dystrophy: effect on lateral curvature.  

PubMed

The purpose of this study was to investigate the hypothesis that a lumbar pad producing extension of the lumbar spine is of value in posture support seats for children with Duchenne muscular dystrophy. Our method was to establish whether or not an increase in lumbar lordosis produced any increase in resistance to static lateral curvature of the supine lumbar spine. Nine boys with Duchenne muscular dystrophy were studied at an age when they were about to go into a wheelchair or had recently become wheelchair mobile. In each case the child lay supine on low-friction material on an x-ray table while the spine was flexed first to the right and then to the left, with and without a lumbar pad, by a predetermined force. The degree of lateral curvature was measured from anteroposterior radiographs. While lateral forces were applied when the boys were supine rather than seated, the results failed to show a difference in curvature with or without the lumbar pad. PMID:3985776

Seeger, B R; Sutherland, A D

1985-04-01

125

Living with oculopharyngeal muscular dystrophy: a phenomenological study.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant form of late-onset muscular dystrophy. Ptosis (droopy eyelids) and dysphagia (difficulty swallowing) are the most common presenting symptoms. The purpose of this phenomenological study was to describe the experience of living with OPMD. Purposeful sampling was used to recruit individuals with genetically confirmed OPMD who displayed ptosis and dysphagia, were 40 years or older, English speaking, and were willing to consent to the tape-recording of the interviews. An unstructured interview format was used to solicit the participants' perspectives of living with droopy eyelids, difficulty swallowing, and a genetic disorder. The interviews were audiotaped and transcribed verbatim. Colaizzi's Method was used to analyze the data, which identified five comprehensive themes. The themes that emerged describing the experience of living with OPMD were "Adjusting to Change", "Managing Misconceptions", "Seeking Normality", "Facing the Future", and "Informing Children". The information derived from this study will assist nurses to identify the burdens of living with OPMD and to intervene appropriately early in the course of the disease. PMID:18432080

Krause-Bachand, Jeanie; Koopman, Wilma

2008-01-01

126

Autophagy as a new therapeutic target in Duchenne muscular dystrophy  

PubMed Central

A resolutive therapy for Duchene muscular dystrophy, a severe degenerative disease of the skeletal muscle, is still lacking. Because autophagy has been shown to be crucial in clearing dysfunctional organelles and in preventing tissue damage, we investigated its pathogenic role and its suitability as a target for new therapeutic interventions in Duchenne muscular dystrophy (DMD). Here we demonstrate that autophagy is severely impaired in muscles from patients affected by DMD and mdx mice, a model of the disease, with accumulation of damaged organelles. The defect in autophagy was accompanied by persistent activation via phosphorylation of Akt, mammalian target of rapamycin (mTOR) and of the autophagy-inhibiting pathways dependent on them, including the translation-initiation factor 4E-binding protein 1 and the ribosomal protein S6, and downregulation of the autophagy-inducing genes LC3, Atg12, Gabarapl1 and Bnip3. The defective autophagy was rescued in mdx mice by long-term exposure to a low-protein diet. The treatment led to normalisation of Akt and mTOR signalling; it also reduced significantly muscle inflammation, fibrosis and myofibre damage, leading to recovery of muscle function. This study highlights novel pathogenic aspects of DMD and suggests autophagy as a new effective therapeutic target. The treatment we propose can be safely applied and immediately tested for efficacy in humans. PMID:23152054

De Palma, C; Morisi, F; Cheli, S; Pambianco, S; Cappello, V; Vezzoli, M; Rovere-Querini, P; Moggio, M; Ripolone, M; Francolini, M; Sandri, M; Clementi, E

2012-01-01

127

[Nasal flaring during hypoxemia in myotonic dystrophy and duchenne muscular dystrophy].  

PubMed

We investigated the relationship between nasal flaring and SpO2 in 19 patients with Duchenne muscular dystrophy (DMD) and 26 patients with myotonic dystrophy (DM1). In DMD patients, nasal flaring was observed when SpO2 was lower than 96%, while it was not seen even at 82% of SpO2 in DM1. None of the DM1 patients could perform voluntary nasal flaring. Nasal flaring is a useful indicator of hypoxemia in DMD but not in DM1. It remains to be elucidated whether the lack of nasal flaring in DM1 patients is due to abnormal respiratory central mechanism or nasal muscle weakness. PMID:19594107

Suzuki, Mikiya; Oya, Yasushi; Murakami, Yoshitake; Ogawa, Masafumi; Kawai, Mitsuru

2009-05-01

128

Dexmedetomidine and fentanyl combination for procedural sedation in a case of Duchenne muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy, an X-linked disorder characterized by progressive muscle weakness, is the most common muscular dystrophy among children leading to death before the end of third decade. Anesthesia in such patients pose a great challenge due to various complications associated with it. The dreaded metabolic and clinical complications occur due to various inhalational anesthetics and succinylcholine in this subset of patients. We are reporting a child with diagnosed Duchenne muscular dystrophy who underwent excision of dentigerous cyst in oral cavity under procedural sedation with combination of dexmedetomidine and fentanyl and thus administration of general anesthesia was avoided.

Kulshrestha, Ashish; Bajwa, Sukhminder Jit Singh; Singh, Amarjit; Kapoor, Vinod

2011-01-01

129

The Intriguing Regulators of Muscle Mass in Sarcopenia and Muscular Dystrophy  

PubMed Central

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

Sakuma, Kunihiro; Aoi, Wataru; Yamaguchi, Akihiko

2014-01-01

130

A functional membrane repair system in Duchenne muscular dystrophy fibroblasts.  

PubMed

Experiments have been performed to determine if fibroblasts from patients with Duchenne muscular dystrophy (DMD) are defective in a process of membrane repair. Normal and DMD fibroblasts were treated with phospholipase C from Clostridium perfringens to degrade plasma membrane phosphatidylcholine, and then phosphatidylcholine synthesis was measured as the incorporation of [3H] choline into lipid. Phosphatidylcholine synthesis was stimulated by phospholipase C treatment to a similar extent in normal and DMD fibroblasts. The activity of CTP: phosphocholine cytidylyltransferase, the enzyme regulating phosphatidylcholine synthesis in phospholipase C-treated mammalian cells, was also stimulated to the same extent in both cell types. The subcellular location of the cytidylyltransferase was changed by phospholipase C treatment from mostly cytosolic to mostly particulate in both normal and DMD fibroblasts. It appears, therefore, that at least one type of membrane repair system functions normally in DMD fibroblasts. PMID:6088703

Wright, P S; McKinney, E; Berry, S; Evers, A; Kent, C

1984-06-01

131

The psychosocial and cognitive impact of Duchenne's muscular dystrophy.  

PubMed

Duchenne's muscular dystrophy (DMD) is the most prevalent and devastating of neuromuscular disorders. Children given this diagnosis not only face inevitable deterioration of physical functioning, but they also become susceptible to emotional/behavioral problems, as well as reduced cognitive functioning and learning problems. This article (1) reviews the emotional/behavioral issues that may impact the child with DMD and the affected child's family members and caregivers; (2) examines the research describing the cognitive and learning issues associated with DMD; (3) provides recommendations for physicians who work with these families; and (4) recommends directions for future research that will help to further elucidate emotional/behavioral issues and cognitive and learning correlates of DMD. PMID:9661245

Polakoff, R J; Morton, A A; Koch, K D; Rios, C M

1998-06-01

132

Oculopharyngeal muscular dystrophy: underdiagnosed disease in Hong Kong.  

PubMed

Despite the advances in the understanding of the molecular basis for oculopharyngeal muscular dystrophy in the last decade, it remains an underdiagnosed disease, especially among the Chinese. In the presence of a positive family history and late-onset ptosis, dysphagia, and proximal muscle weakness (its cardinal features), we suggest that PABPN1 gene analysis should be the first-line investigation to rule out this condition. Muscle biopsy can be reserved for atypical cases. Non-specific mitochondrial changes in the muscle specimens of these patients should be appreciated, so as to avoid diagnostic confusion. It is hoped that greater awareness among medical professionals and judicious use of PABPN1 gene analysis will lead to earlier diagnosis, better management, and avoidance of unnecessary invasive investigations of affected patients. PMID:24310666

Luk, H M; Lo, Ivan F M; Fu, K H; Lui, Colin H T; Tong, Tony M F; Chan, Daniel H C; Lam, Stephen T S

2013-12-01

133

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

Microsoft Academic Search

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

Ruth Shomrat; Eithan Gluck; Cyril Legum; Yosef Shiloh

1994-01-01

134

638. Therapeutic Antisense-Induced Exon Skipping for Duchenne Muscular Dystrophy  

Microsoft Academic Search

The severe Duchenne muscular dystrophy (DMD) is mostly caused by frame disrupting mutations in the dystrophin gene, which result in non-functional dystrophin proteins. Mutations that keep the reading frame intact give rise to internally deleted, semi-functional dystrophins and result in the milder Becker muscular dystrophy (BMD). Antisense oligonucleotides (AONs) have the potential to modulate the pre-mRNA splicing such that a

Annemieke Aartsma-Rus; Anneke A. M. Janson; Wendy E. Kaman; Mattie Bremmer-Bout; Christa L. de Winter; Habte F. Teshale; Gert-Jan B. van Ommen; Johan T. den Dunnen; Judith C. T. van Deutekom

2004-01-01

135

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

Microsoft Academic Search

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

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

1992-01-01

136

Very mild muscular dystrophy associated with the deletion of 46% of dystrophin  

Microsoft Academic Search

DUCHENNE muscular dystrophy (DMD)1 and Becker muscular dystrophy (BMD), a much milder form of the disease where the age of onset can sometimes be as late as the third or fourth decade of life, are caused by mutations in the same X-linked gene2-7, a 14 kilobase (kb) transcript6,7 which is spread over more than 2 megabases of the human X

S. B. England; L. V. B. Nicholson; M. A. Johnson; S. M. Forrest; D. R. Love; E. E. Zubrzycka-Gaarn; D. E. Bulman; J. B. Harris; K. E. Davies

1990-01-01

137

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.

138

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

Microsoft Academic Search

Summary We describe a unique six-generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb-girdle variant of muscular dystrophy (LGMD), with disease onset at 15-30 years and loss of ambulation within a 25-year course.

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

1996-01-01

139

Distinguishing Cardiac Features of a Novel Form of Congenital Muscular Dystrophy (Salih CMD)  

Microsoft Academic Search

.   The cardiac features of a novel form of congenital muscular dystrophy (Salih CMD) are described in two adolescent siblings.\\u000a The patients presented with severe hypotonia at birth, associated with delayed development. They could walk independently\\u000a and managed to maintain walking after 13 years of age. Their muscle immunohistochemistry differed from that seen in Duchenne\\u000a and Becher muscular dystrophy (DMD

S. A. Subahi

2001-01-01

140

Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy  

Microsoft Academic Search

Limb girdle muscular dystrophy is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive or dominant mode. Caveolin-3, the muscle-specific member of the caveolin gene family, is implicated in the patho- genesis of autosomal dominant limb girdle muscular dystrophy 1C. Here we report on a 4-year-old girl presenting with myalgia and muscle cramps due to a

Ralf Herrmann; Volker Straub; Martina Blank; Christian Kutzick; Nicola Franke; Eva Neuen Jacob; Hans-Gerd Lenard; Stephan Kröger; Thomas Voit

2000-01-01

141

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

Microsoft Academic Search

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

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

2011-01-01

142

Oculopharyngeal muscular dystrophy as a cause of progression of weakness in antibody positive myasthenia gravis  

PubMed Central

Many neuromuscular conditions cause bulbar and limb weakness, and when several conditions coexist they present additional diagnostic challenges. Here we describe a case of a 45-year-old woman with antibody positive myasthenia gravis since age 16, who then develops treatment-resistant weakness due to genetically proven oculopharyngeal muscular dystrophy. We conclude that the development of treatment-resistant weakness in myasthenia gravis should spur further work up for other neuromuscular disorders including oculopharyngeal muscular dystrophy. PMID:23453859

Ringel, Steven P.

2014-01-01

143

Merosin positive congenital muscular dystrophy with severe involvement of the central nervous system  

Microsoft Academic Search

Congenital muscular dystrophy (CMD) is one of the most frequent dystrophies of childhood, which is commonly characterized by neonatal muscle impairment with or without clinical evidence of central nervous system involvement. Several variants of CMD have been described and the disease has recently been classified into five clinically distinct forms: the two classical CMDs with and without deficit of the

Nicola De Stefano; Maria Teresa Dotti; Marcello Villanova; Gioacchino Scarano; Antonio Federico

1996-01-01

144

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

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

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

147

MUSCULAR DYSTROPHY IN DAIRY COWS FOLLOWING A CHANGE IN HOUSING TECHNOLOGY  

Microsoft Academic Search

Pavlata L., A. Pechová, J. Illek: Muscular Dystrophy in Dairy Cows Following a Change in Housing Technology. Acta Vet. Brno 2001, 70: 269-275. The objective of the study was to monitor the state of health (in particular damage to muscular tissues) in dairy cows suffering from a marked selenium deficiency. The investigations were conducted in a herd of Bohemian Red

L. PAVLATA; A. PECHOVÁ; J. ILLEK

2001-01-01

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

Transcriptional profiling in facioscapulohumeral muscular dystrophy to identify candidate biomarkers  

PubMed Central

Facioscapulohumeral muscular dystrophy (FSHD) is a progressive neuromuscular disorder caused by contractions of repetitive elements within the macrosatellite D4Z4 on chromosome 4q35. The pathophysiology of FSHD is unknown and, as a result, there is currently no effective treatment available for this disease. To better understand the pathophysiology of FSHD and develop mRNA-based biomarkers of affected muscles, we compared global analysis of gene expression in two distinct muscles obtained from a large number of FSHD subjects and their unaffected first-degree relatives. Gene expression in two muscle types was analyzed using GeneChip Gene 1.0 ST arrays: biceps, which typically shows an early and severe disease involvement; and deltoid, which is relatively uninvolved. For both muscle types, the expression differences were mild: using relaxed cutoffs for differential expression (fold change ?1.2; nominal P value <0.01), we identified 191 and 110 genes differentially expressed between affected and control samples of biceps and deltoid muscle tissues, respectively, with 29 genes in common. Controlling for a false-discovery rate of <0.25 reduced the number of differentially expressed genes in biceps to 188 and in deltoid to 7. Expression levels of 15 genes altered in this study were used as a “molecular signature” in a validation study of an additional 26 subjects and predicted them as FSHD or control with 90% accuracy based on biceps and 80% accuracy based on deltoids. PMID:22988124

Rahimov, Fedik; King, Oliver D.; Leung, Doris G.; Bibat, Genila M.; Emerson, Charles P.; Kunkel, Louis M.; Wagner, Kathryn R.

2012-01-01

150

Esophageal smooth muscle dysfunction in oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a rare genetic disorder with late-onset progressive myopathy affecting mainly head and neck striated muscles. It is more common in certain ethnic communities. Dysphagia was usually attributed to the malfunction of striated pharyngeal muscles. We studied a group of Bukharan immigrants affected by this disorder (N = 13). Esophageal studies, including endoscopy, manometry, and scintigraphic emptying were performed. Very low pharyngeal pressures were measured. Upper esophageal pressures (UEP) were in the normal range in eight patients, and above normal in three patients. Four also had low lower esophageal sphincter pressure. Esophageal body peristaltic activity was grossly impaired in all patients: mainly nonpropulsive, simultaneous, retrograde, and failed activity was recorded. Marked retention of isotopic material was demonstrated in all patients studied, usually in the middle and lower parts of the body, ranging from 17 to 100% retention. The dysphagia in OPMD is due not only to dysfunction of pharyngeal and upper esophageal striated muscle, but also has a significant smooth muscle component. PMID:8689911

Tiomny, E; Khilkevic, O; Korczyn, A D; Kimmel, R; Hallak, A; Baron, J; Blumen, S; Asherov, A; Gilat, T

1996-07-01

151

Muscle phenotypic variability in limb girdle muscular dystrophy 2 G.  

PubMed

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

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

2013-06-01

152

Therapeutic potential of matrix metalloproteinases in Duchenne muscular dystrophy  

PubMed Central

Matrix metalloproteinases (MMPs) are secreted proteinases that have physiologic roles in degradation and remodeling of extracellular matrix (ECM) in almost all tissues. However, their excessive production in disease conditions leads to many pathological features including tissue breakdown, inflammation, cell death, and fibrosis. Duchenne Muscular dystrophy (DMD) is a devastating genetic muscle disorder caused by partial or complete loss of cytoskeletal protein dystrophin. Progressive muscle wasting in DMD is accompanied by myofiber necrosis followed by cycles of regeneration and degeneration and inflammation that eventually result in replacement of myofiber by connective and adipose tissues. Emerging evidence suggests that gene expression and the activity of various MMPs are aberrantly regulated in muscle biopsies from DMD patients and in skeletal muscle of animal models of DMD. Moreover, a few studies employing genetic mouse models have revealed that different MMPs play distinct roles in disease progression in DMD. Modulation of the activity of MMPs improves myofiber regeneration and enhances the efficacy of transplantation and engraftment of muscle progenitor cells in dystrophic muscle in mouse models of DMD. Furthermore, recent reports also suggest that some MMPs especially MMP-9 can serve as a biomarker for diagnosis and prognosis of DMD. In this article, we provide a succinct overview of the regulation of various MMPs and their therapeutic importance in DMD. PMID:25364719

Ogura, Yuji; Tajrishi, Marjan M.; Sato, Shuichi; Hindi, Sajedah M.; Kumar, Ashok

2014-01-01

153

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

154

Genetic heterogeneity in 30 German patients with oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is due to short elongations of a polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. Originally GCG expansions in which (GCG)(6) is extended to (GCG)(7-13) were found. Subsequently five further genotypes with additional GCA- and GCG-trinucleotides were identified in single OPMD patients. This indicated larger genetic heterogeneity and showed that unequal crossing-over and not replication slippage must be the underlying mechanism of elongation.We performed sequencing of the PABPN1 gene in 30 German OPDM index patients to determine the exact genotype. The original GCG expansion ranging from (GCG)(8) to (GCG)(11) was found in 22 patients. In 8 patients, however, three different elongated alleles other than classical (GCG)(7-13) were observed. Two of these genotypes had already been identified in Japanese patients. One genotype was recently identified showing (GCG)(6) followed by inserted (GCA)(3)GCG in four unrelated patients. This study further supports the theory of unequal crossing over as the molecular mechanism leading to elongation. It shows that other genotypes than classical (GCG)(7-13) are rather common in German OPMD patients. The data imply that there is no single founder effect in German OPMD patients. PMID:16619122

Müller, T; Deschauer, M; Kolbe-Fehr, F; Zierz, St

2006-07-01

155

Sarcopenia and Sarcopenic Obesity in Patients with Muscular Dystrophy  

PubMed Central

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

Merlini, Luciano; Vagheggini, Alessandro; Cocchi, Daniela

2014-01-01

156

Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011.  

PubMed

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

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

2012-12-01

157

Latent TGF-?-binding protein 4 modifies muscular dystrophy in mice  

PubMed Central

Most single-gene diseases, including muscular dystrophy, display a nonuniform phenotype. Phenotypic variability arises, in part, due to the presence of genetic modifiers that enhance or suppress the disease process. We employed an unbiased mapping approach to search for genes that modify muscular dystrophy in mice. In a genome-wide scan, we identified a single strong locus on chromosome 7 that influenced two pathological features of muscular dystrophy, muscle membrane permeability and muscle fibrosis. Within this genomic interval, an insertion/deletion polymorphism of 36 bp in the coding region of the latent TGF-?–binding protein 4 gene (Ltbp4) was found. Ltbp4 encodes a latent TGF-?–binding protein that sequesters TGF-? and regulates its availability for binding to the TGF-? receptor. Insertion of 12 amino acids into the proline-rich region of LTBP4 reduced proteolytic cleavage and was associated with reduced TGF-? signaling, decreased fibrosis, and improved muscle pathology in a mouse model of muscular dystrophy. In contrast, a 12-amino-acid deletion in LTBP4 was associated with increased proteolysis, SMAD signaling, and fibrosis. These data identify Ltbp4 as a target gene to regulate TGF-? signaling and modify outcomes in muscular dystrophy. PMID:19884661

Heydemann, Ahlke; Ceco, Ermelinda; Lim, Jackie E.; Hadhazy, Michele; Ryder, Pearl; Moran, Jennifer L.; Beier, David R.; Palmer, Abraham A.; McNally, Elizabeth M.

2009-01-01

158

Detection of partial deletion and partial duplication of dystrophin gene in Japanese patients with Duchenne or Becker muscular dystrophy  

Microsoft Academic Search

Summary The dystrophin gene was analyzed in 59 Japanese patients with Duchenne muscular dystrophy (DMD) from 48 unrelated families, including 11 pairs of siblings, and three patients with Becker muscular dystrophy (BMD) from two unrelated families, including one pair of siblings. The relationship between the type of gene abnormality and clinical symptoms was examined. Twenty-seven of 50 (54.0%) unrelated DMD

Keiko Hiyama; Mieko Kodaira; Chiyoko Satoh; Takenori Karakawa; Hitoshi Kameo; Michio Yamakido

1993-01-01

159

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

E-print Network

of the central nervous system (CNS) although changes in the white matter have been detected by MRI (6 muscular dystrophy in two patients with an internally deleted laminin 2-chain Valérie Allamand1, Yoshihide; Revised and Accepted January 31, 1997 Congenital muscular dystrophy (CMD) is a group of clinically

Campbell, Kevin P.

160

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

161

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

PubMed

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 potential therapeutic target. Here, we review current protein-replacement strategies, discuss the potential benefits of sarcospan expression, and identify important experiments that must be addressed for sarcospan to move to the clinic. PMID:23601082

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

2013-09-01

162

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

163

Gene replacement therapies for Duchenne muscular dystrophy using adeno-associated viral vectors  

PubMed Central

The muscular dystrophies collectively represent a major health challenge, as few significant treatment options currently exist for any of these disorders. Recent years have witnessed a proliferation of novel approaches to therapy, spanning increased testing of existing and new pharmaceuticals, DNA delivery (both anti-sense oligonucleotides and plasmid DNA), gene therapies and stem cell technologies. While none of these has reached the point of being used in clinical practice, all show promise for being able to impact different types of muscular dystrophies. Our group has focused on developing direct gene replacement strategies to treat recessively inherited forms of muscular dystrophy, particularly Duchenne and Becker muscular dystrophy (DMD/BMD). Both forms of dystrophy are caused by mutations in the dystrophin gene and all cases can in theory be treated by gene replacement using synthetic forms of the dystrophin gene. The major challenges for success of this approach are the development of a suitable gene delivery shuttle, generating a suitable gene expression cassette able to be carries by such a shuttle, and achieving safe and effective delivery. This review summarizes the current state of the art in terms of using adeno-associated viral vectors to deliver synthetic dystrophin genes for the purpose of developing gene therapy for DMD. PMID:22533379

Seto, Jane T.; Ramos, Julian N.; Muir, Lindsey; Chamberlain, Jeffrey S.

2014-01-01

164

Myogenic Akt signaling upregulates the utrophin-glycoprotein complex and promotes sarcolemma stability in muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy is caused by dystrophin mutations that lead to structural instability of the sarcolemma membrane, myofiber degeneration/regeneration and progressive muscle wasting. Here we show that myogenic Akt signaling in mouse models of dystrophy promotes increased expression of utrophin, which replaces the function of dystrophin thereby preventing sarcolemma damage and muscle wasting. In contrast to previous suggestions that increased Akt in dystrophy was a secondary consequence of pathology, our findings demonstrate a pivotal role for this signaling pathway such that modulation of Akt can significantly affect disease outcome by amplification of existing, physiological compensatory mechanisms. PMID:18986978

Peter, Angela K.; Ko, Christopher Y.; Kim, Michelle H.; Hsu, Nigel; Ouchi, Noriyuki; Rhie, Suhn; Izumiya, Yasuhiro; Zeng, Ling; Walsh, Kenneth; Crosbie, Rachelle H.

2009-01-01

165

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

PubMed

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

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

2007-05-01

166

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

167

Characteristics of Japanese Duchenne and Becker muscular dystrophy patients in a novel Japanese national registry of muscular dystrophy (Remudy)  

PubMed Central

Background Currently, clinical trials for new therapeutic strategies are being planned for Duchenne and Becker muscular dystrophies (DMD/BMD). However, it is difficult to obtain adequate numbers of patients in clinical trials. As solutions to these problems, patient registries are an important resource worldwide, especially in rare diseases such as DMD/BMD. Methods We developed a national registry of Japanese DMD/BMD patients in collaboration with TREAT-NMD. The registry includes male Japanese DMD/BMD patients whose genetic status has been confirmed by genetic analysis. The registry includes patients throughout Japan. Results As of February 2012, 583 DMD and 105 BMD patients were registered. Most individuals aged less than 20 years. In terms of genetic mutations of registrants of DMD and BMD, deletion of exons was the most frequent (61.4% and 79.0%) followed by point mutations (24.5% and 14.3%) and duplications (13.6% and 4.8%), respectively. 43.6% of DMD are capable of walking, and 76.2% of BMD registrants are able to walk. 41.1% of DMD registrants in the database were treated using steroids. 29.5% of DMD and 23.8% of BMD registrants were prescribed one cardiac medicine at least. 22% of DMD used ventilator support, and non-invasive support was common. Small numbers of DMD and BMD registrants, only 3.9% and 1.0% of them, have received scoliosis surgery. 57 (9.8%) patients were eligible to clinical trial focused on ‘skipping’ exon 51. Conclusions The Remudy has already demonstrated utility in clinical researches and standardization of patients care for DMD/BMD. This new DMD/BMD patient registry facilitates the synchronization of clinical drug development in Japan with that in other countries. PMID:23601510

2013-01-01

168

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

PubMed Central

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

2009-01-01

169

Brain metabolism is abnormal in the mdx model of Duchenne muscular dystrophy  

Microsoft Academic Search

Summary Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder primarily affecting young boys, often causing mental retardation in addition to the well-known progressive muscular weakness. Normal dystrophin expression is lacking in skeletal muscle and the CNS of both DMD children and the mdx mouse model. To date, 3lP-magnetic resonance spectroscopy (MRS) has shown in vivo several abnormalities within skeletal

I. Tracey; J. F. Dunn; G. K. Radda

1996-01-01

170

Gene Expression Profiling in Limb-Girdle Muscular Dystrophy 2A  

Microsoft Academic Search

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are

Amets Sáenz; Margarita Azpitarte; Rubén Armañanzas; Ainhoa Alzualde; Iñaki Inza; Federico García-Bragado; Gaspar de La Herran; Julián Corcuera; Ana Cabello; Carmen Navarro; Carolina de La Torre; Eduard Gallardo; Isabel Illa; Adolfo López de Munain; Antoni L. Andreu

2008-01-01

171

Predictive value of myocardial delayed enhancement in Duchenne muscular dystrophy.  

PubMed

In other cardiomyopathies, cardiac magnetic resonance imaging (CMR)-derived myocardial delayed enhancement (MDE), a marker of myocardial fibrosis, is a risk factor for sudden cardiac death (SCD). In Duchenne muscular dystrophy (DMD), the prognostic value of MDE for ventricular arrhythmias and death is unknown. This study aimed to evaluate associations between MDE and electrocardiographic (ECG) changes, ventricular remodeling, risk of arrhythmias, and death in DMD. This retrospective study included all subjects with DMD who had undergone a CMR between January 2006 and December 2011 and had available ECG and 24-h Holter records from the same period. Left ventricular (LV) MDE was semiquantitatively graded from 0 to 4. Comparisons of demographic and clinical characteristics between MDE and no-MDE groups were made. Cox regression analysis was performed to assess factors associated with death. This study investigated 32 boys with a median age of 13.8 years (range, 7.2-17.4 years) and found MDE present in 25 (78 %) of the boys. Compared with the no-MDE subjects, the MDE subjects were older (15.7 ± 3.3 vs 12.1 ± 4.8 years) and had a wider QT dispersion (QTd: 74 ± 30 vs 55 ± 33 ms), a higher incidence of ventricular tachycardia (40 vs 0 %), a lower LV ejection fraction (46 ± 12 vs 56 ± 9 %), a larger LV end-diastolic volume (124 ± 58 vs 68 ± 14 ml/m(2)), and a larger end-systolic volume (57 ± 29 vs 28 ± 10 ml/m(2)) (p < 0.05 for all). During the study period, six of the subjects (19 %) died. The factors associated with mortality were increased age, advanced grade of MDE, higher LV end-systolic volume, lower LV ejection fraction, use of beta-blockers, and ventricular tachycardia. Myocardial fibrosis detected by CMR is an independent predictor of adverse cardiac remodeling, ventricular arrhythmias, and death in DMD. Cardiac MRI using MDE can be applied as a screening tool to detect patients at risk for ventricular arrhythmias, more advanced disease, adverse LV remodeling, and death. PMID:24830760

Menon, Shaji C; Etheridge, Susan P; Liesemer, Kirk N; Williams, Richard V; Bardsley, Tyler; Heywood, Mason C; Puchalski, Michael D

2014-10-01

172

Prevention of oculopharyngeal muscular dystrophy by muscular expression of Llama single-chain intrabodies in vivo.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a late onset disorder characterized by progressive weakening of specific muscles. It is caused by short expansions of the N-terminal polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1), and it belongs to the group of protein aggregation diseases, such as Huntington's, Parkinson's and Alzheimer diseases. Mutant PABPN1 forms nuclear aggregates in diseased muscles in both patients and animal models. Intrabodies are antibodies that are modified to be expressed intracellularly and target specific antigens in subcellular locations. They are commonly generated by artificially linking the variable domains of antibody heavy and light chains. However, natural single-chain antibodies are produced in Camelids and, when engineered, combined the advantages of being single-chain, small sized and very stable. Here, we determine the in vivo efficiency of Llama intrabodies against PABPN1, using the established Drosophila model of OPMD. Among six anti-PABPN1 intrabodies expressed in muscle nuclei, we identify one as a strong suppressor of OPMD muscle degeneration in Drosophila, leading to nearly complete rescue. Expression of this intrabody affects PABPN1 aggregation and restores muscle gene expression. This approach promotes the identification of intrabodies with high therapeutic value and highlights the potential of natural single-chain intrabodies in treating protein aggregation diseases. PMID:19258344

Chartier, Aymeric; Raz, Vered; Sterrenburg, Ellen; Verrips, C Theo; van der Maarel, Silvère M; Simonelig, Martine

2009-05-15

173

Topographic pattern of the rearrangement of the dystrophin gene in Japanese Duchenne muscular dystrophy  

Microsoft Academic Search

To compare the frequency and distribution of rearrangements in the dystrophin gene in Duchenne muscular dystrophy (DMD) between Japanese DMD patients and those in North America and Europe, Southern blot analyses of the dystrophin gene were carried out in 88 probands classified as DMD. Gene rearrangements were found in 61 (69%) subjects, and they were composed of partial gene deletions

Natsuki Imoto; Tadao Arinami; Kenzo Hamano; Kiichiro Matsumura; Hiroki Yamada; Hideo Hamaguchi; Hitoshi Takita

1993-01-01

174

Gene expression comparison of biopsies from Duchenne muscular dystrophy (DMD) and normal skeletal muscle  

Microsoft Academic Search

The primary cause of Duchenne muscular dystrophy (DMD) is a mutation in the dystrophin gene leading to the absence of the corresponding RNA transcript and protein. Absence of dystrophin leads to disruption of the dystrophin-associated protein complex and substantial changes in skeletal muscle pathology. Although the histological pathology of dystrophic tissue has been well documented, the underlying molecular pathways remain

Judith N. Haslett; Despina Sanoudou; Alvin T. Kho; Richard R. Bennett; Steven A. Greenberg; Isaac S. Kohane; Alan H. Beggs; Louis M. Kunkel

2002-01-01

175

The Status of Exon Skipping as a Therapeutic Approach to Duchenne Muscular Dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is associated with mutations in the dystrophin gene that disrupt the open reading frame whereas the milder Becker's form is associated with mutations which leave an in-frame mRNA transcript that can be translated into a protein that includes the N- and C- terminal functional domains. It has been shown that by excluding specific exons at, or

Qi-Long Lu; Toshifumi Yokota; Shin'ichi Takeda; Luis Garcia; Francesco Muntoni; Terence Partridge

2011-01-01

176

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

Microsoft Academic Search

PURPOSEMutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). DMD is associated with an abnormal electroretinogram (ERG) if the mutation disrupts the translation of retinal dystrophin (Dp260). Our aim was to determine if incomplete ERG abnormalities would be associated with heterozygous carriers of dystrophin gene mutations.METHODSGanzfeld ERGs were obtained under scotopic and photopic testing conditions from a family

Kathleen M Fitzgerald; Gerhard W Cibis; Ann Headrick Gettel; Robert Rinaldi; David J Harris; Robert A White

1999-01-01

177

Heterogeneity of dystrophin expression in patients with Duchenne and Becker muscular dystrophy  

Microsoft Academic Search

This report documents the results of an integrated biochemical and immunocytochemical investigation into the expression of dystrophin (the protein product of the Duchenne muscular dystrophy gene) in muscle biopsies from 226 patients. It is the first study in which dystrophin has been analysed on blots and on tissue sections in such a large number of patients using the same (monoclonal)

L. V. B. Nicholson; M. A. Johnson; D. Gardner-Medwin; S. Bhattacharya; J. B. Harris

1990-01-01

178

Molecular, cellular, and pharmacological therapies for Duchenne\\/Becker muscular dystrophies  

Microsoft Academic Search

Although the molecular defect causing Duchenne\\/Becker muscular dystrophy (DMD\\/BMD) was identified nearly 20 years ago, the development of effective therapeutic strategies has nonetheless re- mained a daunting challenge. Over the years, a variety of different approaches have been explored in an effort to compensate for the lack of the DMD gene product called dystrophin. This review not only pre- sents

Joe V. Chakkalakal; Jennifer Thompson; Robin J. Parks; Bernard J. Jasmin

2005-01-01

179

Microlesions and polymorphisms in the Duchenne\\/Becker muscular dystrophy gene  

Microsoft Academic Search

One third of mutations responsible for Duchenne or Becker muscular dystrophy (DMD\\/BMD) represent point mutations or other small sequence alterations not readily detectable by Southern blot analysis or multiplex amplification. Here, we report results of a comprehensive point mutation search that yielded seven new sequence variations and one novel polymorphism. We also summarize known mutations, polymorphisms and other small nucleotide

Frauke Rininsland; Jochen Reiss

1994-01-01

180

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

181

Dystrophin gene mutation location and the risk of cognitive impairment in Duchenne muscular dystrophy  

Microsoft Academic Search

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

Peter J. Taylor; Grant A. Betts; Sarah Maroulis; Christian Gilissen; Robyn L. Pedersen; David R. Mowat; Heather M. Johnston; Michael F. Buckley

2010-01-01

182

Zebrafish models flex their muscles to shed light on muscular dystrophies  

PubMed Central

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.

2012-01-01

183

Molecular deletion patterns in families from southern France with Duchenne\\/Becker muscular dystrophies  

Microsoft Academic Search

We studied 38 unrelated patients from southern France with Duchenne (DMD) or Decker (BMD) muscular dystrophy for intragenic deletions of the DMD\\/ BMD gene. We used both multiplex amplification of selected exons and cDNA probes. Of the 26 (68%) unrelated individuals found to have deletions, 24 (92%) were detected by multiplex polymerase chain reaction. All these deletions have been delineated

Mireille Claustres; Sylvie Tuffery; Marie-Pierre Chevron; Marie-Pierre Jozelon; Patricia Martinez; Bernard Echenne; Jacques Demaille

1991-01-01

184

Antisense-induced exon skipping for duplications in Duchenne muscular dystrophy  

Microsoft Academic Search

BACKGROUND: Antisense-mediated exon skipping is currently one of the most promising therapeutic approaches for Duchenne muscular dystrophy (DMD). Using antisense oligonucleotides (AONs) targeting specific exons the DMD reading frame is restored and partially functional dystrophins are produced. Following proof of concept in cultured muscle cells from patients with various deletions and point mutations, we now focus on single and multiple

Annemieke Aartsma-Rus; Anneke AM Janson; Gert-Jan B van Ommen

2007-01-01

185

Deletions in the dystrophin gene: analysis of Duchenne and Becker muscular dystrophy patients in Quebec  

Microsoft Academic Search

We have analyzed patient DNA samples in 77 unrelated Duchenne (DMD) and Becker (BMD) muscular dystrophy families, 73 of which were of French Canadian origin. We show that the frequency (68%) and distribution of deletions within the dystrophin gene was neither random nor unique in this population. We localized 33% of the deletions to the proximal portion of the dystrophin

Louise R. Simard; France Gingras; Nathalie Delvoye; Michel Vanasse; Serge B. Melançon; Damian Labuda

1992-01-01

186

Prediction of Dystrophin Phenotype by DNA Analysis in Duchenne\\/Becker Muscular Dystrophy  

Microsoft Academic Search

Allele-specific molecular diagnosis of Duchenne and Becker muscular dystrophies (DMD and BMD) has been largely dependent upon muscle biopsy for dys- trophin protein assay. We performed lymphocyte DNA mutation analysis by polymerase chain reaction on 14 boys presenting with a clinical picture compatible with DMD or BMD. DNA analysis revealed that 12 of 14 boys had a deletion of the

Linda A. Specht; Alan H. Beggs; Bruce Korf; Louis M. Kunkel; Frederic Shapiro

187

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

188

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

189

Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient  

Microsoft Academic Search

We report a patient with congenital muscular dystrophy (CMD), developmental brain defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep tendon reflexes, partial seizures, and secondary microcephaly developed. Brain MRI showed a large area of cortical dysplasia, a thin but complete corpus callosum, and diffuse ventriculomegaly. Nerve

M.-Cl Belpaire-Dethiou; K Saito; Y Fukuyama; E Kondo-Iida; T Toda; Th Duprez; C Verellen-Dumoulin; P. Y. K Van den Bergh

1999-01-01

190

Congenital muscular dystrophy and severe central nervous system atrophy in two siblings  

Microsoft Academic Search

Severe degenerative features of the nervous system of a hitherto unknown kind, associated with a neuromuscular disorder with histopathological features of congenital muscular dystrophy, are reported in two female siblings. The clinical profile was characterized by generalized hypotonia followed by spastic tetraplegia, contractures, polyneuropathy, lack of cognitive development and progressive microcephaly. There was no involvement of the eyes. Neuropathological examination

Q. H. Leyten; P. G. Barth; F. J. M. Gabreëls; K. Renkawek; W. O. Renier; A. A. W. M. Gabreëls-Festen; H. J. ter Laak; M. G. Smits

1995-01-01

191

Muscular Dystrophy: Central Nervous System ?-Dystroglycan Glycosylation Defects and Brain Malformation  

Microsoft Academic Search

The authors describe the case of a patient affected with congenital muscular dystrophy with lack of muscle ?-dystroglycan. Brain gross anatomy showed lissencephaly and pachygyria. Light microscopy showed heterotopias in white matter. The brain stem and cerebellum were normal. They found no expression of ?-dystroglycan either in the frontal cortex or in the heterotopic nuclei, while a normal expression was

Gigliola Fagiolari; Anna Cappellini; Rachele Cagliani; Alessandro Prelle; Valeria Lucchini; Francesco Fortunato; Federica Locatelli; Veronica Crugnola; Giacomo Pietro Comi; Nereo Bresolin; Maurizio Moggio; Costanza Lamperti

2010-01-01

192

Integrin ?7?1 in Muscular Dystrophy/Myopathy of Unknown Etiology  

PubMed Central

To investigate the role of integrin ?7 in muscle pathology, we used a “candidate gene” approach in a large cohort of muscular dystrophy/myopathy patients. Antibodies against the intracellular domain of the integrin ?7A and ?7B were used to stain muscle biopsies from 210 patients with muscular dystrophy/myopathy of unknown etiology. Levels of ?7A and ?7B integrin were found to be decreased in 35 of 210 patients (?17%). In six of these patients no integrin ?7B was detected. Screening for ?7B mutation in 30 of 35 patients detected only one integrin ?7 missense mutation (the mutation on the second allele was not found) in a patient presenting with a congenital muscular dystrophy-like phenotype. No integrin ?7 gene mutations were identified in all of the other patients showing integrin ?7 deficiency. In the process of mutation analysis, we identified a novel integrin ?7 isoform presenting 72-bp deletion. This isoform results from a partial deletion of exon 21 due to the use of a cryptic splice site generated by a G to A missense mutation at nucleotide position 2644 in integrin ?7 cDNA. This spliced isoform is present in about 12% of the chromosomes studied. We conclude that secondary integrin ?7 deficiency is rather common in muscular dystrophy/myopathy of unknown etiology, emphasizing the multiple mechanisms that may modulate integrin function and stability. PMID:12057917

Pegoraro, Elena; Cepollaro, Fulvio; Prandini, Paola; Marin, Alessandra; Fanin, Marina; Trevisan, Carlo P.; El-Messlemani, Abdul Hassib; Tarone, Guido; Engvall, Eva; Hoffman, Eric P.; Angelini, Corrado

2002-01-01

193

Limb-Girdle and Congenital Muscular Dystrophies: Current Diagnostics, Management, and Emerging Technologies  

PubMed Central

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

Rocha, Carolina Tesi; Hoffman, Eric P.

2014-01-01

194

Laminin ?2 deficiency and muscular dystrophy; genotype-phenotype correlation in mutant mice  

Microsoft Academic Search

Deficiency of laminin ?2 is the cause of one of the most severe muscular dystrophies in humans and other species. It is not yet clear how particular mutations in the laminin ?2 chain gene affect protein expression, and how abnormal levels or structure of the protein affect disease. Animal models may be valuable for such genotype-phenotype analysis and for determining

L. T. Guo; X. U. Zhang; W. Kuang; H. Xu; L. A. Liu; J.-T. Vilquin; Y. Miyagoe-Suzuki; S. Takeda; M. A. Ruegg; U. M. Wewer; E. Engvall

2003-01-01

195

Limb girdle muscular dystrophy: A radiologic and manometric study of the pharynx and esophagus  

Microsoft Academic Search

Limb girdle muscular dystrophy (LGMD) is not a recognized cause of dysphagia. However, a systematic study of pharyngoesophageal function in LGMD has not been performed or reported. We determined whether the dystrophic process involves the pharyngoesophageal musculature in 20 LGMD patients with and without complaints of deglutition. Pharyngeal and esophageal function was evaluated by conventional cineradiography and manometry. Abnormalities were

Joerg-Patrick Stfibgen

1996-01-01

196

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 therapy? Use of viral vectors to deliver functional genes to muscle - Adeno associated viral vector (AAV 248 Microgene for dystrophin What is Gene therapy? Use of viral vectors to deliver functional genes

Royal Holloway, University of London

197

Two Children with Muscular Dystrophies Ascertained Due to Referral for Diagnosis of Autism  

Microsoft Academic Search

We report two children who were referred for diagnostic assessment for autism and were subsequently determined to have a muscular dystrophy (MD). Each child had a history of speech delay and social impairments, but also had motor delays that had not previously been investigated. Both children met diagnostic criteria for autism spectrum disorders on standardized assessment. Each child was hypotonic

Lonnie Zwaigenbaum; Mark Tarnopolsky

2003-01-01

198

Missense mutations in dystrophin that trigger muscular dystrophy decrease protein stability  

E-print Network

membrane of muscle cells against the mechanical forces asso- ciated with muscle contraction and stretch of functional dystrophin protein in muscle cells causes muscular dystrophy (MD). More than 50% of missense) refers to a group of degenerative muscle diseases that cause progressive muscle weakness (1). Duchenne

Mallela, Krishna M. G.

199

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

200

Quality of Life, Physical Disability, and Respiratory Impairment in Duchenne Muscular Dystrophy  

Microsoft Academic Search

Rationale: Duchenne muscular dystrophy (DMD) leads to progres- sive, generalized paresis, and to respiratory failure in the second decade of life. The assumption that severe physical disability pre- cludes an acceptable quality of life is common, but has not been specifically evaluated in DMD. Objectives: The purpose of this study was to investigate the quality of life in relation to

Malcolm Kohler; Christian F. Clarenbach; Lukas Boni; Thomas Brack; Erich W. Russi; Konrad E. Bloch

2005-01-01

201

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

202

Mutation spectrum of the dystrophin gene in 442 Duchenne\\/Becker muscular dystrophy cases from one Japanese referral center  

Microsoft Academic Search

Recent developments in molecular therapies for Duchenne muscular dystrophy (DMD) demand accurate genetic diagnosis, because therapies are mutation specific. The KUCG (Kobe University Clinical Genetics) database for DMD and Becker muscular dystrophy is a hospital-based database comprising 442 cases. Using a combination of complementary DNA (cDNA) and chromosome analysis in addition to conventional genomic DNA-based method, mutation detection was successfully

Yasuhiro Takeshima; Mariko Yagi; Yo Okizuka; Hiroyuki Awano; Zhujun Zhang; Yumiko Yamauchi; Hisahide Nishio; Masafumi Matsuo

2010-01-01

203

MLPA analysis\\/complete sequencing of the DMD gene in a group of Bulgarian Duchenne\\/Becker muscular dystrophy patients  

Microsoft Academic Search

Duchenne\\/Becker muscular dystrophy (DMD\\/BMD), the most common X-linked muscular dystrophy is caused by mutations in the enormously large DMD gene, encoding the protein called dystrophin. This gene was screened in a group of 27 unrelated Bulgarian DMD\\/BMD patients by MLPA analysis\\/complete sequencing. We managed to clarify the disease-causing mutation in 96.3% of the analyzed families. The MLPA analysis revealed 17

Albena Todorova; Tihomir Todorov; Bilyana Georgieva; Michaela Lukova; Velina Guergueltcheva; Ivo Kremensky; Vanyo Mitev

2008-01-01

204

Expression of the putative Duchenne muscular dystrophy gene in differentiated myogenic cell cultures and in the brain  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD), a sex-linked degenerative disorder of the muscle, is one of the most common lethal genetic diseases in man. It affects about one male in 3,500, with an estimated one-third of cases being caused by new mutations. A less severe disease, Becker's muscular dystrophy (BMD), maps to the same chromosomal locus and is most probably an allelic

Uri Nudel; Kenneth Robzyk; David Yaffe

1988-01-01

205

Using the full power of linkage analysis in 11 French Canadian families to fine map the oculopharyngeal muscular dystrophy gene  

Microsoft Academic Search

Oculopharyngeal muscular dystrophy (OPMD) is a late onset autosomal dominant muscular dystrophy with a high prevalence in the French Canadian population. We report linkage analysis with 7 chromosome 14q polymorphic markers in 11 large French Canadian families. An observed recombination in one family establishes D14S283 as the new centromeric flanking marker, therefore reducing the previously reported candidate interval from 5cM

Bernard Brais; Jean-Pierre Bouchard; France Gosselin; Ya-Gang Xie; Michel Fardeau; Fernando M. S. Tomé; Guy A. Rouleau

1997-01-01

206

The R482Q lamin A\\/C mutation that causes lipodystrophy does not prevent nuclear targeting of lamin A in adipocytes or its interaction with emerin  

Microsoft Academic Search

Most pathogenic missense mutations in the lamin A\\/C gene identified so far cause autosomal-dominant dilated cardiomyopathy and\\/or Emery-Dreifuss muscular dystrophy. A few specific mutations, however, cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue. We have prepared lamin A with a known FPLD mutation (R482Q) by in vitro mutagenesis. Nuclear

Ian Holt; Lisa Clements; Sushila Manilal; Susan C Brown; Glenn E Morris

2001-01-01

207

RNAi-based Gene Therapy for Dominant Limb Girdle Muscular Dystrophies  

PubMed Central

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

Liu, Jian; Harper, Scott Q.

2014-01-01

208

[Dystrophin gene expression in patients with Duchenne muscular dystrophy after myoblast transplantation].  

PubMed

Based on originally designed technique of myoblast cultivation and in accordance with the approved by the Russian Ministry of Health "one muscle treatment" protocol of myoblast transplantation to the Duchenne muscular dystrophy patients, the first in Russia clinical trial of this gene correction method was carried out. Immonologically related myoblast cultures (30 to 90 million cells per patient) were injected after all preliminary procedures into tibialis anterior muscles of four boys selected from a group of volunteer recipients (Duchenne muscular dystrophy patients) based on the analysis of a number of surface antigens in donor-recipient pairs. The condition of the patients remained satisfactory during the whole period of post-transplantation follow-up (from 6 months to 1.5 years). Six months after myoblast transplantation the presence of donor DNA or dystrophin synthesis was demonstrated in muscle biopsies of three out of four patients. This result confirms efficacy and safety of the procedure used. PMID:11642111

Shishkin, S S; Terekhov, S M; Krokhina, T B; Shakhovskaia, N I; Podobedova, A N; Linnaia, G F; Tarasov, V I; Ovchinnikov, V I; Krakhmaleva, I N; Zakharov, S F; Ershova, E S; Limborskaia, S A; Pogoda, T V; Zotikov, E A; Kut'ina, R M; Tarksh, M A; Sukhorukov, V S; Gerasimova, N L

2001-08-01

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

Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy.  

PubMed

Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper-CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANOS c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy. PMID:25291917

Schneider, Ilka; Stoltenburg, Gisela; Deschauer, Marcus; Winterholler, Martin; Hanisch, Frank

2014-05-01

211

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

212

Limb girdle muscular dystrophy type 2L presenting as necrotizing myopathy.  

PubMed

Recessive mutations in the ANO5 gene, encoding anoctamin 5, cause proximal limb girdle muscular dystrophy (LGMD2L), Miyoshi-type distal myopathy (MM3) and asymptomatic hyper- CKemia. We report a woman with exertion-induced myalgia and weakness in the hip girdle manifesting at the age of 40. Creatine kinase (CK) was increased 20-fold. Histologically the dominating feature was necrotizing myopathy, but long-term immunosuppressive therapy did not change CK level or myopathic symptoms. Molecular genetic investigation led to the finding of the homozygous ANO5 c.191dupA mutation. This is a report of a muscular dystrophy due to ANO5 mutation presenting histologically as necrotizing myopathy. For this reason our finding extends the histological spectrum of myopathies due to ANO5 mutations as well as the possible differential diagnoses for necrotizing myopathy. PMID:24843231

Schneider, Ilka; Stoltenburg, Gisela; Deschauer, Marcus; Winterholler, Martin; Hanisch, Frank

2014-05-01

213

Correlation of clinical and deletion data in Duchenne and Becker muscular dystrophy  

Microsoft Academic Search

Cloned cDNA sequences representing exons from the Duchenne\\/Becker muscular dystrophy (DMD\\/BMD) gene were used for deletion screening in a population of 287 males males affected with DMD or BMD. The clinical phenotypes of affected boys were classified into three clinical severity groups based on the age at which ambulation was lost. Boys in group 1 had DMD, losing ambulation before

S Hodgson; K Hart; S Abbs; J Heckmatt; E Rodillo; M Bobrow; V Dubowitz

1989-01-01

214

Sarcoglycanopathies in Dutch patients with autosomal recessive limb girdle muscular dystrophy  

Microsoft Academic Search

Within a group of 76 sporadic\\/autosomal recessive limb girdle muscular dystrophy (LGMD) patients we tried to identify those\\u000a with LGMD type 2C-E. Muscle biopsy specimens of 40 index patients, who had 22 affected sibs, were analyzed immuno-histochemically\\u000a for the presence of three subunits: ?-, ?-, and ?,-sarcoglycans. Abnormal sarcoglycan expression was established in eight\\u000a patients, with six affected sibs. In

H. B. Ginjaar; A. J. van der Kooi; H. Ceelie; A. L. J. Kneppers; M. van Meegen; P. G. Barth; H. F. M. Busch; J. H. J. Wokke; L. V. B. Anderson; C. G. Bönnemann; M. Jeanpierre; P. A. Bolhuis; A. F. M. Moorman; M. de Visser; E. Bakker; G. J. B. v. Ommen

2000-01-01

215

Noninvasive monitoring of therapeutic gene transfer in animal models of muscular dystrophies  

Microsoft Academic Search

Muscular dystrophies are a genetically and phenotypically heterogeneous group of degenerative muscle diseases. A subset of them are due to genetic deficiencies in proteins which form the dystrophin-associated complex at the membrane of the myofibers. In this report, we utilized recombinant adeno-associated virus containing a U7 cassette carrying an antisense sequence aimed at inducing exon skipping of the dystrophin gene

M Bartoli; J Poupiot; A Goyenvalle; N Perez; L Garcia; O Danos; I Richard

2006-01-01

216

Duchenne\\/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations  

Microsoft Academic Search

.   The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD\\/BMD) shows a marked\\u000a reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations\\u000a upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal\\u000a b-wave amplitude associated with

De-Ann M. Pillers; Kathleen M. Fitzgerald; Nancy M. Duncan; Sean M. Rash; Robert A. White; Shannon J. Dwinnell; Berkley R. Powell; Rhonda E. Schnur; Peter N. Ray; Gerhard W. Cibis; Richard G. Weleber

1999-01-01

217

Duchenne\\/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations  

Microsoft Academic Search

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD\\/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged

De-Ann M. Pillers; K. M. Fitzgerald; N. M. Duncan; S. M. Rash; R. A. White; S. J. Dwinnell; B. R. Powell; R. E. Schnur; P. N. Ray; G. W. Cibis; R. G. Weleber

1999-01-01

218

Proportion and pattern of dystrophin gene deletions in North Indian Duchenne and Becker muscular dystrophy patients  

Microsoft Academic Search

Population-based variations in frequency and distribution of dystrophin gene deletions have been recognized in Duchenne\\/Becker\\u000a (DMD\\/BMD) muscular dystrophy patients. In the present study, DNA samples from 121 unrelated DMD\\/BMD patients from North India\\u000a were analyzed for deletional studies with multiplex PCR and Southern hybridization. A total of 88 (73%) patients showed intragenic\\u000a deletions in the dystrophin gene. The observed proportion

Vinita Singh; Shirish Sinha; Sudhish Mishra; Lakshmi Shankar Chaturvedi; Sunil Pradhan; Rama Devi Mittal; Balraj Mittal

1997-01-01

219

Point mutation and polymorphism in Duchenne\\/Becker Muscular Dystrophy (D\\/BMD) patients  

Microsoft Academic Search

Duchenne and Becker muscular dystrophies (D\\/BMD) are caused by mutations in the dystrophin gene. Two-thirds of patients have large intragenic dele- tions or duplications and the remaining one-third have point mutations, small deletions or insertions. Point mutations are more difficult to detect due to the enormous size (2.4 Mb) of the gene and its large transcript (14 kb). In the

LS Chaturvedi; M Mukherjee; S Srivastava; B Mittal

2001-01-01

220

Molecular genetic characteristics of Duchenne-Becker muscular dystrophy in the Republic of Moldova  

Microsoft Academic Search

Solution to some problems of clinical genealogical and molecular genetic study of Duchenne muscular dystrophy (DMD) in the\\u000a Republic of Moldova and prenatal diagnosis aimed at preventing the birth of infants with this disease is proposed. An integrated\\u000a clinical and molecular genetic study of families with a high risk of DMD has allowed its specific characteristics in the Moldovan\\u000a population

V. Sacare

2008-01-01

221

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

222

Facioscapulohumeral Muscular Dystrophy: A Radiologic and Manometric Study of the Pharynx and Esophagus  

Microsoft Academic Search

Facioscapulohumeral muscular dystrophy (FSHD) is not a recognized neuromuscular cause of dysphagia. However, a study of pharyngoesophageal\\u000a function in FSHD has not been performed or reported. The aim of this study was to ascertain by relatively noninvasive techniques\\u000a whether the dystrophic muscle disease that underlies FSHD involves the pharyngeal and\\/or the esophageal striated and smooth\\u000a muscles. We used conventional cineradiography

Joerg-Patrick Stübgen

2008-01-01

223

[Study of clinical polymorphism of Becker's progressive muscular dystrophy and associated sexual disorders].  

PubMed

Clinical polymorphism of Becker's progressive muscular dystrophy and related sexual disorders were studied in 13 patients aged 19 to 39 years. Characteristic disturbances included inhibited or delayed pubertal development and manifestations of hyposexuality in mature age. Pubertal retardation was diagnosed in 2 patients who also displayed an earlier development of manifestations of the first symptoms of Becker's progressive myodystrophy associated with hyperestrogenemia and hypoprolactinemia. PMID:3434057

Zavadenko, N N

1987-01-01

224

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

Microsoft Academic Search

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

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

1994-01-01

225

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

PubMed Central

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

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

2013-01-01

226

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

227

Evolution of Gastric Electrical Features and Gastric Emptying in Children with Duchenne and Becker Muscular Dystrophy  

Microsoft Academic Search

OBJECTIVES:Although muscular dystrophy (MD) affects primarily striated muscles, smooth muscle cells of the gastrointestinal tract may also be involved. We recorded gastric electrical activity and gastric emptying time (GET) in children with MD at initial presentation and at 3-yr follow-up in order to detect gastric motor abnormalities and study their evolution along the clinical course.METHODS:Twenty children with MD (median age:

Osvaldo Borrelli; Gennaro Salvia; Valentina Mancini; Lucio Santoro; Francesca Tagliente; Erminia Francesca Romeo; Salvatore Cucchiara

2005-01-01

228

Surgical correction of spinal deformity in patients with congenital muscular dystrophy  

Microsoft Academic Search

Background  Congenital muscular dystrophy (CMD), among the myopathic disorders is one form of flaccid neuromuscular disorder (NMD). Patients\\u000a with NMD frequently develop progressive spinal deformity. For NMD patients who have a severe spinal deformity, sitting is\\u000a often difficult and is accompanied by pain and breakdown of the skin. Spinal deformity surgery in these patients has been\\u000a highly effective in stabilizing the

Masashi Takaso; Toshiyuki Nakazawa; Takayuki Imura; Takamitsu Okada; Masaki Ueno; Wataru Saito; Kazuhisa Takahashi; Masashi Yamazaki; Seiji Ohtori

2010-01-01

229

914. Recombinant AAV Gene Delivery of Follistatin for Muscle Enhancement in Models of Muscular Dystrophy  

Microsoft Academic Search

Objective: To determine the efficacy of recombinant adeno-associated virus (rAAV) delivering follistatin (FS), a potent inhibitor of myostatin, to a mouse model for limb-girdle muscular dystrophy and wild-type animals.Background: LGMD2D is a debilitating muscle disease of children and young adults. There is no proven treatment to delay the disease progression. Inhibition of myostatin, a negative growth modulator for muscle, can

Liza Rizo; Chris Shilling; Amanda Haidet; Priya Umapathi Umapathi; Zarife Sahenk; Jerry R. Mendell; Brian K. Kaspar

2006-01-01

230

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

231

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

232

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

PubMed

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

2014-07-01

233

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

PubMed

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

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

2014-10-15

234

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

PubMed Central

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

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

2011-01-01

235

Limb girdle muscular dystrophy type 2B masquerading as inflammatory myopathy: case report  

PubMed Central

Limb girdle muscular dystrophy type 2B is a rare subtype of muscular dystrophy, the predominant feature of which is muscle weakness. The disease is caused by an autosomal recessively inherited reduction/absence of muscle dysferlin due to a mutation in dysferlin gene at 2p12-14. We report a 10 year old boy who presented with severe non-transient right knee pain and swelling, which later became bilateral. His pain was worst in the morning and during rest. Blood tests revealed markedly raised creatine kinase values (highest 22, 297 U/l), raising the possibility of an inflammatory myositis. MRI showed bilateral asymmetrical muscle involvement of thighs and calves with oedematous changes mimicking the imaging appearances of inflammatory myositis. CRP and ESR levels were consistently within normal limits. Over several months his knee pain worsened and limited walking. Muscle biopsy revealed a severe reduction of dysferlin immunostaining, indicating the diagnosis, which was confirmed by 2 compound heterozygous pathogenic mutations in the dysferlin gene. It is not unusual for this subtype of the disease to mimic myositis: however, significant pain is a rare presenting symptom. Given the significant overlap between this form of muscular dystrophy and inflammatory myopathies, a high index of suspicion is needed to ensure an accurate and timely diagnosis. Furthermore, characteristic inflammatory-related morning pain should not rule out consideration of non-inflammatory causes. PMID:23641709

2013-01-01

236

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

PubMed

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

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

2013-02-01

237

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

238

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

239

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; Bonnemann, 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

240

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, Severine; Thepenier, Virginie; Francois, Virginie; Le Guiner, Caroline; Goubin, Helicia; Dutilleul, Maeva; 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

241

Allele frequencies of intragenic, and 5? and 3? markers of the dystrophin gene in Japanese families afflicted with Duchenne or Becker muscular dystrophy  

Microsoft Academic Search

Summary Using the polymerase chain reaction method (PCR), we examined the allele frequencies and heterozygosities of 7 polymorphic sites (pERT87, and CA polymorphisms in the 5' and 3' regions) of the dystrophin gene in 20 Japanese Duchenne muscular dystrophy and Becker muscular dystrophy (DMD or BMD) families consisting of 36 males, including 23 cases of DMD and BMD, and 28

Hiroko Tsukamoto; Koji Inui; Hisao Fukushima; Shintaro Okada

1996-01-01

242

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

243

Muscle Function Recovery in Golden Retriever Muscular Dystrophy After AAV1-U7 Exon Skipping  

PubMed Central

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease. PMID:22968479

Vulin, Adeline; Barthelemy, Ines; Goyenvalle, Aurelie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maeva; Unterfinger, Yves; Lorain, Stephanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stephane; Garcia, Luis

2012-01-01

244

Newborn bloodspot screening for Duchenne Muscular Dystrophy: 21 years experience in Wales (UK)  

PubMed Central

Duchenne muscular dystrophy (DMD), a progressive X-linked neuromuscular disorder, has an estimated worldwide incidence of 1:3500 male births. Currently, there are no curative treatments and the mean age of diagnosis is 5 years. In addition, subsequent pregnancies frequently occur before a diagnosis is made in an index case. An ‘opt in' screening programme was introduced in Wales in 1990 with the aim to: reduce the diagnostic delay, permit reproductive choice and allow planning of the care of the affected boy. Newborn bloodspots were collected routinely as part of the Wales newborn screening programme. Specific consent was obtained for this test separately from the other tests. During the 21-year period, 369?780 bloodspot cards were received from male infants, of these 343?170 (92.8%) were screened using a bloodspot creatine kinase (CK) assay following parental consent. A total of 145 cases had a raised CK activity (?250?U/l) and at follow-up, at 6–8 weeks of age, 79 cases had a normal serum CK (false-positive rate 0.023%) and 66 cases had an elevated serum CK. DMD was confirmed in 56 cases by genotyping/muscle biopsy studies, Becker muscular dystrophy in 5 cases and other rarer forms of muscular dystrophy in 5 cases. This long-term study has so far identified 13 false-negative cases. The incidence of DMD in Wales of 1:5136 during this period is lower than that of 1:4046 before commencement of screening in Wales. Screening has reduced the diagnostic delay enabling reproductive choice for parents of affected boys and earlier administration of current therapies. PMID:23340516

Moat, Stuart J; Bradley, Donald M; Salmon, Rachel; Clarke, Angus; Hartley, Louise

2013-01-01

245

Muscle function recovery in golden retriever muscular dystrophy after AAV1-U7 exon skipping.  

PubMed

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder resulting from lesions of the gene encoding dystrophin. These usually consist of large genomic deletions, the extents of which are not correlated with the severity of the phenotype. Out-of-frame deletions give rise to dystrophin deficiency and severe DMD phenotypes, while internal deletions that produce in-frame mRNAs encoding truncated proteins can lead to a milder myopathy known as Becker muscular dystrophy (BMD). Widespread restoration of dystrophin expression via adeno-associated virus (AAV)-mediated exon skipping has been successfully demonstrated in the mdx mouse model and in cardiac muscle after percutaneous transendocardial delivery in the golden retriever muscular dystrophy dog (GRMD) model. Here, a set of optimized U7snRNAs carrying antisense sequences designed to rescue dystrophin were delivered into GRMD skeletal muscles by AAV1 gene transfer using intramuscular injection or forelimb perfusion. We show sustained correction of the dystrophic phenotype in extended muscle areas and partial recovery of muscle strength. Muscle architecture was improved and fibers displayed the hallmarks of mature and functional units. A 5-year follow-up ruled out immune rejection drawbacks but showed a progressive decline in the number of corrected muscle fibers, likely due to the persistence of a mild dystrophic process such as occurs in BMD phenotypes. Although AAV-mediated exon skipping was shown safe and efficient to rescue a truncated dystrophin, it appears that recurrent treatments would be required to maintain therapeutic benefit ahead of the progression of the disease. PMID:22968479

Vulin, Adeline; Barthélémy, Inès; Goyenvalle, Aurélie; Thibaud, Jean-Laurent; Beley, Cyriaque; Griffith, Graziella; Benchaouir, Rachid; le Hir, Maëva; Unterfinger, Yves; Lorain, Stéphanie; Dreyfus, Patrick; Voit, Thomas; Carlier, Pierre; Blot, Stéphane; Garcia, Luis

2012-11-01

246

Growth Hormone Deficiency in a Patient with Becker Muscular Dystrophy: A Pediatric Case Report  

PubMed Central

Objective. To describe a biochemical growth hormone (GH) deficiency and to evaluate therapeutic result in a six-year-old male with Becker muscular dystrophy (BMD). Methods. GH peak was evaluated after response to arginine and insulin. Bone age was evaluated according to Greulich and Pyle method. Results. The GH-supplementary therapy was very effective in terms of growth gain. Conclusion. The possibility of a growth hormone deficiency and treatment with GH in patients with BMD cannot be excluded, especially considering the good therapeutic response. PMID:23365767

Calcaterra, Valeria; Malvezzi, Annachiara; Toglia, Rossana; Berardinelli, Angela; Bozzola, Elena; Bozzola, Mauro; Larizza, Daniela

2013-01-01

247

An apparently sporadic case of oculopharyngeal muscular dystrophy: the first Italian report.  

PubMed

Here we report the case of a 73-year-old Italian woman affected by genetically confirmed oculopharyngeal muscular dystrophy (OPMD) with a negative family history. As OPMD is usually transmitted as an autosomal-dominant meiotically stable trait, this case allows us to suggest that putative de novo OPMD mutations might occur more frequently than previously thought; moreover, when compatible with a proper clinical phenotype, OPMD might be included in the differential diagnosis even in the absence of a positive family history. PMID:18175083

Tremolizzo, L; Galbussera, A; Tagliabue, E; Fermi, S; Bruttini, M; Lamperti, C; Moggio, M; Curtò, N; Appollonio, I; Ferrarese, C

2007-12-01

248

Rigid spinal muscular dystrophy and rigid spine syndrome: report of 7 children.  

PubMed

Seven children (5 male, 2 female) were seen over the last 16 years with rigid spine syndrome. Six children had rigid spinal muscular dystrophy (selenoprotein N1-related myopathy [SEPN1RM]) and 1 had myopathy associated with rigid spine. The main presenting complaint in all was difficulty in bending the spine. The diagnosis was made on clinical features and imaging of the paraspinal muscles. Muscle histopathology revealed minimal myopathic changes to severe muscle degeneration. Genetic testing, which was only available for the last case, for selenoprotein was negative. PMID:23481446

Koul, Roshan; Al-Yarubi, Saif; Al-Kindy, Hussein; Al-Futaisi, Amna; Al-Thihli, Khalid; Chacko, Poovathoor Alexander; Sankhla, Dilip

2014-11-01

249

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

250

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

PubMed

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

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

2013-07-01

251

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

PubMed

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

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

2011-05-01

252

Calpain 3 is important for muscle regeneration: Evidence from patients with limb girdle muscular dystrophies  

PubMed Central

Background Limb girdle muscular dystrophy (LGMD) type 2A is caused by mutations in the CAPN3 gene and complete lack of functional calpain 3 leads to the most severe muscle wasting. Calpain 3 is suggested to be involved in maturation of contractile elements after muscle degeneration. The aim of this study was to investigate how mutations in the four functional domains of calpain 3 affect muscle regeneration. Methods We studied muscle regeneration in 22 patients with LGMD2A with calpain 3 deficiency, in five patients with LGMD2I, with a secondary reduction in calpain 3, and in five patients with Becker muscular dystrophy (BMD) with normal calpain 3 levels. Regeneration was assessed by using the developmental markers neonatal myosin heavy chain (nMHC), vimentin, MyoD and myogenin and counting internally nucleated fibers. Results We found that the recent regeneration as determined by the number of nMHC/vimentin-positive fibers was greatly diminished in severely affected LGMD2A patients compared to similarly affected patients with LGMD2I and BMD. Whorled fibers, a sign of aberrant regeneration, was highly elevated in patients with a complete lack of calpain 3 compared to patients with residual calpain 3. Regeneration is not affected by location of the mutation in the CAPN3 gene. Conclusions Our findings suggest that calpain 3 is needed for the regenerative process probably during sarcomere remodeling as the complete lack of functional calpain 3 leads to the most severe phenotypes. PMID:22443334

2012-01-01

253

Comparative Genomics of X-linked Muscular Dystrophies: The Golden Retriever Model  

PubMed Central

Duchenne muscular dystrophy (DMD) is a devastating disease that dramatically decreases the lifespan and abilities of affected young people. The primary molecular cause of the disease is the absence of functional dystrophin protein, which is critical to proper muscle function. Those with DMD vary in disease presentation and dystrophin mutation; the same causal mutation may be associated with drastically different levels of disease severity. Also contributing to this variation are the influences of additional modifying genes and/or changes in functional elements governing such modifiers. This genetic heterogeneity complicates the efficacy of treatment methods and to date medical interventions are limited to treating symptoms. Animal models of DMD have been instrumental in teasing out the intricacies of DMD disease and hold great promise for advancing knowledge of its variable presentation and treatment. This review addresses the utility of comparative genomics in elucidating the complex background behind phenotypic variation in a canine model of DMD, Golden Retriever muscular dystrophy (GRMD). This knowledge can be exploited in the development of improved, more personalized treatments for DMD patients, such as therapies that can be tailor-matched to the disease course and genomic background of individual patients. PMID:24403852

Brinkmeyer-Langford, Candice; Kornegay, Joe N.

2013-01-01

254

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

PubMed

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

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

2014-01-01

255

Morphological and ultrastructural evaluation of the golden retriever muscular dystrophy trachea, lungs, and diaphragm muscle.  

PubMed

Duchenne muscular dystrophy (DMD) is a genetic disease, characterized by atrophy and muscle weakness. The respiratory failure is a common cause of early death in patients with DMD. Golden retriever muscular dystrophy (GRMD) is a canine model which has been extensively used for many advances in therapeutics applications. As the patients with DMD, the GRMD frequently died from cardiac and respiratory failure. Observing the respiratory failure in DMD is one of the major causes of mortality we aimed to describe the morphological and ultrastructural data of trachea, lungs (conductive and respiratory portion of the system), and diaphragm muscle using histological and ultrastructural analysis. The diaphragm muscle showed discontinuous fibers architecture, with different diameter; a robust perimysium inflammatory infiltrate and some muscle cells displayed central nuclei. GRMD trachea and lungs presented collagen fibers and in addition, the GRMD lungs showed higher of levels collagen fibers that could limit the alveolar ducts and alveoli distension. Therefore, the most features observed were the collagen areas and fibrosis. We suggested in this study that the collagen remodeling in the trachea, lungs, and diaphragm muscle may increase fibrosis and affect the trachea, lungs, and diaphragm muscle function that can be a major cause of respiratory failure that occur in patients with DMD. Microsc. Res. Tech. 77:857-861, 2014. © 2014 Wiley Periodicals, Inc. PMID:25081087

Lessa, Thais Borges; de Abreu, Dilayla Kelly; Rodrigues, Márcio Nogueira; Brólio, Marina Pandolphi; Miglino, Maria Angélica; Ambrósio, Carlos Eduardo

2014-11-01

256

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

257

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

258

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

259

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

PubMed Central

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

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

2014-01-01

260

Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol  

PubMed Central

Background Although muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD. Methods/Design Evaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments. Discussion This study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention. PMID:24119284

2013-01-01

261

LTBP4 genotype predicts age of ambulatory loss in Duchenne Muscular Dystrophy  

PubMed Central

Objective Duchenne Muscular Dystrophy (DMD) displays a clinical range that is not fully explained by the primary DMD mutations. Ltbp4, encoding latent transforming growth factor-? binding protein 4, was previously discovered in a genomewide scan as a modifier of murine muscular dystrophy. We sought to determine whether LTBP4 genotype influenced DMD severity in a large patient cohort. Methods We analyzed nonsynonymous SNPs from human LTBP4 in 254 nonambulatory subjects with known DMD mutations. These SNPs, V194I, T787A, T820A, and T1140M, form “VTTT” and “IAAM” LTBP4 haplotypes. Results Individuals homozygous for the IAAM LTBP4 haplotype remained ambulatory significantly longer than those heterozygous or homozygous for the VTTT haplotype. Glucocorticoid-treated patients who were IAAM homozygotes lost ambulation at 12.5 ± 3.3 years compared to 10.7 ± 2.1 years for treated VTTT heterozygotes or homozygotes. IAAM fibroblasts exposed to TGF? displayed reduced phospho-SMAD signaling compared to VTTT fibroblasts, consistent with LTBP4's role as regulator of TGF?. Interpretation LTBP4 haplotype influences age at loss of ambulation, and should be considered in the management of DMD patients. PMID:23440719

Flanigan, Kevin M.; Ceco, Ermelinda; Lamar, Kay-Marie; Kaminoh, Yuuki; Dunn, Diane M.; Mendell, Jerry R.; King, Wendy M.; Pestronk, Alan; Florence, Julaine M.; Mathews, Katherine D.; Finkel, Richard S.; Swoboda, Kathryn J.; Gappmaier, Eduard; Howard, Michael T.; Day, John W.; McDonald, Craig; McNally, Elizabeth M.; Weiss, Robert B.

2013-01-01

262

Effects of an Immunosuppressive Treatment in the GRMD Dog Model of Duchenne Muscular Dystrophy  

PubMed Central

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

Barthelemy, Ines; Uriarte, Ane; Drougard, Carole; Unterfinger, Yves; Thibaud, Jean-Laurent; Blot, Stephane

2012-01-01

263

Role of Telomere Dysfunction in Cardiac Failure in Duchenne Muscular Dystrophy  

PubMed Central

Duchenne Muscular Dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin, exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTRKO) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation, and increased oxidative stress. Treatment with anti-oxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTRKO mice. In corroboration, of four DMD patients analyzed, all had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions. PMID:23831727

Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy; Day, John W.; Zhao, Ming-Ming; Kost-Alimova, Maria; Protopopov, Alexei; DePinho, Ronald A.; Bernstein, Daniel; Meeker, Alan K.; Blau, Helen M.

2013-01-01

264

Role of telomere dysfunction in cardiac failure in Duchenne muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTR(KO)) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation and increased oxidative stress. Treatment with antioxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTR(KO) mice. In corroboration, all four of the DMD patients analysed had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions. PMID:23831727

Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy; Day, John W; Zhao, Ming-Ming; Kost-Alimova, Maria; Protopopov, Alexei; DePinho, Ronald A; Bernstein, Daniel; Meeker, Alan K; Blau, Helen M

2013-08-01

265

Enhancement of plasmid-mediated gene therapy for muscular dystrophy by directed plasmid integration  

PubMed Central

Plasmid-mediated gene therapy can restore dystrophin expression in skeletal muscle in the mdx mouse, a model of Duchenne muscular dystrophy. However, sufficient long-term expression and distribution of dystrophin remain a hurdle for translating this technology into a viable treatment for Duchenne muscular dystrophy. To improve plasmid-mediated gene therapy for muscle diseases, we studied the effects of targeted plasmid integration using a phage integrase (?C31) that can mediate the integration of suitably modified plasmids into the mammalian genome. Using a luciferase expression plasmid, we monitored plasmid gene expression noninvasively in living mice by bioluminescence imaging. Coinjection of an integrase plasmid resulted in 5- to 10-fold higher levels of sustained luciferase expression. Likewise, plasmid-mediated dystrophin expression in mdx muscle was enhanced by integration. Using a combination of dystrophin and luciferase plasmids, we analyzed the functional benefit of dystrophin expression in the dystrophic muscle. The expression of dystrophin slowed the loss of luciferase expression associated with muscle degeneration, and that protection was enhanced by targeted integration of the dystrophin plasmid. In the presence of integrase, dystrophin expression was distributed along a much greater length of individual fibers, and this was associated with increased protection against degenerative changes. These data demonstrate the importance of both the level and distribution of dystrophin expression to achieve therapeutic efficacy, and that the efficacy can be enhanced by targeted plasmid integration. PMID:16387861

Bertoni, Carmen; Jarrahian, Sohail; Wheeler, Thurman M.; Li, Yining; Olivares, Eric C.; Calos, Michele P.; Rando, Thomas A.

2006-01-01

266

MMP-10 is required for efficient muscle regeneration in mouse models of injury and muscular dystrophy.  

PubMed

Matrix metalloproteinases (MMPs), a family of endopeptidases that are involved in the degradation of extracellular matrix components, have been implicated in skeletal muscle regeneration. Among the MMPs, MMP-2 and MMP-9 are upregulated in Duchenne muscular dystrophy (DMD), a fatal X-linked muscle disorder. However, inhibition or overexpression of specific MMPs in a mouse model of DMD (mdx) has yielded mixed results regarding disease progression, depending on the MMP studied. Here, we have examined the role of MMP-10 in muscle regeneration during injury and muscular dystrophy. We found that skeletal muscle increases MMP-10 protein expression in response to damage (notexin) or disease (mdx mice), suggesting its role in muscle regeneration. In addition, we found that MMP-10-deficient muscles displayed impaired recruitment of endothelial cells, reduced levels of extracellular matrix proteins, diminished collagen deposition, and decreased fiber size, which collectively contributed to delayed muscle regeneration after injury. Also, MMP-10 knockout in mdx mice led to a deteriorated dystrophic phenotype. Moreover, MMP-10 mRNA silencing in injured muscles (wild-type and mdx) reduced muscle regeneration, while addition of recombinant human MMP-10 accelerated muscle repair, suggesting that MMP-10 is required for efficient muscle regeneration. Furthermore, our data suggest that MMP-10-mediated muscle repair is associated with VEGF/Akt signaling. Thus, our findings indicate that MMP-10 is critical for skeletal muscle maintenance and regeneration during injury and disease. PMID:24123596

Bobadilla, Míriam; Sáinz, Neira; Rodriguez, José Antonio; Abizanda, Gloria; Orbe, Josune; de Martino, Alba; García Verdugo, José Manuel; Páramo, José A; Prósper, Felipe; Pérez-Ruiz, Ana

2014-02-01

267

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

PubMed

Manifestations of Duchenne and Becker muscular dystrophy (DBMD) are present in up to 40% of heterozygous females, but there are few reports of females who exhibit skeletal muscle symptoms in childhood. From the Muscular Dystrophy Surveillance Tracking and Research Network, a multi-site population-based surveillance network for dystrophinopathy, nine symptomatic female heterozygotes with onset of symptoms prior to age 9 years were identified. The median age at diagnosis was 8.3 years, and the median interval from first symptoms to diagnosis was 1.35 years. Of the nine female heterozygotes, four had a positive family history, seven had intellectual disability and five had at least one mental health disorder. Mental health concerns included attention deficit hyperactivity disorder (ADHD), autism spectrum features, bipolar disorder, and depression. The frequency of intellectual and mental health problems in this group is higher than previously reported for affected males and for symptomatic females. These findings may have implications for diagnosis of early manifesting heterozygotes and for their health supervision. © 2014 Wiley Periodicals, Inc. PMID:25125379

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

2014-11-01

268

[Muscular dystrophy due to mutations in anoctamin 5: clinical and molecular genetic findings].  

PubMed

Recessive mutations in the anoctamin 5 (ANO5) gene have been recently identified in families with limb girdle muscular dystrophy (LGMD2L) and distal non-dysferlin Miyoshi myopathy. Anoctamin 5 is supposed to be a putative calcium-activated chloride channel. We report five German patients (four index patients) with muscle dystrophy due to mutations in the ANO5 gene. Sequencing of the ANO5 exons 5, 13 and 20 was performed to screen for a common c.191dupA mutation and two other reported mutations (c.1295C>G and p.R758C). The whole coding region of the ANO5 gene was sequenced to identify new mutations. Phenotypically, three patients showed LGMD and one patient Miyoshi type distal myopathy. One sibling had asymptomatic hyperCKemia. The age at onset was 64, 38 and 40 years in patients with LGMD and 23 years in the patient with distal myopathy. The four symptomatic patients showed remarkable asymmetric muscle involvement. There was marked CK elevation (11 to 30 times). Electron microscopy showed multifocal gaps in the sarcolemmal membrane. All patients harboured the common c.191dupA mutation in at least one allele. Two patients with LGMD were homozygous and the third patient and his asymptomatic sister were compound heterozygous for the c.191dupA mutation and a novel p.T548I mutation. The patient with distal myopathy harboured the p.R758C mutation in the second allele. Mutations in the ANO5 gene seem to be a relatively common cause of muscular dystrophy in Germany. Cases with late onset or asymptomatic hyperCKemia can occur. Clinically, asymmetric manifestation is typical. PMID:21739273

Deschauer, M; Joshi, P R; Gläser, D; Hanisch, F; Stoltenburg, G; Zierz, S

2011-12-01

269

Direct carrier detection by in situ suppression hybridization with cosmid clones of the Duchenne\\/Becker muscular dystrophy locus  

Microsoft Academic Search

A basic problem in genetic counseling of families with Duchenne\\/Becker muscular dystrophy (DMD\\/BMD) concerns the carrier status of female relatives of an affected male. In about 60% of these patients, deletions of one or more exons of the dystrophin gene can be identified. These deletions preferentially include exon 45, which can be detected by multiplex polymerase chain reaction (PCR) and

T. Ried; V. Mahler; P. Vogt; L. Blonden; G. J. B. van Ommen; T. Cremer; M. Cremer

1990-01-01

270

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

E-print Network

: Review Loss of Cytoskeleton-Extracellular Matrix Linkage Kevin P. Campbell Howard Hughes Medical 52242 Muscular dystrophies are a group of diseases that primar- ily affect skeletal muscle and are characterized by progres- sive muscle wasting and weakness. Although these dis- eases have been clinically

Campbell, Kevin P.

271

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

272

Lipid peroxidation and superoxide dismutase activity in muscle and erythrocytes in adult muscular dystrophies and neurogenic atrophies  

Microsoft Academic Search

Lipid peroxidation (LP) and superoxide dismutase (SOD) activity were determined in erythrocytes and skeletal muscle obtained from patients with limb-girdle and facioscapulohumeral muscular dystrophies, neurogenic atrophies and from age-matched control subjects. Neither lipid peroxidation nor SOD activity in erythrocytes of patients differed from control values. SOD activity and LP in muscle specimens were also normal in types of neurogenic atrophy.

Peter Diószeghy; Sándor Imre; Ferenc Mechler

1989-01-01

273

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

274

Sequential study of central and peripheral nervous system involvement in an infant with merosin-deficient congenital muscular dystrophy  

Microsoft Academic Search

Diffuse white matter changes on brain imaging and peripheral neuropathy are associated features of merosin-deficient congenital muscular dystrophy (CMD). In this report we describe the early manifestation and evolution of brain changes, and the involvement of the peripheral nervous system in a female infant with merosin-deficient CMD diagnosed in the neonatal period who had sequential clinical, neurophysiological and magnetic resonance

Eugenio Mercuri; Jackie Pennock; Fiona Goodwin; Caroline Sewry; Frances Cowan; Lilly Dubowitz; Victor Dubowitz; Francesco Muntoni

1996-01-01

275

Changes in Function of Cardiac Receptors Mediating the Effects of the Autonomic Nervous System in the Muscular Dystrophy (MDX) Mouse  

Microsoft Academic Search

S. Lu and A. Hoey. Changes in Function of Cardiac Receptors Mediating the Effects of the Autonomic Nervous System in the Muscular Dystrophy (MDX) Mouse. Journal of Molecular and Cellular Cardiology (2000) 32, 143–152. Adrenergic and muscarinic receptor mediated effects on the force of contraction and heart rate were studied in the isolated left atria and right atria from dystrophin-deficient

Sai Lu; Andrew Hoey

2000-01-01

276

Absence of Extraocular Muscle Pathology in Duchenne's Muscular Dystrophy: Role for Calcium Homeostasis in Extraocular Muscle Sparing  

Microsoft Academic Search

Summary Duchenne muscular dystrophy (DMD) is characterized by clinical weakness and progressive necrosis of striated muscle as a consequence of dystrophin deficiency. While all skeletal muscle groups are thought to be affected, enigmatically, the extraocular muscles (EOM) appear clinically unaffected. Here we show that dystrophin deficiency does not result in myonecrosis or pathologically elevated levels of intracellular calcium ((Ca2+)i) in

Tejvir S. Khurana; Robert A. Prendergast; Hala S. Alameddine; S Micheal Fardeau; S Kiichi Arahata; Louis M. Kunkel

1995-01-01

277

Growth hormone inhibition causes increased selenium levels in Duchenne muscular dystrophy: a possible new approach to therapy  

Microsoft Academic Search

Nine children with Duchenne muscular dystrophy were given Sanorex (mazindol), a growth hormone inhibitor, daily for 6 months. There was no significant change in their muscle function, but there was a significant reduction in weight gain and in levels of growth hormone, somatomedin C, hair zinc, serum zinc, and serum LDH. Selenium and glutathione peroxidase in the serum increased significantly.

P J Collipp; J Kelemen; S Y Chen; M Castro-Magana; M Angulo; A Derenoncourt

1984-01-01

278

EFFECTS OF ECOLOGICAL COMFORT AND ECOLO- GICAL STRESS ON PRODUCTIVE TRAITS OF BROILER TURKEYS WITH EXPERIMENTALLY INDUCED MUSCULAR DYSTROPHY  

Microsoft Academic Search

Summary Oblakova, M., ?. Stoyanchev, N. Bozakova, ?. Lalev & I. Yotova, 2009. Effects of eco- logical comfort and ecological stress on productive traits of broiler turkeys with experimen- tally induced muscular dystrophy. Bulg. J. Vet. Med., 12, No 3, 192?198. The experiment was performed with four groups of broiler turkeys: I - control, reared under condi- tions of ecological

I. YOTOVA

279

The Effect of Enalapril and Carvedilol on Left Ventricular Dysfunction in Middle Childhood and Adolescent Patients With Muscular Dystrophy  

PubMed Central

Background and Objectives In Duchenne and Becker muscular dystrophies, cardiac function deteriorates with time resulting in heart failure which is often fatal. We prospectively evaluated the effect of enalapril and carvedilol on left ventricular (LV) dysfunction in middle childhood and adolescent patients with muscular dystrophy. Subjects and Methods Twenty-three patients with LV dysfunction (22 with Duchenne muscular dystrophy, 1 with Becker muscular dystrophy) were enrolled. We prescribed enalapril (13 patients) or carvedilol (10 patients) randomly from July 2008 to August 2010 and followed up the patients until September 2011. The changes in LV function parameters before and after the treatment were evaluated by echocardiography. Results The mean age at the start of treatment with enalapril or carvedilol was 12.6±3.7 years (median 13 years), and mean follow-up duration was 20.1±8.9 months. In the enalapril group, LV fractional shortening (FS) increased from 25.8±2.1 to 26.6±3.0 (p=0.241). In the carvedilol group, LV FS increased from 26.4±1.1 to 28.6±4.2 (p=0.110). In all 23 patients, LV FS significantly increased from 26.1±1.7 (before) to 27.6±3.7 (after treatment) (p<0.046). Indexed LV dimension at end diastole and LV end-diastolic volume decreased slightly, but without statistical significance by tri-plane volumetry. LV diastolic functional parameters were maintained during follow-up period. Conclusion Enalapril or carvedilol could improve LV systolic function in middle childhood and adolescent patients with muscular dystrophy without significant adverse effects. PMID:22493613

Kwon, Hye Won; Kwon, Bo Sang; Kim, Gi Beom; Chae, Jong Hee; Park, June Dong; Bae, Eun Jung

2012-01-01

280

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

PubMed Central

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

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

2013-01-01

281

Muscular dystrophy  

MedlinePLUS

... is a group of inherited disorders that cause muscle weakness and loss of muscle tissue, which get worse over time. ... of strength in a muscle or group of muscles as an adult Loss in muscle size Problems walking (delayed walking) Intellectual ...

282

Muscular Dystrophy  

MedlinePLUS

... inherited diseases. They all cause muscle weakness and muscle loss. Some forms of MD appear in infancy or childhood. Others may not appear until middle age or later. The different types can vary in whom they affect, which muscles they affect, and what the symptoms are. All ...

283

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, Ruben; Raichle, Katherine A.; Jensen, Mark P.; Miro, Jordi

2011-01-01

284

Congenital generalized lipodystrophy type 4 with muscular dystrophy: clinical and pathological manifestations in early childhood.  

PubMed

A boy with congenital generalized lipodystrophy type 4 with muscular dystrophy presented in infancy with delay in motor milestones and a persistent elevation of CK. There was no associated mental retardation. He was followed up to 3 years and 11 months; he had a homozygous c.696_697insC mutation in polymerase I and transcript release factor (PTRF). He started to walk at 2 years and 6 months although he did not have mental retardation. Insulin resistance appeared at 3 years and 11 months of age. PTRF immunostaining positivity was absent in the muscle but caveolin-3 was preserved in the sarcolemma at 16 months of age. Secondary deficiency of caveolins may be closely associated with disease progression. PMID:23489663

Murakami, Nobuyuki; Hayashi, Yukiko K; Oto, Yuji; Shiraishi, Masahisa; Itabashi, Hisashi; Kudo, Kyoko; Nishino, Ichizo; Nonaka, Ikuya; Nagai, Toshiro

2013-05-01

285

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.

Stollberger, Claudia; Gatterer, Edmund; Jakubiczka, Sibylle

2014-01-01

286

Gene diagnosis of oculopharyngeal muscular dystrophy in a Chinese family by a GeneScan method.  

PubMed

This study aims to perform gene diagnosis for Chinese family patients with Oculopharyngeal muscular dystrophy (OPMD). Genomic DNAs were extracted from the pedigrees' members. Gene diagnosis was performed for these pedigrees' members by approaches, such as DNA sequencing and GeneScan. Sequence analysis and PABPN1 genotyping showed that the mutated allele in affected members of this family has nine trinucleotide repeats of GCG (GCG)(9), whereas the normal allele contains six trinucleotide repeats of GCG (GCG)(6). The above results suggest that mutated GCG repeats in PABPN1 gene may cause OPMD in this family, and PABPN1 genotyping could be used as a convenient, highly effective, and reliable gene diagnostic test for OPMD patients. PMID:21089175

You, Pan; Ma, Qilin; Tao, Tao

2010-01-01

287

Mutation and haplotype analysis of oculopharyngeal muscular dystrophy in Thai patients.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an inherited neuromuscular disease associated with a short trinucleotide repeat expansion in Exon 1 of the PABPN1 gene. OPMD is uncommon in East Asian populations, and there have been no previous reports of Thai patients. We studied clinical and molecular genetic features of six unrelated Thai patients with autosomal dominant OPMD. All patients had expansions of the guanine-cytosine-guanine (GCG) repeat ranging from three to seven additional repeats in the PABPN1 gene. Haplotype analysis showed that these mutations might have originated independently. Analysis of the size of the GCG repeat in the PABPN1 gene in 200 Thai control patients showed that 0.5% of the control subjects possessed (GCG)(7), thereby suggesting that the prevalence of autosomal recessive OPMD in the Thai population was approximately 1 in 160,000. In conclusion, our data suggest that OPMD in Thailand may be more common than previously thought. PMID:21316245

Pulkes, T; Papsing, C; Busabaratana, M; Dejthevaporn, C; Witoonpanich, R

2011-05-01

288

Progressive myopathy in an inducible mouse model of oculopharyngeal muscular dystrophy.  

PubMed

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

2012-01-01

289

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

290

Robust analysis in joint models: an application to a study on muscular dystrophy.  

PubMed

Generalized partial ordinal models occur frequently in biomedical investigations where, along with ordinal longitudinal outcomes, there are time-dependent covariates that act nonparametrically. In these studies, an association between such outcomes and time to an event is of considerable interest to medical practitioners. The primary objective in the present article is to study the robustness of estimators of the parameters of interest in a joint generalized partial ordinal models and a time-to-event model, because in many situations, the estimators in such joint models are sensitive to outliers. A Monte Carlo Metropolis-Hastings Newton Raphson algorithm is proposed for robust estimation. A detailed simulation study was performed to justify the behavior of the proposed estimators. By way of motivation, we consider a data set concerning longitudinal outcomes of children involved in a study on muscular dystrophy. Our analysis revealed some interesting findings that may be useful to medical practitioners. PMID:22815236

Das, Kalyan; Chakraborty, Arindom

2012-12-20

291

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

292

Telomere Position Effect (TPE) Regulates DUX4 in Human Facioscapulohumeral Muscular Dystrophy (FSHD)  

PubMed Central

Telomeres may regulate human disease by at least two independent mechanisms. 1) Replicative senescence occurs once short telomeres generate DNA damage signals that produce a barrier to tumor progression. 2) Telomere Position Effect (TPE) can change gene expression at intermediate telomere lengths in cultured human cells. We here report a human disease, facioscapulohumeral muscular dystrophy (FSHD) where telomere length may well contribute to its pathogenesis. FSHD is age-related and genetically only 25-60 kb from the end of chromosome 4q. We used a floxable telomerase to generate isogenic clones with different telomere lengths from patients and their unaffected siblings. DUX4, the primary candidate for FSHD pathogenesis, is upregulated >10-fold in FSHD myoblasts-myotubes with short versus long telomeres, and its expression is inversely proportional to telomere length. FSHD may represent a human disease in which TPE contributes to its age-related phenotype. PMID:23644600

Stadler, Guido; Rahimov, Fedik; King, Oliver D.; Chen, Jennifer C. J.; Robin, Jerome D.; Wagner, Kathryn R.; Shay, Jerry W.; Emerson, Charles P.; Wright, Woodring E.

2013-01-01

293

Circulating Muscle-specific miRNAs in Duchenne Muscular Dystrophy Patients.  

PubMed

Noninvasive biomarkers with diagnostic value and prognostic applications have long been desired to replace muscle biopsy for Duchenne muscular dystrophy (DMD) patients. Growing evidence indicates that circulating microRNAs are biomarkers to assess pathophysiological status. Here, we show that the serum levels of six muscle-specific miRNAs (miR-1/206/133/499/208a/208b, also known as myomiRs) were all elevated in DMD patients (P < 0.01). The receiver operating characteristic curves of circulating miR-206, miR-499, miR-208b, and miR-133 levels reflected strong separation between Becker's muscular dystrophy (BMD) and DMD patients (P < 0.05). miR-206, miR-499, and miR-208b levels were positively correlated with both age and type IIc muscle fiber content in DMD patients (2-6 years), indicating that they might represent the stage of disease as well as the process of regeneration. miR-499 and miR-208b levels were correlated with slow and fast fiber content and might reflect the ratio of slow to fast fibers in DMD patient (>6 years). Fibroblast growth factor, transforming growth factor-?, and tumor necrosis factor-? could affect the secretion of myomiRs, suggesting that circulating myomiRs might reflect the effects of cytokines and growth factors on degenerating and regenerating muscles. Collectively, our data indicated that circulating myomiRs could serve as promising biomarkers for DMD diagnosis and disease progression. PMID:25050825

Li, Xihua; Li, Yuying; Zhao, Lei; Zhang, Duo; Yao, Xuan; Zhang, Huihui; Wang, Yu-Cheng; Wang, Xin-Yi; Xia, Hongfeng; Yan, Jun; Ying, Hao

2014-01-01

294

[Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].  

PubMed

Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD. PMID:22068479

Kamauchi, Shinya; Urade, Yoshihiro

2011-11-01

295

SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy  

PubMed Central

Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-? (TGF?) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGF? signaling is pathogenic in the muscle itself. Drosophila deleted for the ?/?-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGF? activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGF? signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction. PMID:21138941

Goldstein, Jeffery A.; Kelly, Sean M.; LoPresti, Peter P.; Heydemann, Ahlke; Earley, Judy U.; Ferguson, Edwin L.; Wolf, Matthew J.; McNally, Elizabeth M.

2011-01-01

296

SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophy.  

PubMed

Loss-of-function mutations in the genes encoding dystrophin and the associated membrane proteins, the sarcoglycans, produce muscular dystrophy and cardiomyopathy. The dystrophin complex provides stability to the plasma membrane of striated muscle during muscle contraction. Increased SMAD signaling due to activation of the transforming growth factor-? (TGF?) pathway has been described in muscular dystrophy; however, it is not known whether this canonical TGF? signaling is pathogenic in the muscle itself. Drosophila deleted for the ?/?-sarcoglycan gene (Sgcd) develop progressive muscle and heart dysfunction and serve as a model for the human disorder. We used dad-lacZ flies to demonstrate the signature of TGF? activation in response to exercise-induced injury in Sgcd null flies, finding that those muscle nuclei immediately adjacent to muscle injury demonstrate high-level TGF? signaling. To determine the pathogenic nature of this signaling, we found that partial reduction of the co-SMAD Medea, homologous to SMAD4, or the r-SMAD, Smox, corrected both heart and muscle dysfunction in Sgcd mutants. Reduction in the r-SMAD, MAD, restored muscle function but interestingly not heart function in Sgcd mutants, consistent with a role for activin but not bone morphogenic protein signaling in cardiac dysfunction. Mammalian sarcoglycan null muscle was also found to exhibit exercise-induced SMAD signaling. These data demonstrate that hyperactivation of SMAD signaling occurs in response to repetitive injury in muscle and heart. Reduction of this pathway is sufficient to restore cardiac and muscle function and is therefore a target for therapeutic reduction. PMID:21138941

Goldstein, Jeffery A; Kelly, Sean M; LoPresti, Peter P; Heydemann, Ahlke; Earley, Judy U; Ferguson, Edwin L; Wolf, Matthew J; McNally, Elizabeth M

2011-03-01

297

Developmental Changes in the ECG of a Hamster Model of Muscular Dystrophy and Heart Failure  

PubMed Central

Aberrant autonomic signaling is being increasingly recognized as an important symptom in neuromuscular disorders. The ?-sarcoglycan-deficient BIO TO-2 hamster is recognized as a good model for studying mechanistic pathways and sequelae in muscular dystrophy and heart failure, including autonomic nervous system (ANS) dysfunction. Recent studies using the TO-2 hamster model have provided promising preclinical results demonstrating the efficacy of gene therapy to treat skeletal muscle weakness and heart failure. Methods to accelerate preclinical testing of gene therapy and new drugs for neuromuscular diseases are urgently needed. The purpose of this investigation was to demonstrate a rapid non-invasive screen for characterizing the ANS imbalance in dystrophic TO-2 hamsters. Electrocardiograms were recorded non-invasively in conscious ?9-month old TO-2 hamsters (n?=?10) and non-myopathic F1B control hamsters (n?=?10). Heart rate was higher in TO-2 hamsters than controls (453?±?12?bpm vs. 311?±?25?bpm, P?muscular dystrophies. PMID:22629245

Hampton, Thomas G.; Kale, Ajit; McCue, Scott; Bhagavan, Hemmi N.; VanDongen, Case

2012-01-01

298

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

PubMed

In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4(+)CD49d(hi) T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease. PMID:25261568

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

2014-11-01

299

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

PubMed Central

In the translational process of developing innovative therapies for DMD (Duchenne muscular dystrophy), the last preclinical validation step is often carried out in the most relevant animal model of this human disease, namely the GRMD (Golden Retriever muscular dystrophy) dog. The disease in GRMD dogs mimics human DMD in many aspects, including the inter-individual heterogeneity. This last point can be seen as a drawback for an animal model but is inherently related to the disease in GRMD dogs closely resembling that of individuals with DMD. In order to improve the management of this inter-individual heterogeneity, we have screened a combination of biomarkers in sixty-one 2-month-old GRMD dogs at the onset of the disease and a posteriori we addressed their predictive value on the severity of the disease. Three non-invasive biomarkers obtained at early stages of the disease were found to be highly predictive for the loss of ambulation before 6 months of age. An elevation in the number of circulating CD4+CD49dhi T cells and a decreased stride frequency resulting in a reduced spontaneous speed were found to be strongly associated with the severe clinical form of the disease. These factors can be used as predictive tests to screen dogs to separate them into groups with slow or fast disease progression before their inclusion into a therapeutic preclinical trial, and therefore improve the reliability and translational value of the trials carried out on this invaluable large animal model. These same biomarkers have also been described to be predictive for the time to loss of ambulation in boys with DMD, strengthening the relevance of GRMD dogs as preclinical models of this devastating muscle disease. PMID:25261568

Barthelemy, Ines; Pinto-Mariz, Fernanda; Yada, Erica; Desquilbet, Loic; Savino, Wilson; Silva-Barbosa, Suse Dayse; Faussat, Anne-Marie; Mouly, Vincent; Voit, Thomas; Blot, Stephane; Butler-Browne, Gillian

2014-01-01

300

Myogenic differentiation of muscular dystrophy-specific induced pluripotent stem cells for use in drug discovery.  

PubMed

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; Flynn, Peter

2014-02-01

301

DUX4, a Candidate Gene for Facioscapulohumeral Muscular Dystrophy, Causes p53-Dependent Myopathy In Vivo  

PubMed Central

Objective Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading FSHD pathogenesis models, D4Z4 contractions are proposed to cause epigenetic changes, which ultimately increase expression of genes with myopathic potential. Although no gene has been conclusively linked to FSHD development, recent evidence supports a role for the D4Z4-encoded DUX4 gene in FSHD. In this study, our objective was to test the in vivo myopathic potential of DUX4. Methods We delivered DUX4 to zebrafish and mouse muscle by transposon-mediated transgenesis and adeno-associated viral vectors, respectively. Results Overexpression of DUX4, which encodes a transcription factor, caused abnormalities associated with muscular dystrophy in zebrafish and mice. This toxicity required DNA binding, because a DUX4 DNA binding domain mutant produced no abnormalities. Importantly, we found the myopathic effects of DUX4 were p53 dependent, as p53 inhibition mitigated DUX4 toxicity in vitro, and muscles from p53 null mice were resistant to DUX4-induced damage. Interpretation Our work demonstrates the myopathic potential of DUX4 in animal muscle. Considering previous studies showed DUX4 was elevated in FSHD patient muscles, our data support the hypothesis that DUX4 overexpression contributes to FSHD development. Moreover, we provide a p53-dependent mechanism for DUX4 toxicity that is consistent with previous studies showing p53 pathway activation in FSHD muscles. Our work justifies further investigation of DUX4 and the p53 pathway in FSHD pathogenesis. PMID:21446026

Wallace, Lindsay M.; Garwick, Sara E.; Mei, Wenyan; Belayew, Alexandra; Coppee, Frederique; Ladner, Katherine J.; Guttridge, Denis; Yang, Jing; Harper, Scott Q.

2014-01-01

302

PKC Theta Ablation Improves Healing in a Mouse Model of Muscular Dystrophy  

PubMed Central

Inflammation is a key pathological characteristic of dystrophic muscle lesion formation, limiting muscle regeneration and resulting in fibrotic and fatty tissue replacement of muscle, which exacerbates the wasting process in dystrophic muscles. Limiting immune response is thus one of the therapeutic options to improve healing, as well as to improve the efficacy of gene- or cell-mediated strategies to restore dystrophin expression. Protein kinase C ? (PKC?) is a member of the PKCs family highly expressed in both immune cells and skeletal muscle; given its crucial role in adaptive, but also innate, immunity, it is being proposed as a valuable pharmacological target for immune disorders. In our study we asked whether targeting PKC? could represent a valuable approach to efficiently prevent inflammatory response and disease progression in a mouse model of muscular dystrophy. We generated the bi-genetic mouse model mdx/??/?, where PKC? expression is lacking in mdx mice, the mouse model of Duchenne muscular dystrophy. We found that muscle wasting in mdx/??/? mice was greatly prevented, while muscle regeneration, maintenance and performance was significantly improved, as compared to mdx mice. This phenotype was associated to reduction in inflammatory infiltrate, pro-inflammatory gene expression and pro-fibrotic markers activity, as compared to mdx mice. Moreover, BM transplantation experiments demonstrated that the phenotype observed was primarily dependent on lack of PKC? expression in hematopoietic cells. These results demonstrate a hitherto unrecognized role of immune-cell intrinsic PKC? activity in the development of DMD. Although the immune cell population(s) involved remain unidentified, our findings reveal that PKC? can be proposed as a new pharmacological target to counteract the disease, as well as to improve the efficacy of gene- or cell- therapy approaches. PMID:22348094

Madaro, Luca; Pelle, Andrea; Nicoletti, Carmine; Crupi, Annunziata; Marrocco, Valeria; Bossi, Gianluca; Soddu, Silvia; Bouche, Marina

2012-01-01

303

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

304

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

305

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

306

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

307

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

308

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

Microsoft Academic Search

Deletion mutations of the dystrophin gene may cause either the severe Duchenne muscular dystrophy (DMD) or the milder, allelic Becker muscular dystrophy (BMD) and are clustered in two high-frequency-deletion regions (HFDRs) located, respectively, 500 kb and 1,200 kb downstream from the 5[prime] end of the gene. Three PCR reactions described allowed the analysis of a total of 30 exons and

Risch

1992-01-01

309

Distinguishing the 4qA and 4qB variants is essential for the diagnosis of facioscapulohumeral muscular dystrophy in the Chinese population  

Microsoft Academic Search

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common inherited muscular dystrophy with markedly clinical variability and complex genetic cause. Several reports pertaining to the Caucasian population have confirmed that there are 4qA and 4qB variants of the 4qter subtelomere, and FSHD is uniquely associated with the 4qA variant. However, few data relevant to the Chinese population have been published.

Zhi-Qiang Wang; Ning Wang; Silvere van der Maarel; Shen-Xing Murong; Zhi-Ying Wu; Z-Y Wu

2011-01-01

310

Differences in carrier frequency between mothers of Duchenne and Becker muscular dystrophy patients  

PubMed Central

Duchenne and Becker muscular dystrophies (DMD/BMD) are X-linked inherited muscular disorders caused by mutations in the dystrophin gene. Two-thirds of DMD cases are thought to be caused by inheritance from carrier mothers and this study aimed to clarify and compare the carrier frequency of mothers of DMD and BMD patients according to the mutation type. We included 139 DMD and 19 BMD mothers. Of these, 113 patients (99 DMD and 14 BMD) and 13 patients (12 DMD and 1 BMD) had deletions and duplications of one or more exons, respectively. Small mutations, including nonsense mutations, small deletions/insertions and splice site mutations, were identified in 32 patients (28 DMD and four BMD). The overall carrier frequency for BMD mothers was significantly higher than for DMD (89.5% vs 57.6%, P<0.05), probably as BMD patients can leave descendants. The carrier frequency tended to be lower in mothers of DMD patients with deletion mutations than with duplications and small mutations (53.5%, 66.7% and 67.9%, respectively). It was suggested that de novo mutations are more prevalent for deletions than other mutations. This is the first report to analyze the carrier frequency according to mutation type. PMID:24225992

Lee, Tomoko; Takeshima, Yasuhiro; Kusunoki, Noriko; Awano, Hiroyuki; Yagi, Mariko; Matsuo, Masafumi; Iijima, Kazumoto

2014-01-01

311

A point mutation in the glycerol kinase gene associated with a deletion in the dystrophin gene in a familial X-linked muscular dystrophy: non-contiguous gene syndrome involving Becker muscular dystrophy and glycerol kinase loci  

Microsoft Academic Search

We report a family with an X-linked recessive muscular dystrophy characterised by exercise-induced myalgia, recurrent pigmenturia and mild proximal muscle involvement. Immunocytochemical and immunoblotting analysis in muscle, using the antibody directed against the rod domain of dystrophin, revealed a loss of immunoreactivity, but the immunolabelling using the antibodies directed against the COOH and NH2 domains of dystrophin were almost normal.

Norma Beatriz Romero; Dominique Récan; Odile Rigal; Stéphane Llense; Jean-Claude Barbot; Nathalie Deburgrave; Marie Armelle Cheval; Françoise Deniau; Jean-Claude Kaplan

1997-01-01

312

AMP-activated protein kinase at the nexus of therapeutic skeletal muscle plasticity in Duchenne muscular dystrophy.  

PubMed

Recent studies have highlighted the potential of adenosine monophosphate-activated protein kinase (AMPK) to act as a central therapeutic target in Duchenne muscular dystrophy (DMD). Here, we review the role of AMPK as an important integrator of cell signaling pathways that mediate phenotypic plasticity within the context of dystrophic skeletal muscle. Pharmacological AMPK activation remodels skeletal muscle towards a slower, more oxidative phenotype, which is more pathologically resistant to the lack of dystrophin. Moreover, recent studies suggest that AMPK-activated autophagy may be beneficial for myofiber structure and function in mice with muscular dystrophy. Thus, AMPK may represent an ideal target for intervention because clinically approved pharmacological agonists exist, and because benefits can be derived via two independent yet, complementary biological pathways. The availability of several AMPK activators could therefore lead to the rapid development and implementation of novel and highly effective therapeutics aimed at altering the relentless progression of DMD. PMID:23891277

Ljubicic, Vladimir; Jasmin, Bernard J

2013-10-01

313

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

314

Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene.  

PubMed

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. PMID:21972111

Flanigan, Kevin M; Dunn, Diane M; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T; Sampson, Jacinda B; Swoboda, Kathryn J; Bromberg, Mark B; Mendell, Jerry R; Taylor, Laura E; Anderson, Christine B; Pestronk, Alan; Florence, Julaine M; Connolly, Anne M; Mathews, Katherine D; Wong, Brenda; Finkel, Richard S; Bonnemann, Carsten G; Day, John W; McDonald, Craig; Weiss, Robert B

2011-03-01

315

Non-surgical prevention and management of scoliosis for children with Duchenne muscular dystrophy: What is the evidence?  

PubMed

A review was performed to examine the evidence for non-surgical interventions for preventing scoliosis and the need for scoliosis surgery in children with Duchenne muscular dystrophy. Medline and Embase databases and reference lists from key articles were searched. After the inclusion and exclusion criteria were applied, 13 studies were critically appraised independently by two reviewers. The included studies examined spinal orthoses and steroid therapy. There were no studies with high levels of evidence (randomised or other controlled trials). The studies with the highest level of evidence were non-randomised experimental trials. There is some evidence that children with Duchenne muscular dystrophy who receive steroid therapy might have delayed onset of scoliosis, but more evidence is required about the long-term risks versus benefits of this intervention. There is weak evidence that spinal orthoses do not prevent and only minimally delay the onset of scoliosis. PMID:23560735

Harvey, Adrienne; Baker, Louise; Williams, Katrina

2014-10-01

316

Nonsense mutation-associated Becker muscular dystrophy: interplay between exon definition and splicing regulatory elements within the DMD gene  

PubMed Central

Nonsense mutations are usually predicted to function as null alleles due to premature termination of protein translation. However, nonsense mutations in the DMD gene, encoding the dystrophin protein, have been associated with both the severe Duchenne Muscular Dystrophy (DMD) and milder Becker Muscular Dystrophy (BMD) phenotypes. In a large survey, we identified 243 unique nonsense mutations in the DMD gene, and for 210 of these we could establish definitive phenotypes. We analyzed the reading frame predicted by exons flanking those in which nonsense mutations were found, and present evidence that nonsense mutations resulting in BMD likely do so by inducing exon skipping, confirming that exonic point mutations affecting exon definition have played a significant role in determining phenotype. We present a new model based on the combination of exon definition and intronic splicing regulatory elements for the selective association of BMD nonsense mutations with a subset of DMD exons prone to mutation-induced exon skipping. PMID:21972111

Flanigan, Kevin M.; Dunn, Diane M.; von Niederhausern, Andrew; Soltanzadeh, Payam; Howard, Michael T.; Sampson, Jacinda B.; Swoboda, Kathryn J.; Bromberg, Mark B.; Mendell, Jerry R.; Taylor, Laura; Anderson, Christine B.; Pestronk, Alan; Florence, Julaine; Connolly, Anne M.; Mathews, Katherine D.; Wong, Brenda; Finkel, Richard S.; Bonnemann, Carsten G.; Day, John W.; McDonald, Craig; Weiss, Robert B.

2013-01-01

317

Recombinant adeno-associated viral (rAAV) vectors as therapeutic tools for Duchenne muscular dystrophy (DMD)  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a lethal genetic muscle disorder caused by recessive mutations in the dystrophin gene. The size of the gene (2.4 Mb) and mRNA (14 kb) in addition to immunogenicity problems and inefficient transduction of mature myofibres by currently available vector systems are formidable obstacles to the development of efficient gene therapy approaches. Adeno-associated viral (AAV) vectors

T Athanasopoulos; IR Graham; H Foster; G Dickson

2004-01-01

318

A quantitative polymerase chain reaction (PCR) assay completely discriminates between Duchenne and Becker muscular dystrophy deletion carriers and normal females  

Microsoft Academic Search

Duchenne\\/Becker muscular dystrophy (DMD\\/BMD) is a severe X-linked myopathy. In 65% of the patients, the mutations responsible for the disease are macrodeletions in the dystrophin-encoding gene that can be identified with multiplex polymerase chain reaction (PCR) technology. We developed a method for quantitative PCR analysis of deletion carriers involving the use of phosphorimager-based scanning of radioactive-labelled PCR products. We calculated

Lucio Pastore; Maria Gabriella Caporaso; Giulia Frisso; Anna Orsini; Lucio Santoro; Lucia Sacchetti; Francesco Salvatore

1996-01-01

319

Tandem duplications of two separate fragments of the dystrophin gene in a patient with Duchenne muscular dystrophy  

Microsoft Academic Search

Mutations in the dystrophin gene result in the most common inherited muscle disease, Duchenne muscular dystrophy (DMD). Duplications\\u000a spanning one or more exons have been found to be the second most common disease-causing mutation in the dystrophin gene. Although\\u000a the duplicated exons are commonly thought to be arranged in tandem, rare noncontiguous exon duplications have been disclosed\\u000a without clarifying their

Zhujun Zhang; Yasuhiro Takeshima; Hiroyuki Awano; Atsushi Nishiyama; Yo Okizuka; Mariko Yagi; Masafumi Matsuo

2008-01-01

320

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

321

Wild-type PABPN1 is anti-apoptotic and reduces toxicity of the oculopharyngeal muscular dystrophy mutation  

Microsoft Academic Search

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive disease caused by the abnormal expansion of a polyalanine tract-encoding (GCG)n trinucleotide repeat in the poly-(A) binding protein nuclear 1( PABPN1) gene. OPMD is generally inherited as an autosomal dominant disorder and the polyalanine expansion mutation is thought to confer a toxic gain-of-function on mutant PABPN1 which forms aggregates within skeletal myocyte

Janet E. Davies; Sovan Sarkar; David C. Rubinsztein

2008-01-01

322

Localization of laminin subunits in the central nervous system in Fukuyama congenital muscular dystrophy: an immunohistochemical investigation  

Microsoft Academic Search

We have undertaken an immunohistochemical study of laminin subunits in the central nervous system (CNS) of fetuses and patients\\u000a with Fukuyama congenital muscular dystrophy (FCMD) and of controls including five fetuses. Immunoreaction product deposits\\u000a with antibodies to laminin ?1, ?2, ?1 and ?1, and ?-dystroglycan were detected on the surface and vessels of the CNS of controls.\\u000a No staining with

Tomoko Yamamoto; Noriyuki Shibata; Miho Kanazawa; Makio Kobayashi; Takashi Komori; Kiyoko Ikeya; Eri Kondo; Kayoko Saito; Makiko Osawa

1997-01-01

323

Heterogeneity of Classic Congenital Muscular Dystrophy With Involvement of the Central Nervous System: Report of Five Atypical Cases  

Microsoft Academic Search

A heterogeneous group of patients with congenital muscular dystrophy associated with clinical or radiologic central nervous system involvement other than the severe classic form with merosin deficiency, muscle-eye-brain disease, and Walker-Warburg syndrome is described. A probable hereditary or familial occurrence could be suggested in all patients. One merosin-positive patient presented severe motor incapacity and cerebral atrophy without any clinical manifestation

Umbertina C. Reed; Suely K. Nagahashi Marie; Mariz Vainzof; Lucio F. Gobbo; Juliana E. P. Gurgel; Mary S. Carvalho; Maria Bernadete D. Resende; Adriana A. Espíndola; Mayana Zatz; Aron Diament

2000-01-01

324

Over-expression of BCL2 rescues muscle weakness in a mouse model of oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy caused by a polyalanine expansion mutation in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene. In unaffected individuals, (GCG)(6) encodes the first 6 alanines in a homopolymeric stretch of 10 alanines. In most patients, this (GCG)(6) repeat is expanded to (GCG)(8-13), leading to a stretch of 12-17 alanines in mutant PABPN1, which is thought to confer a toxic gain of function. Thus, OPMD has been modelled by expressing mutant PABPN1 transgenes in the presence of endogenous copies of the gene in cells and mice. In these models, increased apoptosis is seen, but it is unclear whether this process mediates OPMD. The role of apoptosis in the pathogenesis of different muscular dystrophies is unclear. Blocking apoptosis ameliorates muscle disease in some mouse models of muscular dystrophy such as laminin ?-2-deficient mice, but not in others such as dystrophin-deficient (mdx) mice. Here we demonstrate that apoptosis is not only involved in the pathology of OPMD but also is a major contributor to the muscle weakness and dysfunction in this disease. Genetically blocking apoptosis by over-expressing BCL2 ameliorates muscle weakness in our mouse model of OPMD (A17 mice). The effect of BCL2 co-expression on muscle weakness is transient, since muscle weakness is apparent in mice expressing both A17 and BCL2 transgenes at late time points. Thus, while apoptosis is a major pathway that causes muscle weakness in OPMD, other cell death pathways may also contribute to the disease when apoptosis is inhibited. PMID:21199860

Davies, Janet E; Rubinsztein, David C

2011-03-15

325

Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin  

Microsoft Academic Search

Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A–H (refs 2–10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the

Eloisa S. Moreira; Tim J. Wiltshire; Georgine Faulkner; Antje Nilforoushan; Mariz Vainzof; Oscar T. Suzuki; Giorgio Valle; Roger Reeves; Mayana Zatz; Dieter E. Jenne; M. R. Passos-Bueno

2000-01-01

326

261. Recombinant Adeno-Associated Viral (rAAV) Microdystrophin Vectors as Therapeutic Tools for Duchenne Muscular Dystrophy (DMD)  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a lethal genetic muscle disorder affecting 1:3500 male individuals, caused by recessive mutations in the dystrophin gene. The size of the gene (2.4Mb) and mRNA (14kb) in addition to immunogenicity problems and inefficient transduction of mature myofibres by currently available vector systems (that could incorporate the full dystrophin cDNA cassette) are formidable obstacles to the

Takis Athanasopoulos; Ian Graham; Helen Foster; Norma Perez; Adelin Vulin; Vanessa Hill; Stewart Fabb; Luis Garcia; Olivier Danos; George Dickson

2005-01-01

327

Nitric oxide release combined with nonsteroidal antiinflammatory activity prevents muscular dystrophy pathology and enhances stem cell therapy  

Microsoft Academic Search

Duchenne muscular dystrophy is a relatively common disease that affects skeletal muscle, leading to progressive paralysis and death. There is currently no resolutive therapy. We have developed a treatment in which we combined the effects of nitric oxide with nonsteroidal antiinflammatory activity by using HCT 1026, a nitric oxide-releasing derivative of flurbiprofen. Here, we report the results of long-term (1-year)

Silvia Brunelli; Clara Sciorati; G. D'Antona; Anna Innocenzi; Diego Covarello; B. G. Galvez; Cristiana Perrotta; Angela Monopoli; Francesca Sanvito; Roberto Bottinelli; Ennio Ongini; Giulio Cossu; Emilio Clementi

2007-01-01

328

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

PubMed Central

Background Cardiomyopathy is reported in Duchenne and Becker muscle dystrophy patients and female carriers. Brain Natriuretic peptide (BNP) is a hormone produced mainly by ventricular cardiomyocytes and its production is up regulated in reaction to increased wall stretching. N-terminal-proBNP (NT-proBNP) has been shown to be a robust laboratory parameter to diagnose and monitor cardiac failure, and it may be helpful to screen for asymptomatic left ventricular dysfunction. Therefore we tested whether NT-proBNP can distinguish patients with Duchenne or Becker muscular dystrophy patients and carriers of a dystrophin mutation with a dilated cardiomyopathy from those without. Methods In a cohort of Duchenne and Becker muscle dystrophy patients (n?=?143) and carriers (n?=?219) NT-proBNP was measured, and echocardiography was performed to diagnose dilated cardiomyopathy (DCM). Results In total sixty-one patients (17%) fulfilled the criteria for DCM, whereas 283 patients (78%) had an elevated NT-pro BNP. The sensitivity of NT-proBNP for DCM in patients or carriers was 85%, the specificity 23%, area under the ROC-curve?=?0.56. In the specified subgroups there was also no association. Conclusion Measurement of NT-pro BNP in patients suffering from Duchenne or Becker muscular dystrophy and carriers does not distinguish between those with and without dilated cardiomyopathy. PMID:23870371

2013-01-01

329

Dysferlin Deficiency and the Development of Cardiomyopathy in a Mouse Model of Limb-Girdle Muscular Dystrophy 2B  

PubMed Central

Limb-girdle muscular dystrophy 2B, Miyoshi myopathy, and distal myopathy of anterior tibialis are severely debilitating muscular dystrophies caused by genetically determined dysferlin deficiency. In these muscular dystrophies, it is the repair, not the structure, of the plasma membrane that is impaired. Though much is known about the effects of dysferlin deficiency in skeletal muscle, little is known about the role of dysferlin in maintenance of cardiomyocytes. Recent evidence suggests that dysferlin deficiency affects cardiac muscle, leading to cardiomyopathy when stressed. However, neither the morphological location of dysferlin in the cardiomyocyte nor the progression of the disease with age are known. In this study, we examined a mouse model of dysferlinopathy using light and electron microscopy as well as echocardiography and conscious electrocardiography. We determined that dysferlin is normally localized to the intercalated disk and sarcoplasm of the cardiomyocytes. In the absence of dysferlin, cardiomyocyte membrane damage occurs and is localized to the intercalated disk and sarcoplasm. This damage results in transient functional deficits at 10 months of age, but, unlike in skeletal muscle, the cell injury is sublethal and causes only mild cardiomyopathy even at advanced ages. PMID:19875504

Chase, Thomas H.; Cox, Gregory A.; Burzenski, Lisa; Foreman, Oded; Shultz, Leonard D.

2009-01-01

330

Safety and Feasibility of High-pressure Transvenous Limb Perfusion With 0.9% Saline in Human Muscular Dystrophy  

PubMed Central

We evaluated safety and feasibility of the transvenous limb perfusion gene delivery method in muscular dystrophy. A dose escalation study of single limb perfusion with 0.9% saline starting with 5% of limb volume was carried out in adults with muscular dystrophies under intravenous analgesia/anesthesia. Cardiac, vascular, renal, muscle, and nerve functions were monitored. A tourniquet was placed above the knee with inflated pressure of 310 mm Hg. Infusion was carried out with a clinically approved infuser via an intravenous catheter inserted in the saphenous vein with a goal infusion rate of 80 ml/minute. Infusion volume was escalated stepwise to 20% limb volume in seven subjects. No subject complained of any post procedure pain other than due to needle punctures. Safety warning boundaries were exceeded only for transient depression of limb tissue oximetry and transient elevation of muscle compartment pressures; these were not associated with nerve, muscle, or vascular damage. Muscle magnetic resonant imaging (MRI) demonstrated fluid accumulation in muscles of the perfused lower extremity. High-pressure retrograde transvenous limb perfusion with saline up to 20% of limb volume at above infusion parameters is safe and feasible in adult human muscular dystrophy. This study will serve as a basis for future gene transfer clinical trials. PMID:21772257

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

2012-01-01

331

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

PubMed Central

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

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

1994-01-01

332

Divergence of Central Nervous System Involvement in 2 Italian Sisters with Congenital Muscular Dystrophy: A Clinical and Neuroradiological Follow-Up  

Microsoft Academic Search

We report the clinical and neuroradiological follow-up of 2 Italian sisters, 10 and 6 years of age, affected by congenital muscular dystrophy (CMD) with divergent CNS involvement. In both, CMD was diagnosed by finding dystrophic alterations in muscle biopsy and muscular deficit at birth. The elder sister suffered also from marked intellectual deficit and epilepsy, as usually reported in children

Carlo P. Trevisan; Francesco Martinello; Emilia Ferruzza; Corrado Angelini

1995-01-01

333

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

334

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

335

Longitudinal assessment of grip strength using bulb dynamometer in Duchenne Muscular Dystrophy  

PubMed Central

BACKGROUND: Grip strength is used to infer functional status in several pathological conditions, and the hand dynamometer has been used to estimate performance in other areas. However, this relationship is controversial in neuromuscular diseases and studies with the bulb dynamometer comparing healthy children and children with Duchenne Muscular Dystrophy (DMD) are limited. OBJECTIVE: The evolution of grip strength and the magnitude of weakness were examined in boys with DMD compared to healthy boys. The functional data of the DMD boys were correlated with grip strength. METHOD: Grip strength was recorded in 18 ambulant boys with DMD (Duchenne Group, DG) aged 4 to 13 years (mean 7.4±2.1) and 150 healthy volunteers (Control Group, CG) age-matched using a bulb dynamometer (North Coast- NC70154). The follow-up of the DG was 6 to 33 months (3-12 sessions), and functional performance was verified using the Vignos scale. RESULTS: There was no difference between grip strength obtained by the dominant and non-dominant side for both groups. Grip strength increased in the CG with chronological age while the DG remained stable or decreased. The comparison between groups showed significant difference in grip strength, with CG values higher than DG values (confidence interval of 95%). In summary, there was an increment in the differences between the groups with increasing age. Participants with 24 months or more of follow-up showed a progression of weakness as well as maintained Vignos scores. CONCLUSIONS: The amplitude of weakness increased with age in the DG. The bulb dynamometer detected the progression of muscular weakness. Functional performance remained virtually unchanged in spite of the increase in weakness. PMID:25003277

Pizzato, Tatiana M.; Baptista, Cyntia R. J. A.; Souza, Mariana A.; Benedicto, Michelle M. B.; Martinez, Edson Z.; Mattiello-Sverzut, Ana C.

2014-01-01

336

Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy. PMID:18996917

Villalta, S. Armando; Nguyen, Hal X.; Deng, Bo; Gotoh, Tomomi; Tidball, James G.

2009-01-01

337

Sustaining Cardiac Claudin-5 Levels Prevents Functional Hallmarks of Cardiomyopathy in a Muscular Dystrophy Mouse Model  

PubMed Central

Identification of new molecular targets in heart failure could ultimately have a substantial positive impact on both the health and financial aspects of treating the large heart failure population. We originally identified reduced levels of the cell junction protein claudin-5 specifically in heart in the dystrophin/utrophin-deficient (Dmdmdx;Utrn?/?) mouse model of muscular dystrophy and cardiomyopathy, which demonstrates physiological hallmarks of heart failure. We then showed that at least 60% of cardiac explant samples from patients with heart failure resulting from diverse etiologies also have reduced claudin-5 levels. These claudin-5 reductions were independent of changes in other cell junction proteins previously linked to heart failure. The goal of this study was to determine whether sustaining claudin-5 levels is sufficient to prevent the onset of histological and functional indicators of heart failure. Here, we show the proof-of-concept rescue experiment in the Dmdmdx;Utrn?/? model, in which claudin-5 reductions were originally identified. Expression of claudin-5 4 weeks after a single administration of recombinant adeno-associated virus (rAAV) containing a claudin-5 expression cassette prevented the onset of physiological hallmarks of cardiomyopathy and improved histological signs of cardiac damage. This experiment demonstrates that claudin-5 may represent a novel treatment target for prevention of heart failure. PMID:22547149

Delfin, Dawn A; Xu, Ying; Schill, Kevin E; Mays, Tessily A; Canan, Benjamin D; Zang, Kara E; Barnum, Jamie A; Janssen, Paul ML; Rafael-Fortney, Jill A

2012-01-01

338

Development of Multiexon Skipping Antisense Oligonucleotide Therapy for Duchenne Muscular Dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is an incurable, X-linked progressive muscle degenerative disorder that results from the absence of dystrophin protein and leads to premature death in affected individuals due to respiratory and/or cardiac failure typically by age of 30. Very recently the exciting prospect of an effective oligonucleotide therapy has emerged which restores dystrophin protein expression to affected tissues in DMD patients with highly promising data from a series of clinical trials. This therapeutic approach is highly mutation specific and thus is personalised. Therefore DMD has emerged as a model genetic disorder for understanding and overcoming of the challenges of developing personalised genetic medicines. One of the greatest weaknesses of the current oligonucleotide approach is that it is a mutation-specific therapy. To address this limitation, we have recently demonstrated that exons 45–55 skipping therapy has the potential to treat clusters of mutations that cause DMD, which could significantly reduce the number of compounds that would need to be developed in order to successfully treat all DMD patients. Here we discuss and review the latest preclinical work in this area as well as a variety of accompanying issues, including efficacy and potential toxicity of antisense oligonucleotides, prior to human clinical trials. PMID:23984357

Yokota, Toshifumi; Wood, Matthew J. A.

2013-01-01

339

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy  

PubMed Central

Objective: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). Methods: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. Results: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Conclusions: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. Classification of evidence: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period. PMID:21753160

Hache, L.P.; Clemens, P.R.; Cnaan, A.; McDonald, C.M.; Viswanathan, V.; Kornberg, A.J.; Bertorini, T.E.; Nevo, Y.; Lotze, T.; Pestronk, A.; Ryan, M.M.; Monasterio, E.; Day, J.W.; Zimmerman, A.; Arrieta, A.; Henricson, E.; Mayhew, J.; Florence, J.; Hu, F.; Connolly, A.M.

2011-01-01

340

AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm.  

PubMed

Duchenne muscular dystrophy (DMD) is characterized by myofiber death from apoptosis or necrosis, leading in many patients to fatal respiratory muscle weakness. Among other pathological features, DMD muscles show severely deranged metabolic gene regulation and mitochondrial dysfunction. Defective mitochondria not only cause energetic deficiency, but also play roles in promoting myofiber atrophy and injury via opening of the mitochondrial permeability transition pore. Autophagy is a bulk degradative mechanism that serves to augment energy production and eliminate defective mitochondria (mitophagy). We hypothesized that pharmacological activation of AMP-activated protein kinase (AMPK), a master metabolic sensor in cells and on-switch for the autophagy-mitophagy pathway, would be beneficial in the mdx mouse model of DMD. Treatment of mdx mice for 4 weeks with an established AMPK agonist, AICAR (5-aminoimidazole-4-carboxamide-1-?-d-ribofuranoside), potently triggered autophagy in the mdx diaphragm without inducing muscle fiber atrophy. In AICAR-treated mdx mice, the exaggerated sensitivity of mdx diaphragm mitochondria to calcium-induced permeability transition pore opening was restored to normal levels. There were associated improvements in mdx diaphragm histopathology and in maximal force-generating capacity, which were not linked to increased mitochondrial biogenesis or up-regulated utrophin expression. These findings suggest that agonists of AMPK and other inducers of the autophagy-mitophagy pathway can help to promote the elimination of defective mitochondria and may thus serve as useful therapeutic agents in DMD. PMID:22683340

Pauly, Marion; Daussin, Frederic; Burelle, Yan; Li, Tong; Godin, Richard; Fauconnier, Jeremy; Koechlin-Ramonatxo, Christelle; Hugon, Gerald; Lacampagne, Alain; Coisy-Quivy, Marjorie; Liang, Feng; Hussain, Sabah; Matecki, Stefan; Petrof, Basil J

2012-08-01

341

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

342

Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy  

PubMed Central

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

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

2014-01-01

343

Xp21/A translocation: a rarely considered genetic cause for manifesting carriers of duchenne muscular dystrophy.  

PubMed

Clinically manifesting carriers of Duchenne muscular dystrophy (DMD) are rare among the pediatric population. A standardized diagnostic procedure in supposed DMD carriers entails performing a Multiplex Ligation-dependent Probe Amplification analysis of the DMD gene first, then taking a muscle biopsy to confirm reduced dystrophin levels and/or finally a complete sequencing of the DMD gene. We describe a girl with high-elevated creatine kinase, myalgia, and cardiomyopathy. Muscle biopsy showed a dystrophic pattern and nearly absent expression of dystrophin. Diagnosis could not be confirmed by molecular genetic procedures. Because of a mild mental retardation, a chromosome analysis and molecular karyotyping were performed, revealing a balanced translocation t(X;4)(p21;q31).arr(1-22,X)x2 dn with breakpoint on the X-chromosome within an intron of the DMD gene. The inactivation of the nonderivative X-chromosome was found to be in a nonrandom pattern, resulting in a functionally balanced karyotype and thus leading to a manifesting DMD carrier in this case. Chromosome analysis should be recommended in cases of genetically unsolved DMD carriers as a part of the standard genetic procedures. PMID:25046452

Trippe, Heike; Wieczorek, Stefan; Kötting, Judith; Kress, Wolfram; Schara, Ulrike

2014-10-01

344

[Therapeutic readthrough strategy for suppression of nonsense mutations in duchenne muscular dystrophy].  

PubMed

Effective treatment for Duchenne muscular dystrophy (DMD) is currently unavailable. Readthrough of disease-causing premature termination codons might alleviate the symptoms of genetic diseases caused by nonsense mutations. Several ribosome-binding compounds, including selective antibiotics and synthetic novel small molecules, induce translational readthrough, restoring full-length functional proteins. Here in this innovative therapeutic strategy has been summarized with a focus on DMD. We have previously reported that negamycin restored dystrophin expression with less toxicity than gentamicin in mdx mice. To explore more potent readthrough inducers, we established the transgenic mouse called READ (readthrough evaluation and assessment by dural receptor) for readthrough-specific detection. Using READ mice, we discovered drug candidates, including sterically negamycin-like small molecules and aminoglycoside derivatives. The newly developed small molecules induced dose-dependent readthrough with greater potency than ataluren in vitro and promoted the expression of dystrophin and reduction in serum creatine kinase activity in mdx mice. Moreover, the aminoglycoside derivative restored both dystrophin protein and contractile function of mdx skeletal muscles with appreciably higher readthrough activity and lower toxicity than that of gentamicin. Furthermore, we confirmed the efficacy of a thioglycolate-based depilatory agent to enhance the topical delivery of skin-impermeable drugs, including aminoglycosides. These promising new chemotherapeutic agents with beneficial effects on readthrough action, lower toxicity, and transdermal delivery may have significant value in treating or preventing genetic diseases caused by nonsense mutations. PMID:22068478

Shiozuka, Masataka; Matsuda, Ryoichi

2011-11-01

345

Cell surface abnormality in clones of skin fibroblasts from a carrier of Duchenne muscular dystrophy.  

PubMed Central

We have previously reported that skin fibroblasts from patients with Duchenne muscular dystrophy (DMD) have a lower intercellular adhesiveness than control cells, and that cells from carriers of DMD have normal adhesiveness instead of the expected intermediate value. We have now cloned skin fibroblasts from a carrier of DMD (subject AS) who is also heterozygous for G6PD B/G6PD Mediterranean and determined the intercellular adhesiveness and G6PD phenotypes of the clones. G6PD activity was determined using the 2d-G6P/G6P ratio method. Normal cells had a percentage utilisation of 7.31% and uncloned cells from AS a value of 25.16%. Of 16 clones, 15 had normal values (mean 8.72%) while one clone was G6PD Med with a value of 57.5%. Mean intercellular adhesiveness of normal and uncloned cells from AS were 2.95 and 2.90 respectively. Of 11 clones tested, nine had normal values of adhesiveness (mean 3.1) and all these clones were G6PD B. The single G6PD Med clone had a value of 0.88, compared with 1.39 for DMD cells. We have no explanation at present for the single clone that was G6PD B but DMD-like on aggregation. PMID:3989823

Hillier, J; Jones, G E; Statham, H E; Witkowski, J A; Dubowitz, V

1985-01-01

346

The mdx mouse model as a surrogate for Duchenne muscular dystrophy  

PubMed Central

Research into fundamental principles and the testing of therapeutic hypotheses for treatment of human disease is commonly conducted on mouse models of human diseases. Although this is often the only practicable approach, it carries a number of caveats arising from differences between the two species. This article is centred on the example of skeletal muscle disease, in particular muscular dystrophy, to identify some of the principal classes of obstacle to the translation of data from mouse to man. Of these, the difference in scale is one of the most commonly ignored and is of particular interest because it has quite major repercussions for evaluation of some classes of intervention and of assessment criteria while having comparatively little bearing on others. Likewise, interspecies differences and similarities in cell and molecular biological mechanisms underlying development, growth and response to pathological processes should be considered on an individual basis. An awareness of such distinctions is crucial if we are to avoid misjudgement of the likely efficacy in man of results obtained on mouse models. PMID:23551987

Partridge, Terence A.

2014-01-01

347

Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a chinese population.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate-binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2 years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)11/(GCN)12. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)11 polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype. PMID:25283883

Shan, Jingli; Chen, Bin; Lin, Pengfei; Li, Duoling; Luo, Yuebei; Ji, Kunqian; Zheng, Jinfan; Yuan, Yun; Yan, Chuanzhu

2014-12-01

348

Quantitative MRI and loss of free ambulation in Duchenne muscular dystrophy.  

PubMed

The purpose of this ethics approved trial was to correlate quantitative MRI with functional abilities in both ambulant and non-ambulant Duchenne muscular dystrophy (DMD). Twenty patients with genetically confirmed DMD were recruited. Physical assessment was performed using the motor function measurement (MFM) scale. Axial 3T MRI scans of the thighs were acquired using T1-weighted in- and opposed-phase images (TR = 20 ms, TE1 = 2.45 ms, TE2 = 3.68 ms, flip angle = 15°) to calculate the relative fat fraction according to the two-point Dixon method in the knee extensors, flexors, and adductor muscles. The average MFM was 65.3 % and correlated negatively to age (r (2) = 0.60). Overall mean fat fraction correlated positively to age (r (2) = 0.51-0.64). An average of 5 % increase in mean fat fraction per year was calculated. Mean fat fraction of the quadriceps showed a high negative correlation (r (2) = 0.93) to the D1 (standing position and transfers) component of the MFM. A cutoff for mean fat fraction of 50 % predicted loss of ambulation with a sensitivity of 100 % and a specificity of 91 %. Therefore, quantitative muscle MRI seems to be a promising endpoint for short clinical trials evaluating the effect of newer treatments on the time of loss of ambulation in DMD. PMID:23138982

Fischmann, Arne; Hafner, Patricia; Gloor, Monika; Schmid, Maurice; Klein, Andrea; Pohlman, Urs; Waltz, Tanja; Gonzalez, Rocio; Haas, Tanja; Bieri, Oliver; Fischer, Dirk

2013-04-01

349

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

PubMed

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

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

2012-09-01

350

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

351

Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations.  

PubMed Central

In 288 Dutch and Belgian Duchenne and Becker muscular dystrophy families, the parental origin of 41 new deletion or duplication mutations was determined. Twenty seven of the new mutations occurred in the maternal X chromosome and nine in the grandmaternal and five in the grandpaternal X chromosome. The grandparental data are compatible with equal mutation rates for DMD in male and female X chromosomes. New mutations were defined by their presence in one or more progeny and absence in the lymphocytes of the mother or the grandparents. In one family a fraction of the maternal lymphocytes was found to carry the mutation, suggesting somatic mosaicism. In six cases out of 41, the mutation was transmitted more than once by a parent in whom the mutation was absent in lymphocytes, suggesting gonadal mosaicism as the explanation for the multiple transmission. Using our data for the recurrence of the mutations among the total of at risk haplotypes transmitted, we arrive at a recurrence risk of 14% for the at risk haplotype. The observation of this high risk of germinal mosaicism is crucially important for all physicians counselling females in DMD families. Recently, germinal mosaicism has been observed also in a number of other X linked and autosomal disorders. The implications and appropriate diagnostic precautions are discussed. Images PMID:2810338

Bakker, E; Veenema, H; Den Dunnen, J T; van Broeckhoven, C; Grootscholten, P M; Bonten, E J; van Ommen, G J; Pearson, P L

1989-01-01

352

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

PubMed

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

Long, Chengzu; McAnally, John R; Shelton, John M; Mireault, Alex A; Bassel-Duby, Rhonda; Olson, Eric N

2014-09-01

353

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

354

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

355

Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules. PMID:21204267

Barbezier, Nicolas; Chartier, Aymeric; Bidet, Yannick; Buttstedt, Anja; Voisset, Cécile; Galons, Hervé; Blondel, Marc; Schwarz, Elisabeth; Simonelig, Martine

2011-01-01

356

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, Silvere M.

2011-01-01

357

Autologous myoblast transplantation for oculopharyngeal muscular dystrophy: a phase I/IIa clinical study.  

PubMed

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

358

Cystamine suppresses polyalanine toxicity in a mouse model of oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion mutation in the coding region of the gene encoding PABPN1 (polyadenylate-binding protein nuclear 1). Mutant PABPN1 with a polyalanine tract expansion forms aggregates within the nuclei of skeletal muscle fibers. There is currently no effective treatment. We have developed cell and mouse models of OPMD and have identified the aggregation of mutant PABPN1 and apoptosis as therapeutic targets. Here, we show that transglutaminase activity is increased in muscle from OPMD model mice. Elevated transglutaminase 2 expression enhances, whereas TG2 knockdown suppresses, the toxicity and aggregation of mutant PABPN1 in cells. Cystamine protects against the toxicity of mutant PABPN1 and exerts its effect via the inhibition of transglutaminase 2, as cystamine treatment is unable to further reduce the protective effect of transglutaminase 2 knockdown on mutant PABPN1 toxicity in cells. Cystamine also reduces the aggregation and toxicity of mutant PABPN1 in human cells. In a mouse model of OPMD, cystamine treatment reduced the elevated transglutaminase activity, attenuated muscle weakness, reduced aggregate load, and decreased apoptotic markers in muscle. Therefore, inhibitors of transglutaminase 2 should be considered as possible therapeutics for OPMD. PMID:20519718

Davies, Janet E; Rose, Claudia; Sarkar, Sovan; Rubinsztein, David C

2010-06-01

359

Executive functions are impaired in heterozygote patients with oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder caused by a small expansion of a short polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). It presents with adult onset of progressive eyelid drooping, swallowing difficulties and proximal limb weakness, usually without involvement of central nervous system (CNS). However, cognitive decline with relevant behavioural and psychological symptoms has been recently described in homozygous patients. In this study, we performed for the first time an extensive neuropsychological and neuropsychiatric evaluation on 11 OPMD heterozygote patients. We found that they were less efficient than a matched control sample on several tests, particularly those tapping executive functions. Moreover, the presence of negative correlation between GCN expansion size and some neuropsychological scores raises the issue that CNS involvement might be linked to the genetic defect, being worse in patients with larger expansion. Our results might be consistent with the toxic gain-of-function theory in the pathogenesis of OPMD and hint at a possible direct role of PABPN1 in the CNS also in heterozygote patients. PMID:21956377

Dubbioso, Raffaele; Moretta, Pasquale; Manganelli, Fiore; Fiorillo, Chiara; Iodice, Rosa; Trojano, Luigi; Santoro, Lucio

2012-05-01

360

Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/?-catenin pathway.  

PubMed

Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (?-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3?. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3? inhibitor, and observed the enhanced expression of ?-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on ?-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/?-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD. PMID:24091664

Abu-Baker, A; Laganiere, J; Gaudet, R; Rochefort, D; Brais, B; Neri, C; Dion, P A; Rouleau, G A

2013-01-01

361

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

362

Sirtuin inhibition protects from the polyalanine muscular dystrophy protein PABPN1.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is caused by polyalanine expansion in nuclear protein PABPN1 [poly(A) binding protein nuclear 1] and characterized by muscle degeneration. Druggable modifiers of proteotoxicity in degenerative diseases, notably the longevity modulators sirtuins, may constitute useful therapeutic targets. However, the modifiers of mutant PABPN1 are unknown. Here, we report that longevity and cell metabolism modifiers modulate mutant PABPN1 toxicity in the muscle cell. Using PABPN1 nematodes that show muscle cell degeneration and abnormal motility, we found that increased dosage of the sirtuin and deacetylase sir-2.1/SIRT1 exacerbated muscle pathology, an effect dependent on the transcription factor daf-16/FoxO and fuel sensor aak-2/AMPK (AMP-activated protein kinase), while null mutants of sir-2.1, daf-16 and aak-2 were protective. Consistently, the Sir2 inhibitor sirtinol was protective, whereas the Sir2 and AMPK activator resveratrol was detrimental. Furthermore, rescue by sirtinol was dependent on daf-16 and not aak-2, whereas aggravation by resveratrol was dependent on aak-2 and not daf-16. Finally, the survival of mammalian cells expressing mutant PABPN1 was promoted by sirtinol and decreased by resveratrol. Altogether, our data identify Sir2 and AMPK inhibition as therapeutic strategies for muscle protection in OPMD, extending the value of druggable proteins in cell maintenance networks to polyalanine diseases. PMID:18397876

Catoire, Hélène; Pasco, Matthieu Y; Abu-Baker, Aida; Holbert, Sébastien; Tourette, Cendrine; Brais, Bernard; Rouleau, Guy A; Parker, J Alex; Néri, Christian

2008-07-15

363

DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1  

PubMed Central

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder linked to contractions of the D4Z4 repeat array in the subtelomeric region of chromosome 4q. By comparing genome-wide gene expression data from muscle biopsies of patients with FSHD to those of 11 other neuromuscular disorders, paired-like homeodomain transcription factor 1 (PITX1) was found specifically up-regulated in patients with FSHD. In addition, we showed that the double homeobox 4 gene (DUX4) that maps within the D4Z4 repeat unit was up-regulated in patient myoblasts at both mRNA and protein level. We further showed that the DUX4 protein could activate transient expression of a luciferase reporter gene fused to the Pitx1 promoter as well as the endogenous Pitx1 gene in transfected C2C12 cells. In EMSAs, DUX4 specifically interacted with a 30-bp sequence 5?-CGGATGCTGTCTTCTAATTAGTTTGGACCC-3? in the Pitx1 promoter. Mutations of the TAAT core affected Pitx1-LUC activation in C2C12 cells and DUX4 binding in vitro. Our results suggest that up-regulation of both DUX4 and PITX1 in FSHD muscles may play critical roles in the molecular mechanisms of the disease. PMID:17984056

Dixit, Manjusha; Ansseau, Eugenie; Tassin, Alexandra; Winokur, Sara; Shi, Rongye; Qian, Hong; Sauvage, Sebastien; Matteotti, Christel; van Acker, Anne M.; Leo, Oberdan; Figlewicz, Denise; Barro, Marietta; Laoudj-Chenivesse, Dalila; Belayew, Alexandra; Coppee, Frederique; Chen, Yi-Wen

2007-01-01

364

A family with fragile X syndrome, Duchenne muscular dystrophy and ichthyosis transmitted by an asymptomatic carrier.  

PubMed

The human X chromosome carries regions prone to genomic instability: deletions in the Xp22.31 region, involving the steroid sulfatase gene (STS) cause X-linked ichthyosis; rearrangements in the Xp21.2 region are associated with Duchenne or Becker muscular dystrophies (DMD or BMD); and the Xq27.3 unstable region, containing the (CGG)n repeat expansion in the FMR1 gene is associated with fragile X syndrome. We report on a family with two affected boys, the elder diagnosed with fragile X syndrome, the younger with DMD, and both suffering from severe ichthyosis. The family was analyzed by polymerase chain reaction, multiplex ligation-dependent probe amplification and haplotype analysis. The mother proved to be an asymptomatic carrier of all three non-contiguous mutation events, involving the STS gene, the DMD gene and a FMR1 expansion. To the best of our knowledge, this is the first description of an asymptomatic carrier of three different X-linked disorders, involving severe genetic rearrangements on both long and short arms of the X chromosomes. The boy with fragile X syndrome has inherited a triple recombinant maternal X chromosome, this way inheriting the FMR1 expansion and ichthyosis, originating most probably from different maternal Xes and excluding the DMD gene deletion. The transmission of these extremely defective maternal chromosomes to the next generation involved several recombinations. PMID:23574351

Todorova, A; Litvinenko, I; Todorov, T; Tincheva, R; Avdjieva, D; Tincheva, S; Mitev, V

2014-03-01

365

Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy-associated DUX4 gene.  

PubMed

Facioscapulohumeral muscular dystrophy (FSHD) is linked to epigenetic dysregulation of the chromosome 4q35 D4Z4 macrosatellite. However, this does not account for the tissue specificity of FSHD pathology, which requires stable expression of an alternative full-length mRNA splice form of DUX4 (DUX4-fl) from the D4Z4 array in skeletal muscle. Here, we describe the identification of two enhancers, DUX4 myogenic enhancer 1 (DME1) and DME2 which activate DUX4-fl expression in skeletal myocytes but not fibroblasts. Analysis of the chromatin revealed histone modifications and RNA polymerase II occupancy consistent with DME1 and DME2 being functional enhancers. Chromosome conformation capture analysis confirmed association of DME1 and DME2 with the DUX4 promoter in vivo. The strong interaction between DME2 and the DUX4 promoter in both FSHD and unaffected primary myocytes was greatly reduced in fibroblasts, suggesting a muscle-specific interaction. Nucleosome occupancy and methylome sequencing analysis indicated that in most FSHD myocytes, both enhancers are associated with nucleosomes but have hypomethylated DNA, consistent with a permissive transcriptional state, sporadic occupancy, and the observed DUX4 expression in rare myonuclei. Our data support a model in which these myogenic enhancers associate with the DUX4 promoter in skeletal myocytes and activate transcription when epigenetically derepressed in FSHD, resulting in the pathological misexpression of DUX4-fl. PMID:24636994

Himeda, Charis L; Debarnot, Céline; Homma, Sachiko; Beermann, Mary Lou; Miller, Jeffrey B; Jones, Peter L; Jones, Takako I

2014-06-01

366

The intracellular Ca(2+) channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy.  

PubMed

The integrity of the plasma membrane is maintained through an active repair process, especially in skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness. An important cause of these group of diseases is defective repair of sarcolemmal injuries, which normally requires Ca(2+) sensor proteins and Ca(2+)-dependent delivery of intracellular vesicles to the sites of injury. MCOLN1 (also known as TRPML1, ML1) is an endosomal and lysosomal Ca(2+) channel whose human mutations cause mucolipidosis IV (ML4), a neurodegenerative disease with motor disabilities. Here we report that ML1-null mice develop a primary, early-onset MD independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are expressed normally, membrane resealing was defective in ML1-null muscle fibers and also upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca(2+) 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, our data have identified an intracellular Ca(2+) channel that regulates membrane repair in skeletal muscle via Ca(2+)-dependent vesicle exocytosis. PMID:25216637

Cheng, Xiping; Zhang, Xiaoli; Gao, Qiong; Ali Samie, Mohammad; 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

2014-10-01

367

Lithium chloride attenuates cell death in oculopharyngeal muscular dystrophy by perturbing Wnt/?-catenin pathway  

PubMed Central

Expansion of polyalanine tracts causes at least nine inherited human diseases. Among these, a polyalanine tract expansion in the poly (A)-binding protein nuclear 1 (expPABPN1) causes oculopharyngeal muscular dystrophy (OPMD). So far, there is no treatment for OPMD patients. Developing drugs that efficiently sustain muscle protection by activating key cell survival mechanisms is a major challenge in OPMD research. Proteins that belong to the Wnt family are known for their role in both human development and adult tissue homeostasis. A hallmark of the Wnt signaling pathway is the increased expression of its central effector, beta-catenin (?-catenin) by inhibiting one of its upstream effector, glycogen synthase kinase (GSK)3?. Here, we explored a pharmacological manipulation of a Wnt signaling pathway using lithium chloride (LiCl), a GSK-3? inhibitor, and observed the enhanced expression of ?-catenin protein as well as the decreased cell death normally observed in an OPMD cell model of murine myoblast (C2C12) expressing the expanded and pathogenic form of the expPABPN1. Furthermore, this effect was also observed in primary cultures of mouse myoblasts expressing expPABPN1. A similar effect on ?-catenin was also observed when lymphoblastoid cells lines (LCLs) derived from OPMD patients were treated with LiCl. We believe manipulation of the Wnt/?-catenin signaling pathway may represent an effective route for the development of future therapy for patients with OPMD. PMID:24091664

Abu-Baker, A; Laganiere, J; Gaudet, R; Rochefort, D; Brais, B; Neri, C; Dion, P A; Rouleau, G A

2013-01-01

368

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

369

The progress reports on the development of therapies of Duchenne muscular dystrophy  

PubMed Central

Summary The roots of the progress reports on the development of therapies for Duchenne muscular dystrophy (DMD) that since 2000 have been produced at Breitnau/Germany and distributed to the parents of DMD patients cover over 30 years of continual occupation with this disease. The beginning was marked by the development of an early detection programme for the genetic disposition for DMD in infant boys. The next step was the organisation of workshops on the management of DMD and the writing of progress reports on these and other relevant conferences. Getting acquainted with the ideas of the protagonists in the research field by holding interviews was a decisive prerequisite for this activity. This took place in tandem with the development of a new kind of multiplex “family letters” that attempted to answer frequently asked questions to many DMD families at the same time. When – with the beginning of the new millennium – the endeavours towards gene therapies for DMD started to boom all over the scientific world, progress reports designed to keep the families informed about research on DMD treatment were added to the family letters. These reports that give an account of the latest state of the research are written in a plain language that can be understood by laypersons. In the meantime the reports have adopted the character of reviews that are updated annually. They are written in English and German and translated into Spanish and many other languages. PMID:20128138

Scheuerbrandt, G

2009-01-01

370

Oculopharyngeal muscular dystrophy: recent advances in the understanding of the molecular pathogenic mechanisms and treatment strategies.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping, swallowing difficulties and proximal limb weakness. OPMD is caused by a small expansion of a short polyalanine tract in the poly (A) binding protein nuclear 1 protein (PABPN1). The mechanism by which the polyalanine expansion mutation in PABPN1 causes disease is unclear. PABPN1 is a nuclear multi-functional protein which is involved in pre-mRNA polyadenylation, transcription regulation, and mRNA nucleocytoplasmic transport. The distinct pathological hallmark of OPMD is the presence of filamentous intranuclear inclusions (INIs) in patient's skeletal muscle cells. The exact relationship between mutant PABPN1 intranuclear aggregates and pathology is not clear. OPMD is a unique disease sharing common pathogenic features with other polyalanine disorders, as well as with polyglutamine and dystrophic disorders. This chapter aims to review the rapidly growing body of knowledge concerning OPMD. First, we outline the background of OPMD. Second, we compare OPMD with other trinucleotide repeat disorders. Third, we discuss the recent advances in the understanding of the molecular mechanisms underlying OPMD pathogenesis. Finally, we review recent therapeutic strategies for OPMD. PMID:17110089

Abu-Baker, Aida; Rouleau, Guy A

2007-02-01

371

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

2014-01-01

372

Ventilatory Chemosensory Drive Is Blunted in the mdx Mouse Model of Duchenne Muscular Dystrophy (DMD)  

PubMed Central

Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene resulting in an absence of dystrophin in neurons and muscle. Respiratory failure is the most common cause of mortality and previous studies have largely concentrated on diaphragmatic muscle necrosis and respiratory failure component. Here, we investigated the integrity of respiratory control mechanisms in the mdx mouse model of DMD. Whole body plethysmograph in parallel with phrenic nerve activity recordings revealed a lower respiratory rate and minute ventilation during normoxia and a blunting of the hypoxic ventilatory reflex in response to mild levels of hypoxia together with a poor performance on a hypoxic stress test in mdx mice. Arterial blood gas analysis revealed low PaO2 and pH and high PaCO2 in mdx mice. To investigate chemosensory respiratory drive, we analyzed the carotid body by molecular and functional means. Dystrophin mRNA and protein was expressed in normal mice carotid bodies however, they are absent in mdx mice. Functional analysis revealed abnormalities in Dejours test and the early component of the hypercapnic ventilatory reflex in mdx mice. Together, these results demonstrate a malfunction in the peripheral chemosensory drive that would be predicted to contribute to the respiratory failure in mdx mice. These data suggest that investigating and monitoring peripheral chemosensory drive function may be useful for improving the management of DMD patients with respiratory failure. PMID:23922741

Mosqueira, Matias; Baby, Santhosh M.; Khurana, Tejvir S.

2013-01-01

373

TGFBR2 but not SPP1 genotype modulates osteopontin expression in Duchenne muscular dystrophy muscle.  

PubMed

A polymorphism (rs28357094) in the promoter region of the SPP1 gene coding for osteopontin (OPN) is a strong determinant of disease severity in Duchenne muscular dystrophy (DMD). The rare G allele of rs28357094 alters gene promoter function and reduces mRNA expression in transfected HeLa cells. To dissect the molecular mechanisms of increased disease severity associated with the G allele, we characterized SPP1 mRNA and protein in DMD muscle biopsies of patients with defined rs28357094 genotype. We did not find significant differences in osteopontin mRNA or protein expression between patients carrying the T (ancestral allele) or TG/GG genotypes at rs28357094. The G allele was significantly associated with reduced CD4(+) and CD68(+) cells on patient muscle biopsy. We also quantified transforming growth factor-? (TGFB) and TGFB receptor-2 (TGFBR2) mRNA in DMD muscle biopsies, given the ability of TGFB and TGFBR2 to activate SPP1 promoter region and their role in DMD pathogenesis. The amount of TGFB and TGFBR2 mRNA did not predict the amount of SPP1 mRNA or protein, while a polymorphism in the TGFBR2 gene (rs4522809) was found to be a strong predictor of SPP1 mRNA level. Our findings suggest that OPN mediates inflammatory changes in DMD and that TGFB signalling has a role in the complex regulation of osteopontin expression. PMID:22431140

Piva, Luisa; Gavassini, Bruno F; Bello, Luca; Fanin, Marina; Soraru, Gianni; Barp, Andrea; Ermani, Mario; Angelini, Corrado; Hoffman, Eric P; Pegoraro, Elena

2012-10-01

374

'Double trouble': diagnostic challenges in Duchenne muscular dystrophy in patients with an additional hereditary skeletal dysplasia.  

PubMed

Duchenne muscular dystrophy (DMD) is caused by mutations in Dystrophin and affects 1 in 3600-6000 males. It is characterized by progressive weakness leading to loss of ambulation, respiratory insufficiency, cardiomyopathy, and scoliosis. We describe the unusual phenotype of 3 patients with skeletal dysplasias in whom an additional diagnosis of DMD was later established. Two unrelated boys presented with osteogenesis imperfecta due to point mutations in COL1A1 and were both subsequently found to have a 1 bp frameshift deletion in the Dystrophin gene at age 3 and age 15 years, respectively. The third patient had a diagnosis of pseudoachondroplasia caused by a mutation in the COMP gene and was found to have a deletion of exons 48-50 in Dystrophin at age 9. We discuss the atypical presentation caused by the concomitant presence of 2 conditions affecting the musculoskeletal system, emphasizing aspects that may confound the presentation of a well-characterized disease like DMD. Additional series of patients with DMD and a secondary inherited condition are necessary to establish the natural history in this "double trouble" population. The recognition and accurate diagnosis of patients with two independent genetic disease processes is essential for management, prognosis, genetic risk assessment, and discussion regarding potential therapeutic interventions. PMID:24070816

Donkervoort, Sandra; Schindler, Alice; Tesi-Rocha, Carolina; Schreiber, Allison; Leach, Meganne E; Dastgir, Jahannaz; Hu, Ying; Mankodi, Ami; Wagner, Kathryn R; Friedman, Neil R; Bönnemann, Carsten G

2013-12-01

375

Genotype and phenotype study of 34 Spanish patients diagnosed with oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy is an autosomal dominant adult-onset disease with several clinical features. The genetic cause is an expanded (GCN)n mutation coding for polyalanine. Severity and the age of onset are variable and may depend on the size of the unstable triplet. Our objectives were to correlate the genotypic and phenotypic features in 34 affected patients, and to complete the molecular analysis for a control Spanish population in order to confirm the (GCN)n polymorphism frequency observed in other populations. We found a correlation between impaired CPK levels and sex. No statistical differences were found when comparing the length in triplet expansion and other variables. The (GCN)n polymorphism's frequency observed in other countries could not be proven in ours. Moreover, no correlation was observed amongst the size of the mutation, the age of onset, and the phenotype. This fact suggests that other conditions apart from the already known genotype could influence the age of onset and the severity of the symptoms. PMID:22231868

Tondo, Mireia; Gámez, Josep; Gutiérrez-Rivas, Eduardo; Medel-Jiménez, Ramón; Martorell, Loreto

2012-08-01

376

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

377

Sniff nasal inspiratory pressure in the longitudinal assessment of young Duchenne muscular dystrophy children.  

PubMed

Traditional measures of respiratory function in children with Duchenne muscular dystrophy (DMD) are based on maximal inspiratory pressure (PImax) and vital capacity (VC). Sniff nasal inspiratory pressure (SNIP) measurements are easily performed by young children with neuromuscular disorders. The clinical value of SNIP in the longitudinal assessment of respiratory weakness remains to be assessed. The objective of the present study was to assess longitudinally the changes in SNIP, PImax and VC with age in DMD children. We hypothesised that their longitudinal assessment would show an earlier decline in SNIP than VC. A 3-year, prospective follow-up, at 6-month intervals of, 33 steroid-naïve, 5-20-year-old DMD patients was analysed using a linear mixed model. SNIP measurements were reliable (within-session coefficient of variation 8%). SNIP and VC increased until 10.5 and 12.5 years of age, respectively, and declined thereafter, while PImax did not change with age. SNIP was an earlier marker of decline in respiratory muscle strength (at 10.5 years) than VC (at 12.5 years) in young DMD patients. SNIP longitudinal assessment is useful in the detection of inspiratory strength decline in young DMD patients when VC values remain within normal values and as an outcome measure in clinical trials for emerging therapeutics in young DMD patients from the age of 5 years. PMID:23258781

Nève, Véronique; Cuisset, Jean-Marie; Edmé, Jean-Louis; Carpentier, Alain; Howsam, Mike; Leclerc, Olivier; Matran, Régis

2013-09-01

378

Membrane Repair Defects in Muscular Dystrophy Are Linked to Altered Interaction between MG53, Caveolin-3, and Dysferlin*?  

PubMed Central

Defective membrane repair can contribute to the progression of muscular dystrophy. Although mutations in caveolin-3 (Cav3) and dysferlin are linked to muscular dystrophy in human patients, the molecular mechanism underlying the functional interplay between Cav3 and dysferlin in membrane repair of muscle physiology and disease has not been fully resolved. We recently discovered that mitsugumin 53 (MG53), a muscle-specific TRIM (Tri-partite motif) family protein (TRIM72), contributes to intracellular vesicle trafficking and is an essential component of the membrane repair machinery in striated muscle. Here we show that MG53 interacts with dysferlin and Cav3 to regulate membrane repair in skeletal muscle. MG53 mediates active trafficking of intracellular vesicles to the sarcolemma and is required for movement of dysferlin to sites of cell injury during repair patch formation. Mutations in Cav3 (P104L, R26Q) that cause retention of Cav3 in Golgi apparatus result in aberrant localization of MG53 and dysferlin in a dominant-negative fashion, leading to defective membrane repair. Our data reveal that a molecular complex formed by MG53, dysferlin, and Cav3 is essential for repair of muscle membrane damage and also provide a therapeutic target for treatment of muscular and cardiovascular diseases that are linked to compromised membrane repair. PMID:19380584

Cai, Chuanxi; Weisleder, Noah; Ko, Jae-Kyun; Komazaki, Shinji; Sunada, Yoshihide; Nishi, Miyuki; Takeshima, Hiroshi; Ma, Jianjie

2009-01-01

379

MicroRNA expression profiling in patients with lamin A/C-associated muscular dystrophy.  

PubMed

Mutations in the lamin A/C gene (LMNA) cause several disorders referred to as laminopathies, which include premature aging syndromes, lipodystrophy, and striated muscle disorders. There is evidence that lamin A/C plays a role in gene expression. MicroRNAs (miRNAs) are short noncoding RNAs regulating mRNAs involved in various biological processes, including the pathophysiology of striated muscles. Here, we profiled the expression of the miRNA transcriptome in skeletal muscle from patients with LMNA-related muscular dystrophy. Results show that control and patient groups can be distinguished based on their miRNA expression profile. Sixteen miRNAs are significantly dysregulated in patients compared with controls. Pathway enrichment analysis in the predicted targets of these miRNAs revealed pathways involved in muscle repair, such as MAPK, transforming growth factor-?, and Wnt signaling. Interestingly, 9 of these miRNAs (hsa-miR-100, -127-3p, -148a, -136*, -192, -335, -376c, -489, and -502-3p) are highly expressed in fetal muscle, suggesting that the fetal miRNA gene program mediates a regenerative process. Overexpression of these miRNAs in C2C12 mouse myoblasts revealed that 3 of them (miR-100, -192, and -335) participate in muscle proliferation and differentiation. We identified target genes that likely mediate this effect, which include the calcineurin gene PPP3CA. Our findings are the first to demonstrate that miRNA expression is affected in laminopathies. PMID:21840938

Sylvius, Nicolas; Bonne, Gisèle; Straatman, Kees; Reddy, Thimma; Gant, Timothy W; Shackleton, Sue

2011-11-01

380

Assessment of Cardiac Involvement in Myotonic Muscular Dystrophy by T1 Mapping on Magnetic Resonance Imaging  

PubMed Central

Background Patients with DM are at risk for atrioventricular block and left ventricular (LV) dysfunction. Non-invasive detection of diffuse myocardial fibrosis may improve disease management in this population. Objective Our aim was to define functional and post-contrast myocardial T1 time cardiac magnetic resonance (CMR) characteristics in myotonic muscular dystrophy (DM) patients. Methods Thirty-three DM patients (24 with type 1 and 9 with type 2) and 13 healthy volunteers underwent CMR for assessment of LV indices and evaluation of diffuse myocardial fibrosis by T1 mapping. The association of myocardial T1 time to ECG abnormalities and LV indices were examined among DM patients. Results DM patients had lower end-diastolic volume index (68.9 vs. 60.3 ml/m2, p=0.045), cardiac index (2.7 vs. 2.33 L/min/m2, p=0.005) and shorter myocardial T1time (394.5 vs. 441.4 ms, p<0.0001), compared to control subjects. Among DM patients, there was a positive association between higher T1 time and LV mass index (2.2 ms longer per gm/m2, p=0.006), LV end-diastolic volume index (1.3 ms longer per ml/m2, p=0.026), filtered QRS duration (1.2 ms longer per unit, p=0.005) and low-amplitude (<40mcV) late-potential duration (0.9 ms longer per unit, p=0.01). Using multivariate random effects regression, each 10 ms increase in myocardial T1 time of type 1 DM patients was independently associated with 1.3 ms increase in longitudinal PR and QRS intervals during follow-up. Conclusion DM is associated with structural alterations on CMR. Post-contrast myocardial T1 time was shorter in DM patients than controls likely reflecting the presence of diffuse myocardial fibrosis. PMID:22710483

Turkbey, Evrim B.; Gai, Neville; Lima, Joao A. C.; van der Geest, Rob J.; Wagner, Kathryn R.; Tomaselli, Gordon F.; Bluemke, David A.; Nazarian, Saman

2012-01-01

381

Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy.  

PubMed

Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7+ and Myf5-) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD. PMID:24906372

Jiang, Chunhui; Wen, Yefei; Kuroda, Kazuki; Hannon, Kevin; Rudnicki, Michael A; Kuang, Shihuan

2014-08-01

382

Fukuyama-type congenital muscular dystrophy and the Walker-Warburg syndrome.  

PubMed

We compared the neuropathological findings in two cases of the Walker-Warburg syndrome (WWS) with those in 6 of Fukuyama-type congenital muscular dystrophy (FCMD). Remarkable differences were noticed between the two conditions. The central nervous system (CNS) dysplasia in WWS, which involved diffuse agyria and hydrocephalus, was more severe than that in FCMD. In WWS the septum pellucidum was absent, and the corpus callosum, basal ganglia and thalami were markedly hypoplastic. The cerebellum was severely hypoplastic and the vermis was partly absent. The pyramidal tracts could not be identified. On the other hand, the general configuration of the CNS was well preserved in FCMD. The cerebral cortices exhibited diffuse or focal micropolygyria with or without a few pachygyric lesions, but the severity was variable. The cerebellum was not hypoplastic, but exhibited focal micropolygyria. The pyramidal tracts were aberrant. WWS and FCMD, however, did not show any distinct differences on microscopic analysis of the cerebral cortices. There was leptomeningeal glio-mesenchymal overgrowth, and the horizontal lamination of the nerve cells was distorted throughout by proliferating gliovascular bundles or septa. We found in this study that the CNS pathology in WWS was compatible with type II lissencephaly, and thus differed from that in FCMD. Hypoplasia of the cerebellum and a partial absence of the vermis also seemed to be predominant features of WWS, which can be used to differentiate WWS from FCMD. In this study, we concluded that FCMD and WWS are different disease entities because they differ in their clinical manifestations, including eye lesions and CNS pathology, and because no familial concomitance of FCMD and WWS has been reported. PMID:8214343

Kimura, S; Sasaki, Y; Kobayashi, T; Ohtsuki, N; Tanaka, Y; Hara, M; Miyake, S; Yamada, M; Iwamoto, H; Misugi, N

1993-01-01

383

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

PubMed Central

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

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

2014-01-01

384

Two novel missense mutations in the myostatin gene identified in Japanese patients with Duchenne muscular dystrophy  

PubMed Central

Background Myostatin is a negative regulator of skeletal muscle growth. Truncating mutations in the myostatin gene have been reported to result in gross muscle hypertrophy. Duchenne muscular dystrophy (DMD), the most common lethal muscle wasting disease, is a result of an absence of muscle dystrophin. Although this disorder causes a rather uniform pattern of muscle wasting, afflicted patients display phenotypic variability. We hypothesized that genetic variation in myostatin is a modifier of the DMD phenotype. Methods We analyzed 102 Japanese DMD patients for mutations in the myostatin gene. Results Two polymorphisms that are commonly observed in Western countries, p.55A>T and p.153K>R, were not observed in these Japanese patients. An uncommon polymorphism of p.164E>K was uncovered in four cases; each patient was found to be heterozygous for this polymorphism, which had the highest frequency of the polymorphism observed in the Japanese patients. Remarkably, two patients were found to be heterozygous for one of two novel missense mutations (p.95D>H and p.156L>I). One DMD patient carrying a novel missense mutation of p.95D>H was not phenotypically different from the non-carriers. The other DMD patient was found to carry both a novel mutation (p.156L>I) and a known polymorphism (p.164E>K) in one allele, although his phenotype was not significantly modified. Any nucleotide change creating a target site for micro RNAs was not disclosed in the 3' untranslated region. Conclusion Our results indicate that heterozygous missense mutations including two novel mutations did not produce an apparent increase in muscle strength in Japanese DMD cases, even in a patient carrying two missense mutations. PMID:17428346

Nishiyama, Atsushi; Takeshima, Yasuhiro; Saiki, Kayoko; Narukage, Akiko; Oyazato, Yoshinobu; Yagi, Mariko; Matsuo, Masafumi

2007-01-01

385

Community Structure Analysis of Gene Interaction Networks in Duchenne Muscular Dystrophy  

PubMed Central

Duchenne Muscular Dystrophy (DMD) is an important pathology associated with the human skeletal muscle and has been studied extensively. Gene expression measurements on skeletal muscle of patients afflicted with DMD provides the opportunity to understand the underlying mechanisms that lead to the pathology. Community structure analysis is a useful computational technique for understanding and modeling genetic interaction networks. In this paper, we leverage this technique in combination with gene expression measurements from normal and DMD patient skeletal muscle tissue to study the structure of genetic interactions in the context of DMD. We define a novel framework for transforming a raw dataset of gene expression measurements into an interaction network, and subsequently apply algorithms for community structure analysis for the extraction of topological communities. The emergent communities are analyzed from a biological standpoint in terms of their constituent biological pathways, and an interpretation that draws correlations between functional and structural organization of the genetic interactions is presented. We also compare these communities and associated functions in pathology against those in normal human skeletal muscle. In particular, differential enhancements are observed in the following pathways between pathological and normal cases: Metabolic, Focal adhesion, Regulation of actin cytoskeleton and Cell adhesion, and implication of these mechanisms are supported by prior work. Furthermore, our study also includes a gene-level analysis to identify genes that are involved in the coupling between the pathways of interest. We believe that our results serve to highlight important distinguishing features in the structural/functional organization of constituent biological pathways, as it relates to normal and DMD cases, and provide the mechanistic basis for further biological investigations into specific pathways differently regulated between normal and DMD patients. These findings have the potential to serve as fertile ground for therapeutic applications involving targeted drug development for DMD. PMID:23840633

Narayanan, Tejaswini; Subramaniam, Shankar

2013-01-01

386

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

387

Cricopharyngeal dilatation for the long-term treatment of dysphagia in oculopharyngeal muscular dystrophy.  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant, progressive degenerative muscle disorder featuring dysphagia with limited therapeutic options. The aim of this study was to evaluate the safety and efficacy of repeated endoscopic dilatation for OPMD over a 15-year period. All patients seen at our Regional Swallowing Clinic with OPMD confirmed by genetic analysis were included. Cricopharyngeal dilatation was performed as an outpatient procedure using a wire-guided 18-mm (54 Fr) Savary-Gilliard bougie with the patient under sedation. Patients were offered repeat endoscopic dilatation when symptoms recurred. Symptom severity prior to initial dilatation and at follow-up was evaluated using the Sydney Swallow Questionnaire (SSQ). Nine patients (7 female, 2 male) were included for analysis. Median total treatment period was 13 years (range = 3-15), median number of dilatations per patient was 7.2 (range = 1-16), and median interval between treatments was 15 months (range = 4.5-45). All patients recorded sustained symptom improvement. Mean SSQ score (out of 1,700) was 1,108.11 (SD ± 272.85) prior to first dilatation and 297.78 (SD ± 189.14) at last follow-up, representing a 73% decrease (95% CI = 52-94) in degree of dysphagia symptoms (paired t-test, P = 0.0001). All mean scores for individual questions also showed significant improvement (P < 0.05). No adverse events were reported with all patients maintaining oral feeding at last follow-up. Repeated cricopharyngeal dilatation is a safe, effective, well-tolerated, and long-lasting treatment for dysphagia in OPMD. PMID:21805106

Manjaly, Joseph G; Vaughan-Shaw, Peter G; Dale, Oliver T; Tyler, Susan; Corlett, Jonathan C R; Frost, Roger A

2012-06-01

388

Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: A safe alternative to tracheostomy  

PubMed Central

BACKGROUND: Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative. METHODS: The authors’ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported. RESULTS: The mean (± SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8±3.5 years and 0.90±0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8±3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years). CONCLUSIONS: Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone. PMID:23457679

McKim, Douglas A; Griller, Nadia; LeBlanc, Carole; Woolnough, Andrew; King, Judy

2013-01-01

389

Matrix metalloproteinase-9 inhibition ameliorates pathogenesis and improves skeletal muscle regeneration in muscular dystrophy  

PubMed Central

Duchenne muscular dystrophy (DMD) is a fatal X-linked genetic disorder of skeletal muscle caused by mutation in dystrophin gene. Although the degradation of skeletal muscle extracellular matrix, inflammation and fibrosis are the common pathological features in DMD, the underlying mechanisms remain poorly understood. In this study, we have investigated the role and the mechanisms by which increased levels of matrix metalloproteinase-9 (MMP-9) protein causes myopathy in dystrophin-deficient mdx mice. The levels of MMP-9 but not tissue inhibitor of MMPs were drastically increased in skeletal muscle of mdx mice. Besides skeletal muscle, infiltrating macrophages were found to contribute significantly to the elevated levels of MMP-9 in dystrophic muscle. In vivo administration of a nuclear factor-kappa B inhibitory peptide, NBD, blocked the expression of MMP-9 in dystrophic muscle of mdx mice. Deletion of Mmp9 gene in mdx mice improved skeletal muscle structure and functions and reduced muscle injury, inflammation and fiber necrosis. Inhibition of MMP-9 increased the levels of cytoskeletal protein ?-dystroglycan and neural nitric oxide synthase and reduced the amounts of caveolin-3 and transforming growth factor-? in myofibers of mdx mice. Genetic ablation of MMP-9 significantly augmented the skeletal muscle regeneration in mdx mice. Finally, pharmacological inhibition of MMP-9 activity also ameliorated skeletal muscle pathogenesis and enhanced myofiber regeneration in mdx mice. Collectively, our study suggests that the increased production of MMP-9 exacerbates dystrophinopathy and MMP-9 represents as one of the most promising therapeutic targets for the prevention of disease progression in DMD. PMID:19401296

Li, Hong; Mittal, Ashwani; Makonchuk, Denys Y.; Bhatnagar, Shephali; Kumar, Ashok

2009-01-01

390

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

391

Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy  

PubMed Central

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

392

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

Gonzalez-Navarro, Felix F.; Belanche-Munoz, Lluis A.; Silva-Colon, Karen A.

2013-01-01

393

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

394

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

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

Miyake, Masashi; Nakahori, Yutaka; Matsushita, Ikumi [Univ. of Tokyo (Japan)] [and others] [Univ. of Tokyo (Japan); and others

1997-03-01

395

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

PubMed

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

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

2013-01-01

396

Nuclear architecture remodelling in envelopathies.  

PubMed

We performed ultrastructural studies on nuclear abnormalities in muscle from 8 patients with X-linked and autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD) and one case with progeroid syndrome. The diagnosis was based on clinical and molecular findings. We detected various degrees of nuclear architecture remodelling ranging from misshapen shape, nuclear disintegration, nuclear chromatin condensation and decondensation, focal chromatin loss to complete nuclear fragmentation. The most interesting finding was the appearance of tubulofilamentous inclusions inside the nuclear matrix of X-linked EDMD patients. All these nuclear aberrations are considered to be structural indicators of nuclear dysfunction evoked by envelope protein deficiency. PMID:17594594

Fidzia?ska, Anna; Glinka, Zofia

2007-01-01

397

THE SYNTHESIS, STORAGE, AND EXCRETION OF CREATINE, CREATININE, AND GLYCOCYAMINE IN PROGRESSIVE MUSCULAR DYSTROPHY AND THE EFFECTS OF CERTAIN HORMONES ON THESE PROCESSES  

PubMed Central

The diminished excretion of creatinine in progressive muscular dystrophy is a more striking and specific phenomenon than the excess excretion of creatine, marked though this is. While creatinuria is invariably encountered in all cases of long-standing dystrophy, the extent to which the excretion of creatinine is decreased provides a more reliable indication of the severity of the disease since an excess output of creatine may occur physiologically in normal human subjects and in many pathological conditions not known to be associated with muscle disease. In progressive muscular dystrophy the residual muscle mass, as inferred from the excretion of creatinine, provides a useful index of the state of the disease at any given time. Although there is excessive creatinuria in progressive muscular dystrophy, there is no evidence that a deprivation of methyl stores occurs through a loss of urinary creatine. The loss of methyl groups contained in the excess creatine is, under ordinary conditions of diet, almost exactly compensated for by a drop in the excretion of methyl groups in the urinary creatinine. Testosterone propionate, administered over variable periods of time, resulted in the retention of creatine both in normal male children and in male children with progressive muscular dystrophy, as shown in the normal subjects by a diminution in creatine output, and in both by an excess creatinuria for variable periods of time following withdrawal of the hormone. An increase in the excretion of creatine in progressive muscular dystrophy occurred following the administration of methyl testosterone. Neither testosterone propionate nor methyl testosterone appeared to effect any consistent change in the output or urinary creatinine. No effects on the excretion of creatine and creatinine were observed following the prolonged administration of concentrate of gonadotropic and thyrotropic principles of the hypophysis, or from the administration of desoxycorticosterone acetate to patients with progressive muscular dystrophy. Except in one case, in which marked improvement was observed following the administration of testosterone propionate, no effects on the clinical course of the patients with progressive muscular dystrophy were observed as a result of treatment by any of the various hormones employed in this study. PMID:19871467

Hoagland, Charles L.; Gilder, Helena; Shank, Robert E.

1945-01-01

398

microRNA-206 promotes skeletal muscle regeneration and delays progression of Duchenne muscular dystrophy in mice  

PubMed Central

Skeletal muscle injury activates adult myogenic stem cells, known as satellite cells, to initiate proliferation and differentiation to regenerate new muscle fibers. The skeletal muscle–specific microRNA miR-206 is upregulated in satellite cells following muscle injury, but its role in muscle regeneration has not been defined. Here, we show that miR-206 promotes skeletal muscle regeneration in response to injury. Genetic deletion of miR-206 in mice substantially delayed regeneration induced by cardiotoxin injury. Furthermore, loss of miR-206 accelerated and exacerbated the dystrophic phenotype in a mouse model of Duchenne muscular dystrophy. We found that miR-206 acts to promote satellite cell differentiation and fusion into muscle fibers through suppressing a collection of negative regulators of myogenesis. Our findings reveal an essential role for miR-206 in satellite cell differentiation during skeletal muscle regeneration and indicate that miR-206 slows progression of Duchenne muscular dystrophy. PMID:22546853

Liu, Ning; Williams, Andrew H.; Maxeiner, Johanna M.; Bezprozvannaya, Svetlana; Shelton, John M.; Richardson, James A.; Bassel-Duby, Rhonda; Olson, Eric N.

2012-01-01

399

Lethal congenital muscular dystrophy in two sibs with arthrogryposis multiplex: new entity or variant of cobblestone lissencephaly syndrome?  

PubMed

We report on two sisters of first degree cousin parents who were born with severe hypotonia, arthrogryposis multiplex congenita (AMC) and dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. They needed assisted ventilation and each died at the age of 5 months. Both had type II lissencephaly (cobblestone lissencephaly) which was visualized by magnetic resonance imaging (MRI) in the proband. Ophthalmic evaluation revealed no ocular malformations in either of them. Brain auditory evoked potentials (BAEP) revealed bilateral severe sensorineural hearing loss in the proband, whereas an MRI-guided open muscle biopsy of the sartorius muscle (the only remaining thigh muscle) showed features of muscular dystrophy. Immunohistochemistry revealed normal dystrophin, dystrophin-associated glycoproteins (DAG) and merosin. Certain clinical and pathological features distinguish the disease seen in these sisters from reported isolated cases where lethal AMC was associated with brain dysplasia and from the main syndromes of congenital muscular dystrophy/cobblestone lissencephaly. Differences from the Walker-Warburg syndrome, which simulates it in severity, included the absence of severe hydrocephalus, normal creatine kinase (for age) and minimal (mainly periventricular) white matter abnormalities. The findings suggest either an independent entity, in the studied family, or an allelic variation of the cobblestone lissencephaly (type II lissencephaly) syndrome. PMID:9050048

Seidahmed, M Z; Sunada, Y; Ozo, C O; Hamid, F; Campbell, K P; Salih, M A

1996-12-01

400

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

PubMed Central

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

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

2014-01-01

401

MLPA analysis/complete sequencing of the DMD gene in a group of Bulgarian Duchenne/Becker muscular dystrophy patients.  

PubMed

Duchenne/Becker muscular dystrophy (DMD/BMD), the most common X-linked muscular dystrophy is caused by mutations in the enormously large DMD gene, encoding the protein called dystrophin. This gene was screened in a group of 27 unrelated Bulgarian DMD/BMD patients by MLPA analysis/complete sequencing. We managed to clarify the disease-causing mutation in 96.3% of the analyzed families. The MLPA analysis revealed 17 deletions (including a deletion of the very last exon 79), 6 duplications and 1 point mutation. Two additional point mutations (one of them novel) were detected after complete sequencing of the DMD gene. Altogether, 25 carriers and 11 noncarriers were detected in our families. The MLPA test proved to be a powerful tool in detecting deletions/duplications and in some cases point mutations/polymorphisms along the DMD gene. Using this approach in combination with a direct gene sequencing a number of Bulgarian DMD/BMD patients are genetically clarified and prepared for gene therapy in future. PMID:18653336

Todorova, Albena; Todorov, Tihomir; Georgieva, Bilyana; Lukova, Michaela; Guergueltcheva, Velina; Kremensky, Ivo; Mitev, Vanyo

2008-08-01

402

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

PubMed Central

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

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

2012-01-01

403

Differentiation of Duchenne and Becker muscular dystrophy phenotypes with amino- and carboxy-terminal antisera specific for dystrophin.  

PubMed Central

Antibodies directed against the amino- and carboxy-terminal regions of dystrophin have been used to characterize 25 Duchenne muscular dystrophy (DMD), two intermediate, and two Becker muscular dystrophy (BMD) patients. Western blot analysis revealed an altered-size (truncated) immunoreactive dystrophin band in 11 of the 25 DMD patients, in one of the two intermediate patients, and in both BMD patients, when immunostained with antiserum raised against the amino terminus of dystrophin. None of the DMD or intermediate patients demonstrated an immunoreactive dystrophin band when immunostained with an antiserum specific for the carboxy terminus of the protein. In contrast, dystrophin was detected in both BMD patients by the antiserum specific for the carboxy terminus. Quantitative studies indicated that the relative abundance of dystrophin in patients with a severe (DMD), intermediate, or mild (BMD) phenotype may overlap, therefore suggesting that differential diagnosis of disease severity based entirely on dystrophin quantitation may be unsatisfactory. Our results suggest that a differential diagnosis between DMD and BMD would benefit from examination of both the N terminus and C terminus of the protein, in addition to measurements of the relative abundance of the protein. Images Figure 1 Figure 2 Figure 3 PMID:1990838

Bulman, D E; Murphy, E G; Zubrzycka-Gaarn, E E; Worton, R G; Ray, P N

1991-01-01

404

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

PubMed Central

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

2014-01-01

405

Anoctamin 5 muscular dystrophy associated with a silent p.Leu115Leu mutation resulting in exon skipping.  

PubMed

We report a 45year-old patient with an asymmetrical proximal muscle weakness affecting the quadriceps muscle of the right leg starting at the age of 32years. CK was 25-fold increased. MRI of the legs showed signs of fatty degeneration more pronounced in the right side. Biopsy of a thigh muscle showed dystrophic pattern and amyloid deposition in blood vessel walls. The coding region and exon/intron boundaries of the ANO5 gene were amplified and sequenced. The common c.191dupA mutation and a silent novel p.Leu115Leu (c.345G>A) variant were identified. This silent variant was listed neither in the LOVD database nor in the SNP database. To evaluate the pathogenicity of the novel silent mutation in ANO5, cDNA analysis was performed that demonstrated skipping of exon 6. So far, no case with a silent mutation leading to abnormal splicing has been identified in Anoctamin 5 muscular dystrophy. Present findings emphasize that cDNA analysis should be done if a silent variant is not annotated in the databases. In Anoctamin 5 muscular dystrophy a molecular diagnosis is even more important as protein investigation through Western blotting or immunohistochemistry is not yet established. PMID:24239059

Joshi, Pushpa Raj; Gläser, Dieter; Dreßel, Carolin; Kress, Wolfram; Weis, Joachim; Deschauer, Marcus

2014-01-01

406

Membrane-myofibril cross-talk in myofibrillogenesis and in muscular dystrophy pathogenesis: lessons from the zebrafish  

PubMed Central

Striated muscle has a highly ordered structure in which specialized domains of the cell membrane involved in force transmission (costameres) and excitation-contraction coupling (T tubules) as well as the internal membranes of the sarcoplasmic reticulum are organized over specific regions of the sarcomere. Optimal muscle function is dependent on this high level of organization but how it established and maintained is not well understood. Due to its ex utero development and transparency, the zebrafish embryo is an excellent vertebrate model for the study of dynamic relationships both within and between cells during development. Transgenic models have allowed the delineation of cellular migration and complex morphogenic rearrangements during the differentiation of skeletal myocytes and the assembly and organization of new myofibrils. Molecular targeting of genes and transcripts has allowed the identification of key requirements for myofibril assembly and organization. With the recent advances in gene editing approaches, the zebrafish will become an increasingly important model for the study of human myopathies and muscular dystrophies. Its high fecundity and small size make it well suited to high-throughput screenings to identify novel pharmacologic and molecular therapies for the treatment of a broad range of neuromuscular conditions. In this review, we examine the lessons learned from the zebrafish model regarding the complex interactions between the sarcomere and the sarcolemma that pattern the developing myocyte and discuss the potential for zebrafish as a model system to examine the pathophysiology of, and identify new treatments for, human myopathies and muscular dystrophies. PMID:24478725

Raeker, Maide Ö.; Shavit, Jordan A.; Dowling, James J.; Michele, Daniel E.; Russell, Mark W.

2014-01-01

407

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

PubMed

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

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

2013-09-01

408

Identification of carriers of Duchenne\\/Becker muscular dystrophy by a novel method based on detection of junction fragments in the dystrophin gene  

Microsoft Academic Search

We developed a Southern blotting based method that uses rare cutting restriction endonucleases and electrophoresis of single stranded DNA to detect junction fragments resulting from the rearranged dystrophin gene. By conventional Southern blot hybridisation, no junction fragments were detected in 27 unrelated patients with Duchenne (DMD) or Becker (BMD) muscular dystrophy, who had 20 deletions and seven duplications in the

H Yamagishi; S Kato; Y Hiraishi; T Ishihara; J Hata; N Matsuo; T Takano

1996-01-01

409

Complete skipping of exon 66 due to novel mutations of the dystrophin gene was identified in two Japanese families of Duchenne muscular dystrophy with severe mental retardation  

Microsoft Academic Search

Severe mental retardation is a rare complication of Duchenne muscular dystrophy (DMD). Here we report that two DMD cases showing severe mental retardation exhibit the same exon skipping event induced by different intron mutations. In the two Japanese DMD patients studied, the complete sequence of exon 66 of the dystrophin gene was found to be absent from the dystrophin mRNA,

Tri Wibawa; Yasuhiro Takeshima; Izuru Mitsuyoshi; Hiroko Wada; Agus Surono; Hajime Nakamura; Masafumi Matsuo

2000-01-01

410

Targeted Disruption of Exon 52 in the Mouse Dystrophin Gene Induced Muscle Degeneration Similar to That Observed in Duchenne Muscular Dystrophy  

Microsoft Academic Search

Duchenne muscular dystrophy (DMD) is a degenerative disorder of the skeletal muscle in human and is caused by mutations in the dystrophin gene. Themdxmouse is a spontaneous mutant and an animal model for DMD. It has a point mutation in exon 23 of the dystrophin gene that eliminates the expression of dystrophin. However, this mutation does not disrupt the expression

Eiichi Araki; Kenji Nakamura; Kazuki Nakao; Shuhei Kameya; Osamu Kobayashi; Ikuya Nonaka; Takuro Kobayashi; Motoya Katsuki

1997-01-01

411

Comparison of the clinical state and its changes in patients with Duchenne and Becker muscular dystrophy with results of in vivo 31 P magnetic resonance spectroscopy  

Microsoft Academic Search

A total of 14 boys with the Duchenne and Becker forms of muscular dystrophy (DMD, BMD) were examined using 31P magnetic resonance (MR) spectroscopy; 12 boys were examined repeatedly. The results were correlated with clinical findings (including those of genetic tests) and with data obtained from examinations of an age-matched control group. Evaluation of results using principal component analysis revealed

M. Hájek; A. Grosmanová; A. Horská; P. Urban

1993-01-01

412

On the nature of the Duchenne muscular dystrophy locus: a portion of a complex of related gene clusters of recent pseudoautosomal origin?  

Microsoft Academic Search

The current hypothesis that the Duchenne\\/Becker muscular dystrophy locus encodes a single 2000 kb gene is analyzed. The apparent encoding efficiency, the individual and total exon\\/intron ratios, and the heterogeneity of deletions associated with the disease, which are currently interpreted as supporting the single gene hypothesis, are also consistent with the alternative hypothesis that this locus is a portion of

J. P. Infante; V. A. Huszagh

1988-01-01

413

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

SciTech Connect

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

Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. (Harvard Medical School, Boston, MA (United States)); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya (National Inst. of Neuroscience, Tokyo (Japan))

1992-01-15

414

Congenital muscular dystrophy associated with calf hypertrophy, microcephaly and severe mental retardation in three Italian families: evidence for a novel CMD syndrome  

Microsoft Academic Search

We describe four Italian patients (aged 3, 4, 12, and 13 years ) affected by a novel autosomal form of recessive congenital muscular dystrophy. These patients were from three non-consanguineous families and presented an almost identical phenotype. This was characterized by hypotonia at birth, joint contractures associated with severe psychomotor retardation, absent speech, inability to walk and almost no interest

Marcello Villanova; Eugenio Mercuri; Enrico Bertini; Patrizia Sabatelli; Lucia Morandi; Marina Mora; Caroline Sewry; Martin Brockington; Susan C Brown; Ana Ferreiro; Nadir M Maraldi; Tatsushi Toda; Pascale Guicheney; Luciano Merlini; Francesco Muntoni

2000-01-01

415

Relationships of thigh muscle contractile and non-contractile tissue with function, strength, and age in boys with Duchenne muscular dystrophy  

Microsoft Academic Search

The purpose of this study was to assess the contractile and non-contractile content in thigh muscles of patients with Duchenne muscular dystrophy (DMD) and determine the relationship with functional abilities. Magnetic resonance images of the thigh were acquired in 28 boys with DMD and 10 unaffected boys. Muscle strength, timed functional tests, and the Brookes Lower Extremity scale were also

Hiroshi Akima; Donovan Lott; Claudia Senesac; Jasjit Deol; Sean Germain; Ishu Arpan; Roxanna Bendixen; H. Lee Sweeney; Glenn Walter; Krista Vandenborne

416

LINC complex alterations in DMD and EDMD/CMT fibroblasts  

PubMed Central

Emery-Dreifuss muscular dystrophy (EDMD) is a late onset-disease characterized by skeletal muscle wasting and heart defects with associated risk of sudden death. The autosomal dominant form of the disease is caused by mutations in the LMNA gene encoding LaminA and C, the X-linked form results from mutations in the gene encoding the inner nuclear membrane protein Emerin (STA). Both Emerin and LaminA/C interact with the nuclear envelope proteins Nesprin-1 and -2 and mutations in genes encoding C-terminal isoforms of Nesprin-1 and -2 have also been implicated in EDMD. Here we analyse primary fibroblasts from patients affected by either Duchenne muscular dystrophy (DMD) or Emery-Dreifuss muscular dystrophy/Charcot-Marie-Tooth syndrome (EDMD/CMT) that in addition to the disease causing mutations harbour mutations in the Nesprin-1 gene and in the SUN1 and SUN2 gene, respectively. SUN proteins together with the Nesprins form the core of the LINC complex which connects the nucleus with the cytoskeleton. The mutations are accompanied by changes in cell adhesion, cell migration, senescence, and stress response, as well as in nuclear shape and nuclear envelope composition which are changes characteristic for laminopathies. Our results point to a potential influence of mutations in components of the LINC complex on the clinical outcome and the molecular pathology in the patients. PMID:22555292

Taranum, Surayya; Vaylann, Eva; Meinke, Peter; Abraham, Sabu; Yang, Liu; Neumann, Sascha; Karakesisoglou, Iakowos; Wehnert, Manfred; Noegel, Angelika A.

2012-01-01

417

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

Microsoft Academic Search

The presence, degree and frequency of disorders of cardiac conduction and rhythm and of regional or global myocardial dystrophy or myotonia have not previously been studied prospectively and systematically in the same population of patients with myotonic dystrophy. Accordingly, 25 adults with classic Steinert's disease underwent electrocardiography, 24-hour ambulatory electrocardiography, vectorcardiography, chest x-rays, echocardiography, electrophysiologic studies, and technetium-99m angiography. Clinically

Joseph K. Perloff; William G. Stevenson; Nigel K. Roberts; William Cabeen; James Weiss

1984-01-01

418

[The clinical-genealogic and molecular-genetic characteristics of oculopharyngeal muscular dystrophy in the Republic of Sakha (Yakutia)].  

PubMed

The clinical-genealogic and molecular-genetic investigation of oculopharyngeal muscular dystrophy (OPMD) in the Republic of Sakha (Yakutia) was performed. It was investigated 33 unrelated Yakut families with 38 patients and 2 russian families with 2 patients and 59 their healthy relatives as well. The high clinical polymorphism of disease was found in patients with OPMD. The mutation in exon 1 of the PABPN1 gene resulting in the expansion of GCG-repeats up to 10 is revealed. Using direct sequencing of the PABPN1 gene in 17 families (16 Yakut, 1 Russian), we identified a type of this mutation as an insertion of 4 GCG-repeats. Frequency of OPMD in the Yakut population is 1:11 680 that is 10-20 times higher comparing to european populations. This is a first report on the patients with OPMD from the Republic of Sakha with diagnosis confirmed by molecular-genetic analysis. PMID:18577936

Maksimova, N R; Nikolaeva, I A; Korotkov, M N; Ikeuchi, T; Onodera, O; Nishizava, M; Stepanova, S K; Kurtanov, Kh A; Sukhomiasova, A L; Nogovitsyna, A N; Gurinova, E E; Stepanov, V A; Puzyrev, V P

2008-01-01

419

A case of rare recessive oculopharyngeal muscular dystrophy (OPMD) coexisting with hereditary neuropathy with liability to pressure palsies (HNPP).  

PubMed

Oculopharyngeal muscular dystrophy (OPMD) is typically inherited in an autosomal dominant fashion and is characterized by late onset proximal muscle weakness, ptosis and difficulty swallowing. It is caused by expansion mutations in the PABPN1 gene on chromosome 14q11. There is also a rare recessive form of the disease caused by homozygosity of a very small expansion mutation in the same gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder characterized by recurrent peripheral monofocal neuropathies. In this report a patient with both recessive OPMD and HNPP is described. The presence of two genetically unlinked neurological diagnoses in the same individual is a rare event and may have delayed the diagnoses. PMID:18358598

Marsh, Eleanor A; Robinson, David O

2008-05-01

420

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

PubMed Central

This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or