WorldWideScience

Sample records for congenital muscle dystrophy

  1. Muscle-Eye-Brain Disease; a Rare Form of Syndromic Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Gosal Gurinder S

    2011-03-01

    Full Text Available Congenital muscular dystrophy (CMD is a heterogeneous group of disorders characterized by muscular hypotonia since birth and the histologic features of muscular dystrophy. Syndromic congenital muscular dystrophies are clinically similar autosomal recessive disorders characterized by congenital muscular dystrophy, lissencephaly, and eye anomalies. We present a case of a rare form of syndromic congenital muscular dystrophy in an eight year old girl, born of first- degree consanguinity. She had: global developmental delay; a seizure disorder; hypotonia; progressive muscle contractures including bilateral symmetrical flexion contractures of hips, knees, equinus contracture and thoracolumbar scoliosis; diminished deep tendon reflexes: bilateral premature cataract; pseudophakia; and nystagmus. The patient was also highly myopic. Based on clinical features, muscle biopsy and MRI of the brain, a diagnosis of muscle- eye- brain disease was made. Identification of these patients may help to prevent this crippling disorder in the future siblings of probands by utilizing genetic counselling and mutation analysis.

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

    Science.gov (United States)

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

    2017-11-01

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

  3. Magnetic resonance imaging, ultrasound and real-time ultrasound elastography of the thigh muscles in congenital muscle dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Drakonaki, Eleni E. [University of Crete, Radiology Department, Heraklion (Greece); Allen, Gina M. [Green Templeton College, Oxford (United Kingdom)

    2010-04-15

    Congenital muscle dystrophy includes a range of genetic disorders characterized by muscle weakness and contractures. We report the magnetic resonance (MR), ultrasound (US) and real-time sonoelastography (RTE) imaging findings of the thigh muscles of a 15-year-old boy with Bethlem myopathy diagnosed with clinical, electromyographic and histopathological criteria. Ultrasound and MR showed hyperechoic appearance and high signal intensity on T1- and T2-weighted sequences respectively at the periphery of the vastus lateralis and the long head of the biceps femoris muscles, and at a central area within the rectus femoris muscles. RTE was employed to examine the elastic properties of the muscle. The elastograms were presented as colour-coded maps superimposed on the B-mode images and revealed that the elastographic pattern correlated with the MR and US pattern of involvement. The abnormal muscle areas were stiffer (blue) than the normal-appearing areas (green), a finding that probably correlates with the presence of dystrophic collagen at the affected areas. This report suggests that RTE could be used as an additional imaging tool to evaluate the pattern of muscle changes in congenital myopathy. Further studies are needed to investigate the specificity and clinical value of RTE in the diagnosis and monitoring of neuromuscular disease. (orig.)

  4. Magnetic resonance imaging, ultrasound and real-time ultrasound elastography of the thigh muscles in congenital muscle dystrophy

    International Nuclear Information System (INIS)

    Drakonaki, Eleni E.; Allen, Gina M.

    2010-01-01

    Congenital muscle dystrophy includes a range of genetic disorders characterized by muscle weakness and contractures. We report the magnetic resonance (MR), ultrasound (US) and real-time sonoelastography (RTE) imaging findings of the thigh muscles of a 15-year-old boy with Bethlem myopathy diagnosed with clinical, electromyographic and histopathological criteria. Ultrasound and MR showed hyperechoic appearance and high signal intensity on T1- and T2-weighted sequences respectively at the periphery of the vastus lateralis and the long head of the biceps femoris muscles, and at a central area within the rectus femoris muscles. RTE was employed to examine the elastic properties of the muscle. The elastograms were presented as colour-coded maps superimposed on the B-mode images and revealed that the elastographic pattern correlated with the MR and US pattern of involvement. The abnormal muscle areas were stiffer (blue) than the normal-appearing areas (green), a finding that probably correlates with the presence of dystrophic collagen at the affected areas. This report suggests that RTE could be used as an additional imaging tool to evaluate the pattern of muscle changes in congenital myopathy. Further studies are needed to investigate the specificity and clinical value of RTE in the diagnosis and monitoring of neuromuscular disease. (orig.)

  5. Distinct Fiber Type Signature in Mouse Muscles Expressing a Mutant Lamin A Responsible for Congenital Muscular Dystrophy in a Patient

    Directory of Open Access Journals (Sweden)

    Alice Barateau

    2017-04-01

    Full Text Available Specific mutations in LMNA, which encodes nuclear intermediate filament proteins lamins A/C, affect skeletal muscle tissues. Early-onset LMNA myopathies reveal different alterations of muscle fibers, including fiber type disproportion or prominent dystrophic and/or inflammatory changes. Recently, we identified the p.R388P LMNA mutation as responsible for congenital muscular dystrophy (L-CMD and lipodystrophy. Here, we asked whether viral-mediated expression of mutant lamin A in murine skeletal muscles would be a pertinent model to reveal specific muscle alterations. We found that the total amount and size of muscle fibers as well as the extent of either inflammation or muscle regeneration were similar to wildtype or mutant lamin A. In contrast, the amount of fast oxidative muscle fibers containing myosin heavy chain IIA was lower upon expression of mutant lamin A, in correlation with lower expression of genes encoding transcription factors MEF2C and MyoD. These data validate this in vivo model for highlighting distinct muscle phenotypes associated with different lamin contexts. Additionally, the data suggest that alteration of muscle fiber type identity may contribute to the mechanisms underlying physiopathology of L-CMD related to R388P mutant lamin A.

  6. Aberrant Myokine Signaling in Congenital Myotonic Dystrophy

    Directory of Open Access Journals (Sweden)

    Masayuki Nakamori

    2017-10-01

    Full Text Available Summary: Myotonic dystrophy types 1 (DM1 and 2 (DM2 are dominantly inherited neuromuscular disorders caused by a toxic gain of function of expanded CUG and CCUG repeats, respectively. Although both disorders are clinically similar, congenital myotonic dystrophy (CDM, a severe DM form, is found only in DM1. CDM is also characterized by muscle fiber immaturity not observed in adult DM, suggesting specific pathological mechanisms. Here, we revealed upregulation of the interleukin-6 (IL-6 myokine signaling pathway in CDM muscles. We also found a correlation between muscle immaturity and not only IL-6 expression but also expanded CTG repeat length and CpG methylation status upstream of the repeats. Aberrant CpG methylation was associated with transcriptional dysregulation at the repeat locus, increasing the toxic RNA burden that upregulates IL-6. Because the IL-6 pathway is involved in myocyte maturation and muscle atrophy, our results indicate that enhanced RNA toxicity contributes to severe CDM phenotypes through aberrant IL-6 signaling. : Congenital myotonic dystrophy (CDM manifests characteristic genetic (very large CTG repeat expansions, epigenetic (CpG hypermethylation upstream of the repeat, and phenotypic (muscle immaturity features not seen in adult DM. Nakamori et al. find phenotype-genotype and epigenotype correlation in CDM muscle and reveal involvement of the IL-6 myokine signaling pathway in the disease process. Keywords: CTCF, ER stress, IL-6, muscular dystrophy, NF-κB, trinucleotide, cytokine, splicing

  7. A Congenital Muscular Dystrophy with Mitochondrial Structural Abnormalities Caused by Defective De Novo Phosphatidylcholine Biosynthesis

    OpenAIRE

    Mitsuhashi, Satomi; Ohkuma, Aya; Talim, Beril; Karahashi, Minako; Koumura, Tomoko; Aoyama, Chieko; Kurihara, Mana; Quinlivan, Ros; Sewry, Caroline; Mitsuhashi, Hiroaki; Goto, Kanako; Koksal, Burcu; Kale, Gulsev; Ikeda, Kazutaka; Taguchi, Ryo

    2011-01-01

    Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent to...

  8. CONGENITAL MYOTONIC DYSTROPHY – CASE REPORT

    Directory of Open Access Journals (Sweden)

    David Neubauer

    2001-07-01

    Full Text Available Background. Myotonic dystrophy is inherited as an autosomal dominant trait. It is characterized by myotonia, myopathy of voluntary and involuntary muscles, frontal baldness in men, cardiac conduction abnormalities, catharacts, intellectual deterioration and endocrinopathy. Men with this disorder have often gonadal atrophy and infertility. On the other hand women are generally fertile. During pregnancy their myopathy worsens, often causing severe obstetrical complications. Their children may develop congenital form of the disease with signs of myopathy in utero and have great difficulties in maintaining life functions after birth, together with other characteristical signs of this form: bilateral facial weakness, severe hypotonia, feeding difficulties, talipes equinovarus and mental retardation. The authors present a female newborn with such congenital form of myotonic dystrophy.Conclusions. The authors have emphasized the importance of medical history, regular updating of all the cases of neuromuscular diseases in the region and clinical characteristics for the recognition of congenital form of myotonic dystrophy because of possible prenatal diagnostics and better antenatal and postantal care.

  9. Congenital muscular dystrophy with inflammation: Diagnostic considerations

    Directory of Open Access Journals (Sweden)

    Kaumudi Konkay

    2016-01-01

    Full Text Available Background and Purpose: Muscle biopsy features of congenital muscular dystrophies (CMD vary from usual dystrophic picture to normal or nonspecific myopathic picture or prominent fibrosis or striking inflammatory infiltrate, which may lead to diagnostic errors. A series of patients of CMD with significant inflammatory infiltrates on muscle biopsy were correlated with laminin α 2 deficiency on immunohistochemistry (IHC. Material and Methods: Cryostat sections of muscle biopsies from the patients diagnosed as CMD on clinical and muscle biopsy features from 1996 to 2014 were reviewed with hematoxylin and eosin(H&E, enzyme and immunohistochemistry (IHC with laminin α 2. Muscle biopsies with inflammatory infiltrate were correlated with laminin α 2 deficiency. Results: There were 65 patients of CMD, with inflammation on muscle biopsy in 16. IHC with laminin α 2 was available in nine patients, of which six showed complete absence along sarcolemma (five presented with floppy infant syndrome and one with delayed motor milestones and three showed discontinuous, and less intense staining. Conclusions: CMD show variable degrees of inflammation on muscle biopsy. A diagnosis of laminin α 2 deficient CMD should be considered in patients of muscular dystrophy with inflammation, in children with hypotonia/delayed motor milestones.

  10. Muscle Weakness and Fibrosis Due to Cell Autonomous and Non-cell Autonomous Events in Collagen VI Deficient Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Satoru Noguchi

    2017-02-01

    Full Text Available Congenital muscular dystrophies with collagen VI deficiency are inherited muscle disorders with a broad spectrum of clinical presentation and are caused by mutations in one of COL6A1–3 genes. Muscle pathology is characterized by fiber size variation and increased interstitial fibrosis and adipogenesis. In this study, we define critical events that contribute to muscle weakness and fibrosis in a mouse model with collagen VI deficiency. The Col6a1GT/GT mice develop non-progressive weakness from younger age, accompanied by stunted muscle growth due to reduced IGF-1 signaling activity. In addition, the Col6a1GT/GT mice have high numbers of interstitial skeletal muscle mesenchymal progenitor cells, which dramatically increase with repeated myofiber necrosis/regeneration. Our results suggest that impaired neonatal muscle growth and the activation of the mesenchymal cells in skeletal muscles contribute to the pathology of collagen VI deficient muscular dystrophy, and more importantly, provide the insights on the therapeutic strategies for collagen VI deficiency.

  11. Study on the findings of muscle CT in patients with Fukuyama type congenital muscular dystrophy (FCMD)

    Energy Technology Data Exchange (ETDEWEB)

    Sumida, Sawako; Osawa, Makiko; Okada, Noriko and others

    1988-11-01

    This study was carried out to investigate the process of muscle involvement according to age in patients with FCMD (Brain Dev 1981 ; 3:1 - 29) by CT scans. Fourteen patients with FCMD I (age: 5 months-12 years) and two patients with FCMD III or IV (age: 3, 4 years) were studied. The midcalf, midthigh, L3 and shoulder girdle level were the sites chosen. Two types of change were found in FCMD I. One of them was the attenuation of the density in muscle and the other one was decreased area of muscle as a result of low density which started from periphery of the muscle. The latter was found in m. psoas major after age 9, whilst the former was found in other muscles to some degree. The severity of the changes was related to age. In the case which was examined twice, the changes extended even better motor function had been attained. The changes in midcalf preceded those in midthigh, L3, shoulder girdle. The attenuation of density was found early and severely in m. triceps surae, m. adductor magnus, paravertebral muscles and m. subscapularis, whilst those in m. tibialis anterior and posterior, m. gracilis, m. sartorius, m. quadratus lumborum appeared later and relatively mild. The relationship between the process of extension of low density in muscle and joint contractures were also discussed. The changes in CT scan in FCMD III or IV were milder than those of FCMD I and there was no tendency that the change in midcalf preceded those of other scanned level.

  12. Congenital muscular dystrophies--problems of classification.

    Science.gov (United States)

    Lenard, H G

    1991-04-01

    The classification of congenital muscular dystrophies (CMD), based on perceived clinical and morphological similarities or differences, is controversial. CMD without cerebral involvement has sometimes been divided into a mild and a severe form. This distinction is, however, arbitrary and not uncontested. Whether Ullrich's disease, formerly called atonic-sclerotic dystrophy, is a disease entity and if so, whether it is a primary muscle disorder, is uncertain. CMD without cerebral involvement is inherited in an autosomal recessive fashion in the great majority of cases. CMDs with cerebral involvement are usually classified into at least three forms: the Fukuyama type of CMD, occurring almost exclusively in Japanese patients; CMD with hypomyelination, sometimes also called the occidental type of cerebromuscular dystrophy; and Walker-Warburg syndrome. Muscle-eye-brain disease, described in a number of Finnish patients, may or may not belong in this last category. In CMD with cerebral involvement inheritance is also autosomal recessive. It is possible that single sporadic cases are phenocopies due to infectious or other exogenous causes. Reports of clinical and morphological findings from an increasing number of patients show a high degree of variability within and, on the other hand, certain similarities between the forms of CMD with cerebral involvement. In addition, neuroradiological changes are also found with increasing frequency in CMD patients without clinical neuropsychological abnormalities. It is not unreasonable to speculate that molecular genetic techniques will reveal in the near future a variable defect in one gene locus or defects in a few gene loci as the cause of the various clinical forms of CMDs.

  13. Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy

    DEFF Research Database (Denmark)

    Vachon, P H; Xu, H; Liu, L

    1997-01-01

    Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy. Analyses of integrins showed an abnormal expression and localization of alpha7beta1...... isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall. 1996...... in skeletal muscle; (b) indicate a merosin dependence for the accurate expression and membrane localization of alpha7beta1D integrins in myofibers; (c) provide a molecular basis for the critical role of merosin in myofiber survival; and (d) add new insights to the pathogenesis of neuromuscular disorders....

  14. Contribution of dysferlin deficiency to skeletal muscle pathology in asymptomatic and severe dystroglycanopathy models: generation of a new model for Fukuyama congenital muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Motoi Kanagawa

    Full Text Available Defects in dystroglycan glycosylation are associated with a group of muscular dystrophies, termed dystroglycanopathies, that include Fukuyama congenital muscular dystrophy (FCMD. It is widely believed that abnormal glycosylation of dystroglycan leads to disease-causing membrane fragility. We previously generated knock-in mice carrying a founder retrotransposal insertion in fukutin, the gene responsible for FCMD, but these mice did not develop muscular dystrophy, which hindered exploring therapeutic strategies. We hypothesized that dysferlin functions may contribute to muscle cell viability in the knock-in mice; however, pathological interactions between glycosylation abnormalities and dysferlin defects remain unexplored. To investigate contributions of dysferlin deficiency to the pathology of dystroglycanopathy, we have crossed dysferlin-deficient dysferlin(sjl/sjl mice to the fukutin-knock-in fukutin(Hp/- and Large-deficient Largemyd/myd mice, which are phenotypically distinct models of dystroglycanopathy. The fukutin(Hp/- mice do not show a dystrophic phenotype; however, (dysferlin(sjl/sjl: fukutin(Hp/- mice showed a deteriorated phenotype compared with (dysferlinsjl/sjl: fukutin(Hp/+ mice. These data indicate that the absence of functional dysferlin in the asymptomatic fukutin(Hp/- mice triggers disease manifestation and aggravates the dystrophic phenotype. A series of pathological analyses using double mutant mice for Large and dysferlin indicate that the protective effects of dysferlin appear diminished when the dystrophic pathology is severe and also may depend on the amount of dysferlin proteins. Together, our results show that dysferlin exerts protective effects on the fukutin(Hp/- FCMD mouse model, and the (dysferlin(sjl/sjl: fukutin(Hp/- mice will be useful as a novel model for a recently proposed antisense oligonucleotide therapy for FCMD.

  15. Prevalence of congenital muscular dystrophy in Italy

    Science.gov (United States)

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

    2015-01-01

    Objective: We provide a nationwide population study of patients with congenital muscular dystrophy in Italy. Methods: Cases were ascertained from the databases in all the tertiary referral centers for pediatric neuromuscular disorders and from all the genetic diagnostic centers in which diagnostic tests for these forms are performed. Results: The study includes 336 patients with a point prevalence of 0.563 per 100,000. Mutations were identified in 220 of the 336 (65.5%). The cohort was subdivided into diagnostic categories based on the most recent classifications on congenital muscular dystrophies. The most common forms were those with α-dystroglycan glycosylation deficiency (40.18%) followed by those with laminin α2 deficiency (24.11%) and collagen VI deficiency (20.24%). The forms of congenital muscular dystrophy related to mutations in SEPN1 and LMNA were less frequent (6.25% and 5.95%, respectively). Conclusions: Our study provides for the first time comprehensive epidemiologic information and point prevalence figures for each of the major diagnostic categories on a large cohort of congenital muscular dystrophies. The study also reflects the diagnostic progress in this field with an accurate classification of the cases according to the most recent gene discoveries. PMID:25653289

  16. A study on the findings of muscle CT in patients with Fukuyama type congenital muscular dystrophy (FCMD)

    International Nuclear Information System (INIS)

    Sumida, Sawako; Osawa, Makiko; Okada, Noriko

    1988-01-01

    This study was carried out to investigate the process of muscle involvement according to age in patients with FCMD (Brain Dev 1981 ; 3:1 - 29) by CT scans. Fourteen patients with FCMD I (age: 5 months-12 years) and two patients with FCMD III or IV (age: 3, 4 years) were studied. The midcalf, midthigh, L3 and shoulder girdle level were the sites chosen. Two types of change were found in FCMD I. One of them was the attenuation of the density in muscle and the other one was decreased area of muscle as a result of low density which started from periphery of the muscle. The latter was found in m. psoas major after age 9, whilst the former was found in other muscles to some degree. The severity of the changes was related to age. In the case which was examined twice, the changes extended even better motor function had been attained. The changes in midcalf preceded those in midthigh, L3, shoulder girdle. The attenuation of density was found early and severely in m. triceps surae, m. adductor magnus, paravertebral muscles and m. subscapularis, whilst those in m. tibialis anterior and posterior, m. gracilis, m. sartorius, m. quadratus lumborum appeared later and relatively mild. The relationship between the process of extension of low density in muscle and joint contractures were also discussed. The changes in CT scan in FCMD III or IV were milder than those of FCMD I and there was no tendency that the change in midcalf preceded those of other scanned level. (author)

  17. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models

    DEFF Research Database (Denmark)

    Kuang, W; Xu, H; Vachon, P H

    1998-01-01

    Humans and mice with deficiency of the alpha2 subunit of the basement membrane protein laminin-2/merosin suffer from merosin-deficient congenital muscular dystrophy (MCMD). We have expressed a human laminin alpha2 chain transgene under the regulation of a muscle-specific creatine kinase promoter...

  18. Lethal congenital muscular dystrophy with arthrogryposis multiplex congenita : three new cases and review of the literature

    NARCIS (Netherlands)

    Sombekke, B H; Molenaar, W M; Essen, A J van; Schoots, C J

    1994-01-01

    Congenital muscular dystrophy (CMD) comprises a heterogeneous group of muscle disorders. We report on two stillborn sibs with early lethal CMD and a prematurely born boy who died within minutes after birth. The pregnancies were complicated by polyhydramnios. All presented with arthrogryposis

  19. Non-Coding RNAs in Muscle Dystrophies

    Directory of Open Access Journals (Sweden)

    Alessandra Ferlini

    2013-09-01

    Full Text Available ncRNAs are the most recently identified class of regulatory RNAs with vital functions in gene expression regulation and cell development. Among the variety of roles they play, their involvement in human diseases has opened new avenues of research towards the discovery and development of novel therapeutic approaches. Important data come from the field of hereditary muscle dystrophies, like Duchenne muscle dystrophy and Myotonic dystrophies, rare diseases affecting 1 in 7000–15,000 newborns and is characterized by severe to mild muscle weakness associated with cardiac involvement. Novel therapeutic approaches are now ongoing for these diseases, also based on splicing modulation. In this review we provide an overview about ncRNAs and their behavior in muscular dystrophy and explore their links with diagnosis, prognosis and treatments, highlighting the role of regulatory RNAs in these pathologies.

  20. A congenital muscular dystrophy with mitochondrial structural abnormalities caused by defective de novo phosphatidylcholine biosynthesis.

    Science.gov (United States)

    Mitsuhashi, Satomi; Ohkuma, Aya; Talim, Beril; Karahashi, Minako; Koumura, Tomoko; Aoyama, Chieko; Kurihara, Mana; Quinlivan, Ros; Sewry, Caroline; Mitsuhashi, Hiroaki; Goto, Kanako; Koksal, Burcu; Kale, Gulsev; Ikeda, Kazutaka; Taguchi, Ryo; Noguchi, Satoru; Hayashi, Yukiko K; Nonaka, Ikuya; Sher, Roger B; Sugimoto, Hiroyuki; Nakagawa, Yasuhito; Cox, Gregory A; Topaloglu, Haluk; Nishino, Ichizo

    2011-06-10

    Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Importance of Skin Changes in the Differential Diagnosis of Congenital Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Uluç Yis

    2016-01-01

    Full Text Available Megaconial congenital muscular dystrophy (OMIM 602541 is characterized with early-onset hypotonia, muscle wasting, proximal weakness, cardiomyopathy, mildly elevated serum creatine kinase (CK levels, and mild-to-moderate intellectual disability. We report two siblings in a consanguineous family admitted for psychomotor delay. Physical examination revealed proximal muscle weakness, contractures in the knee of elder sibling, diffuse mild generalized muscle atrophy, and dry skin with ichthyosis together with multiple nummular eczema in both siblings. Serum CK values were elevated up to 500 U/L. For genetic work-up, we performed whole exome sequencing (WES after Nimblegen enrichment on the Illumina platform. The WES revealed a novel homozygous missense mutation in the Choline Kinase-Beta (CHKB gene c.1031G>A (p.R344Q in exon 9. Ichthyosis-like skin changes with intense pruritus and nummular eczema may lead to clinical diagnosis in cases with megaconial congenital muscular dystrophy.

  2. Respiratory muscle training in Duchenne muscular dystrophy.

    OpenAIRE

    Rodillo, E; Noble-Jamieson, C M; Aber, V; Heckmatt, J Z; Muntoni, F; Dubowitz, V

    1989-01-01

    Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.

  3. Fukuyama type congenital muscular dystrophy with unusual features

    International Nuclear Information System (INIS)

    Mori, Hideo; Oguni, Hirokazu; Osawa, Makiko; Suzuki, Haruko; Fukuyama, Yukio

    1980-01-01

    The Fukuyama type congenital muscular dystrophy (F-CMD) has been generally recognized as a well delineated subgroup of progressive muscular dystrophy (PMD) with uniform clinical, pathological, and genetic features. However, there are still debate to be solved as to the etiology of the condition, because several neuropathological findings found in F-CMD brain allowed some investigators to hypothesize the intrauterine infection to be a primary causation. The authors reported here two families with two affected siblings in each. In the pedigree A, consanguineous parents produced two sisters, Case 1 (3-year-old) and Case 2 (14-month-old). Two patients in the pedigree B, the products of non-consanguineous parents, Case 3 (4-month-old male) and his elder sister already decreased, were affected with F-CMD and infantile spasms. In all cases, generalized weakness and hypotonia had been remarkable since their early infancy, and muscle atrophy, myopathic facies multiple joint contractures and mental dullness became evident gradually. The above-mentioned clinical features as well as laboratory findings including elevated serum CPK and myogenic EMG were compatible with those of typical F-CMD. However, they were characterized by the following three unusual features. 1. Muscle biopsy: In addition to an overwhelming myogenic change, there was a distinct inflammatory cell infiltration in all cases, and scattered small groups of atrophic fibers were present in Case 2. 2. Brain CT scanning: A symmetrical and extensive low density area was observed in the cerebral white matter in all cases. 3. A favorable response to prednisolone therapy was noted in all cases. (author)

  4. Muscle MRI findings in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Gerevini, Simonetta; Caliendo, Giandomenico; Falini, Andrea [IRCCS San Raffaele Scientific Institute, Neuroradiology Unit, Head and Neck Department, Milan (Italy); Scarlato, Marina; Previtali, Stefano Carlo [IRCCS San Raffaele Scientific Institute, Department of Neurology, INSPE and Division of Neuroscience, Milan (Italy); Maggi, Lorenzo; Pasanisi, Barbara; Morandi, Lucia [Fondazione IRCCS Istituto Neurologico ' ' Carlo Besta' ' , Neuromuscular Diseases and Neuroimmunology Unit, Milan (Italy); Cava, Mariangela [IRCCS San Raffaele Scientific Institute, Department of Radiology and Center for Experimental Imaging, Milan (Italy)

    2016-03-15

    Facioscapulohumeral muscular dystrophy (FSHD) is characterized by extremely variable degrees of facial, scapular and lower limb muscle involvement. Clinical and genetic determination can be difficult, as molecular analysis is not always definitive, and other similar muscle disorders may have overlapping clinical manifestations. Whole-body muscle MRI examination for fat infiltration, atrophy and oedema was performed to identify specific patterns of muscle involvement in FSHD patients (30 subjects), and compared to a group of control patients (23) affected by other myopathies (NFSHD). In FSHD patients, we detected a specific pattern of muscle fatty replacement and atrophy, particularly in upper girdle muscles. The most frequently affected muscles, including paucisymptomatic and severely affected FSHD patients, were trapezius, teres major and serratus anterior. Moreover, asymmetric muscle involvement was significantly higher in FSHD as compared to NFSHD patients. In conclusion, muscle MRI is very sensitive for identifying a specific pattern of involvement in FSHD patients and in detecting selective muscle involvement of non-clinically testable muscles. Muscle MRI constitutes a reliable tool for differentiating FSHD from other muscular dystrophies to direct diagnostic molecular analysis, as well as to investigate FSHD natural history and follow-up of the disease. (orig.)

  5. Cardiac Complications of Fukuyama-Type Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-07-01

    Full Text Available The course of left ventricular function was evaluated using M-mode and Doppler echocardiography in 34 patients with Fukuyama-type congenital muscular dystrophy (FCMD, in a study at the Tokyo Women’s Medical University, Tokyo, Japan.

  6. Neuroimaging study of Fukuyama type congenital muscular dystrophy

    International Nuclear Information System (INIS)

    Murasugi, Hiroko

    1992-01-01

    Fukuyama type congenital muscular dystrophy (FCMD) has been attracting attention in recent years because of its brain malformation and progressive muscular dystrophy. The intravitam recognition of brain malformation has been remarkably enhanced by the advent of noninvasive neuroimaging techniques such as CT and MRI. In this study, 87 cranial CT scans and 22 MRIs of the brain, carried out on 60 patients with FCMD, were systematically surveyed, and the correlation between neuroradiological findings and clinical disabilities, and, in two autopsy cases, neuropathological findings was evaluated. Four cases of lissencephalic, 29 of pachygyric, and one of polymicrogyric (suspected) brain surface, and 2 normal brain surfaces were recognized. The patients with lissencephalic brain surface were compared using Dobyns' criteria. Grading of pachygyria was judged as bilateral II in 52% of cases and bilateral I in 48%. The surface of the occipital lobe could not be confirmed with either CT or MRI. Polymicrogyria was suspected using MRI but could not confirmed with CT. Five caces of lissencephaly had never learned any meaningful words and all but one were bedridden because of poor head control. The abilities of patients were better when the grading of pachygyria was milder. Mental disability and peak motor function correlate more closely with the degree and extent of brain malformation than with muscle degeneration. The decrease in radiodensity in the white matter was remarkable in 12 out of 19 cases (63%), and was usually bilaterally symmetrical. An increase in radiodensity in the white matter with age was observed in 3 patients. The rate of myelination was slower than normal in 3 out of the 6 cases. (author)

  7. Molecular mechanisms of muscle atrophy in myotonic dystrophies

    OpenAIRE

    Timchenko, Lubov

    2013-01-01

    Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) are multisystemic diseases that primarily affect skeletal muscle, causing myotonia, muscle atrophy, and muscle weakness. DM1 and DM2 pathologies are caused by expansion of CTG and CCTG repeats in non-coding regions of the genes encoding myotonic dystrophy protein kinase (DMPK) and Zinc finger protein 9 (ZNF9) respectively. These expansions cause DM pathologies through accumulation of mutant RNAs that alter RNA metabolism in p...

  8. Congenital Muscle Disease Study of Patient and Family Reported Medical Information

    Science.gov (United States)

    2017-05-05

    Congenital Muscular Dystrophy (Including Unspecified/Undiagnosed); Dystroglycanopathy; Congenital Fiber Type Disproportion; Rigid Spine Muscular Dystrophy; Congenital Myopathy (Including Unspecified/Undiagnosed); Collagen VI CMD (Ullrich CMD, Intermediate, Bethlem Myopathy); Laminin Alpha 2 Related Congenital Muscular Dystrophy; LAMA2-CMD/Merosin Deficient/MDC1A; Walker-Warburg Syndrome; Muscle-Eye-Brain Disease; Fukuyama/Fukutin Related Muscular Dystrophy; Integrin Alpha 7 Deficiency; Integrin Alpha 9 Deficiency; LMNA-CMD/Lamin A/C/Laminopathy; SEPN1-Related Myopathy; Bethlem Myopathy; Actin Aggregation Myopathy; Cap Disease; Central Core Disease; Centronuclear Myopathy; Core Rod Myopathy; Hyaline Body Myopathy; Multiminicore Myopathy; Myotubular Myopathy; Nemaline Myopathy; Tubular Aggregate Myopathy; Zebra Body Myopathy; Reducing Body Myopathy; Spheroid Body Myopathy; LGMD1B (LMNA); LGMD1E (DES); LGMD2G (TCAP); LGMD2H (TRIM32); LGMD2I (FKRP); LGMD2J (TTN); LGMD2K (POMT1); LGMD2M (FKTN); LGMD2N (POMT2); LGMD2O (POMGnT1); LGMD2P (DAG1); LGMD2Q (PLEC1); LGMD2R (DES); LGMD2S (TRAPPC11); LGMD2T (GMPPB); LGMD2U (ISPD); LGMD2V (GAA); Ullrich Congenital Muscular Dystrophy; Titinopathy; Choline Kinase B Receptor; Emery-Dreifuss Muscular Dystrophy; RYR1 Related Myopathy; SYNE1/Nesprin Related Muscular Dystrophy; Telethonin Related Muscular Dystrophy (TCAP/Titin-Cap); Congenital Myasthenic Syndrome; Escobar Syndrome; Myofibrillar Myopathy; Malignant Hyperthermia; Alpha-Dystroglycan Related Muscular Dystrophy (DAG1, DPM1, DPM2, DPM3, FKRP, FKTN); Alpha-Dystroglycan Related Muscular Dystrophy (GAA, ISPD, LARGE, POMT1, POMT2, POMGnT1); Alpha-Dystroglycan Related Muscular Dystrophy (Unspecified/Undiagnosed/Other)

  9. Changes of laminin beta 2 chain expression in congenital muscular dystrophy

    DEFF Research Database (Denmark)

    Cohn, R D; Herrmann, R; Wewer, U M

    1997-01-01

    We studied the distribution of laminin beta 2 chain in the skeletal muscle basement membrane of 16 patients with congenital muscular dystrophy (CMD) by immunohistochemistry. A dramatic reduction in the laminin beta 2 staining was observed in four patients with classical merosin-negative CMD....... A moderate reduction of laminin beta 2 labelling was observed in four patients with partial merosin deficiency and two patients with merosin-positive CMD. Two patients with merosin-positive CMD had no apparent changes in the expression of laminin beta 2. In three patients and one fetus diagnosed as Walker...

  10. The paradox of muscle hypertrophy in muscular dystrophy.

    Science.gov (United States)

    Kornegay, Joe N; Childers, Martin K; Bogan, Daniel J; Bogan, Janet R; Nghiem, Peter; Wang, Jiahui; Fan, Zheng; Howard, James F; Schatzberg, Scott J; Dow, Jennifer L; Grange, Robert W; Styner, Martin A; Hoffman, Eric P; Wagner, Kathryn R

    2012-02-01

    Mutations in the dystrophin gene cause Duchenne and Becker muscular dystrophy in humans and syndromes in mice, dogs, and cats. Affected humans and dogs have progressive disease that leads primarily to muscle atrophy. Mdx mice progress through an initial phase of muscle hypertrophy followed by atrophy. Cats have persistent muscle hypertrophy. Hypertrophy in humans has been attributed to deposition of fat and connective tissue (pseudohypertrophy). Increased muscle mass (true hypertrophy) has been documented in animal models. Muscle hypertrophy can exaggerate postural instability and joint contractures. Deleterious consequences of muscle hypertrophy should be considered when developing treatments for muscular dystrophy. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Muscle phenotype in patients with myotonic dystrophy type 1

    DEFF Research Database (Denmark)

    Andersen, Grete; Orngreen, Mette C; Preisler, Nicolai

    2013-01-01

    Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand-held dynamometry. Myotonia...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1994-09-01

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

  13. Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Hauerslev, S; Ørngreen, M C; Hertz, J M

    2013-01-01

    The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A.......The aim of this study was to investigate whether inflammation and regeneration are prominent in mildly affected muscles of patients with facioscapulohumeral muscular dystrophy type 1A (FSHD1A). Inflammation in muscle has been suggested by MRI studies in patients with FSHD1A....

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

    NARCIS (Netherlands)

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

    1995-01-01

    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

  15. Three-Dimensional Human iPSC-Derived Artificial Skeletal Muscles Model Muscular Dystrophies and Enable Multilineage Tissue Engineering

    Directory of Open Access Journals (Sweden)

    Sara Martina Maffioletti

    2018-04-01

    Full Text Available Summary: Generating human skeletal muscle models is instrumental for investigating muscle pathology and therapy. Here, we report the generation of three-dimensional (3D artificial skeletal muscle tissue from human pluripotent stem cells, including induced pluripotent stem cells (iPSCs from patients with Duchenne, limb-girdle, and congenital muscular dystrophies. 3D skeletal myogenic differentiation of pluripotent cells was induced within hydrogels under tension to provide myofiber alignment. Artificial muscles recapitulated characteristics of human skeletal muscle tissue and could be implanted into immunodeficient mice. Pathological cellular hallmarks of incurable forms of severe muscular dystrophy could be modeled with high fidelity using this 3D platform. Finally, we show generation of fully human iPSC-derived, complex, multilineage muscle models containing key isogenic cellular constituents of skeletal muscle, including vascular endothelial cells, pericytes, and motor neurons. These results lay the foundation for a human skeletal muscle organoid-like platform for disease modeling, regenerative medicine, and therapy development. : Maffioletti et al. generate human 3D artificial skeletal muscles from healthy donors and patient-specific pluripotent stem cells. These human artificial muscles accurately model severe genetic muscle diseases. They can be engineered to include other cell types present in skeletal muscle, such as vascular cells and motor neurons. Keywords: skeletal muscle, pluripotent stem cells, iPS cells, myogenic differentiation, tissue engineering, disease modeling, muscular dystrophy, organoids

  16. Muscular dystrophy in a dish: engineered human skeletal muscle mimetics for disease modeling and drug discovery

    Science.gov (United States)

    Smith, Alec S.T.; Davis, Jennifer; Lee, Gabsang; Mack, David L.

    2016-01-01

    Engineered in vitro models using human cells, particularly patient-derived induced pluripotent stem cells (iPSCs), offer a potential solution to issues associated with the use of animals for studying disease pathology and drug efficacy. Given the prevalence of muscle diseases in human populations, an engineered tissue model of human skeletal muscle could provide a biologically accurate platform to study basic muscle physiology, disease progression, and drug efficacy and/or toxicity. Such platforms could be used as phenotypic drug screens to identify compounds capable of alleviating or reversing congenital myopathies, such as Duchene muscular dystrophy (DMD). Here, we review current skeletal muscle modeling technologies with a specific focus on efforts to generate biomimetic systems for investigating the pathophysiology of dystrophic muscle. PMID:27109386

  17. Fetal akinesia-hypokinesia deformation sequence (FADS) in 2 siblings with congenital myotonic dystrophy

    DEFF Research Database (Denmark)

    Lidang Jensen, M; Rix, M; Schrøder, Henrik Daa

    1995-01-01

    or abdominal viscera anomalies and examination of the brain, spinal cord and peripheral nerves did not disclose any pathological changes. Light microscopy, immunohistochemistry and electron microscopy of skeletal muscles demonstrated immature muscles with some fibril disorganisation and abnormal...... immunoreactivity for actin and desmin. Subsequent molecular genetic analysis revealed a maternal diagnosis of myotonic dystrophy. The retarded growth and maturation of skeletal muscle observed in the presented cases correspond with previous findings in neonatal myotonic dystrophy. A well-defined myopathy can thus...

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

    Directory of Open Access Journals (Sweden)

    Luciano Merlini

    2011-01-01

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

  19. Protein-carbohydrate supplements improve muscle protein balance in muscular dystrophy patients after endurance exercise

    DEFF Research Database (Denmark)

    Andersen, Grete; Ørngreen, Mette C; Preisler, Nicolai

    2015-01-01

    In healthy individuals, postexercise protein supplementation increases muscle protein anabolism. In patients with muscular dystrophies, aerobic exercise improves muscle function, but the effect of exercise on muscle protein balance is unknown. Therefore, we investigated 1) muscle protein balance ...

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

    Science.gov (United States)

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

    2014-01-01

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

  1. Skeletal muscle CT of lower extremities in myotonic dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Ryosuke; Imai, Terukuni; Sadashima, Hiromichi; Matsumoto, Sadayuki; Yamamoto, Toru; Kusaka, Hirofumi; Yamasaki, Masahiro; Maya, Kiyomi; Tanabe, Masaya

    1988-02-01

    We evaluated the leg and thigh muscles of 4 control subjects and 10 patients with myotonic dystrophy using computed tomography. Taking previous reports about the skeletal muscle CT of myotonic dystrophy into account, we concluded that the following 5 features are characteristic of myotonic dystrophy: 1. The main change is the appearance of low-density areas in muscles; these areas reflect fat tissue. In addition, the muscle mass decreases in size. 2. The leg is more severely affected than the thigh. 3. In the thigh, although the m. quadriceps femoris, especially the vastus muscles, tends to be affected, the m. adductor longus and magnus tend to be preserved. 4. In the leg, although the m. tibialis anterior and m. triceps surae tend to be affected, the m. peroneus longus, brevis, and m. tibialis posterior tend to be preserved. 5. Compensatory hypertrophy is often observed in the m. rectus femoris, m. adductor longus, m. adductor magnus, m. peroneus longus, and m. peroneus brevis, accompanied by the involvement of their agonist muscles.

  2. Altered cross-bridge properties in skeletal muscle dystrophies

    Directory of Open Access Journals (Sweden)

    Aziz eGuellich

    2014-10-01

    Full Text Available Force and motion generated by skeletal muscle ultimately depends on the cyclical interaction of actin with myosin. This mechanical process is regulated by intracellular Ca2+ through the thin filament-associated regulatory proteins i.e.; troponins and tropomyosin. Muscular dystrophies are a group of heterogeneous genetic affections characterized by progressive degeneration and weakness of the skeletal muscle as a consequence of loss of muscle tissue which directly reduces the number of potential myosin cross-bridges involved in force production. Mutations in genes responsible for skeletal muscle dystrophies have been shown to modify the function of contractile proteins and cross-bridge interactions. Altered gene expression or RNA splicing or post-translational modifications of contractile proteins such as those related to oxidative stress, may affect cross-bridge function by modifying key proteins of the excitation-contraction coupling. Micro-architectural change in myofilament is another mechanism of altered cross-bridge performance. In this review, we provide an overview about changes in cross-bridge performance in skeletal muscle dystrophies and discuss their ultimate impacts on striated muscle function.

  3. Congenital hereditary endothelial dystrophy with progressive sensorineural deafness (Harboyan syndrome

    Directory of Open Access Journals (Sweden)

    Abramowicz Marc

    2008-10-01

    Full Text Available Abstract Harboyan syndrome is a degenerative corneal disorder defined as congenital hereditary endothelial dystrophy (CHED accompanied by progressive, postlingual sensorineural hearing loss. To date, 24 cases from 11 families of various origin (Asian Indian, South American Indian, Sephardi Jewish, Brazilian Portuguese, Dutch, Gypsy, Moroccan, Dominican have been reported. More than 50% of the reported cases have been associated with parental consanguinity. The ocular manifestations in Harboyan syndrome include diffuse bilateral corneal edema occurring with severe corneal clouding, blurred vision, visual loss and nystagmus. They are apparent at birth or within the neonatal period and are indistinguishable from those characteristic of the autosomal recessive CHED (CHED2. Hearing deficit in Harboyan is slowly progressive and typically found in patients 10–25 years old. There are no reported cases with prelinglual deafness, however, a significant hearing loss in children as young as 4 years old has been detected by audiometry, suggesting that hearing may be affected earlier, even at birth. Harboyan syndrome is caused by mutations in the SLC4A11 gene located at the CHED2 locus on chromosome 20p13-p12, indicating that CHED2 and Harboyan syndrome are allelic disorders. A total of 62 different SLC4A11 mutations have been reported in 98 families (92 CHED2 and 6 Harboyan. All reported cases have been consistent with autosomal recessive transmission. Diagnosis is based on clinical criteria, detailed ophthalmological assessment and audiometry. A molecular confirmation of the clinical diagnosis is feasible. A variety of genetic, metabolic, developmental and acquired diseases presenting with clouding of the cornea should be considered in the differential diagnosis (Peters anomaly, sclerocornea, limbal dermoids, congenital glaucoma. Audiometry must be performed to differentiate Harboyan syndrome from CHED2. Autosomal recessive types of CHED (CHED2 and

  4. Congenital muscular dystrophy with fatty liver and infantile-onset cataract caused by TRAPPC11 mutations: broadening of the phenotype.

    Science.gov (United States)

    Liang, Wen-Chen; Zhu, Wenhua; Mitsuhashi, Satomi; Noguchi, Satoru; Sacher, Michael; Ogawa, Megumu; Shih, Hsiang-Hung; Jong, Yuh-Jyh; Nishino, Ichizo

    2015-01-01

    Transport protein particle (TRAPP) is a multiprotein complex involved in endoplasmic reticulum-to-Golgi trafficking. Zebrafish with a mutation in the TRAPPC11 orthologue showed hepatomegaly with steatosis and defects in visual system development. In humans, TRAPPC11 mutations have been reported in only three families showing limb-girdle muscular dystrophy (LGMD) or myopathy with movement disorders and intellectual disability. We screened muscular dystrophy genes using next-generation sequencing and performed associated molecular and biochemical analyses in a patient with fatty liver and cataract in addition to infantile-onset muscle weakness. We identified the first Asian patient with TRAPPC11 mutations. Muscle pathology demonstrated typical dystrophic changes and liver biopsy revealed steatosis. The patient carried compound heterozygous mutations of a previously reported missense and a novel splice-site mutation. The splice-site change produced two aberrantly-spliced transcripts that were both predicted to result in translational frameshift and truncated proteins. Full-length TRAPPC11 protein was undetectable on immunoblotting. This report widens the phenotype of TRAPPC11-opathy as the patient showed the following: (1) congenital muscular dystrophy phenotype rather than LGMD; (2) steatosis and infantile-onset cataract, both not observed in previously reported patients; but (3) no ataxia or abnormal movement, clearly indicating that TRAPPC11 plays a physiological role in multiple tissues in human.

  5. Severe paraspinal muscle involvement in facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Dahlqvist, Julia R; Vissing, Christoffer R; Thomsen, Carsten

    2014-01-01

    OBJECTIVE: In this study, involvement of paraspinal muscles in 50 patients with facioscapulohumeral dystrophy (FSHD) was evaluated using MRI. METHODS: The Dixon MRI technique was used in this observational study to quantify muscle fat content of paraspinal and leg muscles. Muscle strength...... in muscles was significantly higher in patients with FSHD than in controls: paraspinal fat fraction was 38% in patients vs 20% in controls, thigh fat fraction was 36% vs 11%, and calf fat fraction was 37% vs 11%. Increased paraspinal fat fraction correlated with D4Z4 repeat size, FSHD severity score, fat...... fraction of the thigh, and muscle strength in the back. The prevalence of back pain was 3 times higher in patients with FSHD vs controls, but back pain did not correlate with the paraspinal fat fraction. CONCLUSIONS: This study shows a prominent involvement of paraspinal muscles in patients with FSHD...

  6. Bilateral dissociated vertical deviation in a case of congenital hereditary endothelial dystrophy

    Directory of Open Access Journals (Sweden)

    Bhola Rahul

    2006-01-01

    Full Text Available Dissociated vertical deviation (DVD is an intermittent anomaly of the non-fixing eye. Although association of DVD with sensory visual deprivation owing to congenital or acquired opacities of the ocular media has been reported, its association with congenital hereditary endothelial dystrophy (CHED has not been reported hitherto. We report a case having a bilateral asymmetric DVD, in a know case of bilateral CHED.

  7. Genetics Home Reference: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

    Science.gov (United States)

    ... alopecia, and nail dystrophy is a type of severe combined immunodeficiency (SCID), which is a group of disorders characterized ... Diseases Educational Resources (7 links) Boston Children's Hospital: Severe Combined Immunodeficiency Disease InfoSearch: T-cell immunodeficiency, congenital alopecia and ...

  8. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities

    NARCIS (Netherlands)

    van der Knaap, M. S.; Smit, L. M.; Barth, P. G.; Catsman-Berrevoets, C. E.; Brouwer, O. F.; Begeer, J. H.; de Coo, I. F.; Valk, J.

    1997-01-01

    A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (CMD) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed

  9. Magnetic resonance imaging in classification of congenital muscular dystrophies with brain abnormalities

    NARCIS (Netherlands)

    vanderKnaap, MS; Smit, LME; Barth, PG; CatsmanBerrevoets, CE; Brouwer, OF; Begeer, JH; deCoo, IFM; Valk, J.

    A survey was performed of magnetic resonance imaging (MRI) findings in 21 patients with congenital muscular dystrophy (QID) with cerebral abnormalities to evaluate the contribution of MRI to the classification of CMD patients. In 5 patients with Walker-Warburg syndrome (WWS), MRI showed

  10. Tadalafil alleviates muscle ischemia in patients with Becker muscular dystrophy

    Science.gov (United States)

    Martin, Elizabeth A.; Barresi, Rita; Byrne, Barry J.; Tsimerinov, Evgeny I.; Scott, Bryan L.; Walker, Ashley E.; Gurudevan, Swaminatha V.; Anene, Francine; Elashoff, Robert M.; Thomas, Gail D.; Victor, Ronald G.

    2013-01-01

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. Like Duchenne muscular dystrophy (DMD), BMD is caused by mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the muscle sarcolemma. Among these is neuronal nitric oxide synthase (nNOSμ), which requires certain spectrin-like repeats in dystrophin’s rod domain and the adaptor protein α-syntrophin to be targeted to the sarcolemma. When healthy skeletal muscle is subjected to exercise, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates local α-adrenergic vasoconstriction thereby optimizing perfusion of muscle. We found previously that this protective mechanism is defective—causing functional muscle ischemia—in dystrophin-deficient muscles of the mdx mouse (a model of DMD) and of children with DMD, in whom nNOSμ is mislocalized to the cytosol instead of the sarcolemma. Here, we report that this protective mechanism also is defective in men with BMD in whom the most common dystrophin mutations disrupt sarcolemmal targeting of nNOSμ. In these men, the vasoconstrictor response, measured as a decrease in muscle oxygenation, to reflex sympathetic activation is not appropriately attenuated during exercise of the dystrophic muscles. In a randomized placebo-controlled cross-over trial, we show that functional muscle ischemia is alleviated and normal blood flow regulation fully restored in the muscles of men with BMD by boosting NO-cGMP signaling with a single dose of the drug tadalafil, a phosphodiesterase (PDE5A) inhibitor. These results further support an essential role for sarcolemmal nNOSμ in the normal modulation of sympathetic vasoconstriction in exercising human skeletal muscle and implicate the NO-cGMP pathway as a putative new target for treating BMD. PMID:23197572

  11. Congenital torticollis caused by unilateral absence of the sternocleidomastoid muscle

    Energy Technology Data Exchange (ETDEWEB)

    Raman, Subha; Takhtani, Deepak; Wallace, E.C. [UMass Memorial Medical Center, Department of Radiology, Worcester, MA (United States)

    2009-01-15

    Congenital torticollis is most commonly caused by benign fibrosis of the sternocleidomastoid muscle. Absence of the sternocleidomastoid muscle is a rare cause of congenital torticollis. There have been fewer than a dozen reported cases of agenesis of the sternocleidomastoid muscle. We describe a case of congenital absence of the sternocleidomastoid diagnosed by US and confirmed on MRI. (orig.)

  12. Improving Stem Cell-Based Therapy and Developing a Novel Gene Therapy Approach for Treating Duchenne Muscular Dystrophy (DMD)

    OpenAIRE

    Tabebordbar, Mohammadsharif

    2016-01-01

    Genetic mutations in muscle structural genes can compromise myofiber integrity, causing repeated muscle damage that ultimately exhausts muscle regenerative capacity and results in devastating degenerative conditions such as Duchenne Muscular Dystrophy (DMD), Congenital Muscular Dystrophy (CMD) and different forms of Limb Girdle Muscular Dystrophy (LGMD). Gene supplementation and autologous stem cell transplant have been put forward as promising, though still unproven, therapeutic avenues for ...

  13. Congenital fibrosis of the extraocular muscles

    Directory of Open Access Journals (Sweden)

    Pascale Cooymans

    2010-01-01

    Conclusions : CFEOM is a rare, congenital, and non-progressive disorder with multiple extra ocular muscle restrictions. CFEOM can be associated with neuro-radiological abnormalities; its diagnosis and classification is defined by clinical characteristics and genetics. Options for treatment are limited and difficult.

  14. Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors

    Directory of Open Access Journals (Sweden)

    Alessandra eZulian

    2014-11-01

    Full Text Available Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI genes, which encode an extracellular matrix protein; yet mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high conductance channel which causes a shortage in ATP production. We find that melanocytes do not produce collagen VI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myooathy patients display increased size, reduced matrix density and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013 Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy. J Cell Physiol 228, 1323-1331, and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in collagen VI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.

  15. Orthognathic Surgery in Patients With Congenital Myopathies and Congenital Muscular Dystrophies: Case Series and Review of the Literature.

    Science.gov (United States)

    Bezak, Brett J; Arce, Kevin A; Jacob, Adam; Van Ess, James

    2016-03-01

    This case series examined preoperative findings and the surgical, anesthetic, and postoperative management of 6 patients with congenital myopathies (CMs) and congenital muscular dystrophies (CMDs) treated at a tertiary medical institution with orthognathic surgery over 15 years to describe pertinent considerations for performing orthognathic surgery in these complex patients. According to the institutional review board-approved protocol, chart records were reviewed for all orthognathic surgical patients with a clinical, genetic, or muscle biopsy-proved diagnosis of CM or CMD. Six patients (5 male, 1 female) qualified, and they were treated by 4 surgeons in the division of oral and maxillofacial surgery from 1992 through 2007. Average age was 19.5 years at the time of orthognathic surgery. Five patients had Class III malocclusions and 1 patient had Class II malocclusion. All 6 patients had apertognathia with lip incompetence. Nasoendotracheal intubation with a difficulty of 0/3 (0=easiest, 3=most difficult) was performed in all cases. Routine induction and maintenance anesthetics, including halogenated agents and nondepolarizing muscle relaxants, were administered without malignant hyperthermia. All 6 patients underwent Le Fort level osteotomies; 4 also had mandibular setback surgery with or without balancing mandibular inferior border osteotomies. Five patients required planned intensive care unit care postoperatively (average, 18.4 days; range, 4 to 65 days). Postoperative respiratory complications resulting in major blood oxygen desaturations occurred in 5 patients; 4 of these patients required reintubation during emergency code response. Five patients required extended postoperative intubation (average, 4.2 days; range, 3 to 6 days) and ventilatory support. Average hospital length of stay was 21.8 days (range, 6 to 75 days). Average postoperative follow-up interval was 29.8 weeks (range, 6 to 128 weeks). Patients with CMs or CMDs often have characteristic

  16. Three-dimensional brain-surface MR images of brain anomalies in Fukuyama congenital muscular dystrophy and its differentiation from Duchenne muscular dystrophy with severe mental retardation

    Energy Technology Data Exchange (ETDEWEB)

    Toda, Tatsushi; Watanabe, Toshiaki; Shimizu, Teruo; Iwata, Makoto; Kanazawa, Ichiro (Tokyo Univ. (Japan). Faculty of Medicine); Matsumura, Kiichiro

    1993-12-01

    Fukuyama congenital muscular dystrophy (FCMD) is the second most common form of muscular dystrophy in Japan and is peculiarly associated with brain anomalies such as micropolygyria. Since these anomalies are preferentially observed on the brain surface, it is difficult to identify them by either X-ray CT or conventional MRI. In addition, FCMD has an atypical (mild) form in which the patients are capable of walking. In such cases, clinical differential diagnosis from Duchenne muscular dystrophy with severe mental retardation (DMD-MR) is not necessarily easy. We analyzed the brain-surface structures of 4 typical FCMD cases. 1 atypical FCMD case, 4 DMD-MR cases, and 1 undiagnosed case using a method of 3-dimensional (3-D) brain-surface MR imaging; we then compared the results with dystrophin immuno-stainings of the biopsied skeletal muscles. In both typical and atypical FCMD cases, micropolygyria could be clearly demonstrated, with individual variations. The 3-D images were verified by neuropathology. Of the 4 DMD-MR cases, 3 cases showed no gyral abnormality. However, in 1 DMD-MR case the diagnosis was corrected to atypical FCMD because of micropolygyria found on 3-D MRI. The one undiangosed case was diagnosed as DMD-MR on the basis of 3-D MRI. There was a good correspondence between the results of the 3-D imaging and the dystrophin test. Recently, some FCMD cases with a complete deficiency of dystrophin have been reported. Therefore, the detection of brain anomalies is important for the precise diagnosis of FCMD; the present method is considered effective for this purpose. (author).

  17. Three-dimensional brain-surface MR images of brain anomalies in Fukuyama congenital muscular dystrophy and its differentiation from Duchenne muscular dystrophy with severe mental retardation

    International Nuclear Information System (INIS)

    Toda, Tatsushi; Watanabe, Toshiaki; Shimizu, Teruo; Iwata, Makoto; Kanazawa, Ichiro; Matsumura, Kiichiro.

    1993-01-01

    Fukuyama congenital muscular dystrophy (FCMD) is the second most common form of muscular dystrophy in Japan and is peculiarly associated with brain anomalies such as micropolygyria. Since these anomalies are preferentially observed on the brain surface, it is difficult to identify them by either X-ray CT or conventional MRI. In addition, FCMD has an atypical (mild) form in which the patients are capable of walking. In such cases, clinical differential diagnosis from Duchenne muscular dystrophy with severe mental retardation (DMD-MR) is not necessarily easy. We analyzed the brain-surface structures of 4 typical FCMD cases. 1 atypical FCMD case, 4 DMD-MR cases, and 1 undiagnosed case using a method of 3-dimensional (3-D) brain-surface MR imaging; we then compared the results with dystrophin immuno-stainings of the biopsied skeletal muscles. In both typical and atypical FCMD cases, micropolygyria could be clearly demonstrated, with individual variations. The 3-D images were verified by neuropathology. Of the 4 DMD-MR cases, 3 cases showed no gyral abnormality. However, in 1 DMD-MR case the diagnosis was corrected to atypical FCMD because of micropolygyria found on 3-D MRI. The one undiangosed case was diagnosed as DMD-MR on the basis of 3-D MRI. There was a good correspondence between the results of the 3-D imaging and the dystrophin test. Recently, some FCMD cases with a complete deficiency of dystrophin have been reported. Therefore, the detection of brain anomalies is important for the precise diagnosis of FCMD; the present method is considered effective for this purpose. (author)

  18. Transgenic overexpression of ADAM12 suppresses muscle regeneration and aggravates dystrophy in aged mdx mice

    DEFF Research Database (Denmark)

    Jørgensen, Louise Helskov; Jensen, Charlotte Harken; Wewer, Ulla M

    2007-01-01

    Muscular dystrophies are characterized by insufficient restoration and gradual replacement of the skeletal muscle by fat and connective tissue. ADAM12 has previously been shown to alleviate the pathology of young dystrophin-deficient mdx mice, a model for Duchenne muscular dystrophy. The observed...... that ADAM12 could be a candidate for nonreplacement gene therapy of Duchenne muscular dystrophy. We therefore evaluated the long-term effect of ADAM12 overexpression in muscle. Surprisingly, we observed loss of skeletal muscle and accelerated fibrosis and adipogenesis in 1-year-old mdx mice transgenically...... regeneration as a possible factor in development of muscular dystrophy....

  19. Lung and respiratory muscle function in facioscapulohumeral muscular dystrophy.

    Science.gov (United States)

    Stübgen, Joerg-Patrick; Schultz, Cedric

    2009-06-01

    Pulmonary dysfunction is not a well-recognized feature of facioscapulohumeral muscular dystrophy (FSHD). The aim of this study was to establish the prevalence and type of pulmonary and respiratory muscle dysfunction in FSHD. Sixteen patients with moderately advanced FSHD and 16 healthy controls were evaluated. Standard lung and respiratory muscle function tests were performed. Diaphragm muscle inspiratory action was evaluated with transdiaphragmatic pressure measurements. Lung function tests showed an increased residual volume in five patients. There was a significant difference in global respiratory muscle function in patients versus controls; weakness was mild, and it affected expiratory more than inspiratory muscles. There was no significant difference in the diaphragm inspiratory action of patients versus controls. The dystrophic process that underlies FSHD did not significantly involve the muscles of the diaphragm, but it caused mild global respiratory muscle weakness that affected expiratory more than inspiratory muscles. It is probably not necessary to routinely monitor respiratory muscle function in ambulant FSHD patients who lack symptoms or signs of respiratory impairment.

  20. The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Kunihiro eSakuma

    2014-08-01

    Full Text Available 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 (mTOR, 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.

  1. Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

    Directory of Open Access Journals (Sweden)

    Erika Hissong, M.D.

    2016-06-01

    Full Text Available Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

  2. Ultrasound imaging of muscle contraction of the tibialis anterior in patients with facioscapulohumeral dystrophy

    NARCIS (Netherlands)

    Gijsbertse, Kaj; Goselink, Rianne; Lassche, Saskia; Nillesen, Maartje; Sprengers, Andre; Verdonschot, Nico; van Alfen, Nens; De Korte, Chris

    2017-01-01

    In fascioscapulohumeral muscular dystrophy (FSHD) and many other neuromuscular disorders there is a need for biomarkers to diagnose, quantify and longitudinally follow muscle disease. Furthermore, the pathophysiological mechanisms leading to muscle weakness in most neuromuscular disorders are not

  3. B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I.

    Science.gov (United States)

    Thomas, Paul J; Xu, Rui; Martin, Paul T

    2016-09-01

    Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of α dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin α2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo(-) mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo(-) muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo(-) muscles did not cause substantial glycosylation of α dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin α2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression. Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  4. Muscle Activation during Gait in Children with Duchenne Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Juliette Ropars

    Full Text Available The aim of this prospective study was to investigate changes in muscle activity during gait in children with Duchenne muscular Dystrophy (DMD. Dynamic surface electromyography recordings (EMGs of 16 children with DMD and pathological gait were compared with those of 15 control children. The activity of the rectus femoris (RF, vastus lateralis (VL, medial hamstrings (HS, tibialis anterior (TA and gastrocnemius soleus (GAS muscles was recorded and analysed quantitatively and qualitatively. The overall muscle activity in the children with DMD was significantly different from that of the control group. Percentage activation amplitudes of RF, HS and TA were greater throughout the gait cycle in the children with DMD and the timing of GAS activity differed from the control children. Significantly greater muscle coactivation was found in the children with DMD. There were no significant differences between sides. Since the motor command is normal in DMD, the hyper-activity and co-contractions likely compensate for gait instability and muscle weakness, however may have negative consequences on the muscles and may increase the energy cost of gait. Simple rehabilitative strategies such as targeted physical therapies may improve stability and thus the pattern of muscle activity.

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

    Directory of Open Access Journals (Sweden)

    Sonia Paco

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

  6. Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy.

    Science.gov (United States)

    Boland, B J; Silbert, P L; Groover, R V; Wollan, P C; Silverstein, M D

    1996-01-01

    The goals of this study were to describe the clinical course of skeletal, cardiac, and gastrointestinal muscle manifestations and trends in age at diagnosis and survival of Duchenne muscular dystrophy (DMD) patients. A retrospective cohort of 33 male patients with DMD, born between 1953 and 1983 and followed at the Mayo Clinic during their second decade of life, was studied. The mean age at DMD diagnosis was 4.6 years. Skeletal muscle weakness present in all patients at diagnosis progressed to wheelchair dependency in 32 patients (97%) by the age of 13 years (median age 10 years). Cardiac muscle failure developed in 5 patients (15%) (median age 21.5 years). Smooth muscle manifestations related to the digestive and urinary tracts occurred in 7 (21%) and 2 (6%) patients (median age 15 years), respectively. The gastrointestinal dilatations were primary in 2 patients or secondary to surgery or acute respiratory illness in 5 patients. By the end of the study period, 17 deaths had occurred (median age 17 years). Over time, there was a decrease in the time to DMD diagnosis (P = .05) but no significant change in survival (P = .44). Cardiac and smooth muscle manifestations occur late in the course of DMD. Clinical gastrointestinal symptoms related to smooth muscle function most often were secondary to surgery or a respiratory illness. In recent years, the diagnosis of DMD has been made at a younger age, but survival has not changed.

  7. Congenital Fibrosis of the Extraocular Muscles

    Directory of Open Access Journals (Sweden)

    Leyla Niyaz

    2014-08-01

    Full Text Available Congenital fibrosis of the extraocular muscles (CFEOM is a rare disorder characterized by hereditary non-progressive restrictive strabismus and blepharoptosis. Although most of the cases are bilateral and isolated, some patients may have systemic findings. CFEOM is divided into three groups as CFEOM 1, 2, and 3 according to the phenotype. Primary responsible genes are KIF21A for CFEOM type 1 and 3 and PHOX2A/ARIX gene for CFEOM type 2. Studies suggest that abnormal innervation of the extraocular muscles is the cause of muscle fibrosis. Early treatment is important because of the risk of amblyopia. Surgery is the primary treatment option for strabismus and blepharoptosis. (Turk J Ophthalmol 2014; 44: 312-5

  8. Muscle wasting in myotonic dystrophies: a model of premature aging.

    Directory of Open Access Journals (Sweden)

    Alba Judith eMateos-Aierdi

    2015-07-01

    Full Text Available Myotonic dystrophy type I (DM1 or Steinert’s disease and type II (DM2 are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, and other clinical manifestations such as cardiomyopathy, insulin-resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc., including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTGn triplet expansion in the 3’ untranslated region of the DMPK gene, whereas (CCTGn repeats in the first intron of the CNBP/ZNF9 gene cause DM2. The expansions are transcribed into (CUGn and (CCUGn-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL, forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.

  9. Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy

    DEFF Research Database (Denmark)

    Witting, Nanna; Kruuse, Christina; Nyhuus, Bo

    2014-01-01

    OBJECTIVE: Patients with Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects...

  10. Restoring Dystrophin Expression in Duchenne Muscular Dystrophy Muscle

    Science.gov (United States)

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

    2011-01-01

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

  11. Platelet-Derived Growth Factor BB Influences Muscle Regeneration in Duchenne Muscle Dystrophy.

    Science.gov (United States)

    Piñol-Jurado, Patricia; Gallardo, Eduard; de Luna, Noemi; Suárez-Calvet, Xavier; Sánchez-Riera, Carles; Fernández-Simón, Esther; Gomis, Clara; Illa, Isabel; Díaz-Manera, Jordi

    2017-08-01

    Duchenne muscular dystrophy (DMD) is characterized by a progressive loss of muscle fibers, and their substitution by fibrotic and adipose tissue. Many factors contribute to this process, but the molecular pathways related to regeneration and degeneration of muscle are not completely known. Platelet-derived growth factor (PDGF)-BB belongs to a family of growth factors that regulate proliferation, migration, and differentiation of mesenchymal cells. The role of PDGF-BB in muscle regeneration in humans has not been studied. We analyzed the expression of PDGF-BB in muscle biopsy samples from controls and patients with DMD. We performed in vitro experiments to understand the effects of PDGF-BB on myoblasts involved in the pathophysiology of muscular dystrophies and confirmed our results in vivo by treating the mdx murine model of DMD with repeated i.m. injections of PDGF-BB. We observed that regenerating and necrotic muscle fibers in muscle biopsy samples from DMD patients expressed PDGF-BB. In vitro, PDGF-BB attracted myoblasts and activated their proliferation. Analysis of muscles from the animals treated with PDGF-BB showed an increased population of satellite cells and an increase in the number of regenerative fibers, with a reduction in inflammatory infiltrates, compared with those in vehicle-treated mice. Based on our results, PDGF-BB may play a protective role in muscular dystrophies by enhancing muscle regeneration through activation of satellite cell proliferation and migration. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. Muscular Dystrophy

    Science.gov (United States)

    ... The Search for a Cure Print en español Distrofia muscular About MD Muscular dystrophy (MD) is a genetic ... muscles and cause different degrees of muscle weakness. Duchenne muscular dystrophy is the most common and the most ...

  13. Muscular Dystrophy

    Science.gov (United States)

    ... that cause progressive weakness and loss of muscle mass. In muscular dystrophy, abnormal genes (mutations) interfere with the production of proteins needed to form healthy muscle. There are many different kinds of muscular dystrophy. ...

  14. Temporalis muscle hypertrophy and reduced skull eccentricity in Duchenne muscular dystrophy.

    Science.gov (United States)

    Straathof, C S M; Doorenweerd, N; Wokke, B H A; Dumas, E M; van den Bergen, J C; van Buchem, M A; Hendriksen, J G M; Verschuuren, J J G M; Kan, H E

    2014-10-01

    Muscle hypertrophy and muscle weakness are well known in Duchenne muscular dystrophy. Decreased muscle force can have secondary effects on skeletal growth and development such as facial and dental morphology changes. In this study, we quantified temporal muscle thickness, circumference, and eccentricity of the skull and the head on T1-weighted magnetic resonance imaging (MRI) scans of the head of 15 Duchenne muscular dystrophy patients and 15 controls. Average temporal muscle thickness was significantly increased in patients (12.9 ± 5.2 mm) compared to controls (6.8 ± 1.4 mm) (P muscle thickness and skull eccentricity were significantly negatively correlated in patients, and positively in controls. Hypertrophy of the temporal muscles and changes in skull eccentricity appear to occur early in the course of Duchenne muscular dystrophy. Further studies in younger patients are needed to confirm a causal relationship. © The Author(s) 2014.

  15. Ultrasound Imaging of Muscle Contraction of the Tibialis Anterior in Patients with Facioscapulohumeral Dystrophy

    NARCIS (Netherlands)

    Gijsbertse, Kaj; Goselink, Rianne; Lassche, Saskia; Nillesen, Maartje; Sprengers, André; Verdonschot, Nico; van Alfen, Nens; de Korte, Chris

    2017-01-01

    A need exists for biomarkers to diagnose, quantify and longitudinally follow facioscapulohumeral muscular dystrophy (FSHD) and many other neuromuscular disorders. Furthermore, the pathophysiological mechanisms leading to muscle weakness in most neuromuscular disorders are not completely understood.

  16. Skeletal Muscle Homeostasis in Duchenne Muscular Dystrophy: Modulating Autophagy as a Promising Therapeutic Strategy

    OpenAIRE

    De Palma, Clara; Perrotta, Cristiana; Pellegrino, Paolo; Clementi, Emilio; Cervia, Davide

    2014-01-01

    Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive sk...

  17. Allele-specific Gene Silencing of Mutant mRNA Restores Cellular Function in Ullrich Congenital Muscular Dystrophy Fibroblasts

    Directory of Open Access Journals (Sweden)

    Satoru Noguchi

    2014-01-01

    Full Text Available Ullrich congenital muscular dystrophy (UCMD is an inherited muscle disorder characterized clinically by muscle weakness, distal joint hyperlaxity, and proximal joint contractures. Sporadic and recessive mutations in the three collagen VI genes, COL6A1, COL6A2, and COL6A3, are reported to be causative. In the sporadic forms, a heterozygous point mutation causing glycine substitution in the triple helical domain has been identified in higher rate. In this study, we examined the efficacy of siRNAs, which target point mutation site, on specific knockdown toward transcripts from mutant allele and evaluated consequent cellular phenotype of UCMD fibroblasts. We evaluated the effect of siRNAs targeted to silence-specific COL6A1 alleles in UCMD fibroblasts, where simultaneous expression of both wild-type and mutant collagen VI resulted in defective collagen localization. Addition of mutant-specific siRNAs allowed normal extracellular localization of collagen VI surrounding fibroblasts, suggesting selective inhibition of mutant collagen VI. Targeting the single-nucleotide COL6A1 c.850G>A (p.G284R mutation responsible a sporadic autosomal dominant form of UCMD can potently and selectively block expression of mutant collagen VI. These results suggest that allele-specific knockdown of the mutant mRNA can potentially be considered as a therapeutic procedure in UCMD due to COL6A1 point mutations.

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

    Directory of Open Access Journals (Sweden)

    Boel De Paepe

    2013-01-01

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

  19. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2

    DEFF Research Database (Denmark)

    Witting, Nanna; Duno, M; Vissing, J

    2013-01-01

    , and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest......Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic...

  20. Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Feriel Azibani

    2018-03-01

    Full Text Available We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT transcripts. We developed 5′-RNA pre-trans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo.

  1. Congenital hypertrophy of multiple intrinsic muscles of the foot.

    Science.gov (United States)

    Shiraishi, Tomohiro; Park, Susam; Niu, Atushi; Hasegawa, Hiromi

    2014-12-01

    Congenital hypertrophy of a single intrinsic muscle of the foot is rare, and as far as we know, only six cases have been reported. We describe a case of congenital anomaly that showed hypertrophy of multiple intrinsic muscles of the foot; the affected muscles were all the intrinsic muscles of the foot except the extensor digitorum brevis or extensor hallucis. Other tissues such as adipose tissue, nervous tissue, or osseous tissue showed no abnormalities. To reduce the volume of the foot we removed parts of the enlarged muscles.

  2. Longitudinal MRI quantification of muscle degeneration in Duchenne muscular dystrophy.

    Science.gov (United States)

    Godi, Claudia; Ambrosi, Alessandro; Nicastro, Francesca; Previtali, Stefano C; Santarosa, Corrado; Napolitano, Sara; Iadanza, Antonella; Scarlato, Marina; Natali Sora, Maria Grazia; Tettamanti, Andrea; Gerevini, Simonetta; Cicalese, Maria Pia; Sitzia, Clementina; Venturini, Massimo; Falini, Andrea; Gatti, Roberto; Ciceri, Fabio; Cossu, Giulio; Torrente, Yvan; Politi, Letterio S

    2016-08-01

    The aim of this study was to evaluate the usefulness of magnetic resonance imaging (MRI) in detecting the progression of Duchenne muscular dystrophy (DMD) by quantification of fat infiltration (FI) and muscle volume index (MVI, a residual-to-total muscle volume ratio). Twenty-six patients (baseline age: 5-12 years) with genetically proven DMD were longitudinally analyzed with lower limb 3T MRI, force measurements, and functional tests (Gowers, 10-m time, North Star Ambulatory Assessment, 6-min walking test). Five age-matched controls were also examined, with a total of 85 MRI studies. Semiquantitative (scores) and quantitative MRI (qMRI) analyses (signal intensity ratio - SIR, lower limb MVI, and individual muscle MVI) were carried out. Permutation and regression analyses according to both age and functional test-outcomes were calculated. Age-related quantitative reference curves of SIRs and MVIs were generated. FI was present on glutei and adductor magnus in all patients since the age of 5, with a proximal-to-distal progression and selective sparing of sartorius and gracilis. Patients' qMRI measures were significantly different from controls' and among age classes. qMRI were more sensitive than force measurements and functional tests in assessing disease progression, allowing quantification also after loss of ambulation. Age-related curves with percentile values were calculated for SIRs and MVIs, to provide a reference background for future experimental therapy trials. SIRs and MVIs significantly correlated with all clinical measures, and could reliably predict functional outcomes and loss of ambulation. qMRI-based indexes are sensitive measures that can track the progression of DMD and represent a valuable tool for follow-up and clinical studies.

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

    DEFF Research Database (Denmark)

    Morrison-Nozik, Alexander; Anand, Priti; Zhu, Han

    2015-01-01

    in Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. A defined molecular basis underlying these performance-enhancing properties of GCs in skeletal muscle remains obscure. Here, we demonstrate that ergogenic effects of GCs are mediated by direct induction of the metabolic transcription...

  4. Abnormality of Auricular Muscles in Congenital Auricular Deformities.

    Science.gov (United States)

    Yotsuyanagi, Takatoshi; Yamauchi, Makoto; Yamashita, Ken; Sugai, Asuka; Gonda, Ayako; Kitada, Ayaka; Saito, Tamotsu; Urushidate, Satoshi

    2015-07-01

    It has been suggested that there is a close association of abnormality in auricular muscles with various congenital auricular deformities. However, there has been no investigation to determine what muscles are involved and how they affect the deformity. The authors examined abnormalities of auricular muscles for patients with various auricular deformities. The authors examined 77 auricles of 62 patients with congenital auricular deformities, including cryptotia, Stahl's ear, prominent ear, lop ear, and others. The superior and posterior auricular muscles from the extrinsic auricular muscle group and the auricular oblique and transverse muscles from the auricular intrinsic muscle group were investigated. The authors found characteristic features of the abnormality of the muscle for each auricular deformity. In nearly all cases of cryptotia, abnormality was found in the superior auricular, auricular oblique, and auricular transverse muscles. Abnormal insertion was found mainly in the superior auricular muscle and was the main cause of cryptotia. In Stahl's ear, the major abnormality was abnormal insertion of the auricular transverse muscle, which creates an abnormal cartilaginous prominence in the scapha. The abnormality in cases of prominent ear was clearly limited mostly to the auricular transverse muscle and, in some cases, to the posterior auricular muscle. In lop ear, abnormality was mostly found in the auricular transverse muscle, with elongation, and in the superior auricular or auricular oblique muscle in some cases. There is a tendency for a specific muscle abnormality to be found in each deformity. It is important to identify the abnormal muscle and correct the abnormality during the operation.

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

    Science.gov (United States)

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

    2014-01-01

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

  6. Autonomic Dysfunction in Muscular Dystrophy: A Theoretical Framework for Muscle Reflex Involvement

    Directory of Open Access Journals (Sweden)

    Scott Alan Smith

    2014-02-01

    Full Text Available 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.

  7. Comprehensive target capture/next-generation sequencing as a second-tier diagnostic approach for congenital muscular dystrophy in Taiwan.

    Science.gov (United States)

    Liang, Wen-Chen; Tian, Xia; Yuo, Chung-Yee; Chen, Wan-Zi; Kan, Tsu-Min; Su, Yi-Ning; Nishino, Ichizo; Wong, Lee-Jun C; Jong, Yuh-Jyh

    2017-01-01

    Congenital muscular dystrophy (CMD) is a heterogeneous disease entity. The detailed clinical manifestation and causative gene for each subgroup of CMD are quite variable. This study aims to analyze the phenotypes and genotypes of Taiwanese patients with CMD as the epidemiology of CMD varies among populations and has been scantly described in Asia. A total of 48 patients suspected to have CMD were screened and categorized by histochemistry and immunohistochemistry studies. Different genetic analyses, including next-generation sequencing (NGS), were selected, based on the clinical and pathological findings. We identified 17 patients with sarcolemma-specific collagen VI deficiency (SSCD), 6 patients with merosin deficiency, two with reduced alpha-dystroglycan staining, and two with striking lymphocyte infiltration in addition to dystrophic change on muscle pathology. Fourteen in 15 patients with SSCD, were shown to have COL6A1, COL6A2 or COL6A3 mutations by NGS analysis; all showed marked distal hyperlaxity and normal intelligence but the overall severity was less than in previously reported patients from other populations. All six patients with merosin deficiency had mutations in LAMA2. They showed relatively uniform phenotype that were compatible with previous studies, except for higher proportion of mental retardation with epilepsy. With reduced alpha-dystroglycan staining, one patient was found to carry mutations in POMT1 while another patient carried mutations in TRAPPC11. LMNA mutations were found in the two patients with inflammatory change on muscle pathology. They were clinically characterized by neck flexion limitation and early joint contracture, but no cardiac problem had developed yet. Muscle pathology remains helpful in guiding further molecular analyses by direct sequencing of certain genes or by target capture/NGS as a second-tier diagnostic tool, and is crucial for establishing the genotype-phenotype correlation. We also determined the frequencies of

  8. X-rays computed tomographic scans of lower limb and trunk muscles in facioscapulohumeral muscular dystrophy

    International Nuclear Information System (INIS)

    Horikawa, Hirosei; Mano, Yukio; Takayanagi, Tetsuya; Takahashi, Keiichi; Nishio, Hisahide.

    1992-01-01

    X-rays computed tomographic (CT) scans of muscles of the lower limbs and the trunk in 14 patients with facioscapulohumeral muscular dystrophy (FSH) were studied. The CT scans showed that the affected muscles were decreased in density and size. The laterality of muscular involvement was sometimes observed. The muscular lesions in the lower limbs showed proximal distribution. In the thigh, the hamstrings were affected first, the adductor muscles second, and then the muscular involvement progressed to the quadriceps femoris muscle. In the lower leg, the gastrocnemius and soleus muscles were relatively spared as compared with the tibialis anterior muscle. In the lumbar girdle, the abdominal muscles were involved first, the gluteal muscles second, the back muscles third, and the psoas major muscle were relatively spared. The muscular weakness of this distribution exacerbated lumbar lordosis. The neck muscles were less affected than those of the lumbar girdle. The CT scans in FSH demonstrated the characteristic pattern of muscular involvement, which differed from the inherited muscular diseases such as Duchenne muscular dystrophy, myotonic dystrophy, and others. (author)

  9. X-rays computed tomographic scans of lower limb and trunk muscles in facioscapulohumeral muscular dystrophy

    Energy Technology Data Exchange (ETDEWEB)

    Horikawa, Hirosei; Mano, Yukio; Takayanagi, Tetsuya (Nara Medical Univ., Kashihara (Japan)); Takahashi, Keiichi; Nishio, Hisahide

    1992-10-01

    X-rays computed tomographic (CT) scans of muscles of the lower limbs and the trunk in 14 patients with facioscapulohumeral muscular dystrophy (FSH) were studied. The CT scans showed that the affected muscles were decreased in density and size. The laterality of muscular involvement was sometimes observed. The muscular lesions in the lower limbs showed proximal distribution. In the thigh, the hamstrings were affected first, the adductor muscles second, and then the muscular involvement progressed to the quadriceps femoris muscle. In the lower leg, the gastrocnemius and soleus muscles were relatively spared as compared with the tibialis anterior muscle. In the lumbar girdle, the abdominal muscles were involved first, the gluteal muscles second, the back muscles third, and the psoas major muscle were relatively spared. The muscular weakness of this distribution exacerbated lumbar lordosis. The neck muscles were less affected than those of the lumbar girdle. The CT scans in FSH demonstrated the characteristic pattern of muscular involvement, which differed from the inherited muscular diseases such as Duchenne muscular dystrophy, myotonic dystrophy, and others. (author).

  10. Altered expression of cyclin A 1 in muscle of patients with facioscapulohumeral muscle dystrophy (FSHD-1.

    Directory of Open Access Journals (Sweden)

    Anna Pakula

    Full Text Available OBJECTIVES: Cyclin A1 regulates cell cycle activity and proliferation in somatic and germ-line cells. Its expression increases in G1/S phase and reaches a maximum in G2 and M phases. Altered cyclin A1 expression might contribute to clinical symptoms in facioscapulohumeral muscular dystrophy (FSHD. METHODS: Muscle biopsies were taken from the Vastus lateralis muscle for cDNA microarray, RT-PCR, immunohistochemistry and Western blot analyses to assess RNA and protein expression of cyclin A1 in human muscle cell lines and muscle tissue. Muscle fibers diameter was calculated on cryosections to test for hypertrophy. RESULTS: cDNA microarray data showed specifically elevated cyclin A1 levels in FSHD vs. other muscular disorders such as caveolinopathy, dysferlinopathy, four and a half LIM domains protein 1 deficiency and healthy controls. Data could be confirmed with RT-PCR and Western blot analysis showing up-regulated cyclin A1 levels also at protein level. We found also clear signs of hypertrophy within the Vastus lateralis muscle in FSHD-1 patients. CONCLUSIONS: In most somatic human cell lines, cyclin A1 levels are low. Overexpression of cyclin A1 in FSHD indicates cell cycle dysregulation in FSHD and might contribute to clinical symptoms of this disease.

  11. Fukuyama-type congenital muscular dystrophy and defective glycosylation of α-dystroglycan

    Directory of Open Access Journals (Sweden)

    Saito Fumiaki

    2011-06-01

    Full Text Available Abstract Fukuyama-type congenital muscular dystrophy (FCMD is a severe form of muscular dystrophy accompanied by abnormalities in the eye and brain. The incidence of FCMD is particularly high in the Japanese population. Mutations in the fukutin gene have been identified in patients with FCMD. Fukutin is predicted to be a Golgi apparatus resident protein and to be involved in the post-translational modification of cell-surface proteins. Recently, progress has been made in our understanding of the molecular mechanisms by which the mutation of fukutin leads to the phenotype of FCMD. Loss of function of fukutin results in defective glycosylation of α-dystroglycan, a central component of the dystrophin-glycoprotein complex, leading to disruption of the linkage between basal lamina and cytoskeleton. This disruption is implicated in the pathogenesis of both the MD and brain anomalies in FCMD. Furthermore, genetic analyses have revealed that the spectrum of the FCMD phenotype is much wider than originally thought. In this review, we summarize the diverging clinical phenotype of FCMD and its molecular pathomechanisms.

  12. Muscular dystrophy: from pathogenesis to strategy.

    Science.gov (United States)

    Hsu, Yaw-Don

    2004-06-01

    Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. It characterized by progressive muscle wasting and weakness of variable distribution and severity. There are several subgroups including Duchenne/Becker, fascioscapulohumeral, limb-girdle, oculopharngeal, and congenital muscular dystrophy. Diagnosis is dependent to the characteristic clinical features in distribution of predominant muscle weakness, disease course and age onset as well as variable serum concentration creatine kinase, muscle histology, and genetic inheritance. Nearly 30 genes and encoded proteins are known to give rise to various forms of muscular dystrophy. Development of new prospects therapy for the muscular dystrophies is a big challenge. The target of strategies is aimed at inducing of a functional protein and improving the function of muscle weakness. These strategies include gene, cell and pharmacological therapies. However, efficiency of systemic delivery vectors to targets, immune reaction to vector and gene products, and toxicity to vector that must be solved before an effective treatment is available.

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

    OpenAIRE

    De Paepe, Boel; De Bleecker, Jan L.

    2013-01-01

    Duchenne muscular dystrophy is a severe inherited muscle disease that affects 1 in 3500 boys worldwide. Infiltration of skeletal muscle by inflammatory cells is an important facet of disease pathophysiology and is strongly associated with disease severity in the individual patient. In the chronic inflammation that characterizes Duchenne muscle, cytokines and chemokines are considered essential activators and recruiters of inflammatory cells. In addition, they provide potential beneficiary eff...

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

    Science.gov (United States)

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

    2015-05-01

    Animal models of dystrophin deficient muscular dystrophy, most notably canine X-linked muscular dystrophy, play an important role in developing new therapies for human Duchenne muscular dystrophy. Although the canine disease is a model of the human disease, the variable severity of clinical presentations in the canine may be problematic for pre-clinical trials, but also informative. Here we describe a family of Labrador Retrievers with three generations of male dogs having markedly increased serum creatine kinase activity, absence of membrane dystrophin, but with undetectable clinical signs of muscle weakness. Clinically normal young male Labrador Retriever puppies were evaluated prior to surgical neuter by screening laboratory blood work, including serum creatine kinase activity. Serum creatine kinase activities were markedly increased in the absence of clinical signs of muscle weakness. Evaluation of muscle biopsies confirmed a dystrophic phenotype with both degeneration and regeneration. Further evaluations by immunofluorescence and western blot analysis confirmed the absence of muscle dystrophin. Although dystrophin was not identified in the muscles, we did not find any detectable deletions or duplications in the dystrophin gene. Sequencing is now ongoing to search for point mutations. Our findings in this family of Labrador Retriever dogs lend support to the hypothesis that, in exceptional situations, muscle with no dystrophin may be functional. Unlocking the secrets that protect these dogs from a severe clinical myopathy is a great challenge which may have important implications for future treatment of human muscular dystrophies. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. The Ras antagonist, farnesylthiosalicylic acid (FTS, decreases fibrosis and improves muscle strength in dy/dy mouse model of muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Yoram Nevo

    Full Text Available The Ras superfamily of guanosine-triphosphate (GTP-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy(2J/dy(2J mouse model of merosin deficient congenital muscular dystrophy. The dy(2J/dy(2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy(2J/dy(2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy(2J/dy(2J mouse model of congenital muscular dystrophy.

  16. Muscle pathology in myotonic dystrophy: light and electron microscopic investigation in eighteen patients.

    Science.gov (United States)

    Nadaj-Pakleza, A; Lusakowska, A; Sułek-Piątkowska, A; Krysa, W; Rajkiewicz, M; Kwieciński, H; Kamińska, A

    2011-05-01

    Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Two known genetic subtypes include DM1 (myotonic dystrophy type 1) and DM2 (myotonic dystrophy type 2). Genetic testing is considered as the only reliable diagnostic criterion in myotonic dystrophies. Relatively little is known about DM1 and DM2 myopathology. Thus, the aim of our study was to characterise light and electron microscopic features of DM1 and DM2 in patients with genetically proven types of the disease. We studied 3 DM1 cases and 15 DM2 cases from which muscle biopsies were taken for diagnostic purposes during the period from 1973 to 2006, before genetic testing became available at our hospital. The DM1 group included 3 males (age at biopsy 15-19). The DM2 group included 15 patients (5 men and 10 women, age at biopsy 26-60). The preferential type 1 fibre atrophy was seen in all three DM1 cases in light microscopy, and substantial central nucleation was present in two biopsies. Electron microscopy revealed central nuclei in all three examined muscle biopsies. No other structural or degenerative changes were detected, probably due to the young age of our patients. Central nucleation, prevalence of type 2 muscle fibres, and the presence of pyknotic nuclear clumps were observed in DM2 patients in light microscopy. Among the ultrastructural abnormalities observed in our DM2 group, the presence of internal nuclei, severely atrophied muscle fibres, and lipofuscin accumulation were consistent findings. In addition, a variety of ultrastructural abnormalities were identified by us in DM2. It appears that no single ultrastructural abnormality is characteristic for the DM2 muscle pathology. It seems, however, that certain constellations of morphological changes might be indicative of certain types of myotonic dystrophy.

  17. Cranial x-ray CT and MRI in congenital muscular dystrophy

    International Nuclear Information System (INIS)

    Horikawa, Hirosei; Konishi, Toshihiko; Konagaya, Masaaki; Mano, Yukio; Takayanagi, Tetsuya

    1988-01-01

    The involvements of central nervous system in those cases of congenital muscular dystrophy (CMD), especially in Fukuyama type CMD, have been observed both radiologically and pathologically. The recent development of MRI made it easier to detect fine structural changes in brain matter than the X-ray CT. Then, we tried to evaluate the central nervous system abnormalities of six cases of CMD by both X-ray CT and MRI. In one case, X-ray CT revealed diffuse hypodensity of cerebral white matter, and MRI showed high intensity on long spin-echo image and low intensity on inversion-recovery image. In another case, X-ray CT showed no abnormal findings, but long spin-echo image revealed two high intensity spots in cerebral white matter. In other four cases, brain atrophy was demonstrated by X-ray CT and/or MRI, one case of these patients had bilateral congenital arachnoid cysts in the middle cranial fossa and hypogenesis of temporal lobes. Although we could not demonstrate polymicrogyria and agyria in all cases by MRI, white matter changes and structural changes were revealed more clearly than X-ray CT. The combination of X-ray CT and MRI seems to make a noteworthy contribution to estimate the central nervous system abnormalities in CMD. (author)

  18. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions.

    Science.gov (United States)

    Kumaran, Neruban; Moore, Anthony T; Weleber, Richard G; Michaelides, Michel

    2017-09-01

    Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EOSRD) are both genetically and phenotypically heterogeneous, and characterised clinically by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils and markedly reduced/absent full-field electroretinograms. The vast genetic heterogeneity of inherited retinal disease has been established over the last 10 - 20 years, with disease-causing variants identified in 25 genes to date associated with LCA/EOSRD, accounting for 70-80% of cases, with thereby more genes yet to be identified. There is now far greater understanding of the structural and functional associations seen in the various LCA/EOSRD genotypes. Subsequent development/characterisation of LCA/EOSRD animal models has shed light on the underlying pathogenesis and allowed the demonstration of successful rescue with gene replacement therapy and pharmacological intervention in multiple models. These advancements have culminated in more than 12 completed, ongoing and anticipated phase I/II and phase III gene therapy and pharmacological human clinical trials. This review describes the clinical and genetic characteristics of LCA/EOSRD and the differential diagnoses to be considered. We discuss in further detail the diagnostic clinical features, pathophysiology, animal models and human treatment studies and trials, in the more common genetic subtypes and/or those closest to intervention. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  19. Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.

    Science.gov (United States)

    Wei, Christina; Stock, Lauren; Valanejad, Leila; Zalewski, Zachary A; Karns, Rebekah; Puymirat, Jack; Nelson, David; Witte, David; Woodgett, Jim; Timchenko, Nikolai A; Timchenko, Lubov

    2018-01-05

    Myotonic dystrophy type 1 (DM1) is a progressive neuromuscular disease caused by expanded CUG repeats, which misregulate RNA metabolism through several RNA-binding proteins, including CUG-binding protein/CUGBP1 elav-like factor 1 (CUGBP1/CELF1) and muscleblind 1 protein. Mutant CUG repeats elevate CUGBP1 and alter CUGBP1 activity via a glycogen synthase kinase 3β (GSK3β)-cyclin D3-cyclin D-dependent kinase 4 (CDK4) signaling pathway. Inhibition of GSK3β corrects abnormal activity of CUGBP1 in DM1 mice [human skeletal actin mRNA, containing long repeats ( HSA LR ) model]. Here, we show that the inhibition of GSK3β in young HSA LR mice prevents development of DM1 muscle pathology. Skeletal muscle in 1-yr-old HSA LR mice, treated at 1.5 mo for 6 wk with the inhibitors of GSK3, exhibits high fiber density, corrected atrophy, normal fiber size, with reduced central nuclei and normalized grip strength. Because CUG-GSK3β-cyclin D3-CDK4 converts the active form of CUGBP1 into a form of translational repressor, we examined the contribution of CUGBP1 in myogenesis using Celf1 knockout mice. We found that a loss of CUGBP1 disrupts myogenesis, affecting genes that regulate differentiation and the extracellular matrix. Proteins of those pathways are also misregulated in young HSA LR mice and in muscle biopsies of patients with congenital DM1. These findings suggest that the correction of GSK3β-CUGBP1 pathway in young HSA LR mice might have a positive effect on the myogenesis over time.-Wei, C., Stock, L., Valanejad, L., Zalewski, Z. A., Karns, R., Puymirat, J., Nelson, D., Witte, D., Woodgett, J., Timchenko, N. A., Timchenko, L. Correction of GSK3β at young age prevents muscle pathology in mice with myotonic dystrophy type 1.

  20. Magnetic resonance imaging of skeletal muscle in patients with Duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Nagao, Hideo; Morimoto, Takehiko; Sano, Nozomi; Takahashi, Mitsugi; Nagai, Hironao; Tawa, Ritsuko; Yoshimatsu, Makoto; Woo Young-Jong; Matsuda, Hiroshi.

    1991-01-01

    Magnetic resonance imaging of skeletal muscles in thirteen patients with Duchenne muscular dystrophy was performed to estimate pathological changes. Serial axial and sagittal sections of the right lower extremity were recorded. In the early stage, the T 1 values of gastrocnemius and soleus muscles were slightly lower than the control values, and in the late stage, the values were much lower in all muscles examined. In sagittal sections, the gastrocnemius muscle in the early stage showed a high density area at the distal region adjacent to soleus muscle, and the soleus muscle showed a high density area adjacent to the gestrocnemius muscle. In serial axial sections, high density areas of the anterior and posterior tibialis muscles appeared first at their proximal and peripheral regions. It was concluded that the sequence of appearance of pathological changes was different not only among individual muscles but also among various regions of each muscle; the high density changes appeared first at myotendon junctions. (author)

  1. Secreted Protein Acidic and Rich in Cysteine (SPARC) in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Jørgensen, Louise H; Petersson, Stine J; Sellathurai, Jeeva

    2009-01-01

    indicated a function of SPARC in skeletal muscle. We therefore found it of interest to study SPARC expression in human skeletal muscle during development and in biopsies from Duchenne and Becker muscular dystrophy and congenital muscular dystrophy, congenital myopathy, inclusion body myositis...

  2. Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles.

    Directory of Open Access Journals (Sweden)

    Giorgio Tasca

    Full Text Available BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI we observed that T2-short tau inversion recovery (T2-STIR sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease. METHODS: Histopathology, gene expression profiling and real time PCR were performed on biopsies from FSHD muscles with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense. Data were compared with those from inflammatory myopathies, dysferlinopathies and normal controls. In order to validate obtained results, two additional FSHD samples with different MRI pattern were analyzed. RESULTS: Myopathic and inflammatory changes characterized T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states could be easily distinguished from each other by their transcriptional profile. The comparison between T2-STIR hyperintense FSHD muscles and inflammatory myopathy muscles showed peculiar changes, although many alterations were shared among these conditions. CONCLUSIONS: At the single muscle level, different stages of the disease correspond to the two MRI patterns. T2-STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis

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

    OpenAIRE

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

    2014-01-01

    OBJECTIVE: Respiratory complications are the main causes of morbidity and mortality in patients with neuromuscular disease (NMD). The objectives of this study were to determine the effects that routine daily home air-stacking maneuvers have on pulmonary function in patients with spinal muscular atrophy (SMA) and in patients with congenital muscular dystrophy (CMD), as well as to identify associations between spinal deformities and the effects of the maneuvers. METHODS: Eighteen NMD patients (...

  4. MRI for the demonstration of subclinical muscle involvement in muscular dystrophy

    International Nuclear Information System (INIS)

    Sookhoo, S.; MacKinnon, I.; Bushby, K.; Chinnery, P.F.; Birchall, D.

    2007-01-01

    Aim: To compare magnetic resonance imaging (MRI) with clinical examination for the detection of muscle abnormality in patients with muscular dystrophy. Methods: Muscle power in 20 patients with a variety of forms of muscular dystrophy was examined clinically using the Medical Research Council (MRC) grading scale, and patients were subsequently imaged with MRI. MRI and clinical examination for the detection of muscle normality and abnormality were compared using a McNemar chi-squared test to examine differences between the two methods. Results: MRI demonstrated radiological evidence of muscle abnormality more often than clinical examination; 50% of movements assessed as normal on clinical examination were associated with muscle abnormalities on MRI, including a significant proportion where there was severe radiological abnormality, indicating that focally advanced disease may be undetectable clinically. Conclusion: The combination of clinical examination and MRI could improve the accuracy of phenotypic characterization of patients with muscular dystrophy, and this in turn could allow a more focussed molecular analysis through muscle biopsy or genetic investigation. This may also be very helpful in the assessment of the degree of muscle compromise not only in the early phases of the disease but especially during follow-up and can be used in therapeutic trials

  5. Congenital absence of superficial posterior compartment calf muscles.

    Science.gov (United States)

    Tibrewal, Saket; Alyas, Faisal; Vemulapalli, Krishna

    2014-06-01

    Although various congenital abnormalities have been described, congenital absence of calf musculature is extremely rare, with only one report on its complete absence. We are the first to describe a case of congenital absence of muscles of the superficial posterior compartment of the calf presenting in a toddler. The child presented with a history of a painless limp, however no significant difference was found in functional gait analysis. We suggest that such cases should be monitored and parents can be reassured that no immediate treatment is required.

  6. Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Kan, H.E.; Scheenen, T.W.J.; Wohlgemuth, M.; Klomp, D.W.J.; Loosbroek-Wagemans, I.C.W.; Padberg, G.W.A.M.; Heerschap, A.

    2009-01-01

    The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD). Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired

  7. Comparing clinical data and muscle imaging of DYSF and ANO5 related muscular dystrophies

    NARCIS (Netherlands)

    ten Dam, Leroy; van der Kooi, Anneke J.; Rövekamp, Fleur; Linssen, Wim H. J. P.; de Visser, Marianne

    2014-01-01

    In this retrospective cross-sectional study clinical and muscle imaging data of patients with Miyoshi distal myopathy phenotype (MMD1 and MMD3) and limb girdle muscular dystrophy 2L (LGMD2L) were described. MMD1 and MMD3 are genetically heterogenous diseases based on DYSF and ANO5 gene defects. MMD3

  8. Becker muscular dystrophy with widespread muscle hypertrophy and a non-sense mutation of exon 2.

    Science.gov (United States)

    Witting, N; Duno, M; Vissing, J

    2013-01-01

    Becker muscular dystrophy features progressive proximal weakness, wasting and often focal hypertrophy. We present a patient with pain and cramps from adolescence. Widespread muscle hypertrophy, preserved muscle strength and a 10-20-fold raised CPK were noted. Muscle biopsy was dystrophic, and Western blot showed a 95% reduction of dystrophin levels. Genetic analyses revealed a non-sense mutation in exon 2 of the dystrophin gene. This mutation is predicted to result in a Duchenne phenotype, but resulted in a mild Becker muscular dystrophy with widespread muscle hypertrophy. We suggest that this unusual phenotype is caused by translation re-initiation downstream from the mutation site. Copyright © 2012 Elsevier B.V. All rights reserved.

  9. Quantitative muscle ultrasound versus quantitative magnetic resonance imaging in facioscapulohumeral dystrophy.

    Science.gov (United States)

    Janssen, Barbara H; Pillen, Sigrid; Voet, Nicoline B M; Heerschap, Arend; van Engelen, Baziel G M; van Alfen, Nens

    2014-12-01

    Ultrasound and magnetic resonance imaging (MRI) are non-invasive methods that can be performed repeatedly and without discomfort. In the assessment of neuromuscular disorders it is unknown if they provide complementary information. In this study we tested this for patients with facioscapulohumeral muscular dystrophy (FSHD). We performed quantitative muscle ultrasound (QMUS) and quantitative MRI (QMRI) of the legs in 5 men with FSHD. The correlation between QMUS-determined z-scores and QMRI-determined muscle fraction and T1 signal intensity (SI) was very high. QMUS had a wider dynamic range than QMRI, whereas QMRI could detect inhomogeneous distribution of pathology over the length of the muscles. Both QMUS and QMRI are well suited for imaging muscular dystrophy. The wider dynamic range of QMUS can be advantageous in the follow-up of advanced disease stages, whereas QMRI seems preferable in pathologies such as FSHD that affect deep muscle layers and show inhomogeneous abnormality distributions. © 2014 Wiley Periodicals, Inc.

  10. Abnormalities of the oculomotor nerve in congenital fibrosis of the extraocular muscles and congenital oculomotor palsy.

    Science.gov (United States)

    Lim, Key Hwan; Engle, Elizabeth C; Demer, Joseph L

    2007-04-01

    High-resolution magnetic resonance imaging (MRI) can now directly demonstrate innervation to extraocular muscles and quantify optic nerve size. A quantitative MRI technique was developed to study the oculomotor nerve (CN3) and applied to congenital fibrosis of extraocular muscles (CFEOM) and congenital oculomotor palsy. The subarachnoid portions of the CN3s were imaged with a 1.5-T MRI scanner and conventional head coils, acquiring heavily T(2)-weighted oblique axial planes 1-mm thick and parallel to the optic chiasm. Thirteen normal subjects, 14 with CFEOM, and 3 with congenital CN3 palsy were included. Digital image analysis was used to measure CN3 diameter, which was correlated with motility findings. In CFEOM, CN3 diameter was bilaterally subnormal in eight subjects, unilaterally subnormal in three subjects, and normal in three subjects. Mean +/- SD CN3 diameter in CFEOM was 1.14 +/- 0.61 mm, significantly smaller than the diameter in normal subjects, which measured 2.01 +/- 0.36 mm (P congenital CN3 palsy showed bilateral CN3 hypoplasia, but CN3 diameter was normal in two other subjects with congenital CN3 palsy. Unilateral or bilateral hypoplasia of CN3 is quantitatively demonstrable using MRI in many cases of CFEOM and occasionally in congenital CN3 palsy. Variations in CN3 diameter in CFEOM and congenital CN3 palsy suggest mechanistic heterogeneity of these disorders that may be clarified by further imaging and genetic studies.

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

    Science.gov (United States)

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

    2015-11-26

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

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

    Directory of Open Access Journals (Sweden)

    Emma Rybalka

    2015-11-01

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

  13. Merosin-positive congenital muscular dystrophy: neuroimaging findings Distrofia muscular congênita merosina-positiva: achados de neuroimagem

    Directory of Open Access Journals (Sweden)

    André Palma da Cunha Matta

    2007-03-01

    Full Text Available Congenital muscle dystrophy (CMD is a heterogeneous group of autosomal recessive myopathies. It is known that CMD may affect the central nervous system (CNS. Some authors have shown that merosin-negative CMD patients may have encephalic metabolic disturbances. In order to study metabolic changes within the brain, the authors performed a magnetic resonance spectroscopy (MRS study in a 1-year-old girl with merosin-positive CMD (MP-CMD. MRS of brain demonstrated that NAA/Cr ratio was decreased (1.52, while Cho/Cr ratio was increased (1.78. These findings suggest that metabolic changes in CNS can also be found in patients with MP-CMD.A distrofia muscular congênita (DMC é um grupo heterogêneo de miopatias autossômicas recessivas que também podem afetar o sistema nervoso central (SNC. Alguns autores mostraram previamente que pacientes com DMC por deficiência da merosina podem apresentar alterações metabólicas no encéfalo. Com o objetivo de estudar as possíveis alterações metabólicas no SNC, os autores realizaram um estudo por ressonância magnética com espectroscopia em uma paciente de 1 ano com DMC sem deficiência da merosina. A razão NAA/Cr estava reduzida (1,52, enquanto que a razão Cho/Cr estava aumentada (1,78. Estes achados sugerem que alterações metabólicas no SNC também podem ser encontradas em pacientes com DMC merosina-positiva.

  14. Comprehensive target capture/next-generation sequencing as a second-tier diagnostic approach for congenital muscular dystrophy in Taiwan.

    Directory of Open Access Journals (Sweden)

    Wen-Chen Liang

    Full Text Available Congenital muscular dystrophy (CMD is a heterogeneous disease entity. The detailed clinical manifestation and causative gene for each subgroup of CMD are quite variable. This study aims to analyze the phenotypes and genotypes of Taiwanese patients with CMD as the epidemiology of CMD varies among populations and has been scantly described in Asia.A total of 48 patients suspected to have CMD were screened and categorized by histochemistry and immunohistochemistry studies. Different genetic analyses, including next-generation sequencing (NGS, were selected, based on the clinical and pathological findings.We identified 17 patients with sarcolemma-specific collagen VI deficiency (SSCD, 6 patients with merosin deficiency, two with reduced alpha-dystroglycan staining, and two with striking lymphocyte infiltration in addition to dystrophic change on muscle pathology. Fourteen in 15 patients with SSCD, were shown to have COL6A1, COL6A2 or COL6A3 mutations by NGS analysis; all showed marked distal hyperlaxity and normal intelligence but the overall severity was less than in previously reported patients from other populations. All six patients with merosin deficiency had mutations in LAMA2. They showed relatively uniform phenotype that were compatible with previous studies, except for higher proportion of mental retardation with epilepsy. With reduced alpha-dystroglycan staining, one patient was found to carry mutations in POMT1 while another patient carried mutations in TRAPPC11. LMNA mutations were found in the two patients with inflammatory change on muscle pathology. They were clinically characterized by neck flexion limitation and early joint contracture, but no cardiac problem had developed yet.Muscle pathology remains helpful in guiding further molecular analyses by direct sequencing of certain genes or by target capture/NGS as a second-tier diagnostic tool, and is crucial for establishing the genotype-phenotype correlation. We also determined the

  15. Role of Decorin Core Protein in Collagen Organisation in Congenital Stromal Corneal Dystrophy (CSCD.

    Directory of Open Access Journals (Sweden)

    Christina S Kamma-Lorger

    Full Text Available The role of Decorin in organising the extracellular matrix was examined in normal human corneas and in corneas from patients with Congenital Stromal Corneal Dystrophy (CSCD. In CSCD, corneal clouding occurs due to a truncating mutation (c.967delT in the decorin (DCN gene. Normal human Decorin protein and the truncated one were reconstructed in silico using homology modelling techniques to explore structural changes in the diseased protein. Corneal CSCD specimens were also examined using 3-D electron tomography and Small Angle X-ray diffraction (SAXS, to image the collagen-proteoglycan arrangement and to quantify fibrillar diameters, respectively. Homology modelling showed that truncated Decorin had a different spatial geometry to the normal one, with the truncation removing a major part of the site that interacts with collagen, compromising its ability to bind effectively. Electron tomography showed regions of abnormal stroma, where collagen fibrils came together to form thicker fibrillar structures, showing that Decorin plays a key role in the maintenance of the order in the normal corneal extracellular matrix. Average diameter of individual fibrils throughout the thickness of the cornea however remained normal.

  16. Osteoprotegerin and β2-Agonists Mitigate Muscular Dystrophy in Slow- and Fast-Twitch Skeletal Muscles.

    Science.gov (United States)

    Dufresne, Sébastien S; Boulanger-Piette, Antoine; Frenette, Jérôme

    2017-03-01

    Our recent work showed that daily injections of osteoprotegerin (OPG)-immunoglobulin fragment complex (OPG-Fc) completely restore the function of fast-twitch extensor digitorum longus muscles in dystrophic mdx mice, a murine model of Duchenne muscular dystrophy. However, despite marked improvements, OPG-Fc was not as effective in preventing the loss of function of slow-twitch soleus and diaphragm muscles. Because β 2 -agonists enhance the function of slow- and fast-twitch dystrophic muscles and because their use is limited by their adverse effects on bone and cardiac tissues, we hypothesized that OPG-Fc, a bone and skeletal muscle protector, acts synergistically with β 2 -agonists and potentiates their positive effects on skeletal muscles. We observed that the content of β 2 -adrenergic receptors, which are mainly expressed in skeletal muscle, is significantly reduced in dystrophic muscles but is rescued by the injection of OPG-Fc. Most important, OPG-Fc combined with a low dose of formoterol, a member of a new generation of β 2 -agonists, histologically and functionally rescued slow-twitch dystrophic muscles. This combination of therapeutic agents, which have already been tested and approved for human use, may open up new therapeutic avenues for Duchenne muscular dystrophy and possibly other neuromuscular diseases. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  17. Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy.

    Science.gov (United States)

    Kim, Jong-Hee; Kwak, Hyo-Bum; Thompson, LaDora V; Lawler, John M

    2013-02-01

    Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non-specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients.

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

    Science.gov (United States)

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

    2015-05-01

    The purpose of this study was to assess the progression and variation of fatty infiltration of the thigh muscles of Duchenne muscular dystrophy patients. Muscle magnetic resonance imaging was used to measure the degree of fatty infiltration of the thigh muscles of 171 boys with Duchenne muscular dystrophy (mean age, 6.09 ± 2.30 years). Fatty infiltration was assigned using a modified Mercuri's scale 0-5 (normal-severe). The gluteus maximus and adductor magnus were affected in patients less than two years old, followed by the biceps femoris. Quadriceps and semimembranosus were first affected at the age of five to six years; the sartorius, gracilis and adductor longus remained apparently unaffected until seven years of age. Fatty infiltration of all the thigh muscles developed rapidly after seven years of age. The standard deviation of the fatty infiltration scores ranged from 2.41 to 4.87 before five years old, and from 6.84 to 11.66 between six and ten years old. This study provides evidence of highly variable degrees of fatty infiltration in children of different ages with Duchenne muscular dystrophy, and indicates that fatty infiltration progresses more quickly after seven years of age. These findings may be beneficial for the selection of therapeutic regimens and the analysis of future clinical trials. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Noninvasive evaluation of respiratory muscles in pre-clinical model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Daniela M. Oliveira

    2016-04-01

    Full Text Available Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD, the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD employing ultrasonography (US. A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

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

    Science.gov (United States)

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

    2015-12-01

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

  1. Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy

    Science.gov (United States)

    Sander, Mikael; Chavoshan, Bahman; Harris, Shannon A.; Iannaccone, Susan T.; Stull, James T.; Thomas, Gail D.; Victor, Ronald G.

    2000-01-01

    Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutation of the gene encoding the cytoskeletal protein dystrophin. Despite a wealth of recent information about the molecular basis of DMD, effective treatment for this disease does not exist because the mechanism by which dystrophin deficiency produces the clinical phenotype is unknown. In both mouse and human skeletal muscle, dystrophin deficiency results in loss of neuronal nitric oxide synthase, which normally is localized to the sarcolemma as part of the dystrophin–glycoprotein complex. Recent studies in mice suggest that skeletal muscle-derived nitric oxide may play a key role in the regulation of blood flow within exercising skeletal muscle by blunting the vasoconstrictor response to α-adrenergic receptor activation. Here we report that this protective mechanism is defective in children with DMD, because the vasoconstrictor response (measured as a decrease in muscle oxygenation) to reflex sympathetic activation was not blunted during exercise of the dystrophic muscles. In contrast, this protective mechanism is intact in healthy children and those with polymyositis or limb-girdle muscular dystrophy, muscle diseases that do not result in loss of neuronal nitric oxide synthase. This clinical investigation suggests that unopposed sympathetic vasoconstriction in exercising human skeletal muscle may constitute a heretofore unappreciated vascular mechanism contributing to the pathogenesis of DMD. PMID:11087833

  2. Relationship between muscle strength and motor function in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Milene F. Nunes

    2016-07-01

    Full Text Available ABSTRACT Measuring muscle strength and motor function is part of Duchenne muscular dystrophy (DMD assessment. However, the relationship between these variables is controversial. Objective To investigate the relationship between muscle strength and motor function and between these variables and age. Method Muscle strength was measured by Medical Research Council (MRC scale and motor function, by Motor Function Measure (MFM, in 40 non-ambulatory patients. Spearman tests investigated the relationships between muscle strength, motor function and age. Results Total MRC and MFM scores were strongly related to each other (r = 0.94; p 0.05. Strong and moderate relationships between partial muscle strength and motor function scores were found. Higher correlation coefficients were found between total scores and Dimensions 2 (axial/ proximal control and 3 (distal control of MFM. Conclusion Muscle strength and motor function are strongly correlated and seem to decrease proportionally in DMD.

  3. Atrophy, fibrosis, and increased PAX7-positive cells in pharyngeal muscles of oculopharyngeal muscular dystrophy patients.

    Science.gov (United States)

    Gidaro, Teresa; Negroni, Elisa; Perié, Sophie; Mirabella, Massimiliano; Lainé, Jeanne; Lacau St Guily, Jean; Butler-Browne, Gillian; Mouly, Vincent; Trollet, Capucine

    2013-03-01

    Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant inherited dystrophy caused by an abnormal trinucleotide repeat expansion in the poly(A)-binding-protein-nuclear 1 (PABPN1) gene. Primary muscular targets of OPMD are the eyelid elevator and pharyngeal muscles, including the cricopharyngeal muscle (CPM), the progressive involution of which leads to ptosis and dysphagia, respectively. To understand the consequences of PABPN1 polyalanine expansion in OPMD, we studied muscle biopsies from 14 OPMD patients, 3 inclusion body myositis patients, and 9 healthy controls. In OPMD patient CPM (n = 6), there were typical dystrophic features with extensive endomysial fibrosis and marked atrophy of myosin heavy-chain IIa fibers. There were more PAX7-positive cells in all CPM versus other muscles (n = 5, control; n = 3, inclusion body myositis), and they were more numerous in OPMD CPM versus control normal CPM without any sign of muscle regeneration. Intranuclear inclusions were present in all OPMD muscles but unaffected OPMD patient muscles (i.e. sternocleidomastoid, quadriceps, or deltoid; n = 14) did not show evidence of fibrosis, atrophy, or increased PAX7-positive cell numbers. These results suggest that the specific involvement of CPM in OPMD might be caused by failure of the regenerative response with dysfunction of PAX7-positive cells and exacerbated fibrosis that does not correlate with the presence of PABPN1 inclusions.

  4. Characteristic MRI Findings of upper Limb Muscle Involvement in Myotonic Dystrophy Type 1.

    Directory of Open Access Journals (Sweden)

    Kazuma Sugie

    Full Text Available The objective of our study was to evaluate the relation between muscle MRI findings and upper limb weakness with grip myotonia in patients with myotonic dystrophy type 1 (DM1. Seventeen patients with DM1 were evaluated by manual muscle strength testing and muscle MRI of the upper limbs. Many DM1 patients presenting with decreased grasping power frequently showed high intensity signals in the flexor digitorum profundus (FDP muscles on T1-weighted imaging. Patients presenting with upper limb weakness frequently also showed high intensity signals in the flexor pollicis longus, abductor pollicis longus, and extensor pollicis muscles. Disturbances of the distal muscles of the upper limbs were predominant in all DM1 patients. Some DM1 patients with a prolonged disease duration showed involvement of not only distal muscles but also proximal muscles in the upper limbs. Muscle involvement of the upper limbs on MRI strongly correlated positively with the disease duration or the numbers of CTG repeats. To our knowledge, this is the first study to provide a detailed description of the distribution and severity of affected muscles of the upper limbs on MRI in patients with DM1. We conclude that muscle MRI findings are very useful for identifying affected muscles and predicting the risk of muscle weakness in the upper limbs of DM1 patients.

  5. Megaconial muscular dystrophy caused by mitochondrial membrane homeostasis defect, new insights from skeletal and heart muscle analyses.

    Science.gov (United States)

    Vanlander, Arnaud V; Muiño Mosquera, Laura; Panzer, Joseph; Deconinck, Tine; Smet, Joél; Seneca, Sara; Van Dorpe, Jo; Ferdinande, Liesbeth; Ceuterick-de Groote, Chantal; De Jonghe, Peter; Van Coster, Rudy; Baets, Jonathan

    2016-03-01

    Megaconial congenital muscular dystrophy is a disease caused by pathogenic mutations in the gene encoding choline kinase beta (CHKB). Microscopically, the disease is hallmarked by the presence of enlarged mitochondria at the periphery of skeletal muscle fibres leaving the centre devoid of mitochondria. Clinical characteristics are delayed motor development, intellectual disability and dilated cardiomyopathy in half of reported cases. This study describes a patient presenting with the cardinal clinical features, in whom a homozygous nonsense mutation (c.248_249insT; p.Arg84Profs*209) was identified in CHKB and who was treated by heart transplantation. Microscopic evaluation of skeletal and heart muscles typically showed enlarged mitochondria. Spectrophotometric evaluation in both tissues revealed a mild decrease of all OXPHOS complexes. Using BN-PAGE analysis followed by activity staining subcomplexes of complex V were detected in both tissues, indicating incomplete complex V assembly. Mitochondrial DNA content was not depleted in analysed tissues. This is the first report describing the microscopic and biochemical abnormalities in the heart from an affected patient. A likely hypothesis is that the biochemical findings are caused by an abnormal lipid profile in the inner mitochondrial membrane resulting from a defective choline kinase B activity. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.

  6. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    OpenAIRE

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Na?ra; Rau, Fr?d?rique; Jollet, Arnaud; Edom-Vovard, Fr?d?rique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois

    2017-01-01

    International audience; Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded rep...

  7. Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy.

    Science.gov (United States)

    Zhou, Jing; Tan, Jianxin; Ma, Dingyuan; Zhang, Jingjing; Cheng, Jian; Luo, Chunyu; Liu, Gang; Wang, Yuguo; Xu, Zhengfeng

    2018-01-01

    Merosin-deficient CMD type 1A (MDC1A), caused by mutations of laminin subunit alpha 2 (LAMA2), is a predominant subtype of congenital muscular dystrophy (CMD). Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS) and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI) as well as hypointensity on fluid attenuated inversion recovery (FLAIR) image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G) and a frameshift duplication (c.8217dupT) in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo . The frameshift duplication (c.8217dupT), inherited from her mother, was predicted to cause a substitution of Pro (P) to Ser (S) at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G) may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A.

  8. Identification of Two Novel LAMA2 Mutations in a Chinese Patient with Congenital Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Jing Zhou

    2018-02-01

    Full Text Available Merosin-deficient CMD type 1A (MDC1A, caused by mutations of laminin subunit alpha 2 (LAMA2, is a predominant subtype of congenital muscular dystrophy (CMD. Herein, we described a Chinese patient with MDC1A who was admitted to hospital 17 days after birth because of marasmus and feeding difficulties. Mutations were identified by targeted capture and next generation sequencing (NGS and further confirmed by Sanger sequencing. Paternity was confirmed by short tandem repeat analysis. Physical examination showed malnutrition, poor suck and appendicular hypotonia. Her serum CK levels were 2483 and 1962 U/L at 2 and 4 months of age, respectively. Brain magnetic resonance imaging performed at 1 month of age presented hyperintensity on T2-weighted images, T1-weighted images in parietal and occipital lobes, and diffusion-weighted image (DWI as well as hypointensity on fluid attenuated inversion recovery (FLAIR image; however, the cerebellum and corpus arenaceum were normal. At 7 months of age, delayed developmental milestones were observed, and she failed to turn her body over and raise her head up. A point mutation (c.1782+2T > G and a frameshift duplication (c.8217dupT in the LAMA2 gene were identified by targeted capture and NGS and further confirmed by Sanger sequencing. Moreover, genotyping with multiple short tandem repeat markers confirmed paternity to demonstrate that the point mutation is de novo. The frameshift duplication (c.8217dupT, inherited from her mother, was predicted to cause a substitution of Pro (P to Ser (S at the 2740th amino-acid residue and generate a prematurely truncated protein. The in silico analysis suggests that the mutation (c.1782+2T > G may lead to aberrant splicing of LAMA2. Our case further confirms the heterogeneous clinical spectrum of MDC1A and presents two novel LAMA2 mutations to expand the mutation spectrum of MDC1A.

  9. Quantitative MRI and strength measurements in the assessment of muscle quality in Duchenne muscular dystrophy.

    Science.gov (United States)

    Wokke, B H; van den Bergen, J C; Versluis, M J; Niks, E H; Milles, J; Webb, A G; van Zwet, E W; Aartsma-Rus, A; Verschuuren, J J; Kan, H E

    2014-05-01

    The purpose of this study was to assess leg muscle quality and give a detailed description of leg muscle involvement in a series of Duchenne muscular dystrophy patients using quantitative MRI and strength measurements. Fatty infiltration, as well as total and contractile (not fatty infiltrated) cross sectional areas of various leg muscles were determined in 16 Duchenne patients and 11 controls (aged 8-15). To determine specific muscle strength, four leg muscle groups (quadriceps femoris, hamstrings, anterior tibialis and triceps surae) were measured and related to the amount of contractile tissue. In patients, the quadriceps femoris showed decreased total and contractile cross sectional area, attributable to muscle atrophy. The total, but not the contractile, cross sectional area of the triceps surae was increased in patients, corresponding to hypertrophy. Specific strength decreased in all four muscle groups of Duchenne patients, indicating reduced muscle quality. This suggests that muscle hypertrophy and fatty infiltration are two distinct pathological processes, differing between muscle groups. Additionally, the quality of remaining muscle fibers is severely reduced in the legs of Duchenne patients. The combination of quantitative MRI and quantitative muscle testing could be a valuable outcome parameter in longitudinal studies and in the follow-up of therapeutic effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. Autophagy in Skeletal Muscle Homeostasis and in Muscular Dystrophies

    Directory of Open Access Journals (Sweden)

    Paolo Bonaldo

    2012-07-01

    Full Text Available Skeletal muscles are the agent of motion and one of the most important tissues responsible for the control of metabolism. The maintenance of muscle homeostasis is finely regulated by the balance between catabolic and anabolic process. Macroautophagy (or autophagy is a catabolic process that provides the degradation of protein aggregation and damaged organelles through the fusion between autophagosomes and lysosomes. Proper regulation of the autophagy flux is fundamental for the homeostasis of skeletal muscles during physiological situations and in response to stress. Defective as well as excessive autophagy is harmful for muscle health and has a pathogenic role in several forms of muscle diseases. This review will focus on the role of autophagy in muscle homeostasis and diseases.

  11. Muscle MRI findings in patients with limb girdle muscular dystrophy with calpain 3 deficiency (LGMD2A) and early contractures.

    Science.gov (United States)

    Mercuri, Eugenio; Bushby, Kate; Ricci, Enzo; Birchall, Daniel; Pane, Marika; Kinali, Maria; Allsop, Joanna; Nigro, Vincenzo; Sáenz, Amets; Nascimbeni, Annachiara; Fulizio, Luigi; Angelini, Corrado; Muntoni, Francesco

    2005-02-01

    Limb girdle muscular dystrophy 2A is a common variant secondary to mutations in the calpain 3 gene. A proportion of patients has early and severe contractures, which can cause diagnostic difficulties with other conditions. We report clinical and muscle magnetic resonance imaging findings in seven limb girdle muscular dystrophy 2A patients (four sporadic and three familial) who had prominent and early contractures. All patients showed a striking involvement of the posterior thigh muscles. The involvement of the other thigh muscles was variable and was related to clinical severity. Young patients with minimal functional motor impairment showed a predominant involvement of the adductors and semimembranosus muscles while patients with restricted ambulation had a more diffuse involvement of the posterolateral muscles of the thigh and of the vastus intermedius with relative sparing of the vastus lateralis, sartorius and gracilis. At calf level all patients showed involvement of the soleus muscle and of the medial head of the gastrocnemius with relative sparing of the lateral head. MRI findings were correlated to those found in two patients with the phenotype of limb girdle muscular dystrophy 2A without early contractures and the pattern observed was quite similar. However, the pattern observed in limb girdle muscular dystrophy 2A is different from that reported in other muscle diseases such as Emery-Dreifuss muscular dystrophy and Bethlem myopathy which have a significant clinical overlap with limb girdle muscular dystrophy 2A once early contractures are present. Our results suggest that muscle MRI may help in recognising patients with limb girdle muscular dystrophy 2A even when the clinical presentation overlaps with other conditions, and may therefore, be used as an additional investigation to target the appropriate biochemical and genetic tests.

  12. Muscle ultrasound quantifies disease progression over time in infants and young boys with duchenne muscular dystrophy.

    Science.gov (United States)

    Zaidman, Craig M; Malkus, Elizabeth C; Connolly, Anne M

    2015-09-01

    Quantitative muscle ultrasound (QUS) in boys with Duchenne muscular dystrophy (DMD) shows increased echointensity as muscle is replaced with fat and fibrosis. Studies of quantitative ultrasound in infants/young boys with DMD over time have not been reported. We used calibrated muscle backscatter (cMB), a reproducible measure of ultrasound echointensity, to quantify muscle pathology in 5 young boys with DMD (ages 0.5-2.8 years) over 17-29 months. We compared the results with repeated assessments of function (n = 4) and with muscle ultrasound images from a cross-section of 6 male controls (0.6-3.1 years). cMB in boys with DMD increased (worsened) over time (P assessment of young boys with DMD. © 2015 Wiley Periodicals, Inc.

  13. Attenuated muscle regeneration is a key factor in dysferlin-deficient muscular dystrophy

    DEFF Research Database (Denmark)

    Chiu, Yen-Hui; Hornsey, Mark A; Klinge, Lars

    2009-01-01

    Skeletal muscle requires an efficient and active membrane repair system to overcome the rigours of frequent contraction. Dysferlin is a component of that system and absence of dysferlin causes muscular dystrophy (dysferlinopathy) characterized by adult onset muscle weakness, high serum creatine...... kinase levels and a prominent inflammatory infiltrate. We have observed that dysferlinopathy patient biopsies show an excess of immature fibres and therefore investigated the role of dysferlin in muscle regeneration. Using notexin-induced muscle damage, we have shown that regeneration is attenuated...... in a mouse model of dysferlinopathy, with delayed removal of necrotic fibres, an extended inflammatory phase and delayed functional recovery. Satellite cell activation and myoblast fusion appear normal, but there is a reduction in early neutrophil recruitment in regenerating and also needle wounded muscle...

  14. Correlation of Utrophin Levels with the Dystrophin Protein Complex and Muscle Fibre Regeneration in Duchenne and Becker Muscular Dystrophy Muscle Biopsies.

    Science.gov (United States)

    Janghra, Narinder; Morgan, Jennifer E; Sewry, Caroline A; Wilson, Francis X; Davies, Kay E; Muntoni, Francesco; Tinsley, Jonathon

    2016-01-01

    Duchenne muscular dystrophy is a severe and currently incurable progressive neuromuscular condition, caused by mutations in the DMD gene that result in the inability to produce dystrophin. Lack of dystrophin leads to loss of muscle fibres and a reduction in muscle mass and function. There is evidence from dystrophin-deficient mouse models that increasing levels of utrophin at the muscle fibre sarcolemma by genetic or pharmacological means significantly reduces the muscular dystrophy pathology. In order to determine the efficacy of utrophin modulators in clinical trials, it is necessary to accurately measure utrophin levels and other biomarkers on a fibre by fibre basis within a biopsy section. Our aim was to develop robust and reproducible staining and imaging protocols to quantify sarcolemmal utrophin levels, sarcolemmal dystrophin complex members and numbers of regenerating fibres within a biopsy section. We quantified sarcolemmal utrophin in mature and regenerating fibres and the percentage of regenerating muscle fibres, in muscle biopsies from Duchenne, the milder Becker muscular dystrophy and controls. Fluorescent immunostaining followed by image analysis was performed to quantify utrophin intensity and β-dystrogylcan and ɣ -sarcoglycan intensity at the sarcolemma. Antibodies to fetal and developmental myosins were used to identify regenerating muscle fibres allowing the accurate calculation of percentage regeneration fibres in the biopsy. Our results indicate that muscle biopsies from Becker muscular dystrophy patients have fewer numbers of regenerating fibres and reduced utrophin intensity compared to muscle biopsies from Duchenne muscular dystrophy patients. Of particular interest, we show for the first time that the percentage of regenerating muscle fibres within the muscle biopsy correlate with the clinical severity of Becker and Duchenne muscular dystrophy patients from whom the biopsy was taken. The ongoing development of these tools to quantify

  15. Muscle ultrasound elastography and MRI in preschool children with Duchenne muscular dystrophy.

    Science.gov (United States)

    Pichiecchio, Anna; Alessandrino, Francesco; Bortolotto, Chandra; Cerica, Alessandra; Rosti, Cristina; Raciti, Maria Vittoria; Rossi, Marta; Berardinelli, Angela; Baranello, Giovanni; Bastianello, Stefano; Calliada, Fabrizio

    2018-04-13

    The aim of this study was to determine muscle tissue elasticity, measured with shear-wave elastography, in selected lower limb muscles of patients affected by Duchenne muscular dystrophy (DMD) and to correlate the values obtained with those recorded in healthy children and with muscle magnetic resonance imaging (MRI) data from the same DMD children, specifically the pattern on T1-weighted (w) and short-tau inversion recovery (STIR) sequences. Five preschool DMD children and five age-matched healthy children were studied with shear-wave elastography. In the DMD children, muscle stiffness was moderately higher compared with the muscle stiffness in HC, in the rectus femoris, vastus lateralis, adductor magnus and gluteus maximus muscles. On muscle MRI T1-w images showed fatty replacement in 3/5 patients at the level of the GM, while thigh and leg muscles were affected in 2/5; hyperintensity on STIR images was identified in 4/5 patients. No significant correlation was observed between stiffness values and MRI scoring. Our study demonstrated that lower limb muscles of preschool DMD patients show fatty replacement and patchy edema on muscle MRI and increased stiffness on shear-wave elastography. In conclusion, although further studies in larger cohorts are needed, shear-wave elastography could be considered a useful non-invasive tool to easily monitor muscle changes in early stages of the disease. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Characteristic of muscle involvement evaluated by CT scans in early stages of progressive muscular dystrophy

    International Nuclear Information System (INIS)

    Arai, Yumi

    1993-01-01

    Muscle CT scans were performed in order to compare the characteristic distribution of progressive muscle involvement in the early stages of Duchenne type (DMD) and Fukuyama type muscular dystrophy (FCMD). Muscle images at the levels of the 3rd lumbar vertebra, thigh and calf were assessed by visual inspection, and mean CT numbers calculated for individual muscles were statistically analysed. On visual inspection, intramuscular low density areas and muscular atrophy were observed in the muscles of older patients with either disease. These changes were, however, more extensive at thigh level in DMD, and at calf level in FCMD. Nevertheless, the mean CT numbers of muscles in which only slight changes were grossly visible on CT scans displayed progressive decreases with increasing age. Moreover, a significant negative relationship was recognizable between age and mean CT number in almost all muscles examined. Comparison of the slopes of the regression lines revealed that the so-called selective pattern of muscle involvement characteristic of the symptomatic stage had already partially manifested in the preclinical or early stages of both diseases. In FCMD, the rates of decrease in CT numbers were extremely rapid for calf muscles as compared with those in DMD, indicating that this is one reason for FCMD patients never becoming ambulatory. However, for almost all of the other muscles, the CT numbers in FCMD decreased in parallel with the corresponding CT numbers in DMD; thus, these diseases displayed a similarity in the pattern of muscle involvement, despite their different pathogenetic mechanisms and inheritance patterns. (author)

  17. Muscle MRI in Duchenne and Becker muscular dystrophy

    NARCIS (Netherlands)

    Wokke, Beatrijs Henriette Aleid

    2015-01-01

    In this thesis we evaluated several MRI/S methods as outcome parameters to assess muscle pathology in DMD and BMD patients. We applied 3-point Dixon MRI to compare levels of fatty infiltration in muscle of DMD patients with a semi-quantitative method. Dixon MRI showed to be more sensitive to subtle

  18. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds.

    Science.gov (United States)

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F; Furling, Denis

    2017-04-01

    Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. © 2017. Published by The Company of Biologists Ltd.

  19. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    Directory of Open Access Journals (Sweden)

    Ludovic Arandel

    2017-04-01

    Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.

  20. Immortalized human myotonic dystrophy muscle cell lines to assess therapeutic compounds

    Science.gov (United States)

    Arandel, Ludovic; Polay Espinoza, Micaela; Matloka, Magdalena; Bazinet, Audrey; De Dea Diniz, Damily; Naouar, Naïra; Rau, Frédérique; Jollet, Arnaud; Edom-Vovard, Frédérique; Mamchaoui, Kamel; Tarnopolsky, Mark; Puymirat, Jack; Battail, Christophe; Boland, Anne; Deleuze, Jean-Francois; Mouly, Vincent; Klein, Arnaud F.

    2017-01-01

    ABSTRACT Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations. PMID:28188264

  1. Immunohistochemical alterations of dystrophin in congenital muscular dystrophy Alterações imuno-hístoquímicas da distrofina na distrofia muscular congênita

    Directory of Open Access Journals (Sweden)

    Lineu Cesar Werneck

    1995-09-01

    Full Text Available The dystrophin distribution in the plasma muscle membrane using immunohystochemistry was studied in 22 children with congenital muscular dystrophy. The dystrophin was detected by immunofluorescence in muscle biopsy through a polyclonal antibody. All the cases had patchy interruptions of the fluorescence in the plasma membrane. A large patchy interruption of the sarcolemma was found in 17 cases, small interruption in 12, and a combination of large and small patchy discontinuity in 7. Small gaps around the fiber like a rosary were found in 15 cases. The frequency of these abnormalities ranged cases from: all fibers in 5 cases, frequent in 8, occasional in 5, and rare in 4. Five cases had total absence of immunofluorescence. These results suggest that the dystrophin expression is abnormal in this group of children and that this type of abnormalities can not be differentiated from early Becker muscular dystrophy nor childhood autosomal recessive muscular dystrophy through immunohystochemistry alone.Foi estudada a distribuição da distrofina na membrana plasmática das fibras musculares em 22 crianças com distrofia muscular congênita, através de técnicas de imuno-histoquímica. A distrofina foi identificada nas biópsias musculares processadas a fresco, por técnicas de imunofluorescência utilizando anticorpos policlonais. Todos os casos tinham interrupções da imunofluorescência na membrana plasmática. Em 17 elas eram grandes, em 12 eram pequenas e em 7 eram de ambos os tipos. Fibras com interrupções pequenas e constantes, como um rosário, foram vistas em 15 casos. Essas anormalidades estavam presentes em todas as fibras em 5 casos, eram frequentes em 8, ocasionais em 5 e raras em 4. Cinco casos mostraram fibras sem distrofina. Esses dados sugerem que a expressão da distrofina é anormal nesse grupo de crianças. Essas anormalidades podem também ser encontradas em casos precoces de distrofia muscular de Becker e distrofia autoss

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

    Science.gov (United States)

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

    2010-06-01

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

  3. Carrier detection of duchenne and becker muscular dystrophy using muscle dystrophin immunohistochemistry

    Directory of Open Access Journals (Sweden)

    Acary S. Bulle Oliveira

    1992-12-01

    Full Text Available To ascertain whether dystrophin immunohistochemistry could improve DMD/ BMD carrier detection, we analyzed 14 muscle biopsies from 13 DMD and one BMD probable and possible carriers. All women were also evaluated using conventional methods, including genetic analysis, clinical and neurological evaluation, serum CK levels, KMG, and muscle biopsy. In 6 cases, there was a mosaic of dystrophin-positive and dystrophin-deficient fibers that allowed to make the diagnosis of a carrier state. Comparing dystrophin immunohistochemistry to the traditional methods, it was noted that this method is less sensitive than serum CK measuremens, but is more sensitive than EMG and muscle biopsy. The use of dystrophin immunohistochemistry in addition to CK, EMG and muscle biopsy improved the accuracy of carrier detection. This method is also helpful to distinguish manifesting DMD carriers from patients with other neuromuscular diseases like limb-girdle muscular dystrophy and spinal muscular atrophy.

  4. Calf muscle involvement in Becker muscular dystrophy: when size does not matter.

    Science.gov (United States)

    Monforte, Mauro; Mercuri, Eugenio; Laschena, Francesco; Ricci, Enzo; Tasca, Giorgio

    2014-12-15

    Calf hypertrophy is a common feature in Becker muscular dystrophy (BMD), and it is still debated to which extent fatty degeneration or true muscle hypertrophy account for it. We wanted to investigate the relative contribution of these two components using a simple image analysis approach and their possible correlation with disease severity. Twenty-nine BMD patients' MRI scans were analyzed. A semiquantitative visual score assessing fatty replacement of calf muscles (calf MRI score, CMS) was calculated and correlated with the cross sectional area (CSA) of lower leg posterior compartment muscles, digitally measured on acquired images. The correlation between CSA and CMS was not significant. CMS in contrast correlated with disease severity (pcalf hypertrophy is provided by real muscle hypertrophy rather than by fatty degeneration. CMS appears to be a potential surrogate marker of disease severity. Copyright © 2014 Elsevier B.V. All rights reserved.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2011-04-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin{sup -/-} (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a

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

    International Nuclear Information System (INIS)

    Kallestad, Kristen M.; Hebert, Sadie L.; McDonald, Abby A.; Daniel, Mark L.; Cu, Sharon R.; McLoon, Linda K.

    2011-01-01

    The extraocular muscles (EOM) are spared from pathology in aging and many forms of muscular dystrophy. Despite many studies, this sparing remains an enigma. The EOM have a distinct embryonic lineage compared to somite-derived muscles, and we have shown that they continuously remodel throughout life, maintaining a population of activated satellite cells even in aging. These data suggested the hypothesis that there is a population of myogenic precursor cells (mpcs) in EOM that is different from those in limb, with either elevated numbers of stem cells and/or mpcs with superior proliferative capacity compared to mpcs in limb. Using flow cytometry, EOM and limb muscle mononuclear cells were compared, and a number of differences were seen. Using two different cell isolation methods, EOM have significantly more mpcs per mg muscle than limb skeletal muscle. One specific subpopulation significantly increased in EOM compared to limb was positive for CD34 and negative for Sca-1, M-cadherin, CD31, and CD45. We named these the EOMCD34 cells. Similar percentages of EOMCD34 cells were present in both newborn EOM and limb muscle. They were retained in aged EOM, whereas the population decreased significantly in adult limb muscle and were extremely scarce in aged limb muscle. Most importantly, the percentage of EOMCD34 cells was elevated in the EOM from both the mdx and the mdx/utrophin -/- (DKO) mouse models of DMD and extremely scarce in the limb muscles of these mice. In vitro, the EOMCD34 cells had myogenic potential, forming myotubes in differentiation media. After determining a media better able to induce proliferation in these cells, a fusion index was calculated. The cells isolated from EOM had a 40% higher fusion index compared to the same cells isolated from limb muscle. The EOMCD34 cells were resistant to both oxidative stress and mechanical injury. These data support our hypothesis that the EOM may be spared in aging and in muscular dystrophies due to a subpopulation of

  7. Skeletal muscle homeostasis in Duchenne muscular dystrophy: modulating autophagy as a promising therapeutic strategy

    Directory of Open Access Journals (Sweden)

    Clara eDe Palma

    2014-07-01

    Full Text Available Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterised by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD, the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity and chronic local inflammation leading to substitution of myofibres by connective and adipose tissue. DMD patients suffer of continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. The autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels it can be detrimental and contribute to muscle wasting; at low levels it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular levels, the Akt axis is one of the key disregulated pathways, although the molecular events are not completely understood.The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signalling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.

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

    Science.gov (United States)

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

    2016-01-15

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

  9. Systemic Inflammation in Duchenne Muscular Dystrophy: Association with Muscle Function and Nutritional Status

    Science.gov (United States)

    Cruz-Guzmán, Oriana del Rocío; Rodríguez-Cruz, Maricela; Escobar Cedillo, Rosa Elena

    2015-01-01

    Inflammation described in patients with Duchenne muscular dystrophy (DMD) may be related to loss of muscle function or to obesity. It is unknown if circulating proinflammatory cytokines (IL-6, IL-1, and TNF-α) levels are associated with muscle function. The purpose was to evaluate whether an association exists between systemic inflammation with muscle function and nutritional status in DMD patients. In 66 DMD patients without corticosteroid treatment, the following were evaluated in serum: cytokines (IL-1, IL-6, and TNF-α), C-reactive protein (CRP), leptin, adiponectin, and creatine kinase (CK). Muscle function was evaluated using Vignos Scale. Patients with better muscle function had the highest concentration of CK, IL-1, and TNF-α compared with less muscle function. No differences in IL-6 and adiponectin concentration were identified among groups with different levels of muscle function. Also, no differences were observed in the concentration of cytokines among groups with different nutritional status levels (underweight, normal weight, and overweight/obese). However, CRP and leptin were increased in the obese group compared with normal and underweight subjects. Systemic inflammation is increased in patients with better muscle function and decreases in DMD patients with poorer muscle function; nevertheless, systemic inflammation is similar among different levels of nutritional status in DMD patients. PMID:26380303

  10. Systemic Inflammation in Duchenne Muscular Dystrophy: Association with Muscle Function and Nutritional Status

    Directory of Open Access Journals (Sweden)

    Oriana del Rocío Cruz-Guzmán

    2015-01-01

    Full Text Available Inflammation described in patients with Duchenne muscular dystrophy (DMD may be related to loss of muscle function or to obesity. It is unknown if circulating proinflammatory cytokines (IL-6, IL-1, and TNF-α levels are associated with muscle function. The purpose was to evaluate whether an association exists between systemic inflammation with muscle function and nutritional status in DMD patients. In 66 DMD patients without corticosteroid treatment, the following were evaluated in serum: cytokines (IL-1, IL-6, and TNF-α, C-reactive protein (CRP, leptin, adiponectin, and creatine kinase (CK. Muscle function was evaluated using Vignos Scale. Patients with better muscle function had the highest concentration of CK, IL-1, and TNF-α compared with less muscle function. No differences in IL-6 and adiponectin concentration were identified among groups with different levels of muscle function. Also, no differences were observed in the concentration of cytokines among groups with different nutritional status levels (underweight, normal weight, and overweight/obese. However, CRP and leptin were increased in the obese group compared with normal and underweight subjects. Systemic inflammation is increased in patients with better muscle function and decreases in DMD patients with poorer muscle function; nevertheless, systemic inflammation is similar among different levels of nutritional status in DMD patients.

  11. Isometric and eccentric force generation assessment of skeletal muscles isolated from murine models of muscular dystrophies.

    Science.gov (United States)

    Moorwood, Catherine; Liu, Min; Tian, Zuozhen; Barton, Elisabeth R

    2013-01-31

    Critical to the evaluation of potential therapeutics for muscular disease are sensitive and reproducible physiological assessments of muscle function. Because many pre-clinical trials rely on mouse models for these diseases, isolated muscle function has become one of the standards for Go/NoGo decisions in moving drug candidates forward into patients. We will demonstrate the preparation of the extensor digitorum longus (EDL) and diaphragm muscles for functional testing, which are the predominant muscles utilized for these studies. The EDL muscle geometry is ideal for isolated muscle preparations, with two easily accessible tendons, and a small size that can be supported by superfusion in a bath. The diaphragm exhibits profound progressive pathology in dystrophic animals, and can serve as a platform for evaluating many potential therapies countering fibrosis, and promoting myofiber stability. Protocols for routine testing, including isometric and eccentric contractions, will be shown. Isometric force provides assessment of strength, and eccentric contractions help to evaluate sarcolemma stability, which is disrupted in many types of muscular dystrophies. Comparisons of the expected results between muscles from wildtype and dystrophic muscles will also be provided. These measures can complement morphological and biochemical measurements of tissue homeostasis, as well as whole animal assessments of muscle function.

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

    Directory of Open Access Journals (Sweden)

    Hauerslev Simon

    2012-03-01

    Full Text Available Abstract 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.

  13. Sequential muscle biopsy changes in a case of congenital myopathy.

    Energy Technology Data Exchange (ETDEWEB)

    Danon, M. J.; Giometti, C. S.; Manaligod, J. R.; Swisher, C.; Center for Mechanistic Biology and Biotechnology; New York Medical Coll.; Univ. of Illinois at Chicago; Children' s Memorial Hospital

    1997-05-01

    Muscle biopsies at age 7 months in a set of dizygotic male twins born floppy showed typical features of congenital fiber-type disproportion (CFTD). One of the twins died at age 1 year due to respiratory complications. The second one subsequently developed facial diplegia and external ophthalmoplegia. He never walked, remained wheelchair bound, and required continuous ventilatory support. He underwent repeat biopsies at ages 2 and 4, which showed many atrophic type 1 muscle fibers containing central nuclei and severe type 2 fiber deficiency compatible with centronuclear myopathy (CNM). Two-dimensional gel electrophoresis of muscle showed decreases of type II myosin light chains 2 and 3, suggestive of histochemical type I fiber deficiency. The progressive nature of morphological changes in one of our patients cannot be explained by maturational arrest. Repeat biopsies in cases of CFTD with rapid clinical deterioration may very well show CNM.

  14. Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice.

    Science.gov (United States)

    Pandey, Sachchida N; Cabotage, Jennifer; Shi, Rongye; Dixit, Manjusha; Sutherland, Margret; Liu, Jian; Muger, Stephanie; Harper, Scott Q; Nagaraju, Kanneboyina; Chen, Yi-Wen

    2012-07-01

    Paired-like homeodomain transcription factor 1 (PITX1) was specifically up-regulated in patients with facioscapulohumeral muscular dystrophy (FSHD) by comparing the genome-wide mRNA expression profiles of 12 neuromuscular disorders. In addition, it is the only known direct transcriptional target of the double homeobox protein 4 (DUX4) of which aberrant expression has been shown to be the cause of FSHD. To test the hypothesis that up-regulation of PITX1 contributes to the skeletal muscle atrophy seen in patients with FSHD, we generated a tet-repressible muscle-specific Pitx1 transgenic mouse model in which expression of PITX1 in skeletal muscle can be controlled by oral administration of doxycycline. After PITX1 was over-expressed in the skeletal muscle for 5 weeks, the mice exhibited significant loss of body weight and muscle mass, decreased muscle strength, and reduction of muscle fiber diameters. Among the muscles examined, the tibialis anterior, gastrocnemius, quadricep, bicep, tricep and deltoid showed significant reduction of muscle mass, while the soleus, masseter and diaphragm muscles were not affected. The most prominent pathological change was the development of atrophic muscle fibers with mild necrosis and inflammatory infiltration. The affected myofibers stained heavily with NADH-TR with the strongest staining in angular-shaped atrophic fibers. Some of the atrophic fibers were also positive for embryonic myosin heavy chain using immunohistochemistry. Immunoblotting showed that the p53 was up-regulated in the muscles over-expressing PITX1. The results suggest that the up-regulation of PITX1 followed by activation of p53-dependent pathways may play a major role in the muscle atrophy developed in the mouse model.

  15. Conditional over-expression of PITX1 causes skeletal muscle dystrophy in mice

    Directory of Open Access Journals (Sweden)

    Sachchida N. Pandey

    2012-05-01

    Paired-like homeodomain transcription factor 1 (PITX1 was specifically up-regulated in patients with facioscapulohumeral muscular dystrophy (FSHD by comparing the genome-wide mRNA expression profiles of 12 neuromuscular disorders. In addition, it is the only known direct transcriptional target of the double homeobox protein 4 (DUX4 of which aberrant expression has been shown to be the cause of FSHD. To test the hypothesis that up-regulation of PITX1 contributes to the skeletal muscle atrophy seen in patients with FSHD, we generated a tet-repressible muscle-specific Pitx1 transgenic mouse model in which expression of PITX1 in skeletal muscle can be controlled by oral administration of doxycycline. After PITX1 was over-expressed in the skeletal muscle for 5 weeks, the mice exhibited significant loss of body weight and muscle mass, decreased muscle strength, and reduction of muscle fiber diameters. Among the muscles examined, the tibialis anterior, gastrocnemius, quadricep, bicep, tricep and deltoid showed significant reduction of muscle mass, while the soleus, masseter and diaphragm muscles were not affected. The most prominent pathological change was the development of atrophic muscle fibers with mild necrosis and inflammatory infiltration. The affected myofibers stained heavily with NADH-TR with the strongest staining in angular-shaped atrophic fibers. Some of the atrophic fibers were also positive for embryonic myosin heavy chain using immunohistochemistry. Immunoblotting showed that the p53 was up-regulated in the muscles over-expressing PITX1. The results suggest that the up-regulation of PITX1 followed by activation of p53-dependent pathways may play a major role in the muscle atrophy developed in the mouse model.

  16. Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy

    Directory of Open Access Journals (Sweden)

    Hong-Hao Yu

    2016-10-01

    Full Text Available Dystrophinopathy, including Duchenne muscle dystrophy (DMD and Becker muscle dystrophy (BMD is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD. Two piglets were obtained after embryo transfer, one of piglets was identified as DMD-modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD-modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD-modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig.

  17. Porcine Zygote Injection with Cas9/sgRNA Results in DMD-Modified Pig with Muscle Dystrophy.

    Science.gov (United States)

    Yu, Hong-Hao; Zhao, Heng; Qing, Yu-Bo; Pan, Wei-Rong; Jia, Bao-Yu; Zhao, Hong-Ye; Huang, Xing-Xu; Wei, Hong-Jiang

    2016-10-09

    Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease. Here, we successfully achieved precise DMD targeting in Chinese Diannan miniature pigs by co-injecting zygotes with Cas9 mRNA and sgRNA targeting DMD . Two piglets were obtained after embryo transfer, one of piglets was identified as DMD -modified individual via traditional cloning, sequencing and T7EN1 cleavage assay. An examination of targeting rates in the DMD -modified piglet revealed that sgRNA:Cas9-mediated on-target mosaic mutations were 70% and 60% of dystrophin alleles in skeletal and smooth muscle, respectively. Meanwhile, no detectable off-target mutations were found, highlighting the high specificity of genetic modification using CRISPR/Cas9. The DMD -modified piglet exhibited degenerative and disordered phenotypes in skeletal and cardiac muscle, and declining thickness of smooth muscle in the stomach and intestine. In conclusion, we successfully generated myopathy animal model by modifying the DMD via CRISPR/Cas9 system in a miniature pig.

  18. Circulating Muscle-specific miRNAs in Duchenne Muscular Dystrophy Patients

    Directory of Open Access Journals (Sweden)

    Xihua Li

    2014-01-01

    Full Text Available 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 6 years. Fibroblast growth factor, transforming growth factor-β, and tumor necrosis factor-α 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.

  19. Muscular dystrophy

    Science.gov (United States)

    ... during pregnancy. Alternative Names Inherited myopathy; MD Images Superficial anterior muscles References Sarnat HB. Muscular dystrophies. In: ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  20. Increased autophagy and apoptosis contribute to muscle atrophy in a myotonic dystrophy type 1 Drosophila model

    Directory of Open Access Journals (Sweden)

    Ariadna Bargiela

    2015-07-01

    Full Text Available Muscle mass wasting is one of the most debilitating symptoms of myotonic dystrophy type 1 (DM1 disease, ultimately leading to immobility, respiratory defects, dysarthria, dysphagia and death in advanced stages of the disease. In order to study the molecular mechanisms leading to the degenerative loss of adult muscle tissue in DM1, we generated an inducible Drosophila model of expanded CTG trinucleotide repeat toxicity that resembles an adult-onset form of the disease. Heat-shock induced expression of 480 CUG repeats in adult flies resulted in a reduction in the area of the indirect flight muscles. In these model flies, reduction of muscle area was concomitant with increased apoptosis and autophagy. Inhibition of apoptosis or autophagy mediated by the overexpression of DIAP1, mTOR (also known as Tor or muscleblind, or by RNA interference (RNAi-mediated silencing of autophagy regulatory genes, achieved a rescue of the muscle-loss phenotype. In fact, mTOR overexpression rescued muscle size to a size comparable to that in control flies. These results were validated in skeletal muscle biopsies from DM1 patients in which we found downregulated autophagy and apoptosis repressor genes, and also in DM1 myoblasts where we found increased autophagy. These findings provide new insights into the signaling pathways involved in DM1 disease pathogenesis.

  1. Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Marden, Franklin A.; Siegel, Marilyn J.; Rubin, David A. [Mallinckrodt Institute of Radiology at Washington University Medical Center, St. Louis (United States); Barnes-Jewish Hospital, Department of Radiology, St. Louis (United States); Connolly, Anne M. [St. Louis Children' s Hospital, Department of Pediatrics, St. Louis (United States); Barnes-Jewish Hospital, Washington University School of Medicine, Department of Neurology, 660 S. Euclid, Box 8111, St. Louis (United States)

    2005-03-01

    Boys with Duchenne muscular dystrophy (DMD) present by age 5 years with weakness and, untreated, stop walking unaided by age 10 or 11 years. We used magnetic resonance (MR) imaging to study age-related changes in the composition and distribution of diseased muscles. Eleven boys (mean 7.1{+-}1.6 years) with DMD underwent clinical and MR examinations. Quantitative muscle strength and timed functional testing was performed. Thigh muscles were scanned at three levels (hip, mid-thigh, and knee) using T1-weighted spin echo and short-tau inversion recovery (STIR) sequences. Outcome measures included intramuscular fatty infiltration, intermuscle fat deposition, edema, and muscle size. Ten boys completed the study. Older boys demonstrated more prominent fatty infiltration of muscles. Fatty infiltration occurred in a characteristic pattern with the gluteus and adductor magnus muscles most commonly involved and the gracilis most commonly spared. Similarly, patchy increases in free water content suggested a pattern of intramuscular edema or inflammation. Atrophy occurred in muscles heavily infiltrated with fat, and true hypertrophy selectively occurred in those that were spared. While fibrofatty changes have been described in DMD, this study further defines differential involvement and additionally suggests widespread edema or inflammation. Improved imaging techniques to quantify the degree and distribution of these changes may provide a basis for exploring mechanisms of action of medications and perhaps another means for selecting treatment regimens and monitoring their effects. (orig.)

  2. Compositional analysis of muscle in boys with Duchenne muscular dystrophy using MR imaging

    International Nuclear Information System (INIS)

    Marden, Franklin A.; Siegel, Marilyn J.; Rubin, David A.; Connolly, Anne M.

    2005-01-01

    Boys with Duchenne muscular dystrophy (DMD) present by age 5 years with weakness and, untreated, stop walking unaided by age 10 or 11 years. We used magnetic resonance (MR) imaging to study age-related changes in the composition and distribution of diseased muscles. Eleven boys (mean 7.1±1.6 years) with DMD underwent clinical and MR examinations. Quantitative muscle strength and timed functional testing was performed. Thigh muscles were scanned at three levels (hip, mid-thigh, and knee) using T1-weighted spin echo and short-tau inversion recovery (STIR) sequences. Outcome measures included intramuscular fatty infiltration, intermuscle fat deposition, edema, and muscle size. Ten boys completed the study. Older boys demonstrated more prominent fatty infiltration of muscles. Fatty infiltration occurred in a characteristic pattern with the gluteus and adductor magnus muscles most commonly involved and the gracilis most commonly spared. Similarly, patchy increases in free water content suggested a pattern of intramuscular edema or inflammation. Atrophy occurred in muscles heavily infiltrated with fat, and true hypertrophy selectively occurred in those that were spared. While fibrofatty changes have been described in DMD, this study further defines differential involvement and additionally suggests widespread edema or inflammation. Improved imaging techniques to quantify the degree and distribution of these changes may provide a basis for exploring mechanisms of action of medications and perhaps another means for selecting treatment regimens and monitoring their effects. (orig.)

  3. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors.

    Science.gov (United States)

    Miyatake, Shouta; Shimizu-Motohashi, Yuko; Takeda, Shin'ichi; Aoki, Yoshitsugu

    2016-01-01

    Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD.

  4. CT evaluation of the damaged upper limb muscle in patients with Duchenne type progressive muscular dystrophy (DMD)

    International Nuclear Information System (INIS)

    Saito, Hiroshi; Matsuke, Yutaka.

    1992-01-01

    In order to evaluate the changes of CT numbers and cross sectional areas of the muscles, we determined CT scores of the muscle. In twelve patients with Duchenne type progressive muscular dystrophy (DMD), we assessed the difference of CT scores of the muscle and the correlation between CT score of the muscle and 9-stage classification of upper extremities. CT scores of the subscapularis muscle and infraspinatus muscle were significantly lower than deltoideus muscle at the level of the shoulder, and flexor muscles showed also significantly lower than extensor muscles at the level of the upper extremity. Good correlations between CT score of the muscle and 9-stage classification of upper extremities were observed in the muscles of shoulder and upper arm. (author)

  5. Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    V. Marrocco

    2017-02-01

    Research in context: Duchenne muscular dystrophy (DMD is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a “cure” for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ, an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20. We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

  6. Muscular Dystrophy

    Science.gov (United States)

    ... protein helps muscle cells keep their shape and strength. Without it, muscles break down and a person ... EDMD). The heart muscle may also be affected. Limb-girdle muscular dystrophy ... causes weakness in the lower legs. People with this type of MD might ...

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

    Science.gov (United States)

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

    2017-01-01

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

  8. Eye and brain abnormalities in congenital muscular dystrophies caused by fukutin-related protein gene (FKRP) mutations.

    Science.gov (United States)

    Kava, Maina; Chitayat, David; Blaser, Susan; Ray, Peter N; Vajsar, Jiri

    2013-11-01

    Mutations in the fukutin-related protein gene account for a broad spectrum of phenotypes ranging from severe congenital muscular dystrophies to a much milder limb-girdle muscular dystrophy 2I. The involvement of the eyes is variable, with most patients having normal eye examination. We describe eye and brain abnormalities in a 16 month-old-boy with Walker-Warburg syndrome phenotype resulting from a novel fukutin-related protein gene mutation in exon 4 and compare these with other reported patients with fukutin-related protein gene mutation. All patients with reported fukutin-related protein gene mutations who had eye involvement were included. Their clinical features, brain magnetic resonance imaging, and eye findings were compared with our patient. Patients with fukutin-related protein gene mutation tend to have no or mild eye involvement (generally strabismus), with very few cases reported of moderate to severe eye involvement. Our patient with a novel mutation c.558dupC(p.Ala187fs) represents one of the most severe phenotypes described in regard to eye involvement. Copyright © 2013 Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2011-07-01

    Three-dimensional optical coherence tomography (3D-OCT) was used to image the structure and pathology of skeletal muscle tissue from the treadmill-exercised mdx mouse model of human Duchenne muscular dystrophy. Optical coherence tomography (OCT) images of excised muscle samples were compared with co-registered hematoxylin and eosin-stained and Evans blue dye fluorescence histology. We show, for the first time, structural 3D-OCT images of skeletal muscle dystropathology well correlated with co-located histology. OCT could identify morphological features of interest and necrotic lesions within the muscle tissue samples based on intrinsic optical contrast. These findings demonstrate the utility of 3D-OCT for the evaluation of small-animal skeletal muscle morphology and pathology, particularly for studies of mouse models of muscular dystrophy.

  10. Quantitative muscle ultrasound in Duchenne muscular dystrophy: a comparison of techniques.

    Science.gov (United States)

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

    2015-02-01

    Muscle pathology in Duchenne muscular dystrophy (DMD) can be quantified using ultrasound by measuring either the amplitudes of sound-waves scattered back from the tissue [quantitative backscatter analysis (QBA)] or by measuring these backscattered amplitudes after compression into grayscale levels (GSL) obtained from the images. We measured and compared QBA and GSL from 6 muscles of 25 boys with DMD and 25 healthy subjects, aged 2-14 years, with age and, in DMD, with function (North Star Ambulatory Assessment). Both QBA and GSL were measured reliably (intraclass correlation ≥ 0.87) and were higher in DMD than controls (P < 0.0001). In DMD, average QBA and GSL measured from superficial regions of muscle increased (rho ≥ 0.47, P < 0.05) with both higher age and worse function; in contrast, GSL measured from whole regions of muscle did not. QBA and GSL measured from superficial regions of muscle can similarly quantify muscle pathology in DMD. © 2014 Wiley Periodicals, Inc.

  11. Becker muscular dystrophy

    Science.gov (United States)

    ... Names Benign pseudohypertrophic muscular dystrophy; Becker's dystrophy Images Superficial anterior muscles References Amato AA. Disorders of the ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  12. Duchenne muscular dystrophy

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000705.htm Duchenne muscular dystrophy To use the sharing features on this page, please enable JavaScript. Duchenne muscular dystrophy is an inherited disorder. It involves muscle weakness , ...

  13. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Michelle Wehling-Henricks

    2010-05-01

    Full Text Available Duchenne muscular dystrophy (DMD is the most common, lethal disease of childhood. One of 3500 new-born males suffers from this universally-lethal disease. Other than the use of corticosteroids, little is available to affect the relentless progress of the disease, leading many families to use dietary supplements in hopes of reducing the progression or severity of muscle wasting. Arginine is commonly used as a dietary supplement and its use has been reported to have beneficial effects following short-term administration to mdx mice, a genetic model of DMD. However, the long-term effects of arginine supplementation are unknown. This lack of knowledge about the long-term effects of increased arginine metabolism is important because elevated arginine metabolism can increase tissue fibrosis, and increased fibrosis of skeletal muscles and the heart is an important and potentially life-threatening feature of DMD.We use both genetic and nutritional manipulations to test whether changes in arginase metabolism promote fibrosis and increase pathology in mdx mice. Our findings show that fibrotic lesions in mdx muscle are enriched with arginase-2-expressing macrophages and that muscle macrophages stimulated with cytokines that activate the M2 phenotype show elevated arginase activity and expression. We generated a line of arginase-2-null mutant mdx mice and found that the mutation reduced fibrosis in muscles of 18-month-old mdx mice, and reduced kyphosis that is attributable to muscle fibrosis. We also observed that dietary supplementation with arginine for 17-months increased mdx muscle fibrosis. In contrast, arginine-2 mutation did not reduce cardiac fibrosis or affect cardiac function assessed by echocardiography, although 17-months of dietary supplementation with arginine increased cardiac fibrosis. Long-term arginine treatments did not decrease matrix metalloproteinase-2 or -9 or increase the expression of utrophin, which have been reported as beneficial

  14. Protein synthesis in muscle cultures from patients with duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Ionasescu, V.; Zellweger, H.; Ionasescu, R.; Lara-Braud, C.; Cancilla, P.A.

    1976-01-01

    Muscle samples for cultures were obtained from the quadriceps by open biopsy under local anesthesia in five patients with early stage of Duchenne muscular dystrophy (DMD) and 10 controls. Primary cultures were grown in Eagle's Minimum Essential Medium (MEM) with 20 per cent fetal calf serum. After 4 weeks, cells were trypsinized, counted, subcultured for 5 days in MEM with 5 per cent horse serum and finally incubated for 4 h with ( 3 H) leucine. Total protein synthesis showed a significant decrease (ALF OF CONTROL VALUES) only in muscle cultures from patients with DMD. Addition of calcium chloride alone or with A23187 ionophore normalized this defect in protein synthesis. By contrast, myosin heavy chain synthesis was measured and found normal in all patients. (author)

  15. Distrofia muscular congênita e deficiência de merosina Congenital muscular dystrophy and merosin deficiency

    Directory of Open Access Journals (Sweden)

    Lineu Cesar Werneck

    1997-01-01

    Full Text Available Uma proporção variável de pacientes com distrofia muscular congênita (DMC da forma clássica ou ocidental apresenta deficiência da cadeia α2 da merosina, uma proteína da matriz extracelular. Foi realizado estudo das características clínicas, laboratoriais e histopatológicas de 18 pacientes com DMC, relacionadas com o padrão de merosina encontrado na biópsia muscular. Estudo imuno-histoquímico demonstrou que 11 pacientes eram merosina-deficiente (MD e sete pacientes eram merosina-positiva (MP. Nenhum dos nove pacientes MD com idade suficiente para serem avaliados alcançaram a capacidade de deambulação, enquanto quatro dos sete pacientes MP atingiram deambulação sem auxílio. Os níveis de creatinoquinase estavam mais aumentados nos pacientes MD, mas a diferença entre os dois grupos não foi estatisticamente significativa. Estudo da condução nervosa motora foi realizado em 12 pacientes. Todos os quatro pacientes MP apresentaram exames normais, enquanto dois de oito pacientes MD apresentaram diminuição da velocidade de condução nervosa motora. Entre 69 parâmetros de biópsia muscular avaliados, não foi encontrada diferença estatisticamente significativa entre os grupos MP e MD. Esses resultados sugerem que a diferenciação entre os casos MP e MD serve para fins de prognóstico, pois os pacientes MP chegam a deambular. Além disso, este estudo indica que não existe relação entre a ausência de merosina e as alterações histológicas encontradas na biópsia muscular.Merosin α2 chain, an extracellular matrix protein, is deficient in a proportion of patients with classical congenital muscular dystrophy (CMD. A study of clinical, laboratory and histopathological features of 18 patients with CMD was performed in relation to the merosin expression in muscle biopsy. Immunohistochemistry study showed that merosin was deficient in 11 patients and present in 7. None of the 9 merosin-deficient patient: evaluated achieved

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

    Science.gov (United States)

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

    2014-01-01

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

  17. Determination of muscle fatigue index for strength training in patients with Duchenne dystrophy

    Directory of Open Access Journals (Sweden)

    Adriano Rodrigues Oliveira

    Full Text Available INTRODUCTION: Muscle weakness is the most prominent impairment in Duchenne muscular dystrophy (DMD and often involves the loss of functional ability as well as other limitations related to daily living. Thus, there is a need to maintain muscle strength in large muscle groups, such as the femoral quadriceps, which is responsible for diverse functional abilities. However, the load and duration of training for such rehabilitation has proven to be a great unknown, mainly due to the undesired appearance of muscle fatigue, which is a severe factor for the injury of muscle fibers. OBJECTIVES: The aim of the present study was to determine a fatigue index by means of surface electromyography (EMG for the parameterization of muscle strengthening physiotherapy training. METHODS: A cross-sectional study (case series was carried out involving four patients with DMD. Three pairs of surface electrodes were placed on the motor point of the Rectus femoris, Vastus lateralis and Vastus medialis of the dominant limb, maintaining the knee at 60º of flexion. The participants were instructed to perform the extension movement of this joint at four strength levels (100%, 80%, 60% and 40% of maximal voluntary isometric contraction. RESULTS: The slope of the linear regression line was used for the determination of the fatigue index, performed by Pearson's test on the median frequency of each strength level. CONCLUSION: Electromyographic measurements of the strength index for muscle training proved to be a simple accessible assessment method, as well as an extremely valuable tool, allowing the design of a muscle strength training program with an individualized load threshold.

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

    Science.gov (United States)

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

    2015-11-01

    Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in-vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and λ3 (p<0.05) in the TA muscle of DMD patients. In-vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and λ3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between-group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd.

  19. Muscle magnetic resonance imaging in congenital myasthenic syndromes

    Science.gov (United States)

    Morrow, Jasper M.; Rodriguez Cruz, Pedro M.; Sinclair, Christopher D.J.; Fischmann, Arne; Thornton, John S.; Knight, Steve; Norbury, Ray; White, Mel; Al‐hajjar, Michal; Carboni, Nicola; Jayawant, Sandeep; Robb, Stephanie A.; Yousry, Tarek A.; Beeson, David; Palace, Jacqueline

    2016-01-01

    ABSTRACT Introduction In this study we investigated muscle magnetic resonance imaging in congenital myasthenic syndromes (CMS). Methods Twenty‐six patients with 9 CMS subtypes and 10 controls were imaged. T1‐weighted (T1w) and short‐tau inversion recovery (STIR) 3‐Tesla MRI images obtained at thigh and calf levels were scored for severity. Results Overall mean the T1w score was increased in GFPT1 and DPAGT1 CMS. T1w scans of the AChR‐deficiency, COLQ, and CHAT subjects were indistinguishable from controls. STIR images from CMS patients did not differ significantly from those of controls. Mean T1w score correlated with age in the CMS cohort. Conclusions MRI appearances ranged from normal to marked abnormality. T1w images seem to be especially abnormal in some CMS caused by mutations of proteins involved in the glycosylation pathway. A non‐selective pattern of fat infiltration or a normal‐appearing scan in the setting of significant clinical weakness should suggest CMS as a potential diagnosis. Muscle MRI could play a role in differentiating CMS subtypes. Muscle Nerve 54: 211–219, 2016 PMID:26789134

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

    Science.gov (United States)

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

    2014-04-01

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

  1. A case of congenital progressive muscular dystrophy (Fukuyama type) showing improvement of CT scan findings in a low density area of the white matter

    International Nuclear Information System (INIS)

    Ishikawa, Akashi; Murayama, Takashi; Sakuma, Nobuko; Saito, Yoko; Shinoda, Minoru.

    1982-01-01

    The follow-up CT scans of congenital progressive muscular dystrophy (Fukuyama type) were reported. The extensive low-density area around the lateral ventricle and observed at 6 months after birth improved to some extent at the age of 2 years and disappeared almost completely at the age of 3 years and 8 months. When CT improved, high values of serum CPK and aldolase and abnormal EEG at sleep (prominent spindle waves) were still present. This improvement of CT scans resembled that of congenital rubella syndrome, suggesting the possible involvement of intrauterine infection of some virus in onset of this disease. (Chiba, N.)

  2. Case of congenital progressive muscular dystrophy (Fukuyama type) showing improvement of CT scan findings in a low density area of the white matter

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, A.; Murayama, T.; Sakuma, N.; Saito, Y. (Hokkaido Univ., Sapporo (Japan)); Shinoda, M.

    1982-01-01

    The follow-up CT scans of congenital progressive muscular dystrophy (Fukuyama type) were reported. The extensive low-density area around the lateral ventricle and observed at 6 months after birth improved to some extent at the age of 2 years and disappeared almost completely at the age of 3 years and 8 months. When CT improved, high values of serum CPK and aldolase and abnormal EEG at sleep (prominent spindle waves) were still present. This improvement of CT scans resembled that of congenital rubella syndrome, suggesting the possible involvement of intrauterine infection of some virus in onset of this disease.

  3. Noninvasive assessment of respiratory muscle strength and activity in Myotonic dystrophy.

    Directory of Open Access Journals (Sweden)

    Morgana de Araújo Evangelista

    Full Text Available To evaluate sensitivity/specificity of the maximum relaxation rate (MRR of inspiratory muscles, amplitude of electromyographic activity of the sternocleidomastoid (SCM, scalene (SCA, parasternal (2ndIS and rectus abdominis (RA muscles; lung function and respiratory muscle strength in subjects with Myotonic dystrophy type 1 (DM1 compared with healthy subjects.Quasi-experimental observational study with control group. MRR of inspiratory muscles, lung function and amplitude of the electromyographic activity of SCM, SCA, 2ndIS and RA muscles during maximum inspiratory pressure (PImax, maximum expiratory pressure (PEmax and sniff nasal inspiratory pressure (SNIP tests were assessed in eighteen DM1 subjects and eleven healthy.MRR was lower in DM1 group compared to healthy (P = 0.001 and was considered sensitive and specific to identify disease in DM1 and discard it in controls, as well as SNIP% (P = 0.0026, PImax% (P = 0.0077 and PEmax% (P = 0.0002. Contraction time of SCM and SCA was higher in DM1 compared to controls, respectively, during PImax (P = 0.023 and P = 0.017 and SNIP (P = 0.015 and P = .0004. The DM1 group showed lower PImax (P = .0006, PEmax (P = 0.0002, SNIP (P = 0.0014, and higher electromyographic activity of the SCM (P = 0.002 and SCA (P = 0.004 at rest; of 2ndIS (P = 0.003 during PEmax and of SCM (P = 0.02 and SCA (P = 0.03 during SNIP test.MD1 subjects presented restrictive pattern, reduced respiratory muscle strength, muscular electrical activity and MRR when compared to higher compared to controls. In addition, the lower MRR found in MD1 subjects showed to be reliable to sensitivity and specificity in identifying the delayed relaxation of respiratory muscles.

  4. Noninvasive assessment of respiratory muscle strength and activity in Myotonic dystrophy

    Science.gov (United States)

    Evangelista, Morgana de Araújo; Dias, Fernando Augusto Lavezzo; Dourado Júnior, Mário Emílio Teixeira; do Nascimento, George Carlos; Gualdi, Lucien Peroni; Aliverti, Andrea; Resqueti, Vanessa; Fregonezi, Guilherme Augusto de Freitas

    2017-01-01

    Objective To evaluate sensitivity/specificity of the maximum relaxation rate (MRR) of inspiratory muscles, amplitude of electromyographic activity of the sternocleidomastoid (SCM), scalene (SCA), parasternal (2ndIS) and rectus abdominis (RA) muscles; lung function and respiratory muscle strength in subjects with Myotonic dystrophy type 1 (DM1) compared with healthy subjects. Design and methods Quasi-experimental observational study with control group. MRR of inspiratory muscles, lung function and amplitude of the electromyographic activity of SCM, SCA, 2ndIS and RA muscles during maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) and sniff nasal inspiratory pressure (SNIP) tests were assessed in eighteen DM1 subjects and eleven healthy. Results MRR was lower in DM1 group compared to healthy (P = 0.001) and was considered sensitive and specific to identify disease in DM1 and discard it in controls, as well as SNIP% (P = 0.0026), PImax% (P = 0.0077) and PEmax% (P = 0.0002). Contraction time of SCM and SCA was higher in DM1 compared to controls, respectively, during PImax (P = 0.023 and P = 0.017) and SNIP (P = 0.015 and P = .0004). The DM1 group showed lower PImax (P = .0006), PEmax (P = 0.0002), SNIP (P = 0.0014), and higher electromyographic activity of the SCM (P = 0.002) and SCA (P = 0.004) at rest; of 2ndIS (P = 0.003) during PEmax and of SCM (P = 0.02) and SCA (P = 0.03) during SNIP test. Conclusions MD1 subjects presented restrictive pattern, reduced respiratory muscle strength, muscular electrical activity and MRR when compared to higher compared to controls. In addition, the lower MRR found in MD1 subjects showed to be reliable to sensitivity and specificity in identifying the delayed relaxation of respiratory muscles. PMID:28594857

  5. Anti-inflammatory drugs for Duchenne muscular dystrophy: focus on skeletal muscle-releasing factors

    Directory of Open Access Journals (Sweden)

    Miyatake S

    2016-08-01

    Full Text Available Shouta Miyatake,1 Yuko Shimizu-Motohashi,2 Shin’ichi Takeda,1 Yoshitsugu Aoki1 1Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan; 2Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan Abstract: Duchenne muscular dystrophy (DMD, an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects. Recent reports show the therapeutic potential of inhibiting or enhancing pro- or anti-inflammatory factors released from DMD skeletal muscles, resulting in significant recovery from muscle atrophy and dysfunction. We discuss and review the recent findings of DMD inflammation and opportunities for drug development targeting specific releasing factors from skeletal muscles. It has been speculated that nonsteroidal anti-inflammatory drugs targeting specific inflammatory factors are more effective and have less side effects for DMD compared with steroidal drugs. For example, calcium channels, reactive oxygen species, and nuclear factor-κB signaling factors are the most promising targets as master regulators of inflammatory response in DMD skeletal muscles. If they are combined with an oligonucleotide-based exon skipping therapy to restore dystrophin expression, the anti-inflammatory drug therapies may address the present therapeutic limitation of low efficiency for DMD. Keywords: calcium channels, ryanodine receptor 1, exon skipping, NF-κB, myokine, ROS

  6. RNA processing is altered in skeletal muscle nuclei of patients affected by myotonic dystrophy.

    Science.gov (United States)

    Malatesta, Manuela; Giagnacovo, Marzia; Cardani, Rosanna; Meola, Giovanni; Pellicciari, Carlo

    2011-04-01

    Myotonic dystrophies (DMs) are characterised by highly variable clinical manifestations consisting of muscle weakness and atrophy, and a wide spectrum of extramuscular manifestations. In both DM1 and DM2 forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus, thus deregulating the function of some RNA-binding proteins and providing a plausible explanation for the multifactorial phenotype of DM patients. However, at the skeletal muscle level, no mechanistic explanation for the muscle wasting has so far been proposed. We therefore performed a study in situ by immunoelectron microscopy on biceps brachii biopsies from DM1, DM2 and healthy subjects, providing the first ultrastructural evidence on the distribution of some nuclear ribonucleoprotein (RNP)-containing structures and molecular factors involved in pre-mRNA transcription and maturation in dystrophic myonuclei. Our results demonstrated an accumulation of splicing and cleavage factors in myonuclei of both DM1 and DM2 patients, suggesting an impairment of post-transcriptional pre-mRNA pathways. The transcription of the expanded sequences in DM myonuclei would therefore hamper functionality of the whole splicing machinery, slowing down the intranuclear molecular trafficking; this would reduce the capability of myonuclei to respond to anabolic stimuli thus contributing to muscle wasting.

  7. Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration.

    Directory of Open Access Journals (Sweden)

    Barbara H Janssen

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34-76 years, of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D (31P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05, FSHD severity score (p<0.0001, inversely with muscle strength (p<0.0001, and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle's length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001. Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05 and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001, which correlated with initial edema (p<0.01, if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1996-08-01

    The precise localization and semiquantitative correlation of dystrophin, utrophin and {beta}-dystroglycan expression on the sarcolemma of skeletal muscle cells obtained from patients with Becker muscular dystrophy (BMD) was studied using three types of double immunofluorescence. Staining intensity was measured using a confocal laser microscope. Each of these proteins was identified at the same locus on the sarcolemma. The staining intensities of dystrophin and utrophin were approximately reciprocal at sarcolemmal sites where dystrophin expression was obviously observed. The staining intensity of {beta}-dystroglycan was strong in areas where dystrophin staining was also strong and utrophin expression was weak. Quantitative analysis revealed that the staining intensity of {beta}-dystroglycan minus that of dystrophin approximated the staining intensity of utrophin, indicating that the sum of dystrophin and utrophin expression corresponds to that of {beta}-dystroglycan. These results suggest that utrophin may compensate for dystrophin deficiency found in BMD by binding to {beta}-dystroglycan. 35 refs., 3 figs., 1 tab.

  9. Skeletal muscle water T2 as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy.

    Science.gov (United States)

    Mankodi, Ami; Azzabou, Noura; Bulea, Thomas; Reyngoudt, Harmen; Shimellis, Hirity; Ren, Yupeng; Kim, Eunhee; Fischbeck, Kenneth H; Carlier, Pierre G

    2017-08-01

    The purpose of this study was to examine exercise effects on muscle water T 2 in patients with Duchenne muscular dystrophy (DMD). In 12 DMD subjects and 19 controls, lower leg muscle fat (%) was measured by Dixon and muscle water T 2 and R 2 (1/T 2 ) by the tri-exponential model. Muscle water R 2 was measured again at 3 hours after an ankle dorsiflexion exercise. The muscle fat fraction was higher in DMD participants than in controls (p < .001) except in the tibialis posterior muscle. Muscle water T 2 was measured independent of the degree of fatty degeneration in DMD muscle. At baseline, muscle water T 2 was higher in all but the extensor digitorum longus muscles of DMD participants than controls (p < .001). DMD participants had a lower muscle torque (p < .001) and exerted less power (p < .01) during exercise than controls. Nevertheless, muscle water R 2 decreased (T 2 increased) after exercise from baseline in DMD subjects and controls with greater changes in the target muscles of the exercise than in ankle plantarflexor muscles. Skeletal muscle water T 2 is a sensitive biomarker of the disease status in DMD and of the exercise response in DMD patients and controls. Published by Elsevier B.V.

  10. Congenital heart disease in adolescents with gluteal muscle contracture.

    Science.gov (United States)

    You, Tian; Zhang, Xin-tao; Zha, Zhen-gang; Zhang, Wen-tao

    2015-02-01

    Gluteal muscle contracture (GMC), presented with hip abduction and external rotation when crouching, is common in several ethnicities, particularly in Chinese. It remains unclear that the reasons why these children are weak and have no choice to accept repeated intramuscular injection. Here, we found some unique cases which may be useful to explain this question. We describe a series of special GMC patients, who are accompanied with congenital heart disease (CHD). These cases were first observed in preoperative examinations of a patient with atrial septal defect (ASD), which was proved by chest X-ray and cardiac ultrasound. From then on, we gradually identified additional 3 GMC patients with CHD. The original patient with ASD was sent to cardiosurgery department to repair atrial septal first and received arthroscopic surgery later. While the other 3 were cured postoperative of ventricular septal defect (VSD), tetralogy of fallot (TOF), patent ductus arteriosus (PDA), respectively, and had surgery directly. The study gives us 3 proposals: (1) as to CHD children, it is essential to decrease the use of intramuscular injection, (2) paying more attention to cardiac examination especially cardiac ultrasound in perioperative period, and (3) taking 3D-CT to reconstruct gluteal muscles for observing contracture bands clearly in preoperation. However, more larger series of patients are called for to confirm these findings.

  11. Bilateral congenital absence of the abductor pollicis brevis muscle: a case report.

    Science.gov (United States)

    Aydin, Ali; Topal, Murat; Tuncer, Kutsi; Kilic, Mesut

    2013-01-01

    Congenital absence of the abductor pollicis brevis is a very rare condition and is usually associated with other congenital anomalies. Here we report a case of bilateral congenital absence of the abductor pollicis brevis without any other abnormalities, which has not been previously reported. A 24-year-old Caucasian male patient presented to our clinic with flattening in the palmar region, pain and discomfort in writing, and weakness in both hands. USG and MRI revealed bilateral absence of the abductor pollicis brevis muscle. Bilateral congenital absence of the abductor pollicis brevis muscle requires no treatment due to satisfactory hand function, and results in cosmetic problems. Congenital absence of the abductor pollicis brevis muscle should be kept in mind in patients with flattening of the thenar eminences.

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

    Directory of Open Access Journals (Sweden)

    Luca Madaro

    2014-01-01

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

  13. Model Organisms in the Fight against Muscular Dystrophy: Lessons from Drosophila and Zebrafish

    Directory of Open Access Journals (Sweden)

    Emilie Plantié

    2015-04-01

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

  14. Chronic hypoxia impairs muscle function in the Drosophila model of Duchenne's muscular dystrophy (DMD.

    Directory of Open Access Journals (Sweden)

    Matias Mosqueira

    Full Text Available Duchenne's muscular dystrophy (DMD is a severe progressive myopathy caused by mutations in the DMD gene leading to a deficiency of the dystrophin protein. Due to ongoing muscle necrosis in respiratory muscles late-stage DMD is associated with respiratory insufficiency and chronic hypoxia (CH. To understand the effects of CH on dystrophin-deficient muscle in vivo, we exposed the Drosophila model for DMD (dmDys to CH during a 16-day ascent to the summit of Mount Denali/McKinley (6194 meters above sea level. Additionally, dmDys and wild type (WT flies were also exposed to CH in laboratory simulations of high altitude hypoxia. Expression profiling was performed using Affymetrix GeneChips® and validated using qPCR. Hypoxic dmDys differentially expressed 1281 genes, whereas the hypoxic WT flies differentially expressed 56 genes. Interestingly, a number of genes (e.g. heat shock proteins were discordantly regulated in response to CH between dmDys and WT. We tested the possibility that the disparate molecular responses of dystrophin-deficient tissues to CH could adversely affect muscle by performing functional assays in vivo. Normoxic and CH WT and dmDys flies were challenged with acute hypoxia and time-to-recover determined as well as subjected to climbing tests. Impaired performance was noted for CH-dmDys compared to normoxic dmDys or WT flies (rank order: Normoxic-WT ≈ CH-WT> Normoxic-dmDys> CH-dmDys. These data suggest that dystrophin-deficiency is associated with a disparate, pathological hypoxic stress response(s and is more sensitive to hypoxia induced muscle dysfunction in vivo. We hypothesize that targeting/correcting the disparate molecular response(s to hypoxia may offer a novel therapeutic strategy in DMD.

  15. Efficacy of muscle exercise in patients with muscular dystrophy: a systematic review showing a missed opportunity to improve outcomes.

    Directory of Open Access Journals (Sweden)

    Silvia Gianola

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

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

    Directory of Open Access Journals (Sweden)

    Tanyse Bahia Carvalho Marques

    2014-10-01

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

  17. Short somatosensory evoked potentials in patients with Fukuyama type congenital muscular dystrophy. A comparison with CT and MRI findings

    Energy Technology Data Exchange (ETDEWEB)

    Namba, Yukiko; Maegaki, Yoshihiro; Maeoka, Yukinori; Yoshimura, Masaki; Takeshita, Kenzo [Tottori Univ., Yonago (Japan). School of Medicine; Houdou, Sadataka; Ishii, Shougo; Ohtani, Kyoichi

    1995-09-01

    Seven patients with Fukuyama type congenital muscular dystrophy were studied. Low density areas (LDs) in the cerebral white matter on cranial CT were present in all 4 patients younger than 13 years of age and in 1 of 3 adult patients. LDs corresponded to low signals on T{sub 1} weighted MRI image and high signals on T{sub 2} weighted MRI image. The follow-up MRI showed a decreased tendency of the abnormal signals in 2 patients. Short somatosensory evoked potentials (SSEPs) in two infants, aged 4 months and 8 months, showed absent or depressed N1 amplitudes and delayed interpeak latencies from P3 to N1. N1 amplitudes increased on follow-up studies. SSEPs of five patients, who were older than 2 years of age, showed normal N1-P3 latencies. Amplitude of N1 was low in 2 patients with LD. Since the absent or depressed amplitude and delayed latency of N1 improved with the decrease of abnormal signals on MRI, we considered that N1 abnormalities show delayed myelination. (author).

  18. Muscleblind, BSF and TBPH are mislocalized in the muscle sarcomere of a Drosophila myotonic dystrophy model

    Directory of Open Access Journals (Sweden)

    Beatriz Llamusi

    2013-01-01

    Myotonic dystrophy type 1 (DM1 is a genetic disease caused by the pathological expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. In the DMPK transcripts, the CUG expansions sequester RNA-binding proteins into nuclear foci, including transcription factors and alternative splicing regulators such as MBNL1. MBNL1 sequestration has been associated with key features of DM1. However, the basis behind a number of molecular and histological alterations in DM1 remain unclear. To help identify new pathogenic components of the disease, we carried out a genetic screen using a Drosophila model of DM1 that expresses 480 interrupted CTG repeats, i(CTG480, and a collection of 1215 transgenic RNA interference (RNAi fly lines. Of the 34 modifiers identified, two RNA-binding proteins, TBPH (homolog of human TAR DNA-binding protein 43 or TDP-43 and BSF (Bicoid stability factor; homolog of human LRPPRC, were of particular interest. These factors modified i(CTG480 phenotypes in the fly eye and wing, and TBPH silencing also suppressed CTG-induced defects in the flight muscles. In Drosophila flight muscle, TBPH, BSF and the fly ortholog of MBNL1, Muscleblind (Mbl, were detected in sarcomeric bands. Expression of i(CTG480 resulted in changes in the sarcomeric patterns of these proteins, which could be restored by coexpression with human MBNL1. Epistasis studies showed that Mbl silencing was sufficient to induce a subcellular redistribution of TBPH and BSF proteins in the muscle, which mimicked the effect of i(CTG480 expression. These results provide the first description of TBPH and BSF as targets of Mbl-mediated CTG toxicity, and they suggest an important role of these proteins in DM1 muscle pathology.

  19. Lower leg muscle involvement in Duchenne muscular dystrophy: an MR imaging and spectroscopy study

    Energy Technology Data Exchange (ETDEWEB)

    Torriani, Martin [Massachusetts General Hospital and Harvard Medical School, Division of Musculoskeletal Imaging and Intervention, Boston, MA (United States); Massachusetts General Hospital, Musculoskeletal Imaging and Intervention, Department of Radiology, Boston, MA (United States); Townsend, Elise [MGH Institute of Health Professions and Massachusetts General Hospital, Boston, MA (United States); Thomas, Bijoy J.; Bredella, Miriam A.; Ghomi, Reza H. [Massachusetts General Hospital and Harvard Medical School, Division of Musculoskeletal Imaging and Intervention, Boston, MA (United States); Tseng, Brian S. [Massachusetts General Hospital and Harvard Medical School, Pediatric Neuromuscular Clinic, Boston, MA (United States); Novartis Institute of Biomedical Research, Cambridge, MA (United States)

    2012-04-15

    To describe the involvement of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) by using MR imaging (MRI) and spectroscopy (MRS) correlated to indices of functional status. Nine boys with DMD (mean age, 11 years) and eight healthy age- and BMI-matched boys (mean age, 13 years) prospectively underwent lower leg MRI, 1H-MRS of tibialis anterior (TA) and soleus (SOL) for lipid fraction measures, and 31P-MRS for pH and high-energy phosphate measures. DMD subjects were evaluated using the Vignos lower extremity functional rating, and tests including 6 min walk test (6MWT) and 10 m walk. DMD subjects had highest fatty infiltration scores in peroneal muscles, followed by medial gastrocnemius and soleus. Compared to controls, DMD boys showed higher intramuscular fat (P = 0.04), lipid fractions of TA and SOL (P = 0.02 and 0.003, respectively), pH of anterior compartment (P = 0.0003), and lower phosphocreatine/inorganic phosphorus ratio of posterior compartment (P = 0.02). The Vignos rating correlated with TA (r = 0.79, P = 0.01) and SOL (r = 0.71, P = 0.03) lipid fractions. The 6MWT correlated with fatty infiltration scores of SOL (r = -0.76, P = 0.046), medial (r = -0.80, P = 0.03) and lateral (r = -0.84, P = 0.02) gastrocnemius, intramuscular fat (r = -0.80, P = 0.03), and SOL lipid fraction (r = -0.89, P = 0.007). Time to walk 10 m correlated with anterior compartment pH (r = 0.78, P = 0.04). Lower leg muscles of boys with DMD show a distinct involvement pattern and increased adiposity that correlates with functional status. Lower leg MRI and 1H-MRS studies may help to noninvasively demonstrate the severity of muscle involvement. (orig.)

  20. Lower leg muscle involvement in Duchenne muscular dystrophy: an MR imaging and spectroscopy study

    International Nuclear Information System (INIS)

    Torriani, Martin; Townsend, Elise; Thomas, Bijoy J.; Bredella, Miriam A.; Ghomi, Reza H.; Tseng, Brian S.

    2012-01-01

    To describe the involvement of lower leg muscles in boys with Duchenne muscular dystrophy (DMD) by using MR imaging (MRI) and spectroscopy (MRS) correlated to indices of functional status. Nine boys with DMD (mean age, 11 years) and eight healthy age- and BMI-matched boys (mean age, 13 years) prospectively underwent lower leg MRI, 1H-MRS of tibialis anterior (TA) and soleus (SOL) for lipid fraction measures, and 31P-MRS for pH and high-energy phosphate measures. DMD subjects were evaluated using the Vignos lower extremity functional rating, and tests including 6 min walk test (6MWT) and 10 m walk. DMD subjects had highest fatty infiltration scores in peroneal muscles, followed by medial gastrocnemius and soleus. Compared to controls, DMD boys showed higher intramuscular fat (P = 0.04), lipid fractions of TA and SOL (P = 0.02 and 0.003, respectively), pH of anterior compartment (P = 0.0003), and lower phosphocreatine/inorganic phosphorus ratio of posterior compartment (P = 0.02). The Vignos rating correlated with TA (r = 0.79, P = 0.01) and SOL (r = 0.71, P = 0.03) lipid fractions. The 6MWT correlated with fatty infiltration scores of SOL (r = -0.76, P = 0.046), medial (r = -0.80, P = 0.03) and lateral (r = -0.84, P = 0.02) gastrocnemius, intramuscular fat (r = -0.80, P = 0.03), and SOL lipid fraction (r = -0.89, P = 0.007). Time to walk 10 m correlated with anterior compartment pH (r = 0.78, P = 0.04). Lower leg muscles of boys with DMD show a distinct involvement pattern and increased adiposity that correlates with functional status. Lower leg MRI and 1H-MRS studies may help to noninvasively demonstrate the severity of muscle involvement. (orig.)

  1. Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.

    Science.gov (United States)

    Nelson, Michael D; Rosenberry, Ryan; Barresi, Rita; Tsimerinov, Evgeny I; Rader, Florian; Tang, Xiu; Mason, O'Neil; Schwartz, Avery; Stabler, Thomas; Shidban, Sarah; Mobaligh, Neigena; Hogan, Shomari; Elashoff, Robert; Allen, Jason D; Victor, Ronald G

    2015-12-01

    Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSμ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSμ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSμ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

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

    Science.gov (United States)

    Ljubicic, Vladimir; Jasmin, Bernard J

    2013-10-01

    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. Copyright © 2013 Elsevier Ltd. All rights reserved.

  3. Overexpression of microRNA-206 in the skeletal muscle from myotonic dystrophy type 1 patients

    Directory of Open Access Journals (Sweden)

    Angelini Corrado

    2010-05-01

    Full Text Available Abstract Background MicroRNAs are highly conserved, noncoding RNAs involved in post-transcriptional gene silencing. They have been shown to participate in a wide range of biological processes, including myogenesis and muscle regeneration. The goal of this study is to test the hypothesis that myo-miRs (myo = muscle + miR = miRNA expression is altered in muscle from patients affected by myotonic dystrophy type 1 (DM1, the most frequently inherited neuromuscular disease in adults. In order to gain better insights about the role of miRNAs in the DM1 pathogenesis, we have also analyzed the muscular expression of miR-103 and miR-107, which have been identified in silico as attractive candidates for binding to the DMPK mRNA. Methods To this aim, we have profiled the expression of miR-133 (miR-133a, miR-133b, miR-1, miR-181 (miR-181a, miR-181b, miR-181c and miR-206, that are specifically induced during myogenesis in cardiac and skeletal muscle tissues. miR-103 and miR-107, highly expressed in brain, heart and muscle have also been included in this study. QRT-PCR experiments have been performed on RNA from vastus lateralis biopsies of DM1 patients (n = 7 and control subjects (n = 4. Results of miRNAs expression have been confirmed by Northern blot, whereas in situ hybridization technique have been performed to localize misexpressed miRNAs on muscle sections from DM1 and control individuals. Results Only miR-206 showed an over-expression in 5 of 7 DM1 patients (threshold = 2, fold change between 1.20 and 13.22, average = 5.37 compared to the control group. This result has been further confirmed by Northern blot analysis (3.37-fold overexpression, R2 = 0.89. In situ hybridization localized miR-206 to nuclear site both in normal and DM1 tissues. Cellular distribution in DM1 tissues includes also the nuclear regions of centralized nuclei, with a strong signal corresponding to nuclear clumps. Conclusions This work provides, for the first time, evidences about

  4. Dystrophin deficiency compromises force production of the extensor carpi ulnaris muscle in the canine model of Duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Hsiao T Yang

    Full Text Available Loss of muscle force is a salient feature of Duchenne muscular dystrophy (DMD, a fatal disease caused by dystrophin deficiency. Assessment of force production from a single intact muscle has been considered as the gold standard for studying physiological consequences in murine models of DMD. Unfortunately, equivalent assays have not been established in dystrophic dogs. To fill the gap, we developed a novel in situ protocol to measure force generated by the extensor carpi ulnaris (ECU muscle of a dog. We also determined the muscle length to fiber length ratio and the pennation angle of the ECU muscle. Muscle pathology and contractility were compared between normal and affected dogs. Absence of dystrophin resulted in marked histological damage in the ECU muscle of affected dogs. Central nucleation was significantly increased and myofiber size distribution was altered in the dystrophic ECU muscle. Muscle weight and physiological cross sectional area (PCSA showed a trend of reduction in affected dogs although the difference did not reach statistical significance. Force measurement revealed a significant decrease of absolute force, and the PCSA or muscle weight normalized specific forces. To further characterize the physiological defect in affected dog muscle, we conducted eccentric contraction. Dystrophin-null dogs showed a significantly greater force loss following eccentric contraction damage. To our knowledge, this is the first convincing demonstration of force deficit in a single intact muscle in the canine DMD model. The method described here will be of great value to study physiological outcomes following innovative gene and/or cell therapies.

  5. Optical polarization tractography revealed significant fiber disarray in skeletal muscles of a mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Wang, Y; Zhang, K; Wasala, N B; Duan, D; Yao, G

    2015-02-01

    Optical polarization tractography (OPT) was recently developed to visualize tissue fiber architecture with cellular-level resolution and accuracy. In this study, we explored the feasibility of using OPT to study muscle disease in the mdx4cv mouse model of Duchenne muscular dystrophy. The freshly dissected tibialis anterior muscles of mdx4cv and normal mice were imaged. A "fiber disarray index" (FDI) was developed to quantify the myofiber disorganization. In necrotic muscle regions of the mdx4cv mice, the FDI was significantly elevated and can be used to segment the 3D necrotic regions for assessing the overall muscle damage. These results demonstrated the OPT's capability for imaging microscopic fiber alternations in muscle research.

  6. A new model of experimental fibrosis in hindlimb skeletal muscle of adult mdx mouse mimicking muscular dystrophy.

    Science.gov (United States)

    Desguerre, Isabelle; Arnold, Ludovic; Vignaud, Alban; Cuvellier, Sylvain; Yacoub-Youssef, Houda; Gherardi, Romain K; Chelly, Jamel; Chretien, Fabrice; Mounier, Rémi; Ferry, Arnaud; Chazaud, Bénédicte

    2012-06-01

    Duchenne Muscular Dystrophy (DMD) is characterized by the lack of dystrophin that leads to severe myofiber degeneration. We have shown that endomysial fibrosis is correlated with age at ambulation loss in DMD patients. However, the dystrophin-deficient mdx mouse does not have fibrotic lesions in adult limb muscles. Here, we describe a model of chronic mechanical muscle injury that triggers chronic lesions in mdx hindlimb muscle. Micromechanical injuries were performed daily in tibialis anterior muscles for 2 weeks. Endomysial fibrosis appeared beginning 1 week post-injury, remained stable for 3 months and was associated with loss of specific maximal force. Fibrosis was associated with an increased expression of factors involved in fibrogenesis including α-smooth muscle actin, connective tissue growth factor, and lysyl oxidase, which colocalized with collagen deposits. This induced fibrotic dystrophic model may be useful to study mechanisms of fibrosis in dystrophinopathies and to evaluate antifibrotic treatments. Copyright © 2012 Wiley Periodicals, Inc.

  7. Duchenne muscular dystrophy carriers. Proton spin-lattice relaxation times of skeletal muscles on magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Matsumura, K.; Nakano, I. (Shimoshizu National Hospital, Chiba (Japan). Dept. of Neurology); Fukuda, N.; Ikehira, H.; Tateno, Y. (National Inst. of Radiological Sciences, Chiba (Japan). Div. of Clinical Research); Aoki, Y. (National Inst. of Radiological Sciences, Chiba (Japan))

    1989-11-01

    By means of magnetic resonance imaging (MRI), the proton spin-lattice relaxation times (T1 values) of the skeletal muscles were measured in Duchenne muscular dystrophy (DMD) carriers and normal controls. The bound water fraction (BWF) was calculated from the T1 values obtained, according to the fast proton diffusion model. In the DMD carriers, T1 values of the gluteus maximus and quadriceps femoris muscles were significantly higher, and BWFs of these muscles were significantly lower than in normal control. Degenerative muscular changes accompanied by interstitial edema were presumed responsible for this abnormality. No correlation was observed between the muscle T1 and serum creatine kinase values. The present study showed that MRI could be a useful method for studying the dynamic state of water in both normal and pathological skeletal muscles. Its possible utility for DMD carrier detection was discussed briefly. (orig.).

  8. Histological evaluation of levator palpebralis superior muscle in patients with congenital blepharoptosis

    Directory of Open Access Journals (Sweden)

    Sevda Söker

    2011-03-01

    Full Text Available The aim of this study was to examine levator palpebralis superior muscle histologically in patients with congenital blepharoptosis and to investigate the relationship between these findings and age, sex and degree of blefaroptosis in this patient group.Materials and methods: Levator muscle of 13 patients with congenital ptosis, who had applied to Dicle University Medical Faculty Ophthalmology Clinic and had undergone levator palpebralis superior muscle resection between january 2009-january 2010, has been examined histopathologically in Histology and Embriology Deparment. During preoperative period, ptosis amount, levator function (LF, tear functions, Bell’s phenomenon and jaw-winking phenomenon were evaluated. All patients underwent resection of levator palpebralis superior muscle. Received postoperative levator muscle was examined by light microscopy.Results: The average age of 9 (69.2% male and 4 (30.8% female cases were 10.61 ± 4.77 (4- 19 years. In histological examination, the quality and quantity of the levator muscle fibrils have been assessed. There was no relationship detected between histological features of levator palpebralis superior muscle and patient’s age and gender (p>0.05. Patients with weak levator palpebralis superior muscle were detected to have fatty degeneration histologically. The higher the levator palpebralis superior muscle function revealed decreased fatty degeneration and increased skeletal muscle fibrils.Conclusion: More ultrastructural studies in larger populations are needed to support the relationship between structure and function of levator palpebralis superior muscle in patients with congenital blepharoptosis.

  9. Distribution of skeletal muscle involvement in autosomal recessive distal muscular dystrophy. A clinical and computed tomographic study

    Energy Technology Data Exchange (ETDEWEB)

    Mizusawa, Hidehiro; Nakanishi, Takao; Kobayashi, Fumie

    1987-02-01

    Distribution of skeletal muscle involvement in 5 cases with autosomal recessive distal muscular dystrophy was studied clinically and by computed tomography (CT). Manual muscle test showed muscle involvement with a predilection for flexors in the lower leg and adductors in the thigh. Flexion and extension of the thigh and the lower leg was impaired to similar degree. In progressed cases, neck flexors and trunk muscles were also affected mildly. CT disclosed more clearly the preferential involvement of flexors in the lower leg, and involvement of both hamstrings center dot adductors group and extensors group of the thigh to similar degree. However, m. popliteus was curiously well preserved. In addition, there was a stage showing high density and hypertrophy of m. sartorius, m. gracilis, m. adductor, m. biceps femoris, m. semimenbranosus, m. semitendinosus or m. rectus femoris, which in thought to be compensatory hypertrophy. M. gluteus minimus in the pelvic girdle and m. dorsi proprii in the trunk were also liable to be affected. The CT findings are regarded as characteristic features noted clearly before muscle weakness and atrophy become apparent clinically. CT is very useful for distinguishing distal muscular dystrophy from rimmed vacuolar distal myopathy in which m. quadriceps femoris and flexors of the lower leg are usually well preserved without compensatory hypertrophy on CT.

  10. Abnormal lipid metabolism in skeletal muscle tissue of patients with muscular dystrophy: In vitro, high-resolution NMR spectroscopy based observation in early phase of the disease.

    Science.gov (United States)

    Srivastava, Niraj Kumar; Yadav, Ramakant; Mukherjee, Somnath; Pal, Lily; Sinha, Neeraj

    2017-05-01

    Qualitative (assignment of lipid components) and quantitative (quantification of lipid components) analysis of lipid components were performed in skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease as compared to control/normal subjects. Proton nuclear magnetic resonance (NMR) spectroscopy based experiment was performed on the lipid extract of skeletal muscle tissue of patients with muscular dystrophy in early phase of the disease and normal individuals for the analysis of lipid components [triglycerides, phospholipids, total cholesterol and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Specimens of muscle tissue were obtained from patients with Duchenne muscular dystrophy (DMD) [n=11; Age, Mean±SD; 9.2±1.4years; all were males], Becker muscular dystrophy (BMD) [n=12; Age, Mean±SD; 21.4±5.0years; all were males], facioscapulohumeral muscular dystrophy (FSHD) [n=11; Age, Mean±SD; 23.7±7.5years; all were males] and limb girdle muscular dystrophy-2B (LGMD-2B) [n=18; Age, Mean±SD; 24.2±4.1years; all were males]. Muscle specimens were also obtained from [n=30; Mean age±SD 23.1±6.0years; all were males] normal/control subjects. Assigned lipid components in skeletal muscle tissue were triglycerides (TG), phospholipids (PL), total cholesterol (CHOL) and unsaturated fatty acids (arachidonic, linolenic and linoleic acid)]. Quantity of lipid components was observed in skeletal muscle tissue of DMD, BMD, FSHD and LGMD-2B patients as compared to control/normal subjects. TG was significantly elevated in muscle tissue of DMD, BMD and LGMD-2B patients. Increase level of CHOL was found only in muscle of DMD patients. Level of PL was found insignificant for DMD, BMD and LGMD-2B patients. Quantity of TG, PL and CHOL was unaltered in the muscle of patients with FSHD as compared to control/normal subjects. Linoleic acids were significantly reduced in muscle tissue of DMD, BMD, FSHD and LGMD-2B as compared to normal

  11. Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1.

    Science.gov (United States)

    Tarnopolsky, Mark; Mahoney, Douglas; Thompson, Terry; Naylor, Heather; Doherty, Timothy J

    2004-01-01

    Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double-blind, cross-over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, approximately 0.074 g/kg daily) and a placebo for each 4-month phase with a 6-week wash-out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat-free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/beta-adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/beta-ATP content.

  12. Mitochondrial alterations and oxidative stress in an acute transient mouse model of muscle degeneration: implications for muscular dystrophy and related muscle pathologies.

    Science.gov (United States)

    Ramadasan-Nair, Renjini; Gayathri, Narayanappa; Mishra, Sudha; Sunitha, Balaraju; Mythri, Rajeswara Babu; Nalini, Atchayaram; Subbannayya, Yashwanth; Harsha, Hindalahalli Chandregowda; Kolthur-Seetharam, Ullas; Srinivas Bharath, Muchukunte Mukunda

    2014-01-03

    Muscular dystrophies (MDs) and inflammatory myopathies (IMs) are debilitating skeletal muscle disorders characterized by common pathological events including myodegeneration and inflammation. However, an experimental model representing both muscle pathologies and displaying most of the distinctive markers has not been characterized. We investigated the cardiotoxin (CTX)-mediated transient acute mouse model of muscle degeneration and compared the cardinal features with human MDs and IMs. The CTX model displayed degeneration, apoptosis, inflammation, loss of sarcolemmal complexes, sarcolemmal disruption, and ultrastructural changes characteristic of human MDs and IMs. Cell death caused by CTX involved calcium influx and mitochondrial damage both in murine C2C12 muscle cells and in mice. Mitochondrial proteomic analysis at the initial phase of degeneration in the model detected lowered expression of 80 mitochondrial proteins including subunits of respiratory complexes, ATP machinery, fatty acid metabolism, and Krebs cycle, which further decreased in expression during the peak degenerative phase. The mass spectrometry (MS) data were supported by enzyme assays, Western blot, and histochemistry. The CTX model also displayed markers of oxidative stress and a lowered glutathione reduced/oxidized ratio (GSH/GSSG) similar to MDs, human myopathies, and neurogenic atrophies. MS analysis identified 6 unique oxidized proteins from Duchenne muscular dystrophy samples (n = 6) (versus controls; n = 6), including two mitochondrial proteins. Interestingly, these mitochondrial proteins were down-regulated in the CTX model thereby linking oxidative stress and mitochondrial dysfunction. We conclude that mitochondrial alterations and oxidative damage significantly contribute to CTX-mediated muscle pathology with implications for human muscle diseases.

  13. Deregulation of the protocadherin gene FAT1 alters muscle shapes: implications for the pathogenesis of facioscapulohumeral dystrophy.

    Directory of Open Access Journals (Sweden)

    Nathalie Caruso

    2013-06-01

    Full Text Available Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD. FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD.

  14. Deregulation of the Protocadherin Gene FAT1 Alters Muscle Shapes: Implications for the Pathogenesis of Facioscapulohumeral Dystrophy

    Science.gov (United States)

    Caruso, Nathalie; Herberth, Balàzs; Bartoli, Marc; Puppo, Francesca; Dumonceaux, Julie; Zimmermann, Angela; Denadai, Simon; Lebossé, Marie; Roche, Stephane; Geng, Linda; Magdinier, Frederique; Attarian, Shahram; Bernard, Rafaelle; Maina, Flavio; Levy, Nicolas; Helmbacher, Françoise

    2013-01-01

    Generation of skeletal muscles with forms adapted to their function is essential for normal movement. Muscle shape is patterned by the coordinated polarity of collectively migrating myoblasts. Constitutive inactivation of the protocadherin gene Fat1 uncoupled individual myoblast polarity within chains, altering the shape of selective groups of muscles in the shoulder and face. These shape abnormalities were followed by early onset regionalised muscle defects in adult Fat1-deficient mice. Tissue-specific ablation of Fat1 driven by Pax3-cre reproduced muscle shape defects in limb but not face muscles, indicating a cell-autonomous contribution of Fat1 in migrating muscle precursors. Strikingly, the topography of muscle abnormalities caused by Fat1 loss-of-function resembles that of human patients with facioscapulohumeral dystrophy (FSHD). FAT1 lies near the critical locus involved in causing FSHD, and Fat1 mutant mice also show retinal vasculopathy, mimicking another symptom of FSHD, and showed abnormal inner ear patterning, predictive of deafness, reminiscent of another burden of FSHD. Muscle-specific reduction of FAT1 expression and promoter silencing was observed in foetal FSHD1 cases. CGH array-based studies identified deletion polymorphisms within a putative regulatory enhancer of FAT1, predictive of tissue-specific depletion of FAT1 expression, which preferentially segregate with FSHD. Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with FSHD. PMID:23785297

  15. CRISPR/Cas9-Mediated Genome Editing Corrects Dystrophin Mutation in Skeletal Muscle Stem Cells in a Mouse Model of Muscle Dystrophy

    Directory of Open Access Journals (Sweden)

    Pei Zhu

    2017-06-01

    Full Text Available Muscle stem cells (MuSCs hold great therapeutic potential for muscle genetic disorders, such as Duchenne muscular dystrophy (DMD. The CRISP/Cas9-based genome editing is a promising technology for correcting genetic alterations in mutant genes. In this study, we used fibrin-gel culture system to selectively expand MuSCs from crude skeletal muscle cells of mdx mice, a mouse model of DMD. By CRISP/Cas9-based genome editing, we corrected the dystrophin mutation in expanded MuSCs and restored the skeletal muscle dystrophin expression upon transplantation in mdx mice. Our studies established a reliable and feasible platform for gene correction in MuSCs by genome editing, thus greatly advancing tissue stem cell-based therapies for DMD and other muscle disorders.

  16. Cyclooxygenase-2 expression in skeletal muscle of knockout mice suffering Duchenne muscular dystrophy.

    Science.gov (United States)

    de Oliveira, Flavia; Flavia, De Oliveira; Quintana, Hananiah Tardivo; Bortolin, Jeferson André; Gomes, Odair Alfredo; Liberti, Edson Aparecido; Ribeiro, Daniel Araki

    2013-05-01

    The purpose of the present study was to investigate the role of cyclooxygenase-2 (COX-2) expression in fibrotic lesion in mdx mice. A total of six male C57BL/10 mice and six C57BL/10-DMD/mdx were distributed into two groups: control and animals with Duchenne muscular dystrophy (DMD). The medial part of gastrocnemius muscle was evaluated being the specimens stained with hematoxylin and eosin (H&E) and Sirius Red under normal and polarized light to differentiate type I (red and yellow) and III (green) collagen. COX-2 expression was assessed by immunohistochemistry. The results revealed histopathological changes in C57BL/10-DMD/mdx as depicted by regenerating fibers. Sirius Red stain showed a substantial increase in the amount of type I collagen of mdx mice. DMD induced a strong COX-2 immunoexpression in intercellular space. Taken together, our results are consistent with the notion that necrotic and fibrotic lesions are able to increase COX-2 expression in DMD.

  17. Laminin beta 2 chain and adhalin deficiency in the skeletal muscle of Walker-Warburg syndrome (cerebro-ocular dysplasia-muscular dystrophy)

    DEFF Research Database (Denmark)

    Wewer, U M; Durkin, M E; Zhang, X

    1995-01-01

    Muscular dystrophy may be caused by disturbances in a number of muscle proteins that appear to be part of a chain of interacting molecules that includes cytoskeletal, cell membrane, and basement membrane components. We found that the skeletal muscle cells in two cases of Walker-Warburg syndrome w...

  18. Congenital bilateral agenesis of the tibialis anterior muscles: a rare case report.

    Science.gov (United States)

    Htwe, Ohnmar; Swarhib, M; Pei, Tan Sook; Naicker, Amaramalar Selvi; Das, S

    2012-01-01

    Congenital bilateral agenesis of the tibialis anterior muscles is a rare condition. We present a case of congenital absence of bilateral tibialis anterior muscles in a 6-year-old boy who presented with an abnormal gait. He was previously diagnosed to have bilateral congenital talipes equinovarus (CTEV) deformity for which he underwent corrective surgery two times. However, he still had a residual foot problem and claimed to have difficulty in walking. On examination, he walked with a high stepping gait and muscle power of both lower limbs was 5/5 on the medical research council scale (MRCS) except for both ankle dorsiflexors and long toe extensors. The sensation was intact. Magnetic Resonance Imaging (MRI) study of both legs revealed that tibialis anterior muscles were not visualized on both sides suggestive of agenesis of the tibialis anterior muscles. The rest of the muscles appeared mildly atrophied. The electrophysiological study showed normal motor and sensory conduction in both upper and lower limbs. Electromyographic (EMG) study of the vastus medialis was within normal limit and no response could be elicited for EMG of tibialis anterior muscles suggesting possible absence of tibialis anterior muscles, bilaterally. The patient underwent split tibialis posterior tendon transfer to achieve a balanced and functional foot and was well on discharge. The present case describes the normal anatomy and embryology of tibialis anterior muscles as well as possible causes of its agenesis along with its clinical implications.

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

    Science.gov (United States)

    Dowling, Paul; Culligan, Kevin; Ohlendieck, Kay

    2002-02-01

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

  20. Small Fractions of Muscular Dystrophy Embryonic Stem Cells Yield Severe Cardiac and Skeletal Muscle Defects in Adult Mouse Chimeras.

    Science.gov (United States)

    Gonzalez, J Patrick; Kyrychenko, Sergii; Kyrychenko, Viktoriia; Schneider, Joel S; Granier, Celine J; Himelman, Eric; Lahey, Kevin C; Zhao, Qingshi; Yehia, Ghassan; Tao, Yuan-Xiang; Bhaumik, Mantu; Shirokova, Natalia; Fraidenraich, Diego

    2017-03-01

    Duchenne muscular dystrophy (DMD) is characterized by the loss of the protein dystrophin, leading to muscle fragility, progressive weakening, and susceptibility to mechanical stress. Although dystrophin-negative mdx mouse models have classically been used to study DMD, phenotypes appear mild compared to patients. As a result, characterization of muscle pathology, especially in the heart, has proven difficult. We report that injection of mdx embryonic stem cells (ESCs) into Wild Type blastocysts produces adult mouse chimeras with severe DMD phenotypes in the heart and skeletal muscle. Inflammation, regeneration and fibrosis are observed at the whole organ level, both in dystrophin-negative and dystrophin-positive portions of the chimeric tissues. Skeletal and cardiac muscle function are also decreased to mdx levels. In contrast to mdx heterozygous carriers, which show no significant phenotypes, these effects are even observed in chimeras with low levels of mdx ESC incorporation (10%-30%). Chimeric mice lack typical compensatory utrophin upregulation, and show pathological remodeling of Connexin-43. In addition, dystrophin-negative and dystrophin-positive isolated cardiomyocytes show augmented calcium response to mechanical stress, similar to mdx cells. These global effects highlight a novel role of mdx ESCs in triggering muscular dystrophy even when only low amounts are present. Stem Cells 2017;35:597-610. © 2016 AlphaMed Press.

  1. Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy

    Science.gov (United States)

    Pinniger, Gavin J.; Graves, Jamie A.; Grounds, Miranda D.; Arthur, Peter G.

    2016-01-01

    Key points Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis.Cysteine precursor antioxidants such as N‐acetyl cysteine (NAC) and l‐2‐oxothiazolidine‐4‐carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine.We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress.Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug.These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD. Abstract Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l‐2‐oxothiazolidine‐4‐carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx

  2. Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Terrill, Jessica R; Pinniger, Gavin J; Graves, Jamie A; Grounds, Miranda D; Arthur, Peter G

    2016-06-01

    Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis. Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine. We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress. Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug. These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD. Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l-2-oxothiazolidine-4-carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex

  3. Glu20Ter Variant inPLEC1f Isoform Causes Limb-Girdle Muscle Dystrophy with Lung Injury.

    Science.gov (United States)

    Deev, Roman V; Bardakov, Sergei N; Mavlikeev, Mikhail O; Yakovlev, Ivan A; Umakhanova, Zoya R; Akhmedova, Patimat G; Magomedova, Raisat M; Chekmaryeva, Irina A; Dalgatov, Gimat D; Isaev, Artur A

    2017-01-01

    Plectinopathies are orphan diseases caused by PLEC gene mutations. PLEC is encoding the protein plectin, playing a role in linking cytoskeleton components in various tissues. In this study, we describe the clinical case of a 26-year-old patient with an early onset plectinopathy variant "limb-girdle muscle dystrophy type 2Q," report histopathological and ultrastructural findings in m. vastus lateralis biopsy and a novel homozygous likely pathogenic variant (NM_201378.3:c.58G>T, NP_958780.1:p.Glu20Ter) in isoform 1f of the gene PLEC . The patient had an early childhood onset with retarded physical development, moderate weakness in pelvic girdle muscles, progressive weakening of limb-girdle muscles after the age of 21, pronounced atrophy of axial muscles, and hypertrophy of the gastrocnemius, deltoid, and triceps muscles, intermittent dyspnea, and no skin involvement. Findings included: non-infectious bronchiolitis and atelectasis signs, biopsy revealed myodystrophal pattern without macrophage infiltration, muscle fiber cytoskeleton disorganization resulted from the plectin loss, incomplete reparative rhabdomyogenesis, and moderate endomysial fibrosis. We have determined a novel likely pathogenic variant in PLEC 1f isoform that causes limb-girdle muscle dystrophy type 2Q and described the third case concerning an isolated myodystrophic phenotype of LGMD2Q with the likely pathogenic variant in PLEC 1f isoform. In addition, we have demonstrated the presence of severe lung injury in a patient and his siblings with the same myodystrophic phenotype and discussed the possible role of plectin deficiency in its pathogenesis.

  4. Glu20Ter Variant in PLEC 1f Isoform Causes Limb-Girdle Muscle Dystrophy with Lung Injury

    Directory of Open Access Journals (Sweden)

    Roman V. Deev

    2017-07-01

    Full Text Available Plectinopathies are orphan diseases caused by PLEC gene mutations. PLEC is encoding the protein plectin, playing a role in linking cytoskeleton components in various tissues. In this study, we describe the clinical case of a 26-year-old patient with an early onset plectinopathy variant “limb-girdle muscle dystrophy type 2Q,” report histopathological and ultrastructural findings in m. vastus lateralis biopsy and a novel homozygous likely pathogenic variant (NM_201378.3:c.58G>T, NP_958780.1:p.Glu20Ter in isoform 1f of the gene PLEC. The patient had an early childhood onset with retarded physical development, moderate weakness in pelvic girdle muscles, progressive weakening of limb-girdle muscles after the age of 21, pronounced atrophy of axial muscles, and hypertrophy of the gastrocnemius, deltoid, and triceps muscles, intermittent dyspnea, and no skin involvement. Findings included: non-infectious bronchiolitis and atelectasis signs, biopsy revealed myodystrophal pattern without macrophage infiltration, muscle fiber cytoskeleton disorganization resulted from the plectin loss, incomplete reparative rhabdomyogenesis, and moderate endomysial fibrosis. We have determined a novel likely pathogenic variant in PLEC 1f isoform that causes limb-girdle muscle dystrophy type 2Q and described the third case concerning an isolated myodystrophic phenotype of LGMD2Q with the likely pathogenic variant in PLEC 1f isoform. In addition, we have demonstrated the presence of severe lung injury in a patient and his siblings with the same myodystrophic phenotype and discussed the possible role of plectin deficiency in its pathogenesis.

  5. Study on T2 mapping in thigh muscles of patients with Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Ying-yin LIANG

    2015-07-01

    Full Text Available Objective  Use T2 mapping to evaluate the fatty infiltration of thigh muscles in Duchenne muscular dystrophy (DMD patients, so as to analyze the value of T2 mapping and T2 relaxation time in the diagnosis of DMD.  Methods  Sixteen DMD patients who were admitted from January 2004 to January 2013 in our hospital and were diagnosed by clinical confirmation and gene detection have participated into this study. These 16 male patients formed the DMD group. Six age- and sex-matched healthy boys were selected as control group. Clinical functional scale, thigh axial T1WI-turbo spin echo (TSE, T2WI-TSE, spectral attenuated inversion recovery (SPAIR-T2WI and T2 mapping were performed in both 2 groups. T1WI fatty infiltration scale and T2 relaxation time were assessed in adductor magnus, gracilis, adductor longus, sartorius, rectus femoris, vastus intermedius, vastus medialis, vastus lateralis, biceps femoris, semitendinosus and semimembranosus. Spearman rank correlation was conducted to assess the correlation between T2 relaxation time and T1WI fatty infiltration scale or clinical functional scale.  Results  Compared with control group, the T2 relaxation time of 8 muscles (adductor magnus, adductor longus, rectus femoris, vastus intermedius, vastus medialis, vastus lateralis, biceps femoris and semimembranosus in DMD group were prolonged (P < 0.05, for all. The longest average T2 relaxation time was found in adductor magnus. The T2 relaxation time of adductor magnus, vastus intermedius, vastus lateralis, biceps femoris, rectus femoris, adductor longus and vastus medialis was positively correlated with T1WI fatty infiltration scale (P < 0.05, for all, and the T2 relaxation time of adductor magnus and semimembranosus was positively correlated with clinical funetional scale (P < 0.05, for all. A positive correlation was found in adductor magnus between T2 relaxation time and both T1WI fatty infiltration scale (rs = 0.867, P = 0.000 and clinical

  6. Mitochondrial disorders in congenital myopathies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

    Full Text Available The literature review gives data on the role of mitochondrial disorders in the pathogenesis of congenital myopathies: congenital muscular dystrophies and congenital structural myopathies. It describes changes in congenital muscular dystrophies with type VI collagen, in myodystrophy with giant mitochondria, in congenital central core myopathies, myotubular myopathy, etc. Clinical and experimental findings are presented. Approaches to therapy for energy disorders in congenital myopathies are depicted.

  7. Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

    Directory of Open Access Journals (Sweden)

    Amanda J Beck

    Full Text Available Duchenne muscular dystrophy (DMD is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin. In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.

  8. Comparative proteomic profiling of soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscles from the mdx mouse model of Duchenne muscular dystrophy.

    Science.gov (United States)

    Carberry, Steven; Brinkmeier, Heinrich; Zhang, Yaxin; Winkler, Claudia K; Ohlendieck, Kay

    2013-09-01

    Duchenne muscular dystrophy is due to genetic abnormalities in the dystrophin gene and represents one of the most frequent genetic childhood diseases. In the X-linked muscular dystrophy (mdx) mouse model of dystrophinopathy, different subtypes of skeletal muscles are affected to a varying degree albeit the same single base substitution within exon 23 of the dystrophin gene. Thus, to determine potential muscle subtype-specific differences in secondary alterations due to a deficiency in dystrophin, in this study, we carried out a comparative histological and proteomic survey of mdx muscles. We intentionally included the skeletal muscles that are often used for studying the pathomechanism of muscular dystrophy. Histological examinations revealed a significantly higher degree of central nucleation in the soleus and extensor digitorum longus muscles compared with the flexor digitorum brevis and interosseus muscles. Muscular hypertrophy of 20-25% was likewise only observed in the soleus and extensor digitorum longus muscles from mdx mice, but not in the flexor digitorum brevis and interosseus muscles. For proteomic analysis, muscle protein extracts were separated by fluorescence two-dimensional (2D) gel electrophoresis. Proteins with a significant change in their expression were identified by mass spectrometry. Proteomic profiling established an altered abundance of 24, 17, 19 and 5 protein species in the dystrophin-deficient soleus, extensor digitorum longus, flexor digitorum brevis and interosseus muscle, respectively. The key proteomic findings were verified by immunoblot analysis. The identified proteins are involved in the contraction-relaxation cycle, metabolite transport, muscle metabolism and the cellular stress response. Thus, histological and proteomic profiling of muscle subtypes from mdx mice indicated that distinct skeletal muscles are differentially affected by the loss of the membrane cytoskeletal protein, dystrophin. Varying degrees of perturbed protein

  9. Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts' Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model.

    Science.gov (United States)

    Serena, Elena; Zatti, Susi; Zoso, Alice; Lo Verso, Francesca; Tedesco, F Saverio; Cossu, Giulio; Elvassore, Nicola

    2016-12-01

    : Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210-240 µm vs. 40-70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from

  10. Skeletal Muscle Differentiation on a Chip Shows Human Donor Mesoangioblasts’ Efficiency in Restoring Dystrophin in a Duchenne Muscular Dystrophy Model

    Science.gov (United States)

    Serena, Elena; Zatti, Susi; Zoso, Alice; Lo Verso, Francesca; Tedesco, F. Saverio; Cossu, Giulio

    2016-01-01

    Restoration of the protein dystrophin on muscle membrane is the goal of many research lines aimed at curing Duchenne muscular dystrophy (DMD). Results of ongoing preclinical and clinical trials suggest that partial restoration of dystrophin might be sufficient to significantly reduce muscle damage. Different myogenic progenitors are candidates for cell therapy of muscular dystrophies, but only satellite cells and pericytes have already entered clinical experimentation. This study aimed to provide in vitro quantitative evidence of the ability of mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes derived from DMD patients, using a microengineered model. We designed an ad hoc experimental strategy to miniaturize on a chip the standard process of muscle regeneration independent of variables such as inflammation and fibrosis. It is based on the coculture, at different ratios, of human dystrophin-positive myogenic progenitors and dystrophin-negative myoblasts in a substrate with muscle-like physiological stiffness and cell micropatterns. Results showed that both healthy myoblasts and mesoangioblasts restored dystrophin expression in DMD myotubes. However, mesoangioblasts showed unexpected efficiency with respect to myoblasts in dystrophin production in terms of the amount of protein produced (40% vs. 15%) and length of the dystrophin membrane domain (210–240 µm vs. 40–70 µm). These results show that our microscaled in vitro model of human DMD skeletal muscle validated previous in vivo preclinical work and may be used to predict efficacy of new methods aimed at enhancing dystrophin accumulation and distribution before they are tested in vivo, reducing time, costs, and variability of clinical experimentation. Significance This study aimed to provide in vitro quantitative evidence of the ability of human mesoangioblasts to restore dystrophin, in terms of protein accumulation and distribution, within myotubes

  11. Uncoordinated transcription and compromised muscle function in the lmna-null mouse model of Emery- Emery-Dreyfuss muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Viola F Gnocchi

    2011-02-01

    Full Text Available 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 contraction dynamics in the lmna-null mouse model of A-EDMD. We found that there were fewer myonuclei in lmna-null mice, of which ∼50% had morphological abnormalities. Assaying transcriptional activity by examining acetylated histone H3 and PABPN1 levels indicated that there was a lack of coordinated transcription between myonuclei lacking lamin A/C. Myonuclei with abnormal morphology and transcriptional activity were distributed along the length of the myofibre, but accumulated at the myotendinous junction. Indeed, in addition to the presence of abnormal myonuclei, the structure of the myotendinous junction was perturbed, with disorganised sarcomeres and reduced interdigitation with the tendon, together with lipid and collagen deposition. Functionally, muscle contraction became severely affected within weeks of birth, with specific force generation dropping as low as ∼65% and ∼27% of control values in the extensor digitorum longus and soleus muscles respectively. These observations illustrate the importance of lamin A/C for correct myonuclear function, which likely acts synergistically with myotendinous junction disorganisation in the development of A-EDMD, and the consequential reduction in force generation and muscle wasting.

  12. Accessory soleus muscle as a cause of congenital talipes equino varus. A case report.

    Science.gov (United States)

    Rambani, Rohit; Shahid, Muhammad Salim

    2006-10-01

    The authors report a case of congenital clubfoot in a one-year-old male child, in which an accessory soleus muscle was noted intraoperatively, running anteromedially to the Achilles tendon and with a distinct insertion on the postero-medial aspect of the calcaneus. Correction of the varus and equinus of the hindfoot could only be achieved after cutting the tendon of the accessory soleus muscle at its insertion on the calcaneus.

  13. Spectrum of congenital mitral valve abnormalities associated with solitary undifferentiated papillary muscle in adults

    OpenAIRE

    Mohan, Jagdish C.; Shukla, Madhu; Mohan, Vishwas; Sethi, Arvind

    2016-01-01

    Background: Congenital anomaly wherein the mitral valve leaflets are directly attached to the papillary muscle(s) (PM) with or without short under-developed chords is rarely reported in adults. Patients with two PMs with an intervening fibrous bridge have also been included under this head in previous studies. Methods: Echocardiography enables accurate evaluation of the morphology and function of valve leaflets, chordae tendineae, and PM. This report describes a series of six patients aged...

  14. Genetics Home Reference: congenital fibrosis of the extraocular muscles

    Science.gov (United States)

    ... Ophthalmol. 2008 Jan-Feb;23(1):3-8. doi: 10.1080/08820530701745181. Review. Citation on PubMed Lu S, Zhao C, Zhao K, Li N, Larsson C. Novel and recurrent KIF21A mutations in congenital fibrosis of the ... doi: 10.1001/archopht.126.3.388. Citation on ...

  15. Revertant fibers in the mdx murine model of Duchenne muscular dystrophy: an age- and muscle-related reappraisal.

    Directory of Open Access Journals (Sweden)

    Sarah R Pigozzo

    Full Text Available Muscles in Duchenne dystrophy patients are characterized by the absence of dystrophin, yet transverse sections show a small percentage of fibers (termed "revertant fibers" positive for dystrophin expression. This phenomenon, whose biological bases have not been fully elucidated, is present also in the murine and canine models of DMD and can confound the evaluation of therapeutic approaches. We analyzed 11 different muscles in a cohort of 40 mdx mice, the most commonly model used in pre-clinical studies, belonging to four age groups; such number of animals allowed us to perform solid ANOVA statistical analysis. We assessed the average number of dystrophin-positive fibers, both absolute and normalized for muscle size, and the correlation between their formation and the ageing process. Our results indicate that various muscles develop different numbers of revertant fibers, with different time trends; besides, they suggest that the biological mechanism(s behind dystrophin re-expression might not be limited to the early development phases but could actually continue during adulthood. Importantly, such finding was seen also in cardiac muscle, a fact that does not fit into the current hypothesis of the clonal origin of "revertant" myonuclei from satellite cells. This work represents the largest, statistically significant analysis of revertant fibers in mdx mice so far, which can now be used as a reference point for improving the evaluation of therapeutic approaches for DMD. At the same time, it provides new clues about the formation of revertant fibers/cardiomyocytes in dystrophic skeletal and cardiac muscle.

  16. Chronic administration of a leupeptin-derived calpain inhibitor fails to ameliorate severe muscle pathology in a canine model of Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Martin K Childers

    2012-01-01

    Full Text Available Calpains likely play a role in the pathogenesis of Duchenne muscular dystrophy (DMD. Accordingly, calpain inhibition may provide therapeutic benefit to DMD patients. In the present study, we sought to measure benefit from administration of a novel calpain inhibitor, C101, in a canine muscular dystrophy model. Specifically, we tested the hypothesis that treatment with C101 mitigates progressive weakness and severe muscle pathology observed in young dogs with golden retriever muscular dystrophy (GRMD. Young (6 week-old GRMD dogs were treated daily with either C101 (17mg/kg twice daily oral dose, n=9 or placebo (vehicle only, n=7 for 8 weeks. A battery of functional tests, including tibiotarsal joint angle, muscle/fat composition, and pelvic limb muscle strength were performed at baseline and every two weeks during the 8-week study. Results indicate that C101-treated GRMD dogs maintained strength in their cranial pelvic limb muscles (tibiotarsal flexors while placebo-treated dogs progressively lost strength. However, concomitant improvement was not observed in posterior pelvic limb muscles (tibiotarsal extensors. C101 treatment did not mitigate force drop following repeated eccentric contractions and no improvement was seen in the development of joint contractures, lean muscle mass or muscle histopathology. Taken together, these data do not support the hypothesis that treatment with C101 mitigates progressive weakness or ameliorates severe muscle pathology observed in young dogs with GRMD.

  17. A splice site mutation in laminin-α2 results in a severe muscular dystrophy and growth abnormalities in zebrafish.

    Directory of Open Access Journals (Sweden)

    Vandana A Gupta

    Full Text Available Congenital muscular dystrophy (CMD is a clinically and genetically heterogeneous group of inherited muscle disorders. In patients, muscle weakness is usually present at or shortly after birth and is progressive in nature. Merosin deficient congenital muscular dystrophy (MDC1A is a form of CMD caused by a defect in the laminin-α2 gene (LAMA2. Laminin-α2 is an extracellular matrix protein that interacts with the dystrophin-dystroglycan (DGC complex in membranes providing stability to muscle fibers. In an N-ethyl-N-nitrosourea mutagenesis screen to develop zebrafish models of neuromuscular diseases, we identified a mutant fish that exhibits severe muscular dystrophy early in development. Genetic mapping identified a splice site mutation in the lama2 gene. This splice site is highly conserved in humans and this mutation results in mis-splicing of RNA and a loss of protein function. Homozygous lama2 mutant zebrafish, designated lama2(cl501/cl501, exhibited reduced motor function and progressive degeneration of skeletal muscles and died at 8-15 days post fertilization. The skeletal muscles exhibited damaged myosepta and detachment of myofibers in the affected fish. Laminin-α2 deficiency also resulted in growth defects in the brain and eye of the mutant fish. This laminin-α2 deficient mutant fish represents a novel disease model to develop therapies for modulating splicing defects in congenital muscular dystrophies and to restore the muscle function in human patients with CMD.

  18. Meaning of Muscular Dystrophy

    Science.gov (United States)

    ... Living With MD Print en español Qué significa distrofia muscular What Is Muscular Dystrophy? Muscular dystrophy (say: MUS- ... blood test if a kid has Becker or Duchenne MD. Or the doctor might take a small piece of the muscle and look at it under a microscope to ...

  19. Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy.

    Science.gov (United States)

    Mankodi, Ami; Bishop, Courtney A; Auh, Sungyoung; Newbould, Rexford D; Fischbeck, Kenneth H; Janiczek, Robert L

    2016-10-01

    The purpose of this study was to explore the use of iterative decomposition of water and fat with echo asymmetry and least-squares estimation Carr-Purcell-Meiboom-Gill (IDEAL-CPMG) to simultaneously measure skeletal muscle apparent fat fraction and water T 2 (T 2,w ) in patients with Duchenne muscular dystrophy (DMD). In twenty healthy volunteer boys and thirteen subjects with DMD, thigh muscle apparent fat fraction was measured by Dixon and IDEAL-CPMG, with the IDEAL-CPMG also providing T 2,w as a measure of muscle inflammatory activity. A subset of subjects with DMD was followed up during a 48-week clinical study. The study was in compliance with the Patient Privacy Act and approved by the Institutional Review Board. Apparent fat fraction in the thigh muscles of subjects with DMD was significantly increased compared to healthy volunteer boys (p <0.001). There was a strong correlation between Dixon and IDEAL-CPMG apparent fat fraction. Muscle T 2,w measured by IDEAL-CPMG was independent of changes in apparent fat fraction. Muscle T 2,w was higher in the biceps femoris and vastus lateralis muscles of subjects with DMD (p <0.05). There was a strong correlation (p <0.004) between apparent fat fraction in all thigh muscles and six-minute walk distance (6MWD) in subjects with DMD. IDEAL-CPMG allowed independent and simultaneous quantification of skeletal muscle fatty degeneration and disease activity in DMD. IDEAL-CPMG apparent fat fraction and T 2,w may be useful as biomarkers in clinical trials of DMD as the technique disentangles two competing biological processes. Published by Elsevier B.V.

  20. Improved Muscle Function in Duchenne Muscular Dystrophy through L-Arginine and Metformin: An Investigator-Initiated, Open-Label, Single-Center, Proof-Of-Concept-Study.

    Science.gov (United States)

    Hafner, Patricia; Bonati, Ulrike; Erne, Beat; Schmid, Maurice; Rubino, Daniela; Pohlman, Urs; Peters, Thomas; Rutz, Erich; Frank, Stephan; Neuhaus, Cornelia; Deuster, Stefanie; Gloor, Monika; Bieri, Oliver; Fischmann, Arne; Sinnreich, Michael; Gueven, Nuri; Fischer, Dirk

    2016-01-01

    Altered neuronal nitric oxide synthase function in Duchenne muscular dystrophy leads to impaired mitochondrial function which is thought to be one cause of muscle damage in this disease. The study tested if increased intramuscular nitric oxide concentration can improve mitochondrial energy metabolism in Duchenne muscular dystrophy using a novel therapeutic approach through the combination of L-arginine with metformin. Five ambulatory, genetically confirmed Duchenne muscular dystrophy patients aged between 7–10 years were treated with L-arginine (3 x 2.5 g/d) and metformin (2 x 250 mg/d) for 16 weeks. Treatment effects were assessed using mitochondrial protein expression analysis in muscular biopsies, indirect calorimetry, Dual-Energy X-Ray Absorptiometry, quantitative thigh muscle MRI, and clinical scores of muscle performance. There were no serious side effects and no patient dropped out. Muscle biopsy results showed pre-treatment a significantly reduced mitochondrial protein expression and increased oxidative stress in Duchenne muscular dystrophy patients compared to controls. Post-treatment a significant elevation of proteins of the mitochondrial electron transport chain was observed as well as a reduction in oxidative stress. Treatment also decreased resting energy expenditure rates and energy substrate use shifted from carbohydrates to fatty acids. These changes were associated with improved clinical scores. In conclusion pharmacological stimulation of the nitric oxide pathway leads to improved mitochondria function and clinically a slowing of disease progression in Duchenne muscular dystrophy. This study shall lead to further development of this novel therapeutic approach into a real alternative for Duchenne muscular dystrophy patients. ClinicalTrials.gov NCT02516085.

  1. Genetics Home Reference: Duchenne and Becker muscular dystrophy

    Science.gov (United States)

    ... Home Health Conditions Duchenne and Becker muscular dystrophy Duchenne and Becker muscular dystrophy Printable PDF Open All ... by progressive muscle weakness and wasting (atrophy). The Duchenne and Becker types of muscular dystrophy are two ...

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

    OpenAIRE

    NIGRO, VINCENZO; SAVARESE, MARCO

    2014-01-01

    Limb-girdle muscular dystrophies (LGMD) are a highly heterogeneous group of muscle disorders, which first affect the voluntary muscles of the hip and shoulder areas. The definition is highly descriptive and less ambiguous by exclusion: non-Xlinked, non-FSH, non-myotonic, non-distal, nonsyndromic, and non-congenital. At present, the genetic classification is becoming too complex, since the acronym LGMD has also been used for a number of other myopathic disorders with overlapping phenotypes. To...

  3. Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies.

    Science.gov (United States)

    Meilleur, Katherine G; Jain, Minal S; Hynan, Linda S; Shieh, Ching-Yi; Kim, Eunice; Waite, Melissa; McGuire, Michelle; Fiorini, Courtney; Glanzman, Allan M; Main, Marion; Rose, Kristy; Duong, Tina; Bendixen, Roxanna; Linton, Melody M; Arveson, Irene C; Nichols, Carmel; Yang, Kelly; Fischbeck, Kenneth H; Wagner, Kathryn R; North, Kathryn; Mankodi, Ami; Grunseich, Christopher; Hartnett, Elizabeth J; Smith, Michaele; Donkervoort, Sandra; Schindler, Alice; Kokkinis, Angela; Leach, Meganne; Foley, A Reghan; Collins, James; Muntoni, Francesco; Rutkowski, Anne; Bönnemann, Carsten G

    2015-01-01

    Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes. Published by Elsevier B.V.

  4. Structural abnormalities in the levator palpebrae superioris muscle in patients with congenital blepharoptosis.

    Science.gov (United States)

    Iljin, Aleksandra; Zielinska, Anna; Karasek, Michal; Zielinski, Andrzej; Omulecka, Aleksandra

    2007-01-01

    To evaluate structural and ultrastructural abnormalities of the levator palpebrae superioris (LPS) complex in patients with congenital blepharoptosis. Samples of the LPS complex were obtained from patients operated on for congenital blepharoptosis between 2000 and 2001 and studied under light microscopy (15 cases) and electron microscopy (9 cases). Findings of light microscopy evaluation of the LPS complex correlated closely with the clinical grading of congenital blepharoptosis-hypoplasia, decreased number and varying diameter of muscle fibers, and fibrous tissue hyperplasia in the endomysium and perimysium. The Müller's muscle preserved a normal appearance. Mild blepharoptosis revealed proliferation of collagen fibers on electron microscopy. Moderate blepharoptosis showed abnormal distribution of myofibrils and distortion of the tubular system and mitochondria in addition to the changes observed in mild blepharoptosis. Severe blepharoptosis showed mitochondria loss, cytoplasm thinning, and homogenous fiber areas in addition to the changes observed in mild and moderate blepharoptosis. The clinical degree of severity of congenital blepharoptosis correlates positively with the degree of histopathologic changes in the levator palpebrae superioris muscle.

  5. Oral muscles are progressively affected in Duchenne muscular dystrophy : Implications for dysphagia treatment

    NARCIS (Netherlands)

    Bert de Swart; W. Klein; L. van den Engel-Hoek; S. Pillen; J. Hendriks; Alexander Geurts; I. de Groot; L. Sie; C. Erasmus

    2012-01-01

    Dysphagia is reported in advanced stages of Duchenne muscular dystrophy (DMD). The population of DMD is changing due to an increasing survival. We aimed to describe the dysphagia in consecutive stages and to assess the underlying mechanisms of dysphagia in DMD, in order to develop mechanism based

  6. Facioscapulohumeral muscular dystrophy

    Science.gov (United States)

    ... children. Alternative Names Landouzy-Dejerine muscular dystrophy Images Superficial anterior muscles References Preston DC, Shapiro BE. Proximal, ... the principles of the Health on the Net Foundation (www.hon.ch). The information provided herein should ...

  7. CONGENITAL NUTRITIONAL MYODEGENERATION (WHITE MUSCLE DISEASE) IN A GIRAFFE ( GIRAFFA CAMELOPARDALIS) CALF.

    Science.gov (United States)

    Bos, Jan H; Klip, Fokko C; Kik, Marja J L

    2017-12-01

    It is well known that vitamin E and selenium deficiencies in domestic ruminants can lead to white muscle disease. After a clinically normal gestation period at Ouwehand Zoo in the Netherlands, a newborn giraffe ( Giraffa camelopardalis) calf showed clinical signs of white muscle disease almost immediately after birth. The calf was rejected by the mother and was euthanized 3 days later because of deterioration of clinical signs. At necropsy, pulmonary edema and pallor of skeletal and heart muscles was noted. Histologically, there was hyaline degeneration of skeletal muscle myocytes and pulmonary edema. Blood concentrations of vitamin E were ≤ 0.7 mg/L. Based on clinical, biochemical, and gross and microscopic pathological findings, congenital nutritional myodegeneration was diagnosed. This case of neonatal white muscle disease is particularly remarkable given that the diet of the dam contained more than the recommended amount of vitamin E.

  8. Dual AAV therapy ameliorates exercise-induced muscle injury and functional ischemia in murine models of Duchenne muscular dystrophy.

    Science.gov (United States)

    Zhang, Yadong; Yue, Yongping; Li, Liang; Hakim, Chady H; Zhang, Keqing; Thomas, Gail D; Duan, Dongsheng

    2013-09-15

    Neuronal nitric oxide synthase (nNOS) membrane delocalization contributes to the pathogenesis of Duchenne muscular dystrophy (DMD) by promoting functional muscle ischemia and exacerbating muscle injury during exercise. We have previously shown that supra-physiological expression of nNOS-binding mini-dystrophin restores normal blood flow regulation and prevents functional ischemia in transgenic mdx mice, a DMD model. A critical next issue is whether systemic dual adeno-associated virus (AAV) gene therapy can restore nNOS-binding mini-dystrophin expression and mitigate muscle activity-related functional ischemia and injury. Here, we performed systemic gene transfer in mdx and mdx4cv mice using a pair of dual AAV vectors that expressed a 6 kb nNOS-binding mini-dystrophin gene. Vectors were packaged in tyrosine mutant AAV-9 and co-injected (5 × 10(12) viral genome particles/vector/mouse) via the tail vein to 1-month-old dystrophin-null mice. Four months later, we observed 30-50% mini-dystrophin positive myofibers in limb muscles. Treatment ameliorated histopathology, increased muscle force and protected against eccentric contraction-induced injury. Importantly, dual AAV therapy successfully prevented chronic exercise-induced muscle force drop. Doppler hemodynamic assay further showed that therapy attenuated adrenergic vasoconstriction in contracting muscle. Our results suggest that partial transduction can still ameliorate nNOS delocalization-associated functional deficiency. Further evaluation of nNOS binding mini-dystrophin dual AAV vectors is warranted in dystrophic dogs and eventually in human patients.

  9. Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Meng, Jinhong; Counsell, John R; Reza, Mojgan; Laval, Steven H; Danos, Olivier; Thrasher, Adrian; Lochmüller, Hanns; Muntoni, Francesco; Morgan, Jennifer E

    2016-01-27

    Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation.

  10. Spatially localized phosphorous metabolism of skeletal muscle in Duchenne muscular dystrophy patients: 24-month follow-up.

    Science.gov (United States)

    Hooijmans, M T; Doorenweerd, N; Baligand, C; Verschuuren, J J G M; Ronen, I; Niks, E H; Webb, A G; Kan, H E

    2017-01-01

    To assess the changes in phosphodiester (PDE)-levels, detected by 31P magnetic resonance spectroscopy (MRS), over 24-months to determine the potential of PDE as marker for muscle tissue changes in Duchenne Muscular Dystrophy (DMD) patients. Spatially resolved phosphorous datasets were acquired in the right lower leg of 18 DMD patients (range: 5-15.4 years) and 12 age-matched healthy controls (range: 5-14 years) at three time-points (baseline, 12-months, and 24-months) using a 7T MR-System (Philips Achieva). 3-point Dixon images were acquired at 3T (Philips Ingenia) to determine muscle fat fraction. Analyses were done for six muscles that represent different stages of muscle wasting. Differences between groups and time-points were assessed with non-parametric tests with correction for multiple comparisons. Coefficient of variance (CV) were determined for PDE in four healthy adult volunteers in high and low signal-to-noise ratio (SNR) datasets. PDE-levels were significantly higher (two-fold) in DMD patients compared to controls in all analyzed muscles at almost every time point and did not change over the study period. Fat fraction was significantly elevated in all muscles at all time points compared to healthy controls, and increased significantly over time, except in the tibialis posterior muscle. The mean within subject CV for PDE-levels was 4.3% in datasets with high SNR (>10:1) and 5.7% in datasets with low SNR. The stable two-fold increase in PDE-levels found in DMD patients in muscles with different levels of muscle wasting over 2-year time, including DMD patients as young as 5.5 years-old, suggests that PDE-levels may increase very rapidly early in the disease process and remain elevated thereafter. The low CV values in high and low SNR datasets show that PDE-levels can be accurately and reproducibly quantified in all conditions. Our data confirms the great potential of PDE as a marker for muscle tissue changes in DMD patients.

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

    Science.gov (United States)

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

    2015-10-01

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

  12. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies

    NARCIS (Netherlands)

    Maroofian, R.; Riemersma, M.; Jae, L.T.; Zhianabed, N.; Willemsen, M.H.; Wissink-Lindhout, W.M.; Willemsen, M.A.A.P.; Brouwer, A.P.M. de; Mehrjardi, M.Y.V.; Ashrafi, M.R.; Kusters, B.; Kleefstra, T.; Jamshidi, Y.; Nasseri, M.; Pfundt, R.; Brummelkamp, T.R.; Abbaszadegan, M.R.; Lefeber, D.J.; Bokhoven, H. van

    2017-01-01

    BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of alpha-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular

  13. Absence of Dystrophin Disrupts Skeletal Muscle Signaling: Roles of Ca2+, Reactive Oxygen Species, and Nitric Oxide in the Development of Muscular Dystrophy.

    Science.gov (United States)

    Allen, David G; Whitehead, Nicholas P; Froehner, Stanley C

    2016-01-01

    Dystrophin is a long rod-shaped protein that connects the subsarcolemmal cytoskeleton to a complex of proteins in the surface membrane (dystrophin protein complex, DPC), with further connections via laminin to other extracellular matrix proteins. Initially considered a structural complex that protected the sarcolemma from mechanical damage, the DPC is now known to serve as a scaffold for numerous signaling proteins. Absence or reduced expression of dystrophin or many of the DPC components cause the muscular dystrophies, a group of inherited diseases in which repeated bouts of muscle damage lead to atrophy and fibrosis, and eventually muscle degeneration. The normal function of dystrophin is poorly defined. In its absence a complex series of changes occur with multiple muscle proteins showing reduced or increased expression or being modified in various ways. In this review, we will consider the various proteins whose expression and function is changed in muscular dystrophies, focusing on Ca(2+)-permeable channels, nitric oxide synthase, NADPH oxidase, and caveolins. Excessive Ca(2+) entry, increased membrane permeability, disordered caveolar function, and increased levels of reactive oxygen species are early changes in the disease, and the hypotheses for these phenomena will be critically considered. The aim of the review is to define the early damage pathways in muscular dystrophy which might be appropriate targets for therapy designed to minimize the muscle degeneration and slow the progression of the disease. Copyright © 2016 the American Physiological Society.

  14. Congenital diaphragmatic hernia: focus on abnormal muscle formation.

    Science.gov (United States)

    Alaggio, R; Midrio, P; Sgrò, A; Piovan, G; Guzzardo, V; Donato, R; Sorci, G; Lago, P; Gamba, P G

    2015-03-01

    CDH is a major birth defect, characterized by high mortality. How the initial defective mesenchymal substructures affects muscle malformation is unclear. Defects of genes involved in diaphragmatic development, such as friend-of-GATA2 (Fog2), may play an important role in its pathogenesis. We investigated the expression of Fog2 and proteins of myogenesis in a series of CDH and in diaphragms at different fetal ages, in order to clarify the role of muscular components during diaphragmatic development in cases with CDH. Specimen were obtained from seven diaphragms of CDH cases undergoing surgery, 3 entire diaphragms from non repaired CDH, 5 control diaphragms at different gestational ages (16, 17, 22, 32, and 40g.w.), and 3 biopsy samples of normal voluntary muscle. The thickness of diaphragms at the edge of the defect in CDH and in developing diaphragms was measured. All samples were processed for HE staining and immunohistochemistry. Immunohistochemical expression of MyoD, Myf4, Pax7, Mib1 and Fog2 was evaluated. Mean thickness at the edge of the defect was 4.14mm. Contralateral hemi-diaphragm in 3 autopsies and in controls at 32 and 40weeks measured 2.25mm; histology showed a higher density of desmin-positive muscular cells at the edge of defect. CDH displayed scattered Myf4-positive cells (range 0%-10%, mean 2.4%), numerous Pax7-positive cells (range 0%-24%, mean 12.1%) and less than 1% Mib1-positive cells. Controls showed a reduction of positive cell with the progression of gestational age for Myf4 (30% at 16 weeks, 20% at 17 weeks, 5% at 22 weeks, 1% at 32 and 40 weeks), Pax7 (85% at 16 weeks and 17 weeks, 35% at 22 weeks, 11% at 32 weeks) and Mib1 (20% at 16 weeks, 8% at 17 weeks, 7% at 22weeks, 2% at 32 weeks). Fog-2 was diffusely positive in mesenchymal, mesothelial and muscular cells, in diaphragms from 16 to 22 weeks, decreasing to 20% of positive muscular cells in 32-week diaphragm. In CDH only mesothelial and mesenchymal cells were positive. Stem cell

  15. Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy.

    Science.gov (United States)

    Chalkiadaki, Angeliki; Igarashi, Masaki; Nasamu, Armiyaw Sebastian; Knezevic, Jovana; Guarente, Leonard

    2014-07-01

    SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases.

  16. Timed function tests, motor function measure, and quantitative thigh muscle MRI in ambulant children with Duchenne muscular dystrophy: A cross-sectional analysis.

    Science.gov (United States)

    Schmidt, Simone; Hafner, Patricia; Klein, Andrea; Rubino-Nacht, Daniela; Gocheva, Vanya; Schroeder, Jonas; Naduvilekoot Devasia, Arjith; Zuesli, Stephanie; Bernert, Guenther; Laugel, Vincent; Bloetzer, Clemens; Steinlin, Maja; Capone, Andrea; Gloor, Monika; Tobler, Patrick; Haas, Tanja; Bieri, Oliver; Zumbrunn, Thomas; Fischer, Dirk; Bonati, Ulrike

    2018-01-01

    The development of new therapeutic agents for the treatment of Duchenne muscular dystrophy has put a focus on defining outcome measures most sensitive to capture treatment effects. This cross-sectional analysis investigates the relation between validated clinical assessments such as the 6-minute walk test, motor function measure and quantitative muscle MRI of thigh muscles in ambulant Duchenne muscular dystrophy patients, aged 6.5 to 10.8 years (mean 8.2, SD 1.1). Quantitative muscle MRI included the mean fat fraction using a 2-point Dixon technique, and transverse relaxation time (T2) measurements. All clinical assessments were highly significantly inter-correlated with p quantitative muscle MRI values significantly correlated with all clinical assessments with the extensors showing the strongest correlation. In contrast to the clinical assessments, quantitative muscle MRI values were highly significantly correlated with age. In conclusion, the motor function measure and timed function tests measure disease severity in a highly comparable fashion and all tests correlated with quantitative muscle MRI values quantifying fatty muscle degeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Muscle-specific SIRT1 gain-of-function increases slow-twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Angeliki Chalkiadaki

    2014-07-01

    Full Text Available SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases.

  18. NMR-CT in muscular disorders. Muscle T/sub 1/ values in Duchenne muscular dystrophy carriers

    Energy Technology Data Exchange (ETDEWEB)

    Matsumura, Kiichiro; Nakano, Imaharu; Fukuda, Nobuo; Ikehira, Hiroo; Tateno, Yukio

    1987-02-01

    Proton NMR-CT (magnetic field strength 0.1 Tesla, resonant frequency 4.5 MHz) was performed in 10 normal females and 19 Duchenne muscular dystrophy (DMD) carriers. The mean age was 39 +- 12 years for the normal females and 42 +- 6 years for the DMD carriers. In DMD carriers, there were 4 definite, 4 probable, and 11 possible carriers. T/sub 1/ (spin-lattice relaxation time) image was obtained for a slice at the buttock, mid-thigh and calf levels respectively. T/sub 1/ values were measured for the medial portion of the gluteus maximus, the vastus lateralis of the quadriceps femoris, and the gastrocnemius. The bound water fraction (BWF) was calculated from Fullerton's equation based on the fast proton diffusion model. The following results were obtained: (1) In normal females, muscle T/sub 1/ value was highest in the gastrocnemius and lowest in the gluteus maximus. (2) In DMD carriers, T/sub 1/ values of the gluteus maximus and quadriceps femoris were significantly higher than those of the normal females. There was, however, no significant difference in T/sub 1/ value of the gastrocnemius between DMD carriers and normal females. (3) In DMD carriers, BWFs of the gluteus maximus and quadriceps femoris were significantly lower than those of the normal females. (4) In DMD carriers, no significant correlation was observed between the muscle T/sub 1/ values and the serum creatine phosphokinase values. Increased tissue water content in the lower parts of the body due to gravity is considered to be the primary cause of the high T/sub 1/ value in the gastrocnemius of normal females. The presence of the degenerating muscle fibers are presumed responsible for the high T/sub 1/ value and low BWF in the proximal muscles of DMD carriers.

  19. Genetic mapping of human heart-skeletal muscle adenine nucleotide translocator and its relationship to the facioscapulohumeral muscular dystrophy locus

    Energy Technology Data Exchange (ETDEWEB)

    Haraguchi, Y.; Chung, A.B.; Torroni, A.; Stepien, G.; Shoffner, J.M.; Costigan, D.A.; Polak, M. [Emory Univ. School of Medicine, Atlanta, GA (United States); Wasmuth, J.J.; Altherr, M.R.; Winokur, S.T. [Univ. of California, Irvine, CA (United States)] [and others

    1993-05-01

    The mitochondrial heart-skeletal muscle adenine nucleotide translocator (ANT1) was regionally mapped to 4q35-qter using somatic cell hybrids containing deleted chromosome 4. The regional location was further refined through family studies using ANT1 intron and promoter nucleotide polymorphisms recognized by the restriction endonucleases MboII, NdeI, and HaeIII. Two alleles were found, each at a frequency of 0.5. The ANT1 locus was found to be closely linked to D4S139, D4S171, and the dominant skeletal muscle disease locus facioscapulohumeral muscular dystrophy (FSHD). A crossover that separated D4S171 and ANT1 from D4S139 was found. Since previous studies have established the chromosome 4 map order as centromere-D4S171-D4S139-FSHD, it was concluded that ANT1 is located on the side of D4S139, that is opposite from FSHD. This conclusion was confirmed by sequencing the exons and analyzing the transcripts of ANT1 from several FSHD patients and finding no evidence of aberration. 35 refs., 5 figs., 1 tab.

  20. Receptor and post-receptor abnormalities contribute to insulin resistance in myotonic dystrophy type 1 and type 2 skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Laura Valentina Renna

    Full Text Available Myotonic dystrophy type 1 (DM1 and type 2 (DM2 are autosomal dominant multisystemic disorders caused by expansion of microsatellite repeats. In both forms, the mutant transcripts accumulate in nuclear foci altering the function of alternative splicing regulators which are necessary for the physiological mRNA processing. Missplicing of insulin receptor (IR gene (INSR has been associated with insulin resistance, however, it cannot be excluded that post-receptor signalling abnormalities could also contribute to this feature in DM. We have analysed the insulin pathway in skeletal muscle biopsies and in myotube cultures from DM patients to assess whether downstream metabolism might be dysregulated and to better characterize the mechanism inducing insulin resistance. DM skeletal muscle exhibits alterations of basal phosphorylation levels of Akt/PKB, p70S6K, GSK3β and ERK1/2, suggesting that these changes might be accompanied by a lack of further insulin stimulation. Alterations of insulin pathway have been confirmed on control and DM myotubes expressing fetal INSR isoform (INSR-A. The results indicate that insulin action appears to be lower in DM than in control myotubes in terms of protein activation and glucose uptake. Our data indicate that post-receptor signalling abnormalities might contribute to DM insulin resistance regardless the alteration of INSR splicing.

  1. Therapeutic advances in muscular dystrophy

    OpenAIRE

    Leung, Doris G; Wagner, Kathryn R

    2013-01-01

    The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystr...

  2. Characteristic of muscle involvement evaluated by CT scans in early stages of progressive muscular dystrophy; Comparison between Duchenne and Fukuyama types

    Energy Technology Data Exchange (ETDEWEB)

    Arai, Yumi (Tokyo Women' s Medical Coll. (Japan))

    1993-10-01

    Muscle CT scans were performed in order to compare the characteristic distribution of progressive muscle involvement in the early stages of Duchenne type (DMD) and Fukuyama type muscular dystrophy (FCMD). Muscle images at the levels of the 3rd lumbar vertebra, thigh and calf were assessed by visual inspection, and mean CT numbers calculated for individual muscles were statistically analysed. On visual inspection, intramuscular low density areas and muscular atrophy were observed in the muscles of older patients with either disease. These changes were, however, more extensive at thigh level in DMD, and at calf level in FCMD. Nevertheless, the mean CT numbers of muscles in which only slight changes were grossly visible on CT scans displayed progressive decreases with increasing age. Moreover, a significant negative relationship was recognizable between age and mean CT number in almost all muscles examined. Comparison of the slopes of the regression lines revealed that the so-called selective pattern of muscle involvement characteristic of the symptomatic stage had already partially manifested in the preclinical or early stages of both diseases. In FCMD, the rates of decrease in CT numbers were extremely rapid for calf muscles as compared with those in DMD, indicating that this is one reason for FCMD patients never becoming ambulatory. However, for almost all of the other muscles, the CT numbers in FCMD decreased in parallel with the corresponding CT numbers in DMD; thus, these diseases displayed a similarity in the pattern of muscle involvement, despite their different pathogenetic mechanisms and inheritance patterns. (author).

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

    NARCIS (Netherlands)

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

    2015-01-01

    Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal-to-noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential

  4. Effect of Achilles tenotomy on congenital clubfoot-associated calf-muscle atrophy: an ultrasonographic study.

    Science.gov (United States)

    Niki, Hisateru; Nakajima, Hiroshi; Hirano, Takaaki; Okada, Hirokazu; Beppu, Moroe

    2013-07-01

    The Ponseti method for treating congenital clubfoot requires Achilles tenotomy to be performed toward the end of serial casting. However, it remains unclear if Achilles tenotomy has a negative effect on clubfoot-associated calf-muscle atrophy. We therefore investigated this issue by ultrasonographic examination. We studied 36 patients with congenital clubfoot who were treated with the Ponseti method and underwent Achilles tenotomy. Only unilateral cases were evaluated to enable comparison of the severity of atrophy and its changes over time between affected and unaffected sides. Tenotomy was performed at a mean age of 10.2 weeks after birth (range 8-16 weeks). The transverse and anteroposterior diameters of the calf muscles on the unaffected and affected sides were measured ultrasonographically by two examiners. The mean observation period was 27 months (range 24-34 months). Measurements were performed within 6 months after tenotomy, between 7 and 17 months after tenotomy, and at the final assessment. Differences between the diameters of the affected and unaffected sides at each time point, and changes in the diameters over time were determined. The data were analyzed by use of one-way ANOVA and repeated-measures ANOVA. Tendon healing and gliding were achieved in all cases. There were significant differences between the diameters of the unaffected and affected sides at all measurement points (transverse p calf muscles on both sides increased significantly over time (p calf muscles differed significantly between the affected and unaffected sides after Achilles tenotomy, but there were no significant differences in changes over time. These results suggest that Achilles tenotomy had no negative short-term effects on calf-muscle atrophy associated with clubfoot.

  5. Outcomes after muscle flap vs prosthetic patch repair for large congenital diaphragmatic hernias.

    Science.gov (United States)

    Nasr, Ahmed; Struijs, Marie-Chantal; Ein, Sigmund H; Langer, Jacob C; Chiu, Priscilla P L

    2010-01-01

    Repair of large congenital diaphragmatic hernia (CDH) defects still pose a significant challenge, as the defects cannot be repaired primarily. Two techniques have been widely used: autologous anterior abdominal wall muscle flap and prosthetic patch. The latter has been used more often. Our goal was to compare the short-term and long-term outcomes of these 2 approaches. This is a retrospective review of all neonates undergoing CDH repair at our institution from 1969 to 2006. Of 188 children undergoing surgery for CDH, primary repair could not be accomplished in 51 infants (27%). Nineteen had muscle flap repair, and 32 had prosthetic patch repair (Gore-Tex [W.L. Gore and Associates, Flagstaff, AZ], n = 15; Marlex [Bard Inc, Cranston, NJ], n = 9; Surgisis [Cook, Bloomington, IN], n = 5; SILASTIC [Dow Corning, Midland, MI], n = 3). There was no significant difference in gestational age or birth weight between groups. Three patients developed an abdominal wall defect at the muscle flap donor site, but none required surgical intervention. Chest wall deformities were found in 9 patients, 3 after a muscle flap and 6 after a prosthetic patch (P = .7). Postoperative bowel obstruction occurred in 3 muscle flap patients and 1 patch patient (P = .2). There were 10 recurrences among survivors: 2 after a muscle flap and 8 after a prosthetic patch (P = .3) There were 2 deaths among the muscle flap patients (10%), and 3 deaths among the prosthetic patch repair patients (9%) (P = .1). Results were confirmed after controlling for age and comorbidities between both groups in a multivariate logistic regression. These results suggest that autologous anterior abdominal wall muscle flap and prosthetic patch repairs provide similar short-term and long-term outcomes. Copyright 2010 Elsevier Inc. All rights reserved.

  6. Long-term follow-up of MRI changes in thigh muscles of patients with Facioscapulohumeral dystrophy: A quantitative study.

    Directory of Open Access Journals (Sweden)

    Farzad Fatehi

    Full Text Available Facioscapulohumeral muscular dystrophy (FSHD is one of the most common hereditary muscular disorders. Currently FSHD has no known effective treatment and detailed data on the natural history are lacking. Determination of the efficacy of a given therapeutic approach might be difficult in FSHD given the slow and highly variable disease progression. Magnetic resonance imaging (MRI has been widely used to qualitatively and quantitatively evaluate in vivo the muscle alterations in various neuromuscular disorders. The main aim of the present study was to investigate longitudinally the time-dependent changes occurring in thigh muscles of FSHD patients using quantitative MRI and to assess the potential relationships with the clinical findings. Thirty-five FSHD1 patients (17 females were enrolled. Clinical assessment tools including manual muscle testing using medical research council score (MRC, and motor function measure (MFM were recorded each year for a period ranging from 1 to 2 years. For the MRI measurements, we used a new quantitative index, i.e., the mean pixel intensity (MPI calculated from the pixel-intensity distribution in T1 weighted images. The corresponding MPI scores were calculated for each thigh, for each compartment and for both thighs totally (MPItotal. The total mean pixel intensity (MPItotal refers to the sum of each pixel signal intensity divided by the corresponding number of pixels. An increased MPItotal indicates both a raised fat infiltration together with a reduced muscle volume thereby illustrating disease progression. Clinical scores did not change significantly over time whereas MPItotal increased significantly from an initial averaged value of 39.6 to 41.1 with a corresponding rate of 0.62/year. While clinical scores and MPItotal measured at the start of the study were significantly related, no correlation was found between the rate of MPItotal and MRC sum score changes, MFMtotal and MFM subscores. The relative rate of

  7. Restriction of calpain3 expression to the skeletal muscle prevents cardiac toxicity and corrects pathology in a murine model of limb-girdle muscular dystrophy.

    Science.gov (United States)

    Roudaut, Carinne; Le Roy, Florence; Suel, Laurence; Poupiot, Jérôme; Charton, Karine; Bartoli, Marc; Richard, Isabelle

    2013-09-03

    Genetic defects in calpain3 (CAPN3) lead to limb-girdle muscular dystrophy type 2A, a disease of the skeletal muscle that affects predominantly the proximal limb muscles. We previously demonstrated the potential of adeno-associated virus-mediated transfer of the CAPN3 gene to correct the pathological signs in a murine model for limb-girdle muscular dystrophy type 2A after intramuscular and locoregional administrations. Here, we showed that intravenous injection of calpain3-expressing vector in mice can induce mortality in a dose-dependent manner. An anatomopathological investigation revealed large areas of fibrosis in the heart that we related to unregulated proteolytic activity of calpain3. To circumvent this toxicity, we developed new adeno-associated virus vectors with skeletal muscle-restricted expression by using new muscle-specific promoters that include the CAPN3 promoter itself and by introducing a target sequence of the cardiac-specific microRNA-208a in the cassette. Our results show that CAPN3 transgene expression can be successfully suppressed in the cardiac tissue, preventing the cardiac toxicity, whereas expression of the transgene in skeletal muscle reverts the pathological signs of calpain3 deficiency. The molecular strategies used in this study may be useful for any gene transfer strategy with potential toxicity in the heart.

  8. Congenital muscular dystrophy. Part I: a review of phenotypical and diagnostic aspects Distrofia muscular congênita. Parte I: revisão dos aspectos fenotípicos e diagnósticos

    Directory of Open Access Journals (Sweden)

    Umbertina Conti Reed

    2009-03-01

    Full Text Available The congenital muscular dystrophies (CMDs are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. We initially present the main clinical and diagnostic data concerning the CMDs related to changes in the complex dystrophin-associated glycoproteins-extracellular matrix: CMD with merosin deficiency (CMD1A, collagen VI related CMDs (Ullrich CMD and Bethlem myopathy, CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscle-eye-brain disease, Walker-Warburg syndrome, CMD1C, CMD1D, and the much rarer CMD with integrin deficiency. Finally, we present other forms of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex (rigid spine syndrome, CMD1B, CMD with lamin A/C deficiency, and some apparently specific clinical forms not yet associated with a known molecular mechanism. The second part of this review concerning the pathogenesis and therapeutic perspectives of the different subtypes of CMD will be described in a next number.As distrofias musculares congênitas (DMCs são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. São caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. O quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A

  9. Congenital muscular dystrophy. Part II: a review of pathogenesis and therapeutic perspectives Distrofia muscular congênita. Parte II: revisão da patogênese e perspectivas terapêuticas

    Directory of Open Access Journals (Sweden)

    Umbertina Conti Reed

    2009-06-01

    Full Text Available The congenital muscular dystrophies (CMDs are a group of genetically and clinically heterogeneous hereditary myopathies with preferentially autosomal recessive inheritance, that are characterized by congenital hypotonia, delayed motor development and early onset of progressive muscle weakness associated with dystrophic pattern on muscle biopsy. The clinical course is broadly variable and can comprise the involvement of the brain and eyes. From 1994, a great development in the knowledge of the molecular basis has occurred and the classification of CMDs has to be continuously up dated. In the last number of this journal, we presented the main clinical and diagnostic data concerning the different subtypes of CMD. In this second part of the review, we analyse the main reports from the literature concerning the pathogenesis and the therapeutic perspectives of the most common subtypes of CMD: MDC1A with merosin deficiency, collagen VI related CMDs (Ullrich and Bethlem, CMDs with abnormal glycosylation of alpha-dystroglycan (Fukuyama CMD, Muscle-eye-brain disease, Walker Warburg syndrome, MDC1C, MDC1D, and rigid spine syndrome, another much rare subtype of CMDs not related with the dystrophin/glycoproteins/extracellular matrix complex.As distrofias musculares congênitas (DMCs são miopatias hereditárias geralmente, porém não exclusivamente, de herança autossômica recessiva, que apresentam grande heterogeneidade genética e clínica. São caracterizadas por hipotonia muscular congênita, atraso do desenvolvimento motor e fraqueza muscular de início precoce associada a padrão distrófico na biópsia muscular. O quadro clínico, de gravidade variável, pode também incluir anormalidades oculares e do sistema nervoso central. A partir de 1994, os conhecimentos sobre genética e biologia molecular das DMCs progrediram rapidamente, sendo a classificação continuamente atualizada. Os aspectos clínicos e diagnósticos dos principais subtipos de DMC

  10. Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2.

    Science.gov (United States)

    Khan, Arif O; Almutlaq, Mohammed; Oystreck, Darren T; Engle, Elizabeth C; Abu-Amero, Khaled; Bosley, Thomas

    2016-06-01

    Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a distinct non-syndromic form of congenital incomitant strabismus secondary to orbital dysinnervation from recessive mutations in the gene PHOX2A. The phenotype includes bilateral ptosis, very large angle exotropia, ophthalmoplegia, and poorly-reactive pupils. Other than amblyopia, afferent visual dysfunction has not been considered part of CFEOM2; however, we have repeatedly observed non-amblyopic subnormal vision in affected patients. The purpose of this study was to document this recurrent feature of the phenotype. A retrospective case series (2002-2012). Eighteen patients (four families) were identified; all affected individuals had confirmed homozygous recessive PHOX2A mutations except one individual for whom genetic testing was not done because of multiple genetically confirmed family members. Age at assessment ranged from 5-62 years old (median 10 years old). All patients had decreased best-corrected visual acuity not completely explainable by amblyopia in both the preferred and non-preferred eye. In those patients who had further ancillary testing, visual fields (five patients) and electroretinography (10 patients) confirmed abnormalities not ascribable to amblyopia. In addition to a distinct form of congenital incomitant strabismus, the phenotype of CFEOM2 includes subnormal vision consistent with retinal dysfunction. This could be the direct result of PHOX2A mutations or a secondary effect of orbital dysinnervation.

  11. [Central nervous system abnormalities related to congenital fibrosis of extraocular muscles].

    Science.gov (United States)

    Moguel-Ancheita, Silvia; Rodríguez-Garcidueñas, Wendolyn

    2009-01-01

    We undertook this study to describe central nervous system (CNS) abnormalities associated with congenital cranial dysinnervation disorders (CCDD). This was a retrospective, observational, transversal and descriptive study including patients with congenital fibrotic strabismus. We analyzed clinical files of patients from 2001 to 2006. Neurological lesions were reported. Restrictive strabismus was demonstrated in all cases. Sixteen patients were included: nine males and seven females. Different neurological lesions were reported: corpus callosum anomalies, severe cortipathy, epilepsy, cavum vergae, nystagmus, occipital subarachnoid cyst, and hydrocephalus. Mental retardation was reported in 56% of patients. Different malformations were reported: genital malformations, trigonocephalus, camptodactyly, mild facial hypoplasia, low set ears, and agenesis of left ear. Blepharoptosis was present in 81% of patients. The most frequent form of strabismus was exotropia (56%), hypotropia in 37.5%, hypertropia 18.7%, "A" pattern 18.7%, and esotropia in 6.25%. Affection was cranial nerve III, 93.75%; cranial nerve VI, 6.25%; cranial nerve VII, 6.25%; and lesion to cranial nerve II in eight cases (50%). We have suggested that failure in early stages of embryology of the CNS can lead to the development of paralytic strabismus and generate secondary fibrotic changes, not only in muscle structures but also in other orbital tissues. That is the reason why we have used the term "congenital fibrotic strabismus" to report cases included in CCDD. We have demonstrated the strong association of mental retardation and neurological alterations. Multidisciplinary rehabilitation is relevant for these patients.

  12. A Rare Cause of Congenital Hypotonia: Walker Warburg Syndrome

    OpenAIRE

    Cigdem Sivrice

    2014-01-01

    Walker-Warburg syndrome (WWS) is an autosomal recessive rare muscle disease which characterized by type 2 lissencephaly, cerebellar abnormalities, and congenital muscular dystrophy of the retinal abnormalities. In this article, we described a patient who born from 1st degree consanguineous marriage mother and father and admitted to our hospital suction weakness and had been diagnosed Walker- Warburg syndrome with physical examination and laboratory tests as a result of severe hypotonia, atypi...

  13. Leg muscle reflexes mediated by cutaneous A-beta fibres are normal during gait in reflex sympathetic dystrophy.

    Science.gov (United States)

    van der Laan, L; Boks, L M; van Wezel, B M; Goris, R J; Duysens, J E

    2000-04-01

    Reflex sympathetic dystrophy (RSD) is, from the onset, characterized by various neurological deficits such as an alteration of sensation and a decrease in muscle strength. We investigated if afferent A-beta fibre-mediated reflexes are changed in lower extremities affected by acute RSD. The involvement of these fibres was determined by analyzing reflex responses from the tibialis anterior (TA) and biceps femoris (BF) muscles after electrical stimulation of the sural nerve. The reflexes were studied during walking on a treadmill to investigate whether the abnormalities in gait of the patients were related either to abnormal amplitudes or deficient phase-dependent modulation of reflexes. In 5 patients with acute RSD of the leg and 5 healthy volunteers these reflex responses were determined during the early and late swing phase of the step cycle. No significant difference was found between the RSD and the volunteers. During early swing the mean amplitude of the facilitatory P2 responses in BF and TA increased as a function of stimulus intensity (1.5, 2 and 2.5 times the perception threshold) in both groups. At end swing the same stimuli induced suppressive responses in TA. This phase-dependent reflex reversal from facilitation in early swing to suppression in late swing occurred equally in both groups. In the acute phase of RSD of the lower extremity there is no evidence for abnormal A-beta fibre-mediated reflexes or for defective regulation of such reflexes. This finding has implications for both the theory on RSD pathophysiology and RSD models, which are based on abnormal functioning of A-beta fibres.

  14. Frontalis muscle flap suspension for the correction of congenital blepharoptosis in early age children.

    Directory of Open Access Journals (Sweden)

    Dianju Hou

    Full Text Available BACKGROUND: We aimed to report our successful use of frontalis muscle flap suspension for the correction of congenital blepharoptosis in early age children. METHODS: This retrospective study included 61 early age children (41 boys, 20 girls with an average age of 6 years (range, 3-10 years with congenital blepharoptosis who received surgery during the period from March 2007 to January 2011. There were 39 cases of unilateral blepharoptosis and 22 cases of bilateral blepharoptosis, thus a total of 83 eyes were affected. If patient had bilateral blepharoptosis, both eyes were operated on in the same surgery. Patients were followed for 3 months to 5 years. The procedure was performed without complications in all cases. RESULTS: The postoperative healing grade was good in 81 eyes (97.6%; the correction of blepharoptosis was satisfactory, the double eyelid folds were natural and aesthetic, the eyelid position and the curvature were ideal, and the eyes were bilaterally symmetrical. The postoperative healing grade was fair in 2 eyes (2.4%; blepharoptosis was improved compared with that before surgery. At discharge, lagophthalmos was noted in 10 eyes of which 4 cases resolved by the last follow-up. The remaining 6 cases were mild. Eleven eyes received reoperation for residual ptosis after the first surgery. The curvature of the palpebral margin was not natural in 4 eyes. These unnatural curvature possibly was caused by an excessively low lateral fixation point or postoperative avulsion. CONCLUSION: Frontalis muscle flap suspension under general anesthesia for the correction of congenital blepharoptosis in early age children can achieve good surgical results.

  15. Concentration of sulfur-containing amino acids at turkey broilers during and after muscle dystrophy, fed with deficient feed supplemented with oxidised fat

    Directory of Open Access Journals (Sweden)

    K. Stoyanchev

    2017-06-01

    Full Text Available Abstract. The aim of the present study was to reproduce experimentally muscular dystrophy in 50 broiler turkeys, through early nutrition with a diet deficient in vitamin E, selenium and sulfur-containing amino acids, supplemented with oxidised fat and to study blood plasma sulfur containing amino acids (methionine rd and cysteine. The experiments were conducted with 1 day-old broiler turkeys. By the 3 day of life, they were divided into 40 experimental (II group and 10 control birds (I group; the latter were fed a standard compound feed, whereas the former group received a diet deficient in sulfur-containing amino acids methionine and cysteine (reduced up to 50%, vitamin E, and Se (from 0.2 mg/kg in standard feed to 0.01 mg/kg, further supplemented with oxidized fat containing peroxides and aldehydes with peroxide number of the food 8.0 meq O /kg. The clinical signs of experimental muscle dystrophy in broiler turkeys 2 th appeared first by the 25 day of feeding, when the mild clinical form (II A group and the severe clinical form (II B group werewas established. The results indicated clearly that in turkey broilers suffering from muscle dystrophy, the concentrations of sulfur-containing amino acids cysteine and methionine decreased. After the treatment of turkey broilers withmuscle dystrophy, and supplementation with non-deficient forage with Se, vitamin E, but also with sulfurcontaining amino acids cysteine ormethionine with Seled at a dosage 0.06mg/kg, the plasma levels of sulfur-containing amino acids cysteine andmethionine ® was normalized in the mild clinical form (II A group. The birds affected by the severe clinical form of disease (II B group, which were not treated with Seled and whose deficient feed was not corrected, could not recover and levels of sulfur-containing amino acids cysteine and methionine did not normalize.

  16. Roles of Fukutin, the Gene Responsible for Fukuyama-Type Congenital Muscular Dystrophy, in Neurons: Possible Involvement in Synaptic Function and Neuronal Migration

    International Nuclear Information System (INIS)

    Hiroi, Atsuko; Yamamoto, Tomoko; Shibata, Noriyuki; Osawa, Makiko; Kobayashi, Makio

    2011-01-01

    Fukutin is a gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), accompanying ocular and brain malformations represented by cobblestone lissencephaly. Fukutin is related to basement membrane formation via the glycosylation of α-dystoglycan (α-DG), and astrocytes play a crucial role in the pathogenesis of the brain lesion. On the other hand, its precise function in neurons is unknown. In this experiment, the roles of fukutin in mature and immature neurons were examined using brains from control subjects and FCMD patients and cultured neuronal cell lines. In quantitative PCR, the expression level of fukutin looked different depending on the region of the brain examined. A similar tendency in DG expression appears to indicate a relation between fukutin and α-DG in mature neurons. An increase of DG mRNA and core α-DG in the FCMD cerebrum also supports the relation. In immunohistochemistry, dot-like positive reactions for VIA4-1, one of the antibodies detecting the glycosylated α-DG, in Purkinje cells suggest that fukutin is related to at least a post-synaptic function via the glycosylation of α-DG. As for immature neurons, VIA4-1 was predominantly positive in cells before and during migration with expression of fukutin, which suggest a participation of fukutin in neuronal migration via the glycosylation of α-DG. Moreover, fukutin may prevent neuronal differentiation, because its expression was significantly lower in the adult cerebrum and in differentiated cultured cells. A knockdown of fukutin was considered to induce differentiation in cultured cells. Fukutin seems to be necessary to keep migrating neurons immature during migration, and also to support migration via α-DG

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

    Science.gov (United States)

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

    2016-09-01

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

  18. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    DEFF Research Database (Denmark)

    Kamsteeg, Erik-Jan; Kress, Wolfram; Catalli, Claudio

    2012-01-01

    -onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described......, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1......Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late...

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Ravneet S Vohra

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

  1. Muscle involvement in limb-girdle muscular dystrophy with GMPPB deficiency (LGMD2T)

    DEFF Research Database (Denmark)

    Oestergaard, S T; Stojkovic, T; Dahlqvist, Julia Rebecka

    2016-01-01

    affected, followed by involvement of hamstrings. Our results showed a loss of glycosylation of α-dystroglycan as well as secondary loss of merosin expression on Western blotting. The prevalence of LGMD2T in the Danish cohort of patients with LGMD is 1.5%. CONCLUSIONS: The new findings of this study are (1......) the consistent finding of a preferential affection of paraspinal and hamstring muscles in LGMD2T, (2) 3 new mutations in GMPPB, (3) variable loss of glycosylation tested with IIH6 and VIA4 antibodies, and (4) a prevalence of LGMD2T of 1.5% in a well-characterized Danish LGMD cohort....

  2. Análise da expressão do colágeno VI na distrofia muscular congênita Analysis of the expression of collagen VI in congenital muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Regina Toni Loureiro de Freitas

    2005-06-01

    Full Text Available A distrofia muscular congênita (DMC compõe um grupo de miopatias caracterizadas por hipotonia e fraqueza muscular notadas já no primeiro ano de vida. A forma de Ullrich é caracterizada por retrações musculares proximais e hiperextensibilidade distal. Cerca de 40% destes pacientes apresentam mutações em um dos genes que codificam as três sub-unidades do colágeno VI (COL6, acarretando deficiência total ou parcial na marcação da proteína. Analisamos, através de imunofluorescência, a marcação do COL6 em fragmentos musculares de 50 pacientes com DMC, 20 deles com ausência da marcação para merosina. Identificamos 4 casos com deficiência total da marcação do COL6 (8% do total, representando 13% dos casos com marcação normal para merosina. As alterações histológicas musculares dos pacientes com COL6 deficiente eram indistinguíveis das outras formas de DMC, porém mais brandas que as observadas na DMC com deficiência de merosina. Em três dos pacientes com COL6 deficiente observou-se hipotonia e fraqueza muscular, notadas já no período neonatal, atraso do desenvolvimento motor, retrações musculares em joelhos e cotovelos, hiperextensibilidade distal e luxação congênita do quadril (dois pacientes. Um paciente perdeu a capacidade para a marcha, e outro faleceu por problemas respiratórios. A análise da marcação do COL6, assim como da merosina, no tecido muscular de pacientes com DMC pode auxiliar na identificação e caracterização fenotípica dos diversos subtipos de DMC.Congenital muscular dystrophy (CMD composes a group of disorders characterized by hypotonia and muscular weakness noticed in the first year of life. The Ullrich's form is characterized by proximal joint contractures and distal hiperextensibility. About 40% of these patients present mutations in one of the genes that codify the sub-units of the collagen VI protein (COL6, producing total or partial deficiency of the protein expression. We analyzed

  3. Age-related differences in lower-limb muscle cross-sectional area and torque production in boys with Duchenne muscular dystrophy.

    Science.gov (United States)

    Mathur, Sunita; Lott, Donovan J; Senesac, Claudia; Germain, Sean A; Vohra, Ravneet S; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

    2010-07-01

    To examine the relationship between lower-extremity muscle cross-sectional area, muscle strength, specific torque, and age in ambulatory boys with Duchenne muscular dystrophy (DMD) compared with controls. Observational cross-sectional study. University research setting. Volunteer sample of boys with DMD (n=22) and healthy control boys (n=10), ages 5 through 14 years. Not applicable. Maximal muscle cross-sectional area (CSA(max)) assessed by magnetic resonance imaging of quadriceps, plantarflexors (PFs) and dorsiflexors (DFs), peak isometric torque from dynamometry, and timed functional tests. The average CSA(max) of the triceps surae muscle group was approximately 60% higher in boys with DMD compared with controls (39.1+/-13.6 cm(2) vs 24.5+/-9.3 cm(2); P=.002), while the tibialis anterior muscle showed age-appropriate increases in CSA(max). The increase in quadriceps CSA(max) was also distinctly different in boys with DMD compared with controls. Specific torque (ie, peak torque/CSA(max)) was impaired in all 3 muscles groups, with the knee extensor (KE) and PF muscles showing 4-fold, and the DF muscles 2-fold, higher values in controls compared with boys with DMD. Large age-related gains in specific torque were observed in all 3 muscle groups of control subjects, which were absent in ambulatory boys with DMD. Correlations were observed between performance on functional tasks and quadriceps and PF torque production (r=-.45 to -.57, Pmuscle cross-sectional area and specific torque production in lower-extremity muscles showed distinctly different patterns in the KE, PF, and DF muscles of boys with DMD compared with controls. Copyright 2010 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.

  4. Congenital fiber type disproportion.

    Science.gov (United States)

    Kissiedu, Juliana; Prayson, Richard A

    2016-04-01

    Type I muscle fiber atrophy in childhood can be encountered in a variety of neuromuscular disorders. Congenital fiber type disproportion (CFTD) is one such condition which presents as a nonprogressive muscle weakness. The diagnosis is often made after excluding other differential diagnostic considerations. We present a 2-year-9-month-old full term boy who presented at 2 months with an inability to turn his head to the right. Over the next couple of years, he showed signs of muscle weakness, broad based gait and a positive Gower's sign. He had normal levels of creatine kinase and normal electromyography. A biopsy of the vastus lateralis showed a marked variation in muscle fiber type. The adenosine triphosphate (ATP)-ase stains highlighted a marked type I muscle atrophy with rare scattered atrophic type II muscle fibers. No abnormalities were observed on the nicotinamide adenine dinucleotide (NADH), succinate dehydrogenase (SDH) or cytochrome oxidase stained sections. Ragged red fibers were not present on the trichrome stain. Abnormalities of glycogen or lipid deposition were not observed on the periodic acid-Schiff or Oil-Red-O stains. Immunostaining for muscular dystrophy associated proteins showed normal staining. Ultrastructural examination showed a normal arrangement of myofilaments, and a normal number and morphology for mitochondria. A diagnosis of CFTD was made after excluding other causes of type I atrophy including congenital myopathy. The lack of specific clinical and genetic disorder associated with CFTD suggests that it is a spectrum of a disease process and represents a diagnosis of exclusion. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Spectrum of congenital mitral valve abnormalities associated with solitary undifferentiated papillary muscle in adults.

    Science.gov (United States)

    Mohan, Jagdish C; Shukla, Madhu; Mohan, Vishwas; Sethi, Arvind

    Congenital anomaly wherein the mitral valve leaflets are directly attached to the papillary muscle(s) (PM) with or without short under-developed chords is rarely reported in adults. Patients with two PMs with an intervening fibrous bridge have also been included under this head in previous studies. Echocardiography enables accurate evaluation of the morphology and function of valve leaflets, chordae tendineae, and PM. This report describes a series of six patients aged 56-84 years who had abnormal mitral valve with a large solitary and anomalously inserted PM seen over a period of 3 years. Only those patients who had a single pillar or bridge-like PM and either absent tendinous chords or small under-developed chords were included in the analysis. Among 9600 consecutive echocardiograms performed, six patients met the criteria of an abnormal mitral valve with solitary large PM. Two patients underwent mitral valve replacement with partial excision of the PM wherein echocardiographic observations were confirmed. The patients were previously followed with the diagnosis of hypertrophic cardiomyopathy (3) and rheumatic mitral valve disease (3). Multi-planar reconstruction of 3D echocardiographic images provided incremental value in assessing the detailed patho-anatomy of PMs in these cases. In adult patients, a high index of suspicion is required to detect congenital mitral stenosis/regurgitation with large solitary PM (resembling a parachute mitral valve) which may masquerade as hypertrophic cardiomyopathy or rheumatic mitral valve disease. Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.

  6. Defective muscle basement membrane and lack of M-laminin in the dystrophic dy/dy mouse

    DEFF Research Database (Denmark)

    Xu, H; Christmas, P; Wu, X R

    1994-01-01

    -linked Duchenne and Becker muscular dystrophies. We have examined M-laminin expression in mice with autosomal recessive muscular dystrophy caused by the mutation dy. The heavy chain of M-laminin was undetectable in skeletal muscle, heart muscle, and peripheral nerve by immunofluorescence and immunoblotting......M-laminin is a major member of the laminin family of basement membrane proteins. It is prominently expressed in striated muscle and peripheral nerve. M-laminin is deficient in patients with the autosomal recessive Fukuyama congenital muscular dystrophy but is normal in patients with the sex...... tissue from dy/dy mice, suggesting that M-laminin heavy-chain mRNA may be produced at very low levels or is unstable. Information about the chromosomal localization of the M heavy-chain in human and mouse suggests that a mutation in the M-chain gene causes the muscular dystrophy in dy/dy mice. The dy...

  7. Expression of mouse agrin in normal, denervated and dystrophic muscle.

    Science.gov (United States)

    Eusebio, Alexander; Oliveri, Filippo; Barzaghi, Patrizia; Ruegg, Markus A

    2003-06-01

    Agrin is a heparan sulfate proteoglycan that is required for the development of postsynaptic specializations at the neuromuscular junction. An alternatively spliced isoform of agrin that lacks this activity is found in basement membranes of several tissues including embryonic muscle. Overexpression of a miniaturized form of this agrin isoform ameliorates the severe muscle dystrophy of laminin alpha2-deficient mice, a mouse model for merosin-deficient congenital muscle dystrophy. Several lines of evidence indicate that this amelioration is based on the high-affinity binding of the mini-agrin to the laminins and to alpha-dystroglycan. Here, we used antibodies raised against mouse agrin to evaluate protein expression in adult muscle of normal and dystrophic mice. We find that expression of agrin in non-synaptic region varies greatly between different muscles in wild-type mice and that its levels are altered in dystrophic muscle.

  8. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Science.gov (United States)

    Miao, Wen; Man, Fengyuan; Wu, Shaoqin; Lv, Bin; Wang, Zhenchang; Xian, Junfang; Sabel, Bernhard A; He, Huiguang; Jiao, Yonghong

    2015-01-01

    To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1) patients using multimodal MRI imaging. T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls. Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (pabnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  9. Diffusion-Tensor Imaging of Thigh Muscles in Duchenne Muscular Dystrophy: Correlation of Apparent Diffusion Coefficient and Fractional Anisotropy Values With Fatty Infiltration.

    Science.gov (United States)

    Li, Gui Dian; Liang, Ying Yin; Xu, Ping; Ling, Jian; Chen, Ying Ming

    2016-04-01

    The purpose of this study is to investigate the correlation of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values with fatty infiltration in the thigh muscles of patients with Duchenne muscular dystrophy (DMD) using diffusion-tensor imaging (DTI). Twenty-one boys with DMD were recruited. The grade of fatty infiltration and the ADC and FA values of four thigh muscles (rectus femoris, semitendinosus, sartorius, and gracilis) were measured, and the FA and ADC values were compared with the grade of fatty infiltration. Twenty age-matched healthy boys were enrolled as the control group. The differences in the ADC and FA values of the thigh muscles between patients with DMD and the control group were compared. The patients with DMD showed lower FA values and higher ADC values in all measured muscles when compared with the control group. The FA and ADC values were correlated with the grade of fatty infiltration. For the rectus femoris muscle, r = -0.753 and p = 0.007 for FA, and r = 0.685 and p = 0.001 for ADC. For the semitendinosus muscle, r = -0.621 and p = 0.041 for FA, and r = 0.705 and p = 0.021 for ADC. For the sartorius muscle, r = -0.662 and p = 0.027 for FA, and r = 0.701 and p = 0.017 for ADC. For the gracilis muscle, r = -0.618 and p = 0.043 for FA, and r = 0.695 and p = 0.022 for ADC. Damage to the thigh muscles in patients with DMD can be detected by ADC and FA values using DTI. DTI can be used to assess the severity of the disease.

  10. Inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ signaling mediates delayed myogenesis in Duchenne muscular dystrophy fetal muscle.

    Science.gov (United States)

    Farini, Andrea; Sitzia, Clementina; Cassinelli, Letizia; Colleoni, Federica; Parolini, Daniele; Giovanella, Umberto; Maciotta, Simona; Colombo, Augusto; Meregalli, Mirella; Torrente, Yvan

    2016-02-15

    Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder characterized by muscle wasting and premature death. The defective gene is dystrophin, a structural protein, absence of which causes membrane fragility and myofiber necrosis. Several lines of evidence showed that in adult DMD patients dystrophin is involved in signaling pathways that regulate calcium homeostasis and differentiation programs. However, secondary aspects of the disease, such as inflammation and fibrosis development, might represent a bias in the analysis. Because fetal muscle is not influenced by gravity and does not suffer from mechanical load and/or inflammation, we investigated 12-week-old fetal DMD skeletal muscles, highlighting for the first time early alterations in signaling pathways mediated by the absence of dystrophin itself. We found that PLC/IP3/IP3R/Ryr1/Ca(2+) signaling is widely active in fetal DMD skeletal muscles and, through the calcium-dependent PKCα protein, exerts a fundamental regulatory role in delaying myogenesis and in myofiber commitment. These data provide new insights into the origin of DMD pathology during muscle development. © 2016. Published by The Company of Biologists Ltd.

  11. A Rare Cause of Congenital Hypotonia: Walker Warburg Syndrome

    Directory of Open Access Journals (Sweden)

    Cigdem Sivrice

    2014-08-01

    Full Text Available Walker-Warburg syndrome (WWS is an autosomal recessive rare muscle disease which characterized by type 2 lissencephaly, cerebellar abnormalities, and congenital muscular dystrophy of the retinal abnormalities. In this article, we described a patient who born from 1st degree consanguineous marriage mother and father and admitted to our hospital suction weakness and had been diagnosed Walker- Warburg syndrome with physical examination and laboratory tests as a result of severe hypotonia, atypical facial appearance, accompanying eye and brain abnormalities are very high serum creatine phosphokinase levels and wanted to draw attention to this rare muscle disease in the differential diagnosis of hypotonic infants.

  12. Inhibition of extracellular signal-regulated kinase 1/2 signaling has beneficial effects on skeletal muscle in a mouse model of Emery-Dreifuss muscular dystrophy caused by lamin A/C gene mutation

    OpenAIRE

    Muchir, Antoine; Kim, Young Jin; Reilly, Sarah A; Wu, Wei; Choi, Jason C; Worman, Howard J

    2013-01-01

    International audience; BACKGROUND: Autosomal Emery-Dreifuss muscular dystrophy is caused by mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins, intermediate filament proteins of the nuclear envelope. Classically, the disease manifests as scapulo-humeroperoneal muscle wasting and weakness, early joint contractures and dilated cardiomyopathy with conduction block; however, more variable skeletal muscle can be present. Previously, we demonstrated increased activity of extrace...

  13. T₂ mapping provides multiple approaches for the characterization of muscle involvement in neuromuscular diseases: a cross-sectional study of lower leg muscles in 5-15-year-old boys with Duchenne muscular dystrophy.

    Science.gov (United States)

    Arpan, Ishu; Forbes, Sean C; Lott, Donovan J; Senesac, Claudia R; Daniels, Michael J; Triplett, William T; Deol, Jasjit K; Sweeney, H Lee; Walter, Glenn A; Vandenborne, Krista

    2013-03-01

    Skeletal muscles of children with Duchenne muscular dystrophy (DMD) show enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in the MR proton transverse relaxation time (T₂). Therefore, the examination of T₂ changes in individual muscles may be useful for the monitoring of disease progression in DMD. In this study, we used the mean T₂, percentage of elevated pixels and T₂ heterogeneity to assess changes in the composition of dystrophic muscles. In addition, we used fat saturation to distinguish T₂ changes caused by edema and inflammation from fat infiltration in muscles. Thirty subjects with DMD and 15 age-matched controls underwent T₂ -weighted imaging of their lower leg using a 3-T MR system. T₂ maps were developed and four lower leg muscles were manually traced (soleus, medial gastrocnemius, peroneal and tibialis anterior). The mean T₂ of the traced regions of interest, width of the T₂ histograms and percentage of elevated pixels were calculated. We found that, even in young children with DMD, lower leg muscles showed elevated mean T₂, were more heterogeneous and had a greater percentage of elevated pixels than in controls. T₂ measures decreased with fat saturation, but were still higher (P tissue in children with DMD, even in the early stages of the disease. Therefore, T₂ mapping may prove to be clinically useful in the monitoring of muscle changes caused by the disease process or by therapeutic interventions in DMD. Copyright © 2012 John Wiley & Sons, Ltd.

  14. CT findings of muscular dystrophy

    International Nuclear Information System (INIS)

    Saitoh, Hiroshi

    1991-01-01

    CT scans of muscles in patients with limb girdle type (LG), myotonic type (MYD) and Duchenne type (DMD) dystrophies were obtained at five different body levels: the neck, L3 vertebral body, pelvic girdle, thigh and lower leg. CT numbers, cross sectional areas (CSA) and %CSA of muscle or fat were evaluated in each muscle. The characteristic CT patterns for each type of muscular dystrophy were obtained. Compared with DMD, the gracilis and soleus were more severely damaged in LG and the biceps femoris remained relatively preserved among the hamstrings. In addition, the multifidus of the neck and sternocleidomastoid also were more severely damaged in MYD. This study suggests that CT scan will be useful in the differential diagnosis of these types of muscular dystrophy as well as in planning appropriate rehabilitation and detecting damaged muscles. (author)

  15. Avaliação da função motora em crianças com distrofia muscular congênita com deficiência da merosina Motor function evaluation in merosin-deficient congenital muscular dystrophy children

    Directory of Open Access Journals (Sweden)

    Fernanda M. Rocco

    2005-06-01

    Full Text Available A distrofia muscular congênita (DMC compõe um grupo de miopatias caracterizadas por hipotonia e fraqueza muscular notadas até o primeiro ano de vida. Em torno de 40% a 50% dos casos são decorrentes de deficiência primária da proteína merosina (DM, os quais apresentam um fenótipo mais homogêneo, com grave comprometimento motor e respiratório. Foram avaliadas neste estudo onze crianças com diagnóstico clínico e histológico de DMC-DM, com idade de 3 a 15 anos, através de exame de força muscular ("Medical Research Council", análise goniométrica, avaliação das habilidades motoras e das atividades de vida diária (AVDs (indicador de Barthel, com o objetivo de caracterizar as principais limitações funcionais motoras. Os grupos musculares mais comprometidos foram os flexores cervicais, paravertebrais e proximais dos membros. Os grupos musculares dos membros superiores estavam tão comprometidos quanto os dos membros inferiores, enquanto que os extensores encontravam-se mais comprometidos que os flexores. Todas as crianças apresentavam importantes retrações musculares nos quadris, joelhos e cotovelos. Outras deformidades freqüentes foram escoliose e pés eqüino-varo. Nenhuma criança possuía a habilidade motora necessária para engatinhar, ficar de pé ou andar; e todas foram classificadas como dependentes ou semidependentes para a maioria das AVDs estudadas. Nossos achados confirmam o envolvimento difuso e intenso da musculatura esquelética na DMC-DM, acarretando graves limitações funcionais motoras e deformidades músculo-esqueléticas.Congenital muscular dystrophy (CMD is a heterogeneous group of disorders characterized by early onset of hypotonia and weakness. Almost 50% of the cases are caused by primary deficiency of a protein named merosin (MD, and present a homogenous phenotype with a severe motor and respiratory involvement. Eleven children with clinical and histological diagnosis of CMD-MD, aged of 3 to 15 years

  16. Brain Abnormalities in Congenital Fibrosis of the Extraocular Muscles Type 1: A Multimodal MRI Imaging Study.

    Directory of Open Access Journals (Sweden)

    Wen Miao

    Full Text Available To explore the possible brain structural and functional alterations in congenital fibrosis of extraocular muscles type 1 (CFEOM1 patients using multimodal MRI imaging.T1-weighted, diffusion tensor images and functional MRI data were obtained from 9 KIF21A positive patients and 19 age- and gender-matched healthy controls. Voxel based morphometry and tract based spatial statistics were applied to the T1-weighted and diffusion tensor images, respectively. Amplitude of low frequency fluctuations and regional homogeneity were used to process the functional MRI data. We then compared these multimodal characteristics between CFEOM1 patients and healthy controls.Compared with healthy controls, CFEOM1 patients demonstrated increased grey matter volume in bilateral frontal orbital cortex and in the right temporal pole. No diffusion indices changes were detected, indicating unaffected white matter microstructure. In addition, from resting state functional MRI data, trend of amplitude of low-frequency fluctuations increases were noted in the right inferior parietal lobe and in the right frontal cortex, and a trend of ReHo increase (p<0.001 uncorrected in the left precentral gyrus, left orbital frontal cortex, temporal pole and cingulate gyrus.CFEOM1 patients had structural and functional changes in grey matter, but the white matter was unaffected. These alterations in the brain may be due to the abnormality of extraocular muscles and their innervating nerves. Future studies should consider the possible correlations between brain morphological/functional findings and clinical data, especially pertaining to eye movements, to obtain more precise answers about the role of brain area changes and their functional consequence in CFEOM1.

  17. The MRI study of the sphincter muscle complex in congenital anorectal malformations

    International Nuclear Information System (INIS)

    Tang Shaotao; Mao Yongzhong; Wang Yong; Dong Ning; Ruan Qinglan; Peng Zhenjun; Kong Xiangquan; Liu Dingxi

    2007-01-01

    Objective: To evaluate the development of the sphincter muscle complex (SMC) and defecation function in pediatric patients with congenital anorectal malformations (ARM). Methods: A total of 64 children underwent MRI, among whom 39 were patients with ARM, and the others were patients without ARM undergoing MRI because of other dieases. The dimensions of the SMC in different planes were evaluated with different sequences and coils. The relationship between the SMC development and the defecation function was investigated. Results: In control group, the absolute value of SMC width was (3.63 ± 0.22)mm, which had a high correlation with age (r=0.998, P 0.05). The SMCs in intermediate ARM patients [muscle index (MI)=0.47 ± 0.05] and low ARM patients (MI=0.49 ± 0.05) were well developed. The SMCs in a portion of patients with high ARM (MI=0.28 ± 0.06) were poorly developed, when MI≤0.18, anorectal contraction pressure was significantly lower (t=3.55, P 0.18[(0.85 ± 0.20) vs (2.24 ± 1.02) kPa]. The length of anal canal with high-pressure[(10.88 ± 3.64) vs (20.26 ± 4.34)mm] was shorter (t= 5.18, P 0.18, the anorectal angle was less than 90 degrees, and normal continent function was found in 21 of 23 cases (91%). Conclusion: MRI can be employed to evaluate the development of SMC in patients with ARM, MI was an objective criteria to evaluate the development of SMC. When MI≤0.18, maldevelopment of SMC will be highly suspected. (authors)

  18. Read-through compound 13 restores dystrophin expression and improves muscle function in the mdx mouse model for Duchenne muscular dystrophy

    Science.gov (United States)

    Kayali, Refik; Ku, Jin-Mo; Khitrov, Gregory; Jung, Michael E.; Prikhodko, Olga; Bertoni, Carmen

    2012-01-01

    Molecules that induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein hold great therapeutic potential for the treatment of many genetic disorders. Two such read-through compounds, RTC13 and RTC14, were recently identified by a luciferase-independent high-throughput screening assay and were shown to have potential therapeutic functions in the treatment of nonsense mutations in the ATM and the dystrophin genes. We have now tested the ability of RTC13 and RTC14 to restore dystrophin expression into skeletal muscles of the mdx mouse model for Duchenne muscular dystrophy (DMD). Direct intramuscular injection of compound RTC14 did not result in significant read-through activity in vivo and demonstrated the levels of dystrophin protein similar to those detected using gentamicin. In contrast, significant higher amounts of dystrophin were detected after intramuscular injection of RTC13. When administered systemically, RTC13 was shown to partially restore dystrophin protein in different muscle groups, including diaphragm and heart, and improved muscle function. An increase in muscle strength was detected in all treated animals and was accompanied by a significant decrease in creatine kinase levels. These studies establish the therapeutic potential of RTC13 in vivo and advance this newly identified compound into preclinical application for DMD. PMID:22692682

  19. Duchenne muscular dystrophy: Case report and review

    OpenAIRE

    Rupam Sinha; Soumyabrata Sarkar; Tanya Khaitan; Soumyajit Dutta

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or resp...

  20. Altered Pulmonary Artery Endothelial - Smooth Muscle Cell Interactions in Experimental Congenital Diaphragmatic Hernia

    Science.gov (United States)

    Acker, Shannon N.; Seedorf, Gregory J.; Abman, Steven H.; Nozik-Grayck, Eva; Kuhn, Katherine; Partrick, David A.; Gien, Jason

    2014-01-01

    Background Pulmonary hypertension (PH) secondary to vascular remodeling contributes to poor outcomes in congenital diaphragmatic hernia (CDH), however mechanisms responsible are unknown. We hypothesized that pulmonary artery endothelial cell (PAEC) dysfunction contributes to smooth muscle cell (SMC) hyperplasia in experimental CDH. Methods PAEC and SMC were isolated from fetal sheep with experimental CDH and controls. SMC growth was assessed alone and with SOD plus catalase and during co-culture with control or CDH PAEC with and without ET-1 siRNA transfection. ET-1 protein was measured in PAEC and PASMC lysates and supernatant. ROS production was measured in normal and CDH PAECs with and without ET-1 siRNA. PAEC growth and tube formation were measured with SOD plus catalase. Results CDH SMC growth was decreased and and increased with co-culture with CDH PAEC more than control PAEC. Treatment of CDH PAEC with SOD plus catalase or ET-1 siRNA prevented the increase in SMC growth seen with co-culture. ET-1 protein was increased in CDH PAEC and SMC. ROS production was increased in CDH PAEC and decreased with ET-1 SiRNA. SOD plus catalase restored CDH PAEC growth and tube formation. Conclusions PAEC dysfunction in experimental CDH increases SMC proliferation via ET-1 induced ROS production by PAEC. PMID:25580737

  1. Physiology of respiratory disturbances in muscular dystrophies

    OpenAIRE

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-01-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e. when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles an...

  2. Congenital Myopathy

    Science.gov (United States)

    ... results in weakness. Congenital myopathy refers to a group of muscle disorders that appear at birth or in infancy. Typically, an infant with a congenital myopathy will be "floppy," have difficulty breathing or feeding, and will lag behind other babies in meeting ...

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

    Science.gov (United States)

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

    2014-01-01

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

  4. Quantitative Assessment of the T2 Relaxation Time of the Gluteus Muscles in Children with Duchenne Muscular Dystrophy: a Comparative Study Before and After Steroid Treatment

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hee Kyung; Laor, Tal; Wong, Brenda [Cincinnati Children' s Hospital Medical Center, Cincinnati (United States); Horn, Paul S. [University of Cincinnati, Cincinnati (United States)

    2010-06-15

    To determine the feasibility of using T2 mapping as a quantitative method to longitudinally follow the disease activity in children with Duchenne muscular dystrophy (DMD) who are treated with steroids. Eleven boys with DMD (age range: 5-14 years) underwent evaluation with the clinical functional score (CFS), and conventional pelvic MRI and T2 mapping before and during steroid therapy. The gluteus muscle inflammation and fatty infiltration were evaluated on conventional MRI. The histograms and mean T2 relaxation times were obtained from the T2 maps. The CFS, the conventional MRI findings and the T2 values were compared before and during steroid therapy. None of the patients showed interval change of their CFSs. On conventional MRI, none of the images showed muscle inflammation. During steroid treatment, two boys showed increased fatty infiltration on conventional MRI, and both had an increase of the mean T2 relaxation time (p < 0.05). The remaining nine boys had no increase in fatty infiltration. Of these, three showed an increased mean T2 relaxation time (p < 0.05), two showed no change and four showed a decreased mean T2 relaxation time (p < 0.05). T2 mapping is a feasible technique to evaluate the longitudinal muscle changes in those children who receive steroid therapy for DMD. The differences of the mean T2 relaxation time may reflect alterations in disease activity, and even when the conventional MRI and CFS remain stable.

  5. Quantitative Assessment of the T2 Relaxation Time of the Gluteus Muscles in Children with Duchenne Muscular Dystrophy: a Comparative Study Before and After Steroid Treatment

    International Nuclear Information System (INIS)

    Kim, Hee Kyung; Laor, Tal; Wong, Brenda; Horn, Paul S.

    2010-01-01

    To determine the feasibility of using T2 mapping as a quantitative method to longitudinally follow the disease activity in children with Duchenne muscular dystrophy (DMD) who are treated with steroids. Eleven boys with DMD (age range: 5-14 years) underwent evaluation with the clinical functional score (CFS), and conventional pelvic MRI and T2 mapping before and during steroid therapy. The gluteus muscle inflammation and fatty infiltration were evaluated on conventional MRI. The histograms and mean T2 relaxation times were obtained from the T2 maps. The CFS, the conventional MRI findings and the T2 values were compared before and during steroid therapy. None of the patients showed interval change of their CFSs. On conventional MRI, none of the images showed muscle inflammation. During steroid treatment, two boys showed increased fatty infiltration on conventional MRI, and both had an increase of the mean T2 relaxation time (p < 0.05). The remaining nine boys had no increase in fatty infiltration. Of these, three showed an increased mean T2 relaxation time (p < 0.05), two showed no change and four showed a decreased mean T2 relaxation time (p < 0.05). T2 mapping is a feasible technique to evaluate the longitudinal muscle changes in those children who receive steroid therapy for DMD. The differences of the mean T2 relaxation time may reflect alterations in disease activity, and even when the conventional MRI and CFS remain stable

  6. Upper Limb Evaluation in Duchenne Muscular Dystrophy: Fat-Water Quantification by MRI, Muscle Force and Function Define Endpoints for Clinical Trials.

    Directory of Open Access Journals (Sweden)

    Valeria Ricotti

    Full Text Available A number of promising experimental therapies for Duchenne muscular dystrophy (DMD are emerging. Clinical trials currently rely on invasive biopsies or motivation-dependent functional tests to assess outcome. Quantitative muscle magnetic resonance imaging (MRI could offer a valuable alternative and permit inclusion of non-ambulant DMD subjects. The aims of our study were to explore the responsiveness of upper-limb MRI muscle-fat measurement as a non-invasive objective endpoint for clinical trials in non-ambulant DMD, and to investigate the relationship of these MRI measures to those of muscle force and function.15 non-ambulant DMD boys (mean age 13.3 y and 10 age-gender matched healthy controls (mean age 14.6 y were recruited. 3-Tesla MRI fat-water quantification was used to measure forearm muscle fat transformation in non-ambulant DMD boys compared with healthy controls. DMD boys were assessed at 4 time-points over 12 months, using 3-point Dixon MRI to measure muscle fat-fraction (f.f.. Images from ten forearm muscles were segmented and mean f.f. and cross-sectional area recorded. DMD subjects also underwent comprehensive upper limb function and force evaluation.Overall mean baseline forearm f.f. was higher in DMD than in healthy controls (p<0.001. A progressive f.f. increase was observed in DMD over 12 months, reaching significance from 6 months (p<0.001, n = 7, accompanied by a significant loss in pinch strength at 6 months (p<0.001, n = 9 and a loss of upper limb function and grip force observed over 12 months (p<0.001, n = 8.These results support the use of MRI muscle f.f. as a biomarker to monitor disease progression in the upper limb in non-ambulant DMD, with sensitivity adequate to detect group-level change over time intervals practical for use in clinical trials. Clinical validity is supported by the association of the progressive fat transformation of muscle with loss of muscle force and function.

  7. Strabismus surgery in congenital fibrosis of the extraocular muscles: a paradigm.

    Science.gov (United States)

    Sener, Emin Cumhur; Taylan Sekeroglu, Hande; Ural, Ozlem; Oztürk, Banu Turgut; Sanaç, Ali Sefik

    2014-12-01

    Congenital fibrosis of extraocular muscles (CFEOM) is a rare group of disorders with variable phenotypes that result from aberrant innervation to the EOMs leading to synergistic vertical and/or horizontal deviations. We report our experience with the surgical management of patients with CFEOM. We reviewed the clinical findings, the surgical management, and outcomes of 52 consecutive CFEOM patients operated by one surgeon at a university hospital setting between 1993 and 2014. Patients were divided into CFEOM1, 2, or 3 based on clinical and/or molecular genetic findings. Thirty-seven (71.2%) cases were bilateral and 15 (28.8%) were unilateral. Six of the bilateral cases had CFEOM2, and the rest of the patients had either CFEOM1 or CFEOM3. The median age at the first surgery was 10 (1-43) years. Twenty-five were females and 27 were males. Nineteen patients had previous strabismus and/or ptosis surgeries elsewhere. The mean number of operations at our center was 1.6 ± 0.7 (1-4). A temporary stay suture was used in eight patients and permanently in seven. Of the 40 patients with abnormal head position, 18 achieved excellent, 15 good, and seven poor outcomes and ocular alignment in primary position following the latest surgery was excellent in 19, good in 18, and poor in 14 of the patients, as defined in the "Methods" section of the paper. Although patients with CFEOM present significant strabismus surgical challenges because of EOM dysinnervation, fibrosis, and/or heterotopia, satisfactory alignment and improvement of the head posture can be attained in a significant proportion of patients using an individually tailored surgical approach.

  8. Corneal dystrophies

    Directory of Open Access Journals (Sweden)

    Klintworth Gordon K

    2009-02-01

    Full Text Available Abstract The term corneal dystrophy embraces a heterogenous group of bilateral genetically determined non-inflammatory corneal diseases that are restricted to the cornea. The designation is imprecise but remains in vogue because of its clinical value. Clinically, the corneal dystrophies can be divided into three groups based on the sole or predominant anatomical location of the abnormalities. Some affect primarily the corneal epithelium and its basement membrane or Bowman layer and the superficial corneal stroma (anterior corneal dystrophies, the corneal stroma (stromal corneal dystrophies, or Descemet membrane and the corneal endothelium (posterior corneal dystrophies. Most corneal dystrophies have no systemic manifestations and present with variable shaped corneal opacities in a clear or cloudy cornea and they affect visual acuity to different degrees. Corneal dystrophies may have a simple autosomal dominant, autosomal recessive or X-linked recessive Mendelian mode of inheritance. Different corneal dystrophies are caused by mutations in the CHST6, KRT3, KRT12, PIP5K3, SLC4A11, TACSTD2, TGFBI, and UBIAD1 genes. Knowledge about the responsible genetic mutations responsible for these disorders has led to a better understanding of their basic defect and to molecular tests for their precise diagnosis. Genes for other corneal dystrophies have been mapped to specific chromosomal loci, but have not yet been identified. As clinical manifestations widely vary with the different entities, corneal dystrophies should be suspected when corneal transparency is lost or corneal opacities occur spontaneously, particularly in both corneas, and especially in the presence of a positive family history or in the offspring of consanguineous parents. Main differential diagnoses include various causes of monoclonal gammopathy, lecithin-cholesterol-acyltransferase deficiency, Fabry disease, cystinosis, tyrosine transaminase deficiency, systemic lysosomal storage

  9. Duchenne muscular dystrophy carriers

    International Nuclear Information System (INIS)

    Matsumura, K.; Nakano, I.

    1989-01-01

    By means of magnetic resonance imaging (MRI), the proton spin-lattice relaxation times (T1 values) of the skeletal muscles were measured in Duchenne muscular dystrophy (DMD) carriers and normal controls. The bound water fraction (BWF) was calculated from the T1 values obtained, according to the fast proton diffusion model. In the DMD carriers, T1 values of the gluteus maximus and quadriceps femoris muscles were significantly higher, and BWFs of these muscles were significantly lower than in normal control. Degenerative muscular changes accompanied by interstitial edema were presumed responsible for this abnormality. No correlation was observed between the muscle T1 and serum creatine kinase values. The present study showed that MRI could be a useful method for studying the dynamic state of water in both normal and pathological skeletal muscles. Its possible utility for DMD carrier detection was discussed briefly. (orig.)

  10. Muscular Dystrophy

    Science.gov (United States)

    ... Inheritance patterns Muscular dystrophy Symptoms & causes Diagnosis & treatment Advertisement Mayo Clinic does not endorse companies or products. ... a Job Site Map About This Site Twitter Facebook Google YouTube Pinterest Mayo Clinic is a not- ...

  11. Limb-Girdle Muscular Dystrophy (LGMD)

    Science.gov (United States)

    ... Program Funding Opportunities Contact our Research Team For Families Clinical Trials Finder Tool Get Involved How to ... with LGMD normally encode proteins that play vital roles in muscle function, ... genders are affected equally. When limb-girdle muscular dystrophy ...

  12. Functional and molecular effects of arginine butyrate and prednisone on muscle and heart in the mdx mouse model of Duchenne Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Alfredo D Guerron

    2010-06-01

    Full Text Available The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin.In this study, we have treated mdx mice with arginine butyrate, prednisone, or a combination of arginine butyrate and prednisone for 6 months, beginning at 3 months of age, and have comprehensively evaluated the functional, biochemical, histological, and molecular effects of the treatments in this DMD model. Arginine butyrate treatment improved grip strength and decreased fibrosis in the gastrocnemius muscle, but did not produce significant improvement in muscle and cardiac histology, heart function, behavioral measurements, or serum creatine kinase levels. In contrast, 6 months of chronic continuous prednisone treatment resulted in deterioration in functional, histological, and biochemical measures. Arginine butyrate-treated mice gene expression profiling experiments revealed that several genes that control cell proliferation, growth and differentiation are differentially expressed consistent with its histone deacetylase inhibitory activity when compared to control (saline-treated mdx mice. Prednisone and combination treated groups showed alterations in the expression of genes that control fibrosis, inflammation, myogenesis and atrophy.These data indicate that 6 months treatment with arginine butyrate can produce modest beneficial effects on dystrophic pathology in mdx mice by reducing fibrosis and promoting muscle function while chronic continuous treatment with prednisone showed deleterious effects to skeletal and cardiac muscle. Our results clearly indicate the usefulness of multiple assays systems to monitor both beneficial and toxic effects of drugs with broad range of in vivo activity.

  13. Quantitative T2 Combined with Texture Analysis of Nuclear Magnetic Resonance Images Identify Different Degrees of Muscle Involvement in Three Mouse Models of Muscle Dystrophy: mdx, Largemyd and mdx/Largemyd

    Science.gov (United States)

    Martins-Bach, Aurea B.; Malheiros, Jackeline; Matot, Béatrice; Martins, Poliana C. M.; Almeida, Camila F.; Caldeira, Waldir; Ribeiro, Alberto F.; Loureiro de Sousa, Paulo; Azzabou, Noura; Tannús, Alberto; Carlier, Pierre G.; Vainzof, Mariz

    2015-01-01

    Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant—T2—measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p<0.05), in addition to higher muscle T2 in the mdx/Largemyd mice when compared to mdx (p<0.05). The areas with increased muscle T2 in the MRI correlated spatially with the identified histopathological alterations such as necrosis, inflammation, degeneration and regeneration foci. Nevertheless, muscle T2 values were not correlated with the severity of the phenotype in the 3 dystrophic mouse strains, since the severely affected Largemyd showed similar values than both the mild mdx and worst mdx/Largemyd lineages. On the other hand, all studied mouse strains could be unambiguously identified with texture analysis, which reflected the observed differences in the distribution of signals in muscle MRI. Thus, combined T2 intensity maps and texture analysis is a powerful approach for the characterization and differentiation of dystrophic muscles with diverse genotypes and phenotypes. These new findings provide important noninvasive tools in the evaluation of the efficacy of new therapies, and most importantly, can be directly applied in human translational research

  14. Physiology of respiratory disturbances in muscular dystrophies.

    Science.gov (United States)

    Lo Mauro, Antonella; Aliverti, Andrea

    2016-12-01

    Muscular dystrophy is a group of inherited myopathies characterised by progressive skeletal muscle wasting, including of the respiratory muscles. Respiratory failure, i.e . when the respiratory system fails in its gas exchange functions, is a common feature in muscular dystrophy, being the main cause of death, and it is a consequence of lung failure, pump failure or a combination of the two. The former is due to recurrent aspiration, the latter to progressive weakness of respiratory muscles and an increase in the load against which they must contract. In fact, both the resistive and elastic components of the work of breathing increase due to airway obstruction and chest wall and lung stiffening, respectively. The respiratory disturbances in muscular dystrophy are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered breathing. They can be present at different rates according to the type of muscular dystrophy and its progression, leading to different onset of each symptom, prognosis and degree of respiratory involvement. A common feature of muscular dystrophy is respiratory failure, i.e. the inability of the respiratory system to provide proper oxygenation and carbon dioxide elimination.In the lung, respiratory failure is caused by recurrent aspiration, and leads to hypoxaemia and hypercarbia.Ventilatory failure in muscular dystrophy is caused by increased respiratory load and respiratory muscles weakness.Respiratory load increases in muscular dystrophy because scoliosis makes chest wall compliance decrease, atelectasis and fibrosis make lung compliance decrease, and airway obstruction makes airway resistance increase.The consequences of respiratory pump failure are restrictive pulmonary function, hypoventilation, altered thoracoabdominal pattern, hypercapnia, dyspnoea, impaired regulation of breathing, inefficient cough and sleep disordered

  15. Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report.

    Science.gov (United States)

    Nair, Velu; Das, Satyaranjan; Sharma, Ajay; Sharma, Sanjeevan; Kaur, Jasmeet; Mishra, Dk

    2011-06-04

    Diamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental. We report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemia and Duchenne muscular dystrophy who underwent successful allogeneic hematopoietic stem cell transplantation. He is transfusion-independent, and his Duchenne muscular dystrophy has shown no clinical deterioration over the past 45 months. His creatine phosphokinase levels have significantly decreased to 300 U/L from 14,000 U/L pre-transplant. The patient is 100% donor chimera in the hematopoietic system, and his muscle tissue has shown 8% to 10.4% cells of donor origin. Our patient's Diamond-Blackfan anemia was cured by allogeneic hematopoietic stem cell transplantation. The interesting clinical observation of a possible benefit in Duchenne muscular dystrophy cannot be ruled out. However, further clinical follow-up with serial muscle biopsies and molecular studies are needed to establish this finding.

  16. Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report

    Directory of Open Access Journals (Sweden)

    Kaur Jasmeet

    2011-06-01

    Full Text Available Abstract Introduction Diamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental. Case presentation We report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemia and Duchenne muscular dystrophy who underwent successful allogeneic hematopoietic stem cell transplantation. He is transfusion-independent, and his Duchenne muscular dystrophy has shown no clinical deterioration over the past 45 months. His creatine phosphokinase levels have significantly decreased to 300 U/L from 14,000 U/L pre-transplant. The patient is 100% donor chimera in the hematopoietic system, and his muscle tissue has shown 8% to 10.4% cells of donor origin. Conclusion Our patient's Diamond-Blackfan anemia was cured by allogeneic hematopoietic stem cell transplantation. The interesting clinical observation of a possible benefit in Duchenne muscular dystrophy cannot be ruled out. However, further clinical follow-up with serial muscle biopsies and molecular studies are needed to establish this finding.

  17. Spectrum of congenital mitral valve abnormalities associated with solitary undifferentiated papillary muscle in adults

    Directory of Open Access Journals (Sweden)

    Jagdish C. Mohan

    2016-09-01

    Conclusion: In adult patients, a high index of suspicion is required to detect congenital mitral stenosis/regurgitation with large solitary PM (resembling a parachute mitral valve which may masquerade as hypertrophic cardiomyopathy or rheumatic mitral valve disease.

  18. The Link Between Stress Disorders and Autonomic Dysfunction in Muscular Dystrophy

    OpenAIRE

    Rasna eSabharwal

    2014-01-01

    Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this p...

  19. Implications of compound heterozygous insulin receptor mutations in congenital muscle fibre type disproportion myopathy for the receptor kinase activation

    DEFF Research Database (Denmark)

    Klein, H H; Müller, R; Vestergaard, H

    1999-01-01

    We studied insulin receptor kinase activation in two brothers with congenital muscle fibre type disproportion myopathy and compound heterozygous mutations of the insulin receptor gene, their parents, and their unaffected brother. In the father who has a heterozygote Arg1174-->Gln mutation, in situ...... activation of the receptor kinase in skeletal muscle was reduced about 70%. Selection of only those receptors that bound to anti-phosphotyrosine antibody showed that these receptors had normal kinase activity and that the reduction in overall kinase activity was due to the inability of about 70......% of the receptors to become insulin-dependently activated. The mother carries a point mutation at the last base pair in exon 17 which, due to abnormal alternative splicing, could lead to normally transcribed receptor or truncated receptor lacking the kinase region. Kinase activation was normal in the mother...

  20. Structural myocardial involvement in adult patients with type 1 myotonic dystrophy

    Directory of Open Access Journals (Sweden)

    Upinder K. Dhand

    2013-03-01

    Full Text Available Myotonic dystrophy type 1 (DM1 is the commonest muscular dystrophy in adults, affecting multiple organs in addition to skeletal muscles. Cardiac conduction system abnormalities are well recognized as an important component of DM1 phenotype; however, primary structural myocardial abnormalities, which may predispose these patients to congestive heart failure, are not as well characterized. We reviewed the retrospective analysis of the clinical and echocardiographic findings in adult patients with DM1. Among 27 patients (16 male; age 19-61 years with DM1, the echocardiogram (ECHO was abnormal in 10 (37% including one of 6 patients (16% with congenital myotonic dystrophy. Reduced left ventricular ejection fraction (LVEF ≤50% was noted in 5, diastolic dysfunction in 4, left atrial dilatation in 3, left ventricular hypertrophy in 2, apical hypokinesia in 1 and mitral valve prolapse in 3 patients. One patient had paradoxical septal movement in the setting of left bundle branch block. Echocardiographic abnormalities significantly correlated with older age; however, patients with systolic dysfunction on echocardiogram ranged in age from 27 to 52 years including 2 patients aged 27 and 34 years. We can conclude that echocardiographic abnormalities are frequent in adult patients with DM1. The incidence is similar in the classical and congenital type of DM1. Overall, echocardiographic abnormalities in DM1 correlate with increasing age; however, reduced LVEF is observed even at young age. Cardiac assessment and monitoring in adult patients with DM1 should include evaluation for primary myocardial involvement.

  1. Congenital myopathies with secondary neuromuscular transmission defects; a case report and review of the literature.

    Science.gov (United States)

    Rodríguez Cruz, Pedro M; Sewry, Caroline; Beeson, David; Jayawant, Sandeep; Squier, Waney; McWilliam, Robert; Palace, Jacqueline

    2014-12-01

    Congenital myopathies are a clinically and genetically heterogeneous group of disorders characterized by early onset hypotonia, weakness and characteristic, but not pathognomonic, structural abnormalities in muscle fibres. The clinical features overlap with muscular dystrophies, myofibrillar myopathies, neurogenic conditions and congenital myasthenic syndromes. We describe a case of cap myopathy with myasthenic features due to a mutation in the TPM2 gene that responded to anticholinesterase therapy. We also review other published cases of congenital myopathies with neuromuscular transmission abnormalities. This report expands the spectrum of congenital myopathies with secondary neuromuscular transmission defects. The recognition of these cases is important since these conditions can benefit from treatment with drugs enhancing neuromuscular transmission. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations.

    Science.gov (United States)

    Demer, Joseph L; Clark, Robert A; Tischfield, Max A; Engle, Elizabeth C

    2010-09-01

    Orbital magnetic resonance imaging (MRI) was used to investigate the structural basis of motility abnormalities in congenital fibrosis of the extraocular muscles type 3 (CFEOM3), a disorder resulting from missense mutations in TUBB3, which encodes neuron-specific beta-tubulin isotype III. Ophthalmic examinations in 13 volunteers from four CFEOM3 pedigrees and normal control subjects, were correlated with TUBB3 mutation and MRI findings that demonstrated extraocular muscle (EOM) size, location, contractility, and innervation. Volunteers included clinically affected and clinically unaffected carriers of R262C and D417N TUBB3 amino acid substitutions and one unaffected, mutation-negative family member. Subjects with CFEOM3 frequently had asymmetrical blepharoptosis, limited vertical duction, variable ophthalmoplegia, exotropia, and paradoxical abduction in infraduction. MRI demonstrated variable, asymmetrical levator palpebrae superioris and superior rectus EOM atrophy that correlated with blepharoptosis, deficient supraduction, and small orbital motor nerves. Additional EOMs exhibited variable hypoplasia that correlated with duction deficit, but the superior oblique muscle was spared. Ophthalmoplegia occurred only when the subarachnoid width of CN3 was muscle misinnervation by CN3. Optic nerve (ON) cross sections were subnormal, but rectus pulley locations were normal. CFEOM3 caused by TUBB3 R262C and D417N amino acid substitutions features abnormalities of EOM innervation and function that correlate with subarachnoid CN3 hypoplasia, occasional abducens nerve hypoplasia, and subclinical ON hypoplasia that can resemble CFEOM1. Clinical and MRI findings in CFEOM3 are more variable than those in CFEOM1 and are often asymmetrical. Apparent LR innervation by the inferior rectus motor nerve is an overlapping feature of Duane retraction syndrome and CFEOM1. These findings suggest that CFEOM3 is an asymmetrical, variably penetrant, congenital cranial dysinnervation disorder

  3. Muscle magnetic resonance imaging and histopathology in ACTA1-related congenital nemaline myopathy.

    Science.gov (United States)

    Castiglioni, Claudia; Cassandrini, Denis; Fattori, Fabiana; Bellacchio, Emanuele; D'Amico, Adele; Alvarez, Karin; Gejman, Roger; Diaz, Jorge; Santorelli, Filippo M; Romero, Norma B; Bertini, Enrico; Bevilacqua, Jorge A

    2014-12-01

    Muscle biopsy is usually diagnostic in nemaline myopathy (NM), but some patients may show nonspecific findings, leading to pitfalls in diagnosis. Muscle MRI is a helpful complementary tool. We assessed the clinical, histopathological, MRI, and molecular findings in a 19-year-old patient with NM in whom 2 muscle biopsies with ultrastructural examination showed no nemaline bodies. We analyzed the degree and pattern of muscle MRI involvement of the entire body, including the tongue and pectoral muscles. Muscle MRI abnormalities in sartorius, adductor magnus, and anterior compartment muscles of the leg suggested NM. A previously unreported fatty infiltration of the tongue was found. A third biopsy after the muscle MRI showed scant nemaline bodies. A novel heterozygous de novo ACTA1 c.611C>T/p.Thr204Ile mutation was detected. We highlight the contribution of muscle imaging in addressing the genetic diagnosis of ACTA1-related NM. © 2014 Wiley Periodicals, Inc.

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

    NARCIS (Netherlands)

    Negroni, E.; Henault, E.; Chevalier, F.; Gilbert-Sirieix, M.; Kuppevelt, T.H. van; Papy-Garcia, D.; Uzan, G.; Albanese, P.

    2014-01-01

    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

  5. Deletion of Galgt2 (B4Galnt2) reduces muscle growth in response to acute injury and increases muscle inflammation and pathology in dystrophin-deficient mice.

    Science.gov (United States)

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

    2015-10-01

    Transgenic overexpression of Galgt2 (official name B4Galnt2) in skeletal muscle stimulates the glycosylation of α dystroglycan (αDG) and the up-regulation of laminin α2 and dystrophin surrogates known to inhibit muscle pathology in mouse models of congenital muscular dystrophy 1A and Duchenne muscular dystrophy. Skeletal muscle Galgt2 gene expression is also normally increased in the mdx mouse model of Duchenne muscular dystrophy compared with the wild-type mice. To assess whether this increased endogenous Galgt2 expression could affect disease, we quantified muscular dystrophy measures in mdx mice deleted for Galgt2 (Galgt2(-/-)mdx). Galgt2(-/-) mdx mice had increased heart and skeletal muscle pathology and inflammation, and also worsened cardiac function, relative to age-matched mdx mice. Deletion of Galgt2 in wild-type mice also slowed skeletal muscle growth in response to acute muscle injury. In each instance where Galgt2 expression was elevated (developing muscle, regenerating muscle, and dystrophic muscle), Galgt2-dependent glycosylation of αDG was also increased. Overexpression of Galgt2 failed to inhibit skeletal muscle pathology in dystroglycan-deficient muscles, in contrast to previous studies in dystrophin-deficient mdx muscles. This study demonstrates that Galgt2 gene expression and glycosylation of αDG are dynamically regulated in muscle and that endogenous Galgt2 gene expression can ameliorate the extent of muscle pathology, inflammation, and dysfunction in mdx mice. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Duchenne muscular dystrophy.

    Science.gov (United States)

    Yiu, Eppie M; Kornberg, Andrew J

    2015-08-01

    Duchenne muscular dystrophy, an X-linked disorder, has an incidence of one in 5000 boys and presents in early childhood with proximal muscle weakness. Untreated boys become wheelchair bound by the age of 12 years and die of cardiorespiratory complications in their late teens to early 20s. The use of corticosteroids, non-invasive respiratory support, and active surveillance and management of associated complications have improved ambulation, function, quality of life and life expectancy. The clinical features, investigations and management of Duchenne muscular dystrophy are reviewed, as well as the latest in some of the novel therapies. © 2015 The Authors. Journal of Paediatrics and Child Health © 2015 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

  7. The quantitative in vivo analysis of the muscle degeneration in Duchenne type muscular dystrophy using NMR-CT

    International Nuclear Information System (INIS)

    Ikehira, Hiroo; Aoki, Yoshio; Matsumura, Kiichiro

    1986-01-01

    In order to develop a simple noninvasive method to determine progressive stages of Duchenne type muscular dystrophy (DMD), we proposed two muscular degeneration parameters calculated from NMR-CT data. The parameters are W.C.P. (water concentration parameter) and F.C.P. (fat concentration parameter). We examined 15 normal male and 10 normal female volunteers, 19 carrier females and 21 DMD patients. The normal value indicated 0 to 30 % F.C.P., while the results of DMD patients showed abnormally high W.C.P. at the early stage and increased F.C.P. corresponding to the clinical stages (Ueda's disability stages). But there was not any difference between the DMD carrier's data and the control data. The present study suggested the possibilities of clinical stagings and early detection of DMD with the parameters. (author)

  8. Prednisone Therapy for Duchenne Dystrophy

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2005-02-01

    Full Text Available The effects of prednisone on muscle function and the extent of steroid-related adverse effects were studied in 17 ambulant children with Duchenne muscular dystrophy (DMD at University Hospital, Groningen; Rehabilitation Centre, Utrecht; and Leiden University Medical Centre, the Netherlands.

  9. Faecal incontinence in myotonic dystrophy

    OpenAIRE

    Abercrombie, J; Rogers, J; Swash, M

    1998-01-01

    Two siblings with myotonic dystrophy presented for treatment of faecal incontinence. The pathophysiology of this functional disorder is described with the results of anorectal manometry, EMG, and biopsy of smooth and striated muscle of the anorectal sphincters. Both medical and surgical management of the incontinence was unsatisfactory in the long term. Involvement of gastrointestinal musculature is a characteristic feature the disease.



  10. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    International Nuclear Information System (INIS)

    Wu, Hsu-Pin; Hsu, Shu-Yuan; Wu, Wen-Ai; Hu, Ji-Wei; Ouyang, Pin

    2014-01-01

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB +/− mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity

  11. Transgenic mice expressing mutant Pinin exhibit muscular dystrophy, nebulin deficiency and elevated expression of slow-type muscle fiber genes

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Hsu-Pin; Hsu, Shu-Yuan [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Wu, Wen-Ai; Hu, Ji-Wei [Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Ouyang, Pin, E-mail: ouyang@mail.cgu.edu.tw [Department of Anatomy, Chang Gung University Medical College, Taiwan (China); Transgenic Mouse Core Laboratory, Chang Gung University, Taiwan (China); Molecular Medicine Research Center, Chang Gung University, Taiwan (China)

    2014-01-03

    Highlights: •Pnn CCD domain functions as a dominant negative mutant regulating Pnn expression and function. •Pnn CCD mutant Tg mice have a muscle wasting phenotype during development and show dystrophic histological features. •Pnn mutant muscles are susceptible to slow fiber type gene transition and NEB reduction. •The Tg mouse generated by overexpression of the Pnn CCD domain displays many characteristics resembling NEB{sup +/−} mice. -- Abstract: Pinin (Pnn) is a nuclear speckle-associated SR-like protein. The N-terminal region of the Pnn protein sequence is highly conserved from mammals to insects, but the C-terminal RS domain-containing region is absent in lower species. The N-terminal coiled-coil domain (CCD) is, therefore, of interest not only from a functional point of view, but also from an evolutionarily standpoint. To explore the biological role of the Pnn CCD in a physiological context, we generated transgenic mice overexpressing Pnn mutant in skeletal muscle. We found that overexpression of the CCD reduces endogenous Pnn expression in cultured cell lines as well as in transgenic skeletal muscle fibers. Pnn mutant mice exhibited reduced body mass and impaired muscle function during development. Mutant skeletal muscles show dystrophic histological features with muscle fibers heavily loaded with centrally located myonuclei. Expression profiling and pathway analysis identified over-representation of genes in gene categories associated with muscle contraction, specifically those related to slow type fiber. In addition nebulin (NEB) expression level is repressed in Pnn mutant skeletal muscle. We conclude that Pnn downregulation in skeletal muscle causes a muscular dystrophic phenotype associated with NEB deficiency and the CCD domain is incapable of replacing full length Pnn in terms of functional capacity.

  12. Dystrophin analysis in carriers of Duchenne and Becker muscular dystrophy

    NARCIS (Netherlands)

    Hoogerwaard, Edo M.; Ginjaar, Ieke B.; Bakker, Egbert; de Visser, Marianne

    2005-01-01

    Associations between clinical phenotype (muscle weakness, dilated cardiomyopathy) and dystrophin abnormalities in muscle tissue among definite carriers of Duchenne (DMD) and Becker muscular dystrophy (BMD) were investigated. No associations between dystrophin abnormalities and clinical variables in

  13. Signs and symptoms of Duchenne muscular dystrophy and Becker muscular dystrophy among carriers in the Netherlands : a cohort study

    NARCIS (Netherlands)

    Hoogerwaard, EM; Bakker, E; Ippel, PF; Oosterwijk, JC; Majoor-Krakauer, DF; Leschot, NJ; Van Essen, AJ; Brunner, HG; van der Wouw, PA; Wilde, AAM; de Visser, Marianne

    1999-01-01

    Background Carriers of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) may show muscle weakness or dilated cardiomyopathy. Studies focusing on skeletal-muscle involvement were done before DNA analysis was possible. We undertook a cross-sectional study in a population of

  14. Immunohistochemistry of sarcolemmal membrane-associated proteins in formalin-fixed and paraffin-embedded skeletal muscle tissue: a promising tool for the diagnostic evaluation of common muscular dystrophies.

    Science.gov (United States)

    Suriyonplengsaeng, Chinnawut; Dejthevaporn, Charungthai; Khongkhatithum, Chaiyos; Sanpapant, Suda; Tubthong, Nattha; Pinpradap, Koset; Srinark, Nippa; Waisayarat, Jariya

    2017-02-20

    The analysis of fresh frozen muscle specimens is standard following routine muscle biopsy, but this service is not widely available in countries with limited medical facilities, such as Thailand. Nevertheless, immunohistochemistry (IHC) analysis is essential for the diagnosis of patients with a strong clinical suspicion of muscular dystrophy, in the absence of mutations detected by molecular genetics. As the successful labelling of sarcolemmal membrane-associated proteins in formalin-fixed and paraffin-embedded (FFPE) muscle sections using IHC staining has rarely been described, this study aimed to develop a reproducible IHC method for such an analysis. Thirteen cases were studied from the files of the Department of Pathology, Mahidol University. Diagnoses included three Duchenne muscular dystrophy (DMD), one Becker muscular dystrophy (BMD), one dysferlinopathy, and several not-specified muscular dystrophies. IHC was performed on FFPE sections at different thicknesses (3 μm, 5 μm, and 8 μm) using the heat-mediated antigen retrieval method with citrate/EDTA buffer, followed by an overnight incubation with primary antibodies at room temperature. Antibodies against spectrin, dystrophin (rod domain, C-terminus, and N-terminus), dysferlin, sarcoglycans (α, β, and γ), and β-dystroglycan were used. Frozen sections were tested in parallel for comparative analysis. Antibodies labelling spectrin, dystrophin (rod domain and C-terminus), dysferlin, sarcoglycans (α, β, and γ), and β-dystroglycan clearly exhibited sarcolemmal staining in FFPE sections. However, staining of FFPE sections using the antibody directed against the N-terminus of dystrophin was unsuccessful. The absence of labeling for dystrophins and dysferlin in FFPE sections was documented in all three DMD patients and the dysferlinopathy patient. The BMD diagnosis could not be made using IHC in FFPE sections alone because of a lack of staining for the dystrophin N-terminus, indicating a limitation of

  15. CT finding and cerebrospinal fluid proteins in muscular dystrophy patients

    International Nuclear Information System (INIS)

    Hirase, Tsutomu; Ide, Masami; Araki, Shukuro; Okamoto, Hiroshi; Kawasaki, Shoichiro; Imamura, Shigehiro.

    1983-01-01

    We analyzed the microcomponents of protein fractions in the cerebrospinal fluid of patients with various types of muscular dystrophy. The degenerative pattern is characterized by an increase in the prealbumin and a decrease in the γ-globulin fraction is shown in the Duchenne and congenital muscular dystrophy. The increase in CSF IgG, γ-globulin fraction is shown in the myotonic dystrophy. In addition to the abnormality of IQ, EEG, and brain CT, abnormal CSF proteins obviously suggest the presence of CNS involvement in muscular dystrophy. (author)

  16. Analysis of fatty infiltration and inflammation of the pelvic and thigh muscles in boys with Duchenne muscular dystrophy (DMD): grading of disease involvement on MR imaging and correlation with clinical assessments.

    Science.gov (United States)

    Kim, Hee Kyung; Merrow, Arnold C; Shiraj, Sahar; Wong, Brenda L; Horn, Paul S; Laor, Tal

    2013-10-01

    Prior reports focus primarily on muscle fatty infiltration in Duchenne muscular dystrophy (DMD). However, the significance of muscle edema is uncertain. To evaluate the frequency and degree of muscle fat and edema, and correlate these with clinical function. Forty-two boys (ages 5-19 years) with DMD underwent pelvic MRI. Axial T1- and fat-suppressed T2-weighted images were evaluated to grade muscle fatty infiltration (0-4) and edema (0-3), respectively. Degree and frequency of disease involvement were compared to clinical evaluations. Gluteus maximus had the greatest mean fatty infiltration score, followed by adductor magnus and gluteus medius muscles, and had the most frequent and greatest degree of fatty infiltration. Gluteus maximus also had the greatest mean edema score, followed by vastus lateralis and gluteus medius muscles. These muscles had the most frequent edema, although the greatest degree of edema was seen in other muscles. There was correlation between cumulative scores of fatty infiltration and all clinical evaluations (P < 0.05). In DMD, the muscles with the most frequent fatty infiltration had the greatest degree of fatty infiltration and correlated with patient function. However, the muscles with the most frequent edema were different from those with the greatest degree of edema. Thus, edema may not predict patient functional status.

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

    National Research Council Canada - National Science Library

    Gonzalez, Nestor F

    2008-01-01

    ...) Wt MDSC express an embryonic stem cell marker Oct-4 and cells positive for this marker were located in vivo in the skeletal muscle using a transgenic mouse model that detects Oct-4 expression with a reporter gene; 3...

  18. Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy.

    Science.gov (United States)

    Viggiano, Emanuela; Ergoli, Manuela; Picillo, Esther; Politano, Luisa

    2016-07-01

    Duchenne and Becker dystrophinopathies (DMD and BMD) are X-linked recessive disorders caused by mutations in the dystrophin gene that lead to absent or reduced expression of dystrophin in both skeletal and heart muscles. DMD/BMD female carriers are usually asymptomatic, although about 8 % may exhibit muscle or cardiac symptoms. Several mechanisms leading to a reduced dystrophin have been hypothesized to explain the clinical manifestations and, in particular, the role of the skewed XCI is questioned. In this review, the mechanism of XCI and its involvement in the phenotype of BMD/DMD carriers with both a normal karyotype or with X;autosome translocations with breakpoints at Xp21 (locus of the DMD gene) will be analyzed. We have previously observed that DMD carriers with moderate/severe muscle involvement, exhibit a moderate or extremely skewed XCI, in particular if presenting with an early onset of symptoms, while DMD carriers with mild muscle involvement present a random XCI. Moreover, we found that among 87.1 % of the carriers with X;autosome translocations involving the locus Xp21 who developed signs and symptoms of dystrophinopathy such as proximal muscle weakness, difficulty to run, jump and climb stairs, 95.2 % had a skewed XCI pattern in lymphocytes. These data support the hypothesis that skewed XCI is involved in the onset of phenotype in DMD carriers, the X chromosome carrying the normal DMD gene being preferentially inactivated and leading to a moderate-severe muscle involvement.

  19. Phenotype-Genotype Analysis of Chinese Patients with Early-Onset LMNA-Related Muscular Dystrophy.

    Directory of Open Access Journals (Sweden)

    Dandan Tan

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

  20. Merosin/laminin-2 and muscular dystrophy

    DEFF Research Database (Denmark)

    Wewer, U M; Engvall, E

    1996-01-01

    and skin. Merosin is the collective name for laminins that share a common subunit, the laminin alpha 2 chain. Merosin-deficient congenital muscular dystrophy (CMD) is caused by mutations in the laminin alpha 2 chain gene. The skin disease Herlitz junctional epidermolysis bullosa is caused by mutations...

  1. Inspiratory muscle strength training in infants with congenital heart disease and prolonged mechanical ventilation: a case report.

    Science.gov (United States)

    Smith, Barbara K; Bleiweis, Mark S; Neel, Cimaron R; Martin, A Daniel

    2013-02-01

    Inspiratory muscle strength training (IMST) has been shown to improve maximal pressures and facilitate ventilator weaning in adults with prolonged mechanical ventilation (MV). The purposes of this case report are: (1) to describe the rationale for IMST in infants with MV dependence and (2) to summarize the device modifications used to administer training. Two infants with congenital heart disease underwent corrective surgery and were referred for inspiratory muscle strength evaluation after repeated weaning failures. It was determined that IMST was indicated due to inspiratory muscle weakness and a rapid, shallow breathing pattern. In order to accommodate small tidal volumes of infants, 2 alternative training modes were devised. For infant 1, IMST consisted of 15-second inspiratory occlusions. Infant 2 received 10-breath sets of IMST through a modified positive end-expiratory pressure valve. Four daily IMST sets separated by 3 to 5 minutes of rest were administered 5 to 6 days per week. The infants' IMST tolerance was evaluated by vital signs and daily clinical reviews. Maximal inspiratory pressure (MIP) and rate of pressure development (dP/dt) were the primary outcome measures. Secondary outcome measures included the resting breathing pattern and MV weaning. There were no adverse events associated with IMST. Infants generated training pressures through the adapted devices, with improved MIP, dP/dt, and breathing pattern. Both infants weaned from MV to a high-flow nasal cannula, and neither required subsequent reintubation during their hospitalization. This case report describes pediatric adaptations of an IMST technique used to improve muscle performance and facilitate weaning in adults. Training was well tolerated in 2 infants with postoperative weaning difficulty and inspiratory muscle dysfunction. Further systematic examination will be needed to determine whether IMST provides a significant performance or weaning benefit.

  2. Congenital agenesis of the superficial posterior compartment calf muscles in a 13-month-old infant.

    Science.gov (United States)

    Kang, Jin Young; Jang, Dae-Hyun

    2014-11-01

    Muscle agenesis may induce cosmetic and functional deficits, particularly if the muscle is an axial limb or a large muscle. Limb muscle agenesis is a rare condition. Here, the authors report the case of a 13-mo-old girl with unilateral atrophic calf and gait abnormality. Magnetic resonance imaging confirmed agenesis of the posterior superficial compartment of the calf. The patient showed an out-toeing calcaneal gait and fibular length discrepancy secondarily during growth. Normal embryology and the differential diagnostic point of foot deformity as well as the clinical implications of calf agenesis are described.

  3. Congenital tri-cavernous hemangiomas of the right buccal region, right accessory parotid gland, and masseter muscle region.

    Science.gov (United States)

    Yang, Tao; Gu, Yongchun; Zhang, Li; Hua, Zequan

    2014-03-01

    We report a rare case of congenital tri-cavernous hemangiomas of the right buccal region, right accessory parotid gland, and masseter muscle region in an adult. The patient, a 25-year-old woman, complained of 3 masses in her right midcheek. Ultrasonographic and computed tomographic findings showed an irregular-shaped mass (multiple calcifications) with a well-defined margin in the masseter muscle region, an ellipse-shaped mass (multiple calcifications) with a well-defined margin in the right buccal region, and a comma-shaped mass (no calcifications) with a well-defined margin separate from the parotid gland in the right accessory parotid gland region. These iconographic findings suggested that the masses were all hemangiomas separately originating from the parotid gland, accessory parotid gland, and masseter muscle. The masses were completely removed through a standard parotid incision without postoperative facial palsy, skin deformity, and difficulty in secreting saliva. Findings from histologic examination of the tumor revealed multiple, thin-walled, and dilated blood vessels, confirming the diagnosis of cavernous hemangiomas. Ultrasonographic and computed tomographic findings were extremely useful in diagnosing the mass/masses as hemangioma before surgery, clarifying relationships between the mass and adjacent structures, and determining the surgical approach to the mass/masses.

  4. Muscular Dystrophy

    Science.gov (United States)

    ... weakness typically begin? Ranges from early childhood to late adulthood Which muscles usually show weakness first? Shoulders, hips ... When does muscle weakness typically begin? Ranges from late teens to adulthood Which muscles usually show weakness first? Lower arms, ...

  5. Duchenne muscular dystrophy: current cell therapies.

    Science.gov (United States)

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

    2015-07-01

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

  6. Duchenne muscular dystrophy: current cell therapies

    OpenAIRE

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

    2015-01-01

    Duchenne muscular dystrophy is a genetically determined X-linked disease and the most common, progressive pediatric muscle disorder. For decades, research has been conducted to find an effective therapy. This review presents current therapeutic methods for Duchenne muscular dystrophy, based on scientific articles in English published mainly in the period 2000 to 2014. We used the PubMed database to identify and review the most important studies. An analysis of contemporary studies of stem cel...

  7. Modulation of Stem Cells Differentiation and Myostatin as an approach to Counteract fibrosis in Muscle Dystrophy and Regeneration after Injury

    Science.gov (United States)

    2010-03-01

    from umbilical cord blood differentiate into myotubes and express dystrophin in vitro only after exposure to in vivo muscle environment. Biol Cell...and may be painful during intercourse. Despite its typical fibrotic histopathology, this condition is not associated with other localized or diffuse...synthase (PnNOS) and its regulatory proteins are present in hypothalamic and spinal cord regions involved in the control of penile erection. J Compar

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

    Science.gov (United States)

    2008-03-01

    Fibroblast differentiation in wound healing and fibrosis. Int Rev Cytol 2007; 257:143-79 48: Carrier S , Nagaraju P, Morgan DM, Baba K, Nunes L, Lue TF...147 141–154. Sulyok S , Wankell M, Alzheimer C & Werner S 2004 Activin: an important regulator of wound repair, fibrosis, and neuroprotection...McCroskery S , Thomas M, Platt L, Hennebry A, Nishimura T, McLeay L, Sharma M, Kambadur R. Improved muscle healing through enhanced regen- eration and

  9. The Sonographic Correlation between The Sternocleidomastoid Muscle Thickness and the Prognosis of Congenital Muscular Torticollis

    International Nuclear Information System (INIS)

    Lim, Dae Keon; Kwon, Woo Cheol; Cha, Seung Whan; Yoo, Ho Seok; Lim, Sang Hyeok; Park, Jeong Mee; Kim, Myung Soon

    2009-01-01

    We wanted to predict the prognosis of patients with CMT by the A/N ratio of the thickness and the circumference of the SCM muscle on ultrasonography, and we wanted to correlate the echogenecity of the affected muscle and the prognosis. Ultrasonography was performed on 24 patients from June 2004 to March 2007. We measured the thickness and the cross sectional circumference of the SCM muscle at three levels; below the mastoid process, at the level of the carotid artery bifurcation and at the level of the sternum and clavicle. The ratio of the affected side to the normal side (the A/N ratio) of the SCM muscle was calculated. We performed followed up ultrasonography at 2 months intervals until the end of treatment. The Wilcoxon signed-rank test was used to correlate the A/N ratio before and after the treatment. Spearman's rank test was used to correlate the A/N ratio and the total treatment duration. Paired T-tests were used to correlate the echogenecity of the SCM muscle and the treatment duration divided by less than or greater than 12 months. With measuring the thickness of the SCM muscle, the A/N ratio after treatment (1.36) was decreased compared with the initial A/N ratio (2.31) (p<0.05). The correlation between the A/N ratio of the thickness with the total treatment duration was statistically significant (p<0.05). The echogenecity of the affected SCM muscle was not correlated with the duration of treatment. The A/N ratio of the thickness of the SCM muscle is useful to predict the prognosis of patients with CMT

  10. Clinical, radiological, and genetic survey of patients with muscle-eye-brain disease caused by mutations in POMGNT1.

    Science.gov (United States)

    Yiş, Uluç; Uyanik, Gökhan; Rosendahl, Deborah Morris; Carman, Kürşat Bora; Bayram, Erhan; Heise, Marisol; Cömertpay, Gamze; Kurul, Semra Hız

    2014-05-01

    To evaluate clinical, genetic, and radiologic features of our patients with muscle-eye-brain disease. The data of patients who were diagnosed with muscle-eye-brain disease from a cohort of patients with congenital muscular dystrophy in the Division of Pediatric Neurology of Dokuz Eylül University School of Medicine and Gaziantep Children's Hospital between 2005 and 2013 were analyzed retrospectively. From a cohort of 34 patients with congenital muscular dystrophy, 12 patients from 10 families were diagnosed with muscle-eye-brain disease. The mean age of the patients was 9 ± 5.5 years (2-19 years). Mean serum creatine kinase value was 2485.80 ± 1308.54 IU/L (700-4267 IU/L). All patients presented with muscular hypotonia at birth followed by varying degrees of spasticity and exaggerated deep tendon reflexes in later stages of life. Three patients were able to walk. The most common ophthalmologic and radiologic abnormalities were cataracts, retinal detachment, periventricular white matter abnormalities, ventriculomegaly, pontocerebellar hypoplasia, and multiple cerebellar cysts. All of the patients had mutations in the POMGNT1 gene. The most common mutation detected in 66% of patients was c.1814 G > A (p.R605H). Two novel mutations were identified. We suggest that muscle-eye-brain disease is a relatively common muscular dystrophy in Turkey. It should be suspected in patients with muscular hypotonia, increased creatine kinase, and structural eye and brain abnormalities. The c.1814 G > A mutation in exon 21 of the POMGNT1 gene is apparently a common mutation in the Turkish population. Individuals with this mutation show classical features of muscle-eye-brain disease, but others may exhibit a milder phenotype and retain the ability to walk independently. Congenital muscular dystrophy patients from Turkey carrying the clinical and radiologic features of muscle-eye-brain disease should be evaluated for mutations in POMGNT1 gene. Copyright © 2014 Elsevier Inc. All

  11. Magnetic resonance imaging patterns of muscle involvement in genetic muscle diseases: a systematic review.

    Science.gov (United States)

    Leung, Doris G

    2017-07-01

    A growing body of the literature supports the use of magnetic resonance imaging as a potential biomarker for disease severity in the hereditary myopathies. We performed a systematic review of the medical literature to evaluate patterns of fat infiltration observed in magnetic resonance imaging studies of muscular dystrophy and congenital myopathy. Searches were performed using MEDLINE, EMBASE, and grey literature databases. Studies that described fat infiltration of muscles in patients with muscular dystrophy or congenital myopathy were selected for full-length review. Data on preferentially involved or spared muscles were extracted for analysis. A total of 2172 titles and abstracts were screened, and 70 publications met our criteria for inclusion in the systematic review. There were 23 distinct genetic disorders represented in this analysis. In most studies, preferential involvement and sparing of specific muscles were reported. We conclude that magnetic resonance imaging studies can be used to identify distinct patterns of muscle involvement in the hereditary myopathies. However, larger studies and standardized methods of reporting are needed to develop imaging as a diagnostic tool in these diseases.

  12. Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with Duchenne muscular dystrophy: a multicenter cross sectional study.

    Directory of Open Access Journals (Sweden)

    Sean C Forbes

    Full Text Available Duchenne muscular dystrophy (DMD is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that (1H2O T2 derived using (1H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.MR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years and 31 healthy controls (age 9.7 SD 2.3 years using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia. T2-weighted multi-slice spin echo (SE axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1H2O T2.MRI-T2, (1H2O T2, and lipid fraction were greater (p<0.05 in DMD compared to controls. In the youngest age group, DMD values were different (p<0.05 than controls for the soleus MRI-T2, (1H2O T2 and lipid fraction and vastus lateralis MRI-T2 and (1H2O T2. In the boys with DMD, MRI-T2 and lipid fraction were greater (p<0.05 in the oldest age group (11-14 years than the youngest age group (5-6.9 years, while 1H2O T2 was lower in the oldest age group compared to the young age group.Overall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys.

  13. Skeletal muscles of ambulant children with Duchenne muscular dystrophy: validation of multicenter study of evaluation with MR imaging and MR spectroscopy.

    Science.gov (United States)

    Forbes, Sean C; Walter, Glenn A; Rooney, William D; Wang, Dah-Jyuu; DeVos, Soren; Pollaro, Jim; Triplett, William; Lott, Donovan J; Willcocks, Rebecca J; Senesac, Claudia; Daniels, Michael J; Byrne, Barry J; Russman, Barry; Finkel, Richard S; Meyer, James S; Sweeney, H Lee; Vandenborne, Krista

    2013-10-01

    To validate a multicenter protocol that examines lower extremity skeletal muscles of children with Duchenne muscular dystrophy (DMD) by using magnetic resonance (MR) imaging and MR spectroscopy in terms of reproducibility of these measurements within and across centers. This HIPAA-compliant study was approved by the institutional review boards of all participating centers, and informed consent was obtained from each participant or a guardian. Standardized procedures with MR operator training and quality assurance assessments were implemented, and data were acquired at three centers by using different 3-T MR imaging instruments. Measures of maximal cross-sectional area (CSAmax), transverse relaxation time constant (T2), and lipid fraction were compared among centers in two-compartment coaxial phantoms and in two unaffected adult subjects who visited each center. Also, repeat MR measures were acquired twice on separate days in 30 boys with DMD (10 per center) and 10 unaffected boys. Coefficients of variation (CVs) were computed to examine the repeated-measure variabilities within and across centers. CSAmax, T2 from MR imaging and MR spectroscopy, and lipid fraction were consistent across centers in the phantom (CV, <3%) and in the adult subjects who traveled to each site (CV, 2%-7%). High day-to-day reproducibility in MR measures was observed in boys with DMD (CSAmax, CV = 3.7% [25th percentile, 1.3%; 75th percentile, 5.1%]; contractile area, CV = 4.2% [25th percentile, 0.8%; 75th percentile, 4.9%]; MR imaging T2, CV = 3.1% [25th percentile, 1.2%; 75th percentile, 4.7%]; MR spectroscopy T2, CV = 3.9% [25th percentile, 1.5%; 75th percentile, 5.1%]; and lipid fraction, CV = 4.7% [25th percentile, 1.0%; 75th percentile, 5.3%]). The MR protocol implemented in this multicenter study achieved highly reproducible measures of lower extremity muscles across centers and from day to day in ambulatory boys with DMD. © RSNA, 2013.

  14. An unusual presentation of muscle-eye-brain disease: severe eye abnormalities with mild muscle and brain involvement.

    Science.gov (United States)

    Demir, Ercan; Gucuyener, Kivilcim; Akturk, Aysima; Talim, Beril; Konus, Oznur; Del Bo, Roberto; Ghezzi, Serena; Comi, Giacomo P

    2009-10-01

    Muscle-eye-brain disease (MEB) is characterised by congenital muscular dystrophy, structural brain malformations and eye abnormalities. We report a MEB case whose presenting sign was congenital blindness. She was investigated primarily for eye abnormalities at onset. She had bilateral retinal detachment and microphthalmia. Mild axial hypotonia and motor retardation were attributed to cerebral disorder in another center. Muscle biopsy showed mild myopathic changes and significant alpha-dystroglycan deficiency. Analysis of the POMGnT1 showed a novel homozygous mutation 1814G>C, causing p.Arg605Pro change. This case expands the clinical spectrum of MEB with unusually severe eye abnormalities compared to mild skeletal muscle and brain involvement.

  15. Defective collagen VI ?6 chain expression in the skeletal muscle of patients with collagen VI-related myopathies

    OpenAIRE

    Tagliavini, F.; Pellegrini, C.; Sardone, F.; Squarzoni, S.; Paulsson, M.; Wagener, R.; Gualandi, F.; Trabanelli, C.; Ferlini, A.; Merlini, L.; Santi, S.; Maraldi, N.M.; Faldini, C.; Sabatelli, P.

    2014-01-01

    Collagen VI is a non-fibrillar collagen present in the extracellular matrix (ECM) as a complex polymer; the mainly expressed form is composed of ?1, ?2 and ?3 chains; mutations in genes encoding these chains cause myopathies known as Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM). The collagen VI ?6 chain is a recently identified component of the ECM of the human skeletal muscle. Here we report that the ?6 chain was dramatically reduced in s...

  16. Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy

    DEFF Research Database (Denmark)

    Vestergaard, H; Klein, H H; Hansen, T

    1995-01-01

    severe insulin resistance of both liver and peripheral tissues. The impaired insulin-stimulated glucose disposal to peripheral tissues was primarily due to reduced nonoxidative glucose metabolism. These changes were paralleled by reduced basal values of muscle GS total activity, allosterical activation...

  17. Congenital nutritional myodegeneration (white muscle disease) in a Giraffe (Giraffa camelopardalis) calf

    NARCIS (Netherlands)

    Bos, J.H.; Klip, Fokko C; Kik, M.J.L.

    2017-01-01

    © Copyright 2017 by American Association of Zoo Veterinarians. It is well known that vitamin E and selenium deficiencies in domestic ruminants can lead to white muscle disease. After a clinically normal gestation period at Ouwehand Zoo in the Netherlands, a newborn giraffe (Giraffa camelopardalis)

  18. Severe insulin-resistant diabetes mellitus in patients with congenital muscle fiber type disproportion myopathy

    DEFF Research Database (Denmark)

    Vestergaard, H; Klein, H H; Hansen, T

    1995-01-01

    . Insulin receptor function and glycogen synthase (GS) activity and expression were examined in biopsies of vastus lateralis muscle. Despite a 45-90-fold increase in both fasting and postprandial serum insulin levels, both CFTDM patients had diabetes mellitus. Clamp studies revealed that the oldest boy had...

  19. Circulating Biomarkers for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-07-22

    Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput - omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products.

  20. The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease.

    Science.gov (United States)

    Davignon, Laurianne; Chauveau, Claire; Julien, Cédric; Dill, Corinne; Duband-Goulet, Isabelle; Cabet, Eva; Buendia, Brigitte; Lilienbaum, Alain; Rendu, John; Minot, Marie Christine; Guichet, Agnès; Allamand, Valérie; Vadrot, Nathalie; Fauré, Julien; Odent, Sylvie; Lazaro, Leïla; Leroy, Jean Paul; Marcorelles, Pascale; Dubourg, Odile; Ferreiro, Ana

    2016-04-15

    Despite recent progress in the genetic characterization of congenital muscle diseases, the genes responsible for a significant proportion of cases remain unknown. We analysed two branches of a large consanguineous family in which four patients presented with a severe new phenotype, clinically marked by neonatal-onset muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies showed the unreported association of multi-minicores, caps and dystrophic lesions. Genome-wide linkage analysis followed by gene and exome sequencing in patients identified a homozygous nonsense mutation in TRIP4 encoding Activating Signal Cointegrator-1 (ASC-1), a poorly characterized transcription coactivator never associated with muscle or with human inherited disease. This mutation resulted in TRIP4 mRNA decay to around 10% of control levels and absence of detectable protein in patient cells. ASC-1 levels were higher in axial than in limb muscles in mouse, and increased during differentiation in C2C12 myogenic cells. Depletion of ASC-1 in cultured muscle cells from a patient and in Trip4 knocked-down C2C12 led to a significant reduction in myotube diameter ex vivo and in vitro, without changes in fusion index or markers of initial myogenic differentiation. This work reports the first TRIP4 mutation and defines a novel form of congenital muscle disease, expanding their histological, clinical and molecular spectrum. We establish the importance of ASC-1 in human skeletal muscle, identify transcriptional co-regulation as novel pathophysiological pathway, define ASC-1 as a regulator of late myogenic differentiation and suggest defects in myotube growth as a novel myopathic mechanism. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. Isolation and characterization of sex chromosome rearrangements generating male muscle dystrophy and female abnormal oogenesis in the silkworm, Bombyx mori.

    Science.gov (United States)

    Fujii, T; Yokoyama, T; Ninagi, O; Kakehashi, K; Obara, Y; Nenoi, M; Ishikawa, T; Mita, K; Shimada, T; Abe, H

    2007-07-01

    In deletion-mapping of W-specific RAPD (W-RAPD) markers and putative female determinant gene (Fem), we used X-ray irradiation to break the translocation-carrying W chromosome (W( Ze )). We succeeded in obtaining a fragment of the W( Ze ) chromosome designated as Ze (W), having 3 of 12 W-RAPD markers (W-Bonsai, W-Yukemuri-S, W-Yukemuri-L). Inheritance of the Ze (W) fragment by males indicates that it does not include the Fem gene. On the basis of these results, we determined the relative positions of W-Yukemuri-S and W-Yukemuri-L, and we narrowed down the region where Fem gene is located. In addition to the Ze (W) fragment, the Z chromosome was also broken into a large fragment (Z(1)) having the +( sch ) (1-21.5) and a small fragment (Z(2)) having the +( od ) (1-49.6). Moreover, a new chromosomal fragment (Ze (W)Z(2)) was generated by a fusion event between the Ze (W) and the Z(2) fragments. We analyzed the genetic behavior of the Z(1) fragment and the Ze (W)Z(2) fragment during male (Z/Z(1) Ze (W)Z(2)) and female (Z(1) Ze (W)Z(2)/W) meiosis using phenotypic markers. It was observed that the Z(1) fragment and the Z or the W chromosomes separate without fail. On the other hand, non-disjunction between the Ze (W)Z(2) fragment and the Z chromosome and also between the Ze (W)Z(2) fragment and the W chromosome occurred. Furthermore, the females (2A: Z/Ze (W)Z(2)/W) and males (2A: Z/Z(1)) resulting from non-disjunction between the Ze (W)Z(2) fragment and the W chromosome had phenotypic defects: namely, females exhibited abnormal oogenesis and males were flapless due to abnormal indirect flight muscle structure. These results suggest that Z(2) region of the Z chromosome contains dose-sensitive gene(s), which are involved in oogenesis and indirect flight muscle development.

  2. Surgically mismanaged ptosis in a patient with congenital fibrosis of the extraocular muscles type I.

    Science.gov (United States)

    Tawfik, Hatem A; Rashad, Mohamed A

    2012-10-01

    Fibrosis syndromes comprise a rare form of severe limitation of ocular motility. An 11-year-old girl was referred for the correction of eyelid retraction. The eyelid retraction occurred immediately following levator resection surgery performed by a plastic surgeon who missed the restrictive extraocular muscle abnormalities. On examination, both eyes were fixed in an infraducted position (20 prism diopters (Δ)), with a chin-up position and significant lagophthalmos. Bilateral 12-mm inferior rectus recession with adjustable sutures was performed, which resulted in significant reduction of lagophthalmos and elimination of the head tilt.

  3. Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

    NARCIS (Netherlands)

    Kamsteeg, E.J.; Kress, W.; Catalli, C.; Hertz, J.M.; Witsch-Baumgartner, M.; Buckley, M.F.; Engelen, B.G.M. van; Schwartz, M.; Scheffer, H.

    2012-01-01

    Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to

  4. Strength training and albuterol in facioscapulohumeral muscular dystrophy.

    NARCIS (Netherlands)

    Kooi, E.L. van der; Vogels, O.J.M.; Asseldonk, R.J. van; Lindeman, E.J.M.; Hendriks, J.C.M.; Wohlgemuth, M.; Maarel, S.M. van der; Padberg, G.W.A.M.

    2004-01-01

    BACKGROUND: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  5. Strength training and albuterol in facioscapulohumeral muscular dystrophy

    NARCIS (Netherlands)

    van der Kooi, EL; Vogels, OJM; van Asseldonk, RJGP; Lindeman, E; Hendriks, JCM; Wohlgemuth, M; van der Maarel, SM; Padberg, GW

    2004-01-01

    Background: In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of

  6. Genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies.

    Science.gov (United States)

    Hightower, Rylie M; Alexander, Matthew S

    2018-01-01

    Muscular dystrophy is defined as the progressive wasting of skeletal muscles that is caused by inherited or spontaneous genetic mutations. Next-generation sequencing has greatly improved the accuracy and speed of diagnosis for different types of muscular dystrophy. Advancements in depth of coverage, convenience, and overall reduced cost have led to the identification of genetic modifiers that are responsible for phenotypic variability in affected patients. These genetic modifiers have been postulated to explain key differences in disease phenotypes, including age of loss of ambulation, steroid responsiveness, and the presence or absence of cardiac defects in patients with the same form of muscular dystrophy. This review highlights recent findings on genetic modifiers of Duchenne and facioscapulohumeral muscular dystrophies based on animal and clinical studies. These genetic modifiers hold great promise to be developed into novel therapeutic targets for the treatment of muscular dystrophies. Muscle Nerve 57: 6-15, 2018. © 2017 Wiley Periodicals, Inc.

  7. B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.

    Science.gov (United States)

    Maroofian, Reza; Riemersma, Moniek; Jae, Lucas T; Zhianabed, Narges; Willemsen, Marjolein H; Wissink-Lindhout, Willemijn M; Willemsen, Michèl A; de Brouwer, Arjan P M; Mehrjardi, Mohammad Yahya Vahidi; Ashrafi, Mahmoud Reza; Kusters, Benno; Kleefstra, Tjitske; Jamshidi, Yalda; Nasseri, Mojila; Pfundt, Rolph; Brummelkamp, Thijn R; Abbaszadegan, Mohammad Reza; Lefeber, Dirk J; van Bokhoven, Hans

    2017-12-22

    The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.

  8. Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy.

    Science.gov (United States)

    Weleber, Richard G; Pennesi, Mark E; Wilson, David J; Kaushal, Shalesh; Erker, Laura R; Jensen, Lauren; McBride, Maureen T; Flotte, Terence R; Humphries, Margaret; Calcedo, Roberto; Hauswirth, William W; Chulay, Jeffrey D; Stout, J Timothy

    2016-07-01

    To provide an initial assessment of the safety of a recombinant adeno-associated virus vector expressing RPE65 (rAAV2-CB-hRPE65) in adults and children with retinal degeneration caused by RPE65 mutations. Nonrandomized, multicenter clinical trial. Eight adults and 4 children, 6 to 39 years of age, with Leber congenital amaurosis (LCA) or severe early-childhood-onset retinal degeneration (SECORD). Patients received a subretinal injection of rAAV2-CB-hRPE65 in the poorer-seeing eye, at either of 2 dose levels, and were followed up for 2 years after treatment. The primary safety measures were ocular and nonocular adverse events. Exploratory efficacy measures included changes in best-corrected visual acuity (BCVA), static perimetry central 30° visual field hill of vision (V30) and total visual field hill of vision (VTOT), kinetic perimetry visual field area, and responses to a quality-of-life questionnaire. All patients tolerated subretinal injections and there were no treatment-related serious adverse events. Common adverse events were those associated with the surgical procedure and included subconjunctival hemorrhage in 8 patients and ocular hyperemia in 5 patients. In the treated eye, BCVA increased in 5 patients, V30 increased in 6 patients, VTOT increased in 5 patients, and kinetic visual field area improved in 3 patients. One subject showed a decrease in BCVA and 2 patients showed a decrease in kinetic visual field area. Treatment with rAAV2-CB-hRPE65 was not associated with serious adverse events, and improvement in 1 or more measures of visual function was observed in 9 of 12 patients. The greatest improvements in visual acuity were observed in younger patients with better baseline visual acuity. Evaluation of more patients and a longer duration of follow-up will be needed to determine the rate of uncommon or rare side effects or safety concerns. Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  9. Identification of three distinguishable phenotypes in golden retriever muscular dystrophy

    OpenAIRE

    AMBROSIO, C. E.; FADEL, L.; GAIAD, T. P.; MARTINS, D. S.; ARAUJO, K. P. C.; ZUCCONI, E.; BROLIO, M. P.; GIGLIO, R. F.; MORINI, A. C.; JAZEDJE, T.; FROES, T. R.; FEITOSA, M. L. T.; VALADARES, M. C.; BELTRAO-BRAGA, P. C. B.; MEIRELLES, F. V.

    2009-01-01

    Duchenne muscular dystrophy (DMD) is a human disease characterized by progressive and irreversible skeletal muscle degeneration caused by mutations in genes coding for important muscle proteins. Unfortunately, there is no efficient treatment for this disease; it causes progressive loss of motor and muscular ability until death. The canine model (golden retriever muscular dystrophy) is similar to DMD, showing similar clinical signs. Fifteen dogs were followed from birth and closely observed fo...

  10. Reflex sympathetic dystrophy.

    Science.gov (United States)

    Miller, Ruth L S

    2003-01-01

    Reflex sympathetic dystrophy, also known as complex regional pain syndrome type I, is a multisymptom syndrome usually affecting one or more extremities. It is inadequately understood and, therefore, often frustrating to treat. This article presents a case study of a 23-year career nurse who developed reflex sympathetic dystrophy of the left knee. It also reviews the rationale for reflex sympathetic dystrophy, treatment, and life-care planning for a patient with reflex sympathetic dystrophy.

  11. Skeletal muscle laminin and MDC1A: pathogenesis and treatment strategies

    Directory of Open Access Journals (Sweden)

    Gawlik Kinga I

    2011-03-01

    Full Text Available Abstract Laminin-211 is a cell-adhesion molecule that is strongly expressed in the basement membrane of skeletal muscle. By binding to the cell surface receptors dystroglycan and integrin α7β1, laminin-211 is believed to protect the muscle fiber from damage under the constant stress of contractions, and to influence signal transmission events. The importance of laminin-211 in skeletal muscle is evident from merosin-deficient congenital muscular dystrophy type 1A (MDC1A, in which absence of the α2 chain of laminin-211 leads to skeletal muscle dysfunction. MDC1A is the commonest form of congenital muscular dystrophy in the European population. Severe hypotonia, progressive muscle weakness and wasting, joint contractures and consequent impeded motion characterize this incurable disorder, which causes great difficulty in daily life and often leads to premature death. Mice with laminin α2 chain deficiency have analogous phenotypes, and are reliable models for studies of disease mechanisms and potential therapeutic approaches. In this review, we introduce laminin-211 and describe its structure, expression pattern in developing and adult muscle and its receptor interactions. We will also discuss the molecular pathogenesis of MDC1A and advances toward the development of treatment.

  12. Indicators of Apoptosis in Duchenne Muscular Dystrophy Patients ...

    African Journals Online (AJOL)

    Background: Tissue sections of dystrophic muscle demonstrate apoptotic myonuclei in degenerating muscle fibers of Duchene muscle dystrophy (DMD) patients. The apoptosis cascade can be triggered by 2 main pathways, via an intrinsic, endogenous system such as the mitochondrial Bax/Bcl-2 or via an extrinsic system ...

  13. Quantitative assessment of calf circumference in Duchenne muscular dystrophy patients

    NARCIS (Netherlands)

    Beenakker, EAC; de Vries, Joeke; Fock, JM; van Tol, M; Brouwer, OF; Maurits, NM; van der Hoeven, JH

    2002-01-01

    Duchenne muscular dystrophy is clinically characterised by progressive muscle weakness and a gradual increase in the size of some affected muscles, especially calf muscles. The extent of calf enlargement is usually determined by subjective visual assessment. The purpose of this study was to

  14. Ex vivo gene editing of the dystrophin gene in muscle stem cells mediated by peptide nucleic acid single stranded oligodeoxynucleotides induces stable expression of dystrophin in a mouse model for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nik-Ahd, Farnoosh; Bertoni, Carmen

    2014-07-01

    Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients. © 2014 AlphaMed Press.

  15. Pneumothoraces in collagen VI-related dystrophy: a case series and recommendations for management

    Directory of Open Access Journals (Sweden)

    Kristin L. Fraser

    2017-06-01

    Full Text Available Collagen VI-related dystrophy (collagen VI-RD is a rare neuromuscular condition caused by mutations in the COL6A1, COL6A2 or COL6A3 genes. The phenotypic spectrum includes early-onset Ullrich congenital muscular dystrophy, adult-onset Bethlem myopathy and an intermediate phenotype. The disorder is characterised by distal hyperlaxity and progressive muscle weakness, joint contractures and respiratory insufficiency. Respiratory insufficiency is attributed to chest wall contractures, scoliosis, impaired diaphragmatic function and intercostal muscle weakness. To date, intrinsic parenchymal lung disease has not been implicated in the inevitable respiratory decline of these patients. This series focuses on pneumothorax, an important but previously under-recognised disease manifestation of collagen VI-RD. We describe two distinct clinical presentations within collagen VI-RD patients with pneumothorax. The first cohort consists of neonates and children with a single pneumothorax in the setting of large intrathoracic pressure changes. The second group is made up of adult patients with recurrent pneumothoraces, associated with chest computed tomography scan evidence of parenchymal lung disease. We describe treatment challenges in this unique population with respect to expectant observation, tube thoracostomy and open pleurodesis. Based on this experience, we offer recommendations for early identification of lung disease in collagen VI-RD and definitive intervention.

  16. A Drosophila model for Duchenne muscular dystrophy

    NARCIS (Netherlands)

    Plas, Mariska Cathelijne van der

    2008-01-01

    Duchenne Muscular Dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle wasting and sometimes mild mental retardation. The disease is caused by mutations in the dystrophin gene. DMD is correlated with the absence of Dp427, which is located along the sarcolemma in skeletal

  17. Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD)

    NARCIS (Netherlands)

    Goselink, R.J.M.; Schreuder, T.H.A.; Mul, K.; Voermans, N.C.; Pelsma, M.; Groot, I.J.M. de; Alfen, N. van; Franck, B.A.M.; Theelen, T.; Lemmers, R.J.; Mah, J.K.; Maarel, S.M. van der; Engelen, B.G.M. van; Erasmus, C.E.

    2016-01-01

    BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic

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

    NARCIS (Netherlands)

    Lassche, S.; Ottenheijm, C.A.C.; Voermans, N.C.; Westeneng, H.J.; Janssen, B.H.; Maarel, S.M. van der; Hopman, M.T.E.; Padberg, G.W.A.M.; Stienen, G.J.; Engelen, B.G.M. van

    2013-01-01

    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,

  19. Defective [U-14 C] palmitic acid oxidation in Duchenne muscular dystrophy

    International Nuclear Information System (INIS)

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

    1985-01-01

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

  20. Age of onset of RNA toxicity influences phenotypic severity: evidence from an inducible mouse model of myotonic dystrophy (DM1.

    Directory of Open Access Journals (Sweden)

    Jordan T Gladman

    Full Text Available Myotonic dystrophy type 1 (DM1 is the most common muscular dystrophy in adults. It is caused by an expanded (CTGn tract in the 3' UTR of the Dystrophia Myotonica Protein Kinase (DMPK gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1. More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3' UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.

  1. Congenital gluteus maximus contracture.

    Science.gov (United States)

    Ganel, A; Blankstein, A

    1989-01-01

    Muscle contractures are infrequent in Israel. This report discusses one case of a congenital contracture associated with a skin dimple treated in Israel. A 3-year-old boy presented with difficulty in running, riding a bicycle, and squatting. Flexion of the right hip in adduction was impossible. The hip could be fully flexed in abduction. Congenital contracture of the right gluteus maximus muscle was successfully treated by surgical release.

  2. Dismantling Limb-Girdle Muscular Dystrophy

    OpenAIRE

    Narayanaswami, Pushpa

    2015-01-01

    Muscular dystrophy encompasses a diverse group of genetically determined muscle disorders. The first clinical description of the disorder is attributed to Giovanni Semmola, who, in 1829, described 2 boys affected by a disorder with prominent muscular hypertrophy.1 Between 1850 and 1868, Aran, Meryon, and Duchenne described a progressive atrophy of voluntary muscles, ultimately termed pseudohypertrophic muscular paralysis of children by Duchenne.1,2 Other descriptions followed: familial atroph...

  3. Identification of new dystroglycan complexes in skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Eric K Johnson

    Full Text Available The dystroglycan complex contains the transmembrane protein β-dystroglycan and its interacting extracellular mucin-like protein α-dystroglycan. In skeletal muscle fibers, the dystroglycan complex plays an important structural role by linking the cytoskeletal protein dystrophin to laminin in the extracellular matrix. Mutations that affect any of the proteins involved in this structural axis lead to myofiber degeneration and are associated with muscular dystrophies and congenital myopathies. Because loss of dystrophin in Duchenne muscular dystrophy (DMD leads to an almost complete loss of dystroglycan complexes at the myofiber membrane, it is generally assumed that the vast majority of dystroglycan complexes within skeletal muscle fibers interact with dystrophin. The residual dystroglycan present in dystrophin-deficient muscle is thought to be preserved by utrophin, a structural homolog of dystrophin that is up-regulated in dystrophic muscles. However, we found that dystroglycan complexes are still present at the myofiber membrane in the absence of both dystrophin and utrophin. Our data show that only a minority of dystroglycan complexes associate with dystrophin in wild type muscle. Furthermore, we provide evidence for at least three separate pools of dystroglycan complexes within myofibers that differ in composition and are differentially affected by loss of dystrophin. Our findings indicate a more complex role of dystroglycan in muscle than currently recognized and may help explain differences in disease pathology and severity among myopathies linked to mutations in DAPC members.

  4. Physiotherapy, based on the Bobath concept, may influence the gait pattern in persons with limb-girdle muscle dystrophy: a multiple case series study.

    Science.gov (United States)

    Oygard, Kjellaug; Haestad, Helge; Jørgensen, Lone

    2011-03-01

     There are few studies on possible effects of physiotherapy for adults with muscular dystrophy. The aim of this study was to examine if treatment based on the Bobath concept may influence specific gait parameters in some of these patients.   A single-subject experimental design with A-B-A-A phases was used, and four patients, three with limb-girdle muscular dystrophy (LGMD) and one with fascioscapulohumeral muscular dystrophy (FSHD), were included. The patients had 1 hour of individually tailored physiotherapy at each working day for a period of 3 weeks. Step length, step width and gait velocity were measured during the A-B-A-A phases by use of an electronic walkway. Walking distance and endurance were measured by use of the '6 minute walk test'.  . The three LGMD patients, who initially walked with a wide base of support, had a narrower, velocity-adjusted step width after treatment, accompanied with the same or even longer step length. These changes lasted throughout follow-up. Moreover, two of the patients were able to walk a longer distance within 6 minutes after the treatment period. The fourth patient (with FSHD) had a normal step width at baseline, which did not change during the study.   The results indicate that physiotherapy treatment based on the Bobath concept may influence the gait pattern in patients with LGMD. However, in order to evaluate the effectiveness of physiotherapy to patients with muscular dystrophies, we call for larger studies and controlled trials. Copyright © 2010 John Wiley & Sons, Ltd.

  5. Identifying Non-Duchenne Muscular Dystrophy-Positive and False Negative Results in Prior Duchenne Muscular Dystrophy Newborn Screening Programs: A Review.

    Science.gov (United States)

    Gatheridge, Michele A; Kwon, Jennifer M; Mendell, Jerry M; Scheuerbrandt, Günter; Moat, Stuart J; Eyskens, François; Rockman-Greenberg, Cheryl; Drousiotou, Anthi; Griggs, Robert C

    2016-01-01

    Duchenne muscular dystrophy (DMD) is a candidate for the recommended universal screening panel based on evidence that early corticosteroid treatment improves outcomes and on new genetic therapies that require early diagnosis for effectiveness. Elevated creatine kinase levels in the neonatal period are the initial screening marker in DMD newborn screening programs but is found in inherited muscle disorders other than DMD. Data are needed to inform protocols for future screening and follow-up testing and care in these patients. To review non-DMD muscle disorders identified by prior DMD screening programs and to investigate whether these programs failed to identify patients later diagnosed as having DMD (false-negative findings). Since 1975, 10 DMD newborn screening programs have provided opportunities to study screening protocols, outcomes, and parental responses. These programs used elevated creatine kinase levels in dried blood spots for the initial screening, with the diagnosis of DMD based on findings of clinical follow-up, muscle biopsy, or direct mutational testing of the DMD gene. Literature regarding these prior programs was reviewed in PubMed, and the programs were discussed directly with the directors when possible to identify diagnoses of non-DMD disorders and false negative results from 1975 to July 12, 2015. Data were collected from screening programs, which were active between 1975 and December 2011. Data were analyzed from March 26, 2015, to August 24, 2015. The 10 screening programs screened more than 1.8 million newborns between 1975 and 2011, and 344 were diagnosed with DMD. Of those screened, the majority were boys. Across all programs, 80 patients had positive results for non-DMD disorders, including Becker muscular dystrophy and forms of limb-girdle and congenital muscular dystrophies, and 21 patients had false-negative findings for DMD. Screening for DMD will result in identification of other muscle diseases. Future screening protocols should

  6. Neuromuscular imaging in inherited muscle diseases

    International Nuclear Information System (INIS)

    Wattjes, Mike P.; Kley, Rudolf A.; Fischer, Dirk

    2010-01-01

    Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies. (orig.)

  7. Neuromuscular imaging in inherited muscle diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wattjes, Mike P. [VU University Medical Center, Department of Radiology, De Boelelaan 1117, HV, Amsterdam (Netherlands); Kley, Rudolf A. [Klinken Bergmannsheil, Ruhr-University, Department of Neurology, Neuromuscular Centre Ruhrgebiet, Bochum (Germany); Fischer, Dirk [University Hospital of Basel, Department of Neurology, Basel (Switzerland); University Children' s Hospital Basel, Department of Neuropaediatrics, Basel (Switzerland)

    2010-10-15

    Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies. (orig.)

  8. Outside in: The matrix as a modifier of muscular dystrophy.

    Science.gov (United States)

    Quattrocelli, Mattia; Spencer, Melissa J; McNally, Elizabeth M

    2017-03-01

    Muscular dystrophies are genetic conditions leading to muscle degeneration and often, impaired regeneration. Duchenne Muscular Dystrophy is a prototypical form of muscular dystrophy, and like other forms of genetically inherited muscle diseases, pathological progression is variable. Variability in muscular dystrophy can arise from differences in the manner in which the primary mutation impacts the affected protein's function; however, clinical heterogeneity also derives from secondary mutations in other genes that can enhance or reduce pathogenic features of disease. These genes, called genetic modifiers, regulate the pathophysiological context of dystrophic degeneration and regeneration. Understanding the mechanistic links between genetic modifiers and dystrophic progression sheds light on pathologic remodeling, and provides novel avenues to therapeutically intervene to reduce muscle degeneration. Based on targeted genetic approaches and unbiased genomewide screens, several modifiers have been identified for muscular dystrophy, including extracellular agonists of signaling cascades. This review will focus on identification and possible mechanisms of recently identified modifiers for muscular dystrophy, including osteopontin, latent TGFβ binding protein 4 (LTBP4) and Jagged1. Moreover, we will review the investigational approaches that aim to target modifier pathways and thereby counteract dystrophic muscle wasting. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Genetics Home Reference: congenital stromal corneal dystrophy

    Science.gov (United States)

    ... the cornea appears cloudy and may have an irregular surface. These corneal changes lead to visual impairment, ... IGF I) epitopes recognized by monoclonal and polyclonal antibodies to IGF I. Endocrinology. 1990 Jun;126(6): ...

  10. Genetics Home Reference: Fukuyama congenital muscular dystrophy

    Science.gov (United States)

    ... incidence of 2 to 4 per 100,000 Japanese infants. Related Information What information about a genetic ... of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville Pike, Bethesda, MD 20894, USA HONCode ...

  11. The superhealing MRL background improves muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Heydemann Ahlke

    2012-12-01

    Full Text Available Abstract 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 γ-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.

  12. Duchenne muscular dystrophy: Case report and review.

    Science.gov (United States)

    Sinha, Rupam; Sarkar, Soumyabrata; Khaitan, Tanya; Dutta, Soumyajit

    2017-01-01

    Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD) is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  13. Duchenne muscular dystrophy: Case report and review

    Directory of Open Access Journals (Sweden)

    Rupam Sinha

    2017-01-01

    Full Text Available Muscular dystrophies are a clinically and heterogeneous group of disorders that all share clinical characteristics of progressive muscular weakness. Duchenne muscular dystrophy (DMD is the most common X-linked disorder muscular dystrophy in children, presenting in early childhood and characterized by proximal muscle weakness and calf hypertrophy in affected boys. There is usually delay in motor development and eventually wheelchair confinement followed by premature death from cardiac or respiratory complications. Treatment modalities such as corticosteroid therapy and use of intermittent positive pressure ventilation have provided improvements in function, ambulation, quality of life, and life expectancy, although novel therapies still aim to provide a cure for this devastating disorder. Here, we present a case of DMD in a 12-year-old male with remarkable clinical and oral manifestations.

  14. Mitochondrial disorders in progressive muscular dystrophies

    Directory of Open Access Journals (Sweden)

    D. A. Kharlamov

    2014-01-01

    Full Text Available The literature review gives data on the role of mitochondrial disorders in the pathogenesis of different progressive muscular dystrophies. It describes changes in Duchenne, limb-girdle, facial scapulohumeral (Landuzi—Degerina muscular dystrophies. The review is based on both clinical and experimental animal studies. Along with the implication of mitochondria in the pathogenesis of the diseases, it describes muscular dystrophy treatment options compensating for energy disorders and overcoming oxidative stress and mitochondrial dysfunction. Mitochondrial studies in different muscle diseases hand physicians treatment modalities that fail to lead to recovery, but compensate for disorders caused by mutations in the genetic apparatus. 

  15. Targeted massively parallel sequencing and histological assessment of skeletal muscles for the molecular diagnosis of inherited muscle disorders.

    Science.gov (United States)

    Nishikawa, Atsuko; Mitsuhashi, Satomi; Miyata, Naomasa; Nishino, Ichizo

    2017-02-01

    Inherited skeletal muscle diseases are genetically heterogeneous diseases caused by mutations in more than 150 genes. This has made it challenging to establish a high-throughput screening method for identifying causative gene mutations in clinical practice. In the present study, we developed a useful method for screening gene mutations associated with the pathogenesis of skeletal muscle diseases. We established four target gene panels, each covering all exonic and flanking regions of genes involved in the pathogenesis of the following muscle diseases: (1) muscular dystrophy (MD), (2) congenital myopathy/congenital myasthenic syndrome, (3) metabolic myopathy and (4) myopathy with protein aggregations/rimmed vacuoles. We assigned one panel to each patient based on the results of clinical and histological analyses of biopsied muscle samples and performed high-throughput sequencing by using Ion PGM next-generation sequencer. We also performed protein analysis to confirm defective proteins in patients with major muscular dystrophies. Further, we performed muscle-derived cDNA analysis to identify splice-site mutations. We identified possible causative gene mutations in 33% of patients (62/188) included in this study. Our results showed that the MD panel was the most useful, with a diagnostic rate of 46.2%. Thus, we developed a high-throughput sequencing technique for diagnosing inherited muscle diseases. The use of this technique along with histological and protein analyses may be useful and cost-effective for screening mutations in patients with inherited skeletal muscle diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  16. Non-Targeted Metabolomics Analysis of Golden Retriever Muscular Dystrophy-Affected Muscles Reveals Alterations in Arginine and Proline Metabolism, and Elevations in Glutamic and Oleic Acid In Vivo

    Directory of Open Access Journals (Sweden)

    Muhammad Abdullah

    2017-07-01

    Full Text Available Background: Like Duchenne muscular dystrophy (DMD, the Golden Retriever Muscular Dystrophy (GRMD dog model of DMD is characterized by muscle necrosis, progressive paralysis, and pseudohypertrophy in specific skeletal muscles. This severe GRMD phenotype includes atrophy of the biceps femoris (BF as compared to unaffected normal dogs, while the long digital extensor (LDE, which functions to flex the tibiotarsal joint and serves as a digital extensor, undergoes the most pronounced atrophy. A recent microarray analysis of GRMD identified alterations in genes associated with lipid metabolism and energy production. Methods: We, therefore, undertook a non-targeted metabolomics analysis of the milder/earlier stage disease GRMD BF muscle versus the more severe/chronic LDE using GC-MS to identify underlying metabolic defects specific for affected GRMD skeletal muscle. Results: Untargeted metabolomics analysis of moderately-affected GRMD muscle (BF identified eight significantly altered metabolites, including significantly decreased stearamide (0.23-fold of controls, p = 2.89 × 10−3, carnosine (0.40-fold of controls, p = 1.88 × 10−2, fumaric acid (0.40-fold of controls, p = 7.40 × 10−4, lactamide (0.33-fold of controls, p = 4.84 × 10−2, myoinositol-2-phosphate (0.45-fold of controls, p = 3.66 × 10−2, and significantly increased oleic acid (1.77-fold of controls, p = 9.27 × 10−2, glutamic acid (2.48-fold of controls, p = 2.63 × 10−2, and proline (1.73-fold of controls, p = 3.01 × 10−2. Pathway enrichment analysis identified significant enrichment for arginine/proline metabolism (p = 5.88 × 10−4, FDR 4.7 × 10−2, where alterations in L-glutamic acid, proline, and carnosine were found. Additionally, multiple Krebs cycle intermediates were significantly decreased (e.g., malic acid, fumaric acid, citric/isocitric acid, and succinic acid, suggesting that altered energy metabolism may be underlying the observed GRMD BF muscle

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

    OpenAIRE

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

    2013-01-01

    Becker’s Muscular Dystrophy (BMD) is a dystrophinopathy manifested as progressive muscle degeneration. Autologous Bone Marrow Mononuclear Cells (BMMNCs) have shown some myogenic potential. The paracrine effects of the BMMNCs reduce the inflammation and are thought to reduce muscle degeneration. We treated a 39 year old dental surgeon suffering from BMD. Muscle strength was reduced when measured using modified Medical Research Council’s Manual Muscle Testing (mMRC-MMT). Static sitting balance ...

  18. Congenital neurogenic muscular atrophy in megaconial myopathy due to a mutation in CHKB gene.

    Science.gov (United States)

    Castro-Gago, Manuel; Dacruz-Alvarez, David; Pintos-Martínez, Elena; Beiras-Iglesias, Andrés; Arenas, Joaquín; Martín, Miguel Ángel; Martínez-Azorín, Francisco

    2016-01-01

    Choline kinase beta gene (CHKB) mutations have been identified in Megaconial Congenital Muscular Dystrophy (MDCMC) patients, a very rare inborn error of metabolism with 21 cases reported worldwide. We report the case of a Spanish boy of Caucasian origin who presented a generalized congenital muscular hypotonia, more intense at lower limb muscles, mildly elevated creatine kinase (CK), serum aspartate transaminase (AST) and lactate. Electromyography (EMG) showed neurogenic potentials in the proximal muscles. Histological studies of a muscle biopsy showed neurogenic atrophy with enlarged mitochondria in the periphery of the fibers, and complex I deficiency. Finally, genetic analysis showed the presence of a homozygous mutation in the gene for choline kinase beta (CHKB: NM_005198.4:c.810T>A, p.Tyr270(∗)). We describe here the second Spanish patient whit mutation in CHKB gene, who despite having the same mutation, presented an atypical aspect: congenital neurogenic muscular atrophy progressing to a combined neuropathic and myopathic phenotype (mixed pattern). Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  19. Congenital cranial dysinnervation disorders.

    Science.gov (United States)

    Singh, Anupam; Pandey, P K; Agrawal, Ajai; Mittal, Sanjeev Kumar; Rana, Kartik Maheshbhai; Bahuguna, Chirag

    2017-12-01

    The European Neuromuscular Centre (ENMC) derived the term Congenital Cranial Dysinnervation Disorders in 2002 at an international workshop for a group of congenital neuromuscular diseases. CCDDs are congenital, non-progressive ophthalmoplegia with restriction of globe movement in one or more fields of gaze. This group of sporadic and familial strabismus syndromes was initially referred to as the 'congenital fibrosis syndromes' because it was assumed that the primary pathologic process starts in the muscles of eye motility. Over the last few decades, evidence has accumulated to support that the primary pathologic process of these disorders is neuropathic rather than myopathic. This is believed that for normal development of extra ocular muscles and for preservation of muscle fiber anatomy, normal intra-uterine development of the innervation to these muscles is essential. Congenital dysinnervation to these EOMs can lead to abnormal muscle structure depending upon the stage and the extent of such innervational defects. Over last few years new genes responsible for CCDD have been identified, permitting a better understanding of associated phenotypes, which can further lead to better classification of these disorders. Introduction of high-resolution MRI has led to detailed study of cranial nerves courses and muscles supplied by them. Thus, due to better understanding of pathophysiology and genetics of CCDDs, various treatment modalities can be developed to ensure good ocular alignment and better quality of life for patients suffering from the same.

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

    Sabharwal, Rasna

    2014-01-01

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

  2. The Link Between Stress Disorders and Autonomic Dysfunction in Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Rasna eSabharwal

    2014-01-01

    Full Text Available 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.

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

    Science.gov (United States)

    Sabharwal, Rasna

    2014-01-01

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

  4. CINRG: Infrastructure for Clinical Trials in Duchenne Dystrophy

    Science.gov (United States)

    2012-09-01

    function in patients with muscular dystrophy. We evaluated its utility as an earlier marker of cardiac dysfunction with the goal of using it as...SPP1) gene (-66 T>G -rs28357094) on longitudinal functional measures. Saliva samples for DNA genotyping were available for 280 DMD participants...muscle testing; TGF- transforming growth factor-; TNF- tumor necrosis factor-. Duchenne muscular dystrophy (DMD) is the most common type of

  5. Pulmonary Endpoints in Duchenne Muscular Dystrophy. A Workshop Summary.

    Science.gov (United States)

    Finder, Jonathan; Mayer, Oscar Henry; Sheehan, Daniel; Sawnani, Hemant; Abresch, R Ted; Benditt, Joshua; Birnkrant, David J; Duong, Tina; Henricson, Erik; Kinnett, Kathi; McDonald, Craig M; Connolly, Anne M

    2017-08-15

    Development of novel therapeutics for treatment of Duchenne muscular dystrophy (DMD) has led to clinical trials that include pulmonary endpoints that allow assessment of respiratory muscle status, especially in nonambulatory subjects. Parent Project Muscular Dystrophy (PPMD) convened a workshop in Bethesda, Maryland, on April 14 and 15, 2016, to summarize published respiratory data in DMD and give guidance to clinical researchers assessing the effect of interventions on pulmonary outcomes in DMD.

  6. Animal Models for Muscular Dystrophy Show Different Patterns of Sarcolemmal Disruption

    OpenAIRE

    Straub, Volker; Rafael, Jill A.; Chamberlain, Jeffrey S.; Campbell, Kevin P.

    1997-01-01

    Genetic defects in a number of components of the dystrophin–glycoprotein complex (DGC) lead to distinct forms of muscular dystrophy. However, little is known about how alterations in the DGC are manifested in the pathophysiology present in dystrophic muscle tissue. One hypothesis is that the DGC protects the sarcolemma from contraction-induced damage. Using tracer molecules, we compared sarcolemmal integrity in animal models for muscular dystrophy and in muscular dystrophy patient samples. Ev...

  7. Protein Turnover and Cellular Stress in Mildly and Severely Affected Muscles from Patients with Limb Girdle Muscular Dystrophy Type 2I

    DEFF Research Database (Denmark)

    Hauerslev, Simon; Sveen, Marie-Louise; Vissing, John

    2013-01-01

    by using the developmental markers embryonic myosin heavy chain (eMHC) and neural cell adhesion molecule (NCAM) and also assessing satellite cell activation status by myogenin positivity. Severe muscle histopathology was occasionally observed in the proximal muscles of patients with LGMD2I whereas distal...... muscles were always relatively spared. No difference was found in the regeneration markers internally nucleated fibers, actively regenerating fibers or activation status of satellite cells between proximal and distal muscles. Protein turnover, both synthesis and breakdown, as well as cellular stress were...

  8. A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups

    Directory of Open Access Journals (Sweden)

    Matthew Emerson Randolph

    2015-10-01

    Full Text Available The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies, such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some muscular dystrophies. The biology of muscle stem cells varies depending on their embryologic origins and the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease.

  9. Intramuscular degeneration process in Duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Hasegawa, Takeshi; Matsumra, Kiichiro; Hashimoto, Takahiro; Ikehira, Hiroo; Fukuda, Hiroshi; Tateno, Yukio.

    1992-01-01

    Intramuscular degeneration process of Duchenne dystrophy skeletal muscles was investigated by longitudinal skeletal muscle imaging with high-field-strength NMR-CT of 1.5 Tesla. Thigh muscles in 10 cases ranging in age from 4 to 19 years were examined by T 1 -weighted longitudinal images (TR=215∼505 ms, TE=19∼20 ms). The following results were obtained. Skeletal muscle degeneration was depicted as high signal intensity area reflecting its high fat contents. These high signal intensity areas had a longitudinally streaky appearance in parallel direction with myofibers. These findings were more prominent toward myotendon junction than muscle bellies. Skeletal muscle degeneration progressed rapidly between 7 to 10 years of age, and reached a plateau after that. (author)

  10. Extracellular matrix and nuclear abnormalities in skeletal muscle of a patient with Walker-Warburg syndrome caused by POMT1 mutation.

    Science.gov (United States)

    Sabatelli, Patrizia; Columbaro, Marta; Mura, Isabella; Capanni, Cristina; Lattanzi, Giovanna; Maraldi, Nadir M; Beltràn-Valero de Barnabè, Daniel; van Bokoven, Hans; Squarzoni, Stefano; Merlini, Luciano

    2003-05-20

    Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by congenital muscular dystrophy, structural eye abnormalities and severe brain malformations. We performed an immunohistochemical and electron microscopy study of a muscle biopsy from a patient affected by WWS carrying a homozygous frameshift mutation in O-mannosyltransferase 1 gene (POMT1). alpha-Dystroglycan glycosylated epitope was not detected in muscle fibers and intramuscular peripheral nerves. Laminin alpha2 chain and perlecan were reduced in muscle fibers and well preserved in intramuscular peripheral nerves. The basal lamina in several muscle fibers showed discontinuities and detachment from the plasmalemma. Most nuclei, including myonuclei and satellite cell nuclei, showed detachment or complete absence of peripheral heterochromatin from the nuclear envelope. Apoptotic changes were detected in 3% of muscle fibers. The particular combination of basal lamina and nuclear changes may suggest that a complex pathogenetic mechanism, affecting several subcellular compartments, underlies the degenerative process in WWS muscle.

  11. Effect of cleft palate repair on the susceptibility to contraction-induced injury of single permeabilized muscle fibers from congenitally-clefted goat palates.

    Science.gov (United States)

    Rader, Erik P; Cederna, Paul S; McClellan, William T; Caterson, Stephanie A; Panter, Kip E; Yu, Deborah; Buchman, Steven R; Larkin, Lisa M; Faulkner, John A; Weinzweig, Jeffrey

    2008-03-01

    Despite cleft palate repair, velopharyngeal competence is not achieved in approximately 15% of patients, often necessitating secondary surgical correction. Velopharyngeal competence postrepair may require the conversion of levator veli palatini muscle fibers from injury-susceptible type 2 fibers to injury-resistant type 1 fibers. As an initial step to determining the validity of this theory, we tested the hypothesis that, in most cases, repair induces the transformation to type 1 fibers, thus diminishing susceptibility to injury. Single permeabilized levator veli palatini muscle fibers were obtained from normal palates and nonrepaired congenitally-clefted palates of young (2 months old) and adult (14 to 15 months old) goats and from repaired palates of adult goats (8 months old). Repair was done at 2 months of age using a modified von Langenbeck technique. Fiber type was determined by contractile properties and susceptibility to injury was assessed by force deficit, the decrease in maximum force following a lengthening contraction protocol expressed as a percentage of initial force. For normal palates and cleft palates of young goats, the majority of the fibers were type 2 with force deficits of approximately 40%. Following repair, 80% of the fibers were type 1 with force deficits of 20% +/- 2%; these deficits were 45% of those for nonrepaired cleft palates of adult goats (p < .0001). The decrease in the percentage of type 2 fibers and susceptibility to injury may be important for the development of a functional levator veli palatini muscle postrepair.

  12. The congenital cranial dysinnervation disorders.

    Science.gov (United States)

    Gutowski, N J; Chilton, J K

    2015-07-01

    Congenital cranial dysinnervation disorders (CCDD) encompass a number of related conditions and includes Duane syndrome, congenital fibrosis of the external ocular muscles, Möbius syndrome, congenital ptosis and hereditary congenital facial paresis. These are congenital disorders where the primary findings are non-progressive and are caused by developmental abnormalities of cranial nerves/nuclei with primary or secondary dysinnervation. Several CCDD genes have been found, which enhance our understanding of the mechanisms involved in brain stem development and axonal guidance. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. [Human myopathy and animal muscular dystrophy].

    Science.gov (United States)

    Schapira, G; Dreyfus, J C; Schapira, F

    1977-08-01

    Two hereditary muscular dystrophies similar to human progressive muscular dystrophy (P.M.D. Duchenne type) have been isolated in animals, one in mouse, the other in chicken. The decrease in the activity of glycogenolytic enzymes is similar to that observed in denervated muscle. Isozymic fetal types for several muscular enzymes have been observed as well in chicken as in man, but this fetal type may also be found in neurogenic atrophy. The release in circulation of muscle enzymes seems more specific. But the origin of the genetic lesion is still unknown. We describe here the three different theories about this problem: i.e. neurogenic, vascular, or myogenic. This last theory implies a trouble of membrane permeability.

  14. Morphologic imaging in muscular dystrophies and inflammatory myopathies

    Energy Technology Data Exchange (ETDEWEB)

    Degardin, Adrian; Lacour, Arnaud; Vermersch, Patrick [CHU de Lille, Clinique neurologique, Lille (France); Morillon, David; Cotten, Anne [CHRU de Lille, Service de Radiologie Osteoarticulaire, Hopital Roger Salengro, Lille (France); Stojkovic, Tanya [G-H Pitie-Salpetriere, Institut de Myologie, Paris (France)

    2010-12-15

    To determine if magnetic resonance imaging (MR imaging) is useful in the diagnostic workup of muscular dystrophies and idiopathic inflammatory myopathies for describing the topography of muscle involvement. MR imaging was performed in 31 patients: 8 with dystrophic myotony types 1 (n = 4) or 2 (n = 4); 11 with limb-girdle muscular dystrophy, including dysferlinopathy, calpainopathy, sarcoglycanopathy, and dystrophy associated with fukutin-related protein mutation; 3 with Becker muscular dystrophy; and 9 with idiopathic inflammatory myopathies, including polymyositis, dermatomyositis, and sporadic inclusion body myositis. Analysis of T1 images enabled us to describe the most affected muscles and the muscles usually spared for each muscular disease. In particular, examination of pelvis, thigh, and leg muscles demonstrated significant differences between the muscular diseases. On STIR images, hyperintensities were present in 62% of our patients with muscular dystrophies. A specific pattern of muscular involvement was established for each muscular disease. Hyperintensities observed on STIR images precede fatty degeneration and are not specific for inflammatory myopathies. (orig.)

  15. Nutrition Considerations in Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Davis, Jillian; Samuels, Emily; Mullins, Lucille

    2015-08-01

    Duchenne muscular dystrophy (DMD) is a serious degenerative muscular disease affecting males. Diagnosis usually occurs in childhood and is confirmed through genetic testing and/or muscle biopsy. Accompanying the disease are several nutrition-related concerns: growth, body composition, energy and protein requirements, constipation, swallowing difficulties, bone health, and complementary medicine. This review article addresses the nutrition aspects of DMD. © 2015 American Society for Parenteral and Enteral Nutrition.

  16. Congenital penile pathology is associated with abnormal development of the dartos muscle: a prospective study of primary penile surgery at a tertiary referral center.

    Science.gov (United States)

    Spinoit, A-F; Van Praet, C; Groen, L-A; Van Laecke, E; Praet, M; Hoebeke, P

    2015-05-01

    Pathophysiological mechanisms leading to chordee in patients with hypospadias and to the hidden state of buried penis in the prepubic fat remain unclear. Resection of dartos tissue usually makes the penis straight in patients with hypospadias and corrects it in those with buried penis, suggesting a common pathophysiology related to dartos tissue. Tissue samples from 113 children undergoing primary penile surgery for hypospadias (94 patients), epispadias (1) or buried penis (18) were collected between November 2011 and September 2013. Tissue samples from 79 children undergoing circumcision for nonmedical reasons served as controls. All samples were stained with smooth muscle actin and analyzed by the same pathologist, who was blinded to indication for surgery. Chi-square and Fisher exact tests were applied. Three different dartos tissue patterns were observed. Pattern I (normal) consisted of smooth muscle fibers of dartos tissue organized in a parallel configuration in the subcutaneous tissue. Pattern II was characterized by poorly developed and hypotrophic smooth muscle fibers. Pattern III was determined by randomly distributed smooth muscle fibers in the subcutaneous tissue, without parallel configuration. Pattern I was observed in 45 circumcision specimens (64%). Of buried penis cases 78% were considered abnormal (pattern II in 4 cases and III in 10, p = 0.001). Of hypospadias cases 70% were considered abnormal (pattern II in 31 cases, III in 32, and mixed II and III in 3, p Congenital penile pathology (hypospadias, buried penis) is associated with structural anomalies in dartos tissue. Further research is needed to unveil the pathophysiology of the condition. Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  17. Upper girdle imaging in facioscapulohumeral muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Giorgio Tasca

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

  18. A fluorescent microscopy study of biopsied muscles from infantile neuromuscular disorders.

    Science.gov (United States)

    Miike, T; Tamari, H; Ohtani, Y; Nakamura, H; Matsuda, I; Miyoshino, S

    1983-01-01

    The Acridine Orange (AO) stain for muscle biopsies is particularly useful to identify regenerating and ongoing hypertrophic muscle fibers under fluorescent microscopy. This method was applied to muscle biopsies from 65 patients who suffered from various childhood neuromuscular disorders. While normal fibers showed dull green cytoplasm with small green-yellow nuclei, striking fluorescent fibers were observed in eight cases of congenital muscular dystrophy (CMD) and 12 cases of Duchenne muscular dystrophy (DMD); these fibers were characterized as follows: (1) small fibers with big oval or spherical nuclei which fluoresced strongly with a bright orange color; (2) fibers of various sizes and different degrees of orange fluorescence; and (3) opaque fibers with bright yellow cytoplasm. The small diameter fibers in Werdnig-Hoffmann (WH) disease, nemaline myopathy, and congenital fiber type disproportion failed to show apparent AO-RNA fluorescence. Although all the atrophic fibers in Kugelberg-Welander (KW) disease showed a vague orange fluorescent color, this was obviously different from that of regenerating fibers seen in CMD and DMD. In addition to these findings, the hypertrophic fibers in a case of unclassified myopathy also showed moderate orange fluorescence around the entire periphery of the cytoplasm.

  19. Common recessive limb girdle muscular dystrophies differential diagnosis: why and how?

    Directory of Open Access Journals (Sweden)

    Ana Cotta

    2014-09-01

    Full Text Available Limb girdle muscular dystrophies are heterogeneous autosomal hereditary neuromuscular disorders. They produce dystrophic changes on muscle biopsy and they are associated with mutations in several genes involved in muscular structure and function. Detailed clinical, laboratorial, imaging, diagnostic flowchart, photographs, tables, and illustrated diagrams are presented for the differential diagnosis of common autosomal recessive limb girdle muscular dystrophy subtypes diagnosed nowadays at one reference center in Brazil. Preoperative image studies guide muscle biopsy site selection. Muscle involvement image pattern differs depending on the limb girdle muscular dystrophy subtype. Muscle involvement is conspicuous at the posterior thigh in calpainopathy and fukutin-related proteinopathy; anterior thigh in sarcoglycanopathy; whole thigh in dysferlinopathy, and telethoninopathy. The precise differential diagnosis of limb girdle muscular dystrophies is important for genetic counseling, prognostic orientation, cardiac and respiratory management. Besides that, it may probably, in the future, provide specific genetic therapies for each subtype.

  20. Clinical features and molecular characterization of a patient with muscle-eye-brain disease: a novel mutation in the POMGNT1 gene.

    Science.gov (United States)

    Raducu, Madalina; Cotarelo, Rocío P; Simón, Rogelio; Camacho, Ana; Rubio-Fernández, Marcos; Hernández-Laín, Aurelio; Cruces, Jesús

    2014-02-01

    Muscle-eye-brain disease is a congenital muscular dystrophy characterized by structural brain and eye defects. Here, we describe a 12-year-old boy with partial agenesis of corpus callosum, ventriculomegaly, flattened brain stem, diffuse pachygyria, blindness, profound cognitive deficiencies, and generalized muscle weakness, yet without a clear dystrophic pattern on muscle biopsy. There was no glycosylation of α-dystroglycan and the genetic screening revealed a novel truncating mutation, c.1545delC (p.Tyr516Thrfs*21), and a previously identified missense mutation, c.1469G>A (p.Cys490Tyr), in the protein O-mannose beta-1,2-N-acetylglucosaminyltransferase 1 (POMGNT1) gene. These findings broaden the clinical spectrum of muscle-eye-brain disease to include pronounced hypotonia with severe brain and eye malformations, yet with mild histopathologic changes in the muscle specimen, despite the absence of glycosylated α-dystroglycan.

  1. Rhabdomyolysis featuring muscular dystrophies.

    Science.gov (United States)

    Lahoria, Rajat; Milone, Margherita

    2016-02-15

    Rhabdomyolysis is a potentially life threatening condition of various etiology. The association between rhabdomyolysis and muscular dystrophies is under-recognized in clinical practice. To identify muscular dystrophies presenting with rhabdomyolysis at onset or as predominant feature. We retrospectively reviewed clinical and laboratory data of patients with a genetically confirmed muscular dystrophy in whom rhabdomyolysis was the presenting or main clinical manifestation. Thirteen unrelated patients (males=6; females=7) were identified. Median age at time of rhabdomyolysis was 18 years (range, 2-47) and median duration between the first episode of rhabdomyolysis and molecular diagnosis was 2 years. Fukutin-related protein (FKRP) muscular dystrophy (n=6) was the most common diagnosis, followed by anoctaminopathy-5 (n=3), calpainopathy-3 (n=2) and dystrophinopathy (n=2). Four patients experienced recurrent rhabdomyolysis. Eight patients were asymptomatic and 3 reported myalgia and exercise intolerance prior to the rhabdomyolysis. Exercise (n=6) and fever (n=4) were common triggers; rhabdomyolysis was unprovoked in 3 patients. Twelve patients required hospitalization. Baseline CK levels were elevated in all patients (median 1200 IU/L; range, 600-3600). Muscular dystrophies can present with rhabdomyolysis; FKRP mutations are particularly frequent in causing such complication. A persistently elevated CK level in patients with rhabdomyolysis warrants consideration for underlying muscular dystrophy. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Muscular dystrophies: key elements for everyday diagnosis and management

    Directory of Open Access Journals (Sweden)

    Alberto Palladino

    2013-12-01

    Full Text Available Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy, associated with progressive weakness. Weakness may be noted at birth or develop in late adult life. In recent years, cardiac involvement has been observed in a growing number of genetic muscle diseases, and considerable progress has been made in understanding the relationships between disease skeletal muscle and cardiac muscle disease. This review will focus on the skeletal muscle diseases most commonly associated with cardiac complications that can be diagnosed by echocardiography, such as dystrophinopathies including Duchenne (DMD and Becker (BMD muscular dystrophies, cardiomyopathy of DMD/BMD carriers and X-L dilated cardiomyopathy.

  3. Fatal cardiac arrhythmia and long-QT syndrome in a new form of congenital generalized lipodystrophy with muscle rippling (CGL4 due to PTRF-CAVIN mutations.

    Directory of Open Access Journals (Sweden)

    Anna Rajab

    2010-03-01

    Full Text Available We investigated eight families with a novel subtype of congenital generalized lipodystrophy (CGL4 of whom five members had died from sudden cardiac death during their teenage years. ECG studies revealed features of long-QT syndrome, bradycardia, as well as supraventricular and ventricular tachycardias. Further symptoms comprised myopathy with muscle rippling, skeletal as well as smooth-muscle hypertrophy, leading to impaired gastrointestinal motility and hypertrophic pyloric stenosis in some children. Additionally, we found impaired bone formation with osteopenia, osteoporosis, and atlanto-axial instability. Homozygosity mapping located the gene within 2 Mbp on chromosome 17. Prioritization of 74 candidate genes with GeneDistiller for high expression in muscle and adipocytes suggested PTRF-CAVIN (Polymerase I and transcript release factor/Cavin as the most probable candidate leading to the detection of homozygous mutations (c.160delG, c.362dupT. PTRF-CAVIN is essential for caveolae biogenesis. These cholesterol-rich plasmalemmal vesicles are involved in signal-transduction and vesicular trafficking and reside primarily on adipocytes, myocytes, and osteoblasts. Absence of PTRF-CAVIN did not influence abundance of its binding partner caveolin-1 and caveolin-3. In patient fibroblasts, however, caveolin-1 failed to localize toward the cell surface and electron microscopy revealed reduction of caveolae to less than 3%. Transfection of full-length PTRF-CAVIN reestablished the presence of caveolae. The loss of caveolae was confirmed by Atomic Force Microscopy (AFM in combination with fluorescent imaging. PTRF-CAVIN deficiency thus presents the phenotypic spectrum caused by a quintessential lack of functional caveolae.

  4. Analysis of cardiac exams: electrocardiogram and echocardiogram use In Duchenne muscular dystrophies

    OpenAIRE

    Bachur, Cynthia Kallás; Garcia, Marlon Hermógenes; Bernardino, Camila Araújo; Requel, Rogério Camillo; Bachur, José Alexandre

    2014-01-01

    Introduction Duchenne Muscular Dystrophies (DMD) is a genetic muscle disorder that causes degeneration and atrophy of skeletal muscle and heart. Objective The aim of this survey is accomplish an evaluation electrocardiographic and echocardiography in the patients bearers of Duchene Muscular Dystrophies (DMD), to observe which alterations, which the degree of cardiac compromising these patient present and the effectiveness of these exams in the evaluation cardiologic. Methods Nine patients of ...

  5. TNF inhibits Notch-1 in skeletal muscle cells by Ezh2 and DNA methylation mediated repression: implications in duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Swarnali Acharyya

    2010-08-01

    Full Text Available Classical NF-kappaB signaling functions as a negative regulator of skeletal myogenesis through potentially multiple mechanisms. The inhibitory actions of TNFalpha on skeletal muscle differentiation are mediated in part through sustained NF-kappaB activity. In dystrophic muscles, NF-kappaB activity is compartmentalized to myofibers to inhibit regeneration by limiting the number of myogenic progenitor cells. This regulation coincides with elevated levels of muscle derived TNFalpha that is also under IKKbeta and NF-kappaB control.Based on these findings we speculated that in DMD, TNFalpha secreted from myotubes inhibits regeneration by directly acting on satellite cells. Analysis of several satellite cell regulators revealed that TNFalpha is capable of inhibiting Notch-1 in satellite cells and C2C12 myoblasts, which was also found to be dependent on NF-kappaB. Notch-1 inhibition occurred at the mRNA level suggesting a transcriptional repression mechanism. Unlike its classical mode of action, TNFalpha stimulated the recruitment of Ezh2 and Dnmt-3b to coordinate histone and DNA methylation, respectively. Dnmt-3b recruitment was dependent on Ezh2.We propose that in dystrophic muscles, elevated levels of TNFalpha and NF-kappaB inhibit the regenerative potential of satellite cells via epigenetic silencing of the Notch-1 gene.

  6. Bestrophin-3 (vitelliform macular dystrophy 2-like 3 protein) is essential for the cGMP-dependent calcium-activated chloride conductance in vascular smooth muscle cells

    DEFF Research Database (Denmark)

    Matchkov, Vladimir; Larsen, Per; Bouzinova, Elena V.

    2008-01-01

    that bestrophins are a new Cl(-) channel family were based on heterologous expression in cell culture studies. Our present results demonstrate that at least 1 family member, bestrophin-3, is essential for a well-defined endogenous Ca(2+)-activated Cl(-) current in smooth muscles in the intact vascular wall....

  7. How Is Muscular Dystrophy Diagnosed?

    Science.gov (United States)

    ... Research Information Find a Study Resources and Publications Osteogenesis Imperfecta (OI) Condition Information NICHD Research Information Find ... Print How is muscular dystrophy diagnosed? The first step in diagnosing muscular dystrophy (MD) is a visit ...

  8. Possible rare congenital dysinnervation disorder: congenital ptosis associated with adduction.

    Science.gov (United States)

    Mendes, Sílvia; Beselga, Diana; Campos, Sónia; Neves, Arminda; Campos, Joana; Carvalho, Sílvia; Silva, Eduardo; Castro Sousa, João Paulo

    2015-01-01

    Ptosis is defined as an abnormally low position of the upper eyelid margin. It can be congenital or acquired, uni or bilateral, and isolated or associated with other ocular and nonocular defects. We report a case of a female child, aged 8 years, with congenital right ptosis increased on right adduction and with left ptosis on left adduction. There was no horizontal ocular movement limitation. Apparent underaction of the right inferior oblique muscle was also present. We believe that within the possible mechanisms it is more likely that it is a congenital innervation dysgenesis syndrome (CID)/congenital cranial dysinnervation disorder (CCDD).

  9. Perspectives of stem cell therapy in Duchenne muscular dystrophy.

    Science.gov (United States)

    Meregalli, Mirella; Farini, Andrea; Belicchi, Marzia; Parolini, Daniele; Cassinelli, Letizia; Razini, Paola; Sitzia, Clementina; Torrente, Yvan

    2013-09-01

    Muscular dystrophies are heritable and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle, usually caused by mutations in the proteins forming the link between the cytoskeleton and the basal lamina. As a result of mutations in the dystrophin gene, Duchenne muscular dystrophy patients suffer from progressive muscle atrophy and an exhaustion of muscular regenerative capacity. No efficient therapies are available. The evidence that adult stem cells were capable of participating in the regeneration of more than their resident organ led to the development of potential stem cell treatments for degenerative disorder. In the present review, we describe the different types of myogenic stem cells and their possible use for the progression of cell therapy in Duchenne muscular dystrophy. © 2012 The Authors Journal compilation © 2012 FEBS.

  10. Duchenne muscular dystrophy: alpha-dystroglycan immunoexpression in skeletal muscle and cognitive performance Distrofia muscular de Duchenne: imunoexpressão da alfa-distroglicana em musculatura esquelética e performance cognitiva

    Directory of Open Access Journals (Sweden)

    Conceição Campanario da Silva Pereira

    2005-12-01

    Full Text Available The Duchenne muscular systrophy (DMD is a muscular dystrophy with cognitive impairment present in 20-30% of the cases. In the present study, in order to study the relationship between the alpha-dystroglycan (alpha-DG immunostaining in skeletal muscle and cognitive performance in DMD patients, 19 were assessed. Twelve patients performed the intelligence quotient (IQ below the average. Among the 19 patients, two were assessed by the Stanford-Binet test and 17 by Wechsler Intelligence Scale for Children-III (WISC-III. Nine patients performed a verbal IQ below the average, only three patients performed an average verbal IQ. The muscle biopsies immunostained with antibodies to alpha-DG showed that 17 patients presented a low expression, below 25% of the total fibers. Two patients presented alpha-DG immunostaining above 40% and an IQ within the average. No significant statistical relationship was demonstrated among total IQ, verbal IQ and execution IQ and alpha-DG immunostaining at these patients muscle samples.A distrofia muscular de Duchenne (DMD é uma distrofia muscular com comprometimento cognitivo presente em 20-30% dos casos. No presente estudo, com a finalidade de estudar a relação entre a imunoexpressão da alfa-distroglicana (alfa-DG em musculatura esquelética e a performance cognitiva em pacientes com DMD, foram avaliadas 19 crianças. Doze pacientes apresentaram o quociente de inteligência (QI abaixo da média. Entre os 19 pacientes, dois foram avaliados pelo teste de Stanford-Binet e 17 pelo Wechsler Intelligence Scale para crianças-III (WISC-III. Nove apresentaram QI verbal abaixo da média, e apenas três QI verbal na média. As biopsias musculares com os anticorpos para alfa-DG mostraram que 17 pacientes apresentaram baixa expressão, abaixo de 25% do total de fibras. Dois pacientes apresentaram a imunoexpressão da alfa-DG acima de 40% e QI dentro da média. Não foi demonstrada relação estatisticamente significante entre o QI

  11. The Effect of Cleft Palate Repair on Contractile Properties of Single Permeabilized Muscle Fibers From Congenitally Cleft Goats Palates

    Science.gov (United States)

    A cleft palate goat model was used to study the contractile properties of the levator veli palatini (LVP) muscle which is responsible for the movement of the soft palate. In 15-25% of patients that undergo palatoplasty, residual velopharyngeal insufficiency (VPI) remains a problem and often require...

  12. Cardiac involvement in patients with limb-girdle muscular dystrophy type 2 and Becker muscular dystrophy

    DEFF Research Database (Denmark)

    Sveen, Marie-Louise; Thune, Jens Jakob; Køber, Lars

    2008-01-01

    OBJECTIVE: To investigate the extent of cardiac involvement in patients with 1 of the 12 groups of recessively inherited limb-girdle muscular dystrophy type 2 (LGMD2A-L) and Becker muscular dystrophy (BMD). DESIGN: Prospective screening. SETTING: Neuromuscular Clinic and Department of Cardiology......-I and in 14 of 30 patients (47%) with BMD. Only a few patients with LGMD2A and unclassified LGMD2 had mild cardiac involvement, whereas 29% and 67% of patients with LGMD2I and LGMD2E, respectively, had cardiac involvement. Cardiac involvement was not correlated with age, muscle strength, or the level...... of dystrophic changes on muscle biopsy. CONCLUSIONS: This study demonstrates a high prevalence of cardiac involvement in patients with LGMD2I, LGMD2E, and BMD. Patients with LGMD2A, LGMD2D, and unclassified LGMD2 have a much lower and milder prevalence of cardiac involvement....

  13. Pain characterization in Duchenne muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Talita Dias da Silva

    Full Text Available ABSTRACT Duchenne muscular dystrophy (DMD is an X-linked recessive disorder, characterized by progressive muscle weakness. Historically, pain has not been considered to be a major symptom in DMD. Objective To investigate the relationship between DMD and pain. Methods We conducted a systematic review in Medline/PubMed and BVS (virtual library in health databases. We searched for articles that showed the terms “Muscular Dystrophy, Duchenne” and “Pain” in all fields. All studies included boys diagnosed with DMD and the occurrence/amount of pain on this population. Results Initially, there were 175 studies. 167 articles were excluded for not meeting the inclusion criteria. The remaining eight eligible studies, involving pain assessment in DMD, were analyzed. Conclusion Pain is a frequent problem in this population and this symptom is potentially tractable. Studies conclude that pain can directly influence the quality of life of this population.

  14. Computed tomographic findings in manifesting carriers of Duchenne muscular dystrophy

    NARCIS (Netherlands)

    de Visser, M.; Verbeeten, B.

    1985-01-01

    Clinical and computed tomographic (CT) findings in 3 manifesting carriers of Duchenne muscular dystrophy are reported. CT proved to be an important adjunct to the clinical examination: in all our 3 cases a decrease in density was found in various non-paretic muscles

  15. Antisense mediated exon skipping therapy for duchenne muscular dystrophy (DMD)

    DEFF Research Database (Denmark)

    Brolin, Camilla; Shiraishi, Takehiko

    2011-01-01

    Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in the dystrophin gene (DMD) that result in the absence of essential muscle protein dystrophin. Among many different approaches for DMD treatment, exon skipping, mediated by antisense oligonucleotides, is one of the most...

  16. MRI as outcome measure in facioscapulohumeral muscular dystrophy

    DEFF Research Database (Denmark)

    Andersen, Grete; Dahlqvist, Julia R; Vissing, Christoffer R

    2017-01-01

    There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly...... muscle groups. The clinical severity FSHD score worsened (10%, P hip (8%), neck (8%), and back (17%) (P

  17. Emerging drugs for Duchenne muscular dystrophy.

    Science.gov (United States)

    Malik, Vinod; Rodino-Klapac, Louise R; Mendell, Jerry R

    2012-06-01

    Duchenne muscular dystrophy (DMD) is the most common, severe childhood form of muscular dystrophy. Treatment is limited to glucocorticoids that have the benefit of prolonging ambulation by approximately 2 years and preventing scoliosis. Finding a more satisfactory treatment should focus on maintaining long-term efficacy with a minimal side effect profile. Authors discuss different therapeutic strategies that have been used in pre-clinical and clinical settings. Multiple treatment approaches have emerged. Most attractive are molecular-based therapies that can express the missing dystrophin protein (exon skipping or mutation suppression) or a surrogate gene product (utrophin). Other approaches include increasing the strength of muscles (myostatin inhibitors), reducing muscle fibrosis and decreasing oxidative stress. Additional targets include inhibiting NF-κB to reduce inflammation or promoting skeletal muscle blood flow and muscle contractility using phosphodiesterase inhibitors or nitric oxide (NO) donors. The potential for each of these treatment strategies to enter clinical trials is a central theme of discussion. The review emphasizes that the goal of treatment should be to find a product at least as good as glucocorticoids with a lower side effect profile or with a significant glucocorticoid sparing effect.

  18. Rimmed vacuoles in Becker muscular dystrophy have similar features with inclusion myopathies.

    Science.gov (United States)

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

    2012-01-01

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

  19. Transcriptional changes and developmental abnormalities in a zebrafish model of myotonic dystrophy type 1

    Directory of Open Access Journals (Sweden)

    Peter K. Todd

    2014-01-01

    Full Text Available Myotonic dystrophy type I (DM1 is a multi-system, autosomal dominant disorder caused by expansion of a CTG repeat sequence in the 3′UTR of the DMPK gene. The size of the repeat sequence correlates with age at onset and disease severity, with large repeats leading to congenital forms of DM1 associated with hypotonia and intellectual disability. In models of adult DM1, expanded CUG repeats lead to an RNA toxic gain of function, mediated at least in part by sequestering specific RNA splicing proteins, most notably muscleblind-related (MBNL proteins. However, the impact of CUG RNA repeat expression on early developmental processes is not well understood. To better understand early developmental processes in DM1, we utilized the zebrafish, Danio rerio, as a model system. Direct injection of (CUG91 repeat-containing mRNA into single-cell embryos induces toxicity in the nervous system and muscle during early development. These effects manifest as abnormal morphology, behavioral abnormalities and broad transcriptional changes, as shown by cDNA microarray analysis. Co-injection of zebrafish mbnl2 RNA suppresses (CUG91 RNA toxicity and reverses the associated behavioral and transcriptional abnormalities. Taken together, these findings suggest that early expression of exogenously transcribed CUG repeat RNA can disrupt normal muscle and nervous system development and provides a new model for DM1 research that is amenable to small-molecule therapeutic development.

  20. Computed tomography in Duchenne type muscular dystrophy

    International Nuclear Information System (INIS)

    Kawai, Mitsuru; Kunimoto, Masanari; Motoyoshi, Yasufumi; Kuwata, Takashi; Nakano, Imaharu

    1985-01-01

    The computed tomography (CT) scan was performed on 91 Duchenne type muscular dystrophy (DMD) patients on the following four levels; (1) at the level of L3 vertebra, (2) 2-3cm above the symphysis pubica, (3) midposition of the thigh, (4) largest-diameter section of the lower leg. The CT of muscles common to most of the DMD patients were as follows: 1. Muscle atrophy: Muscle atrophy was shown as a reduction in the cross-sectional area of the muscles. Very mild muscle atrophy could be detected either by the clearly identified muscle border or by scattered low-density areas of so-called ''moth-eaten'' appearance within muscles. 2. Fat infiltration: The decrease in radio-density of muscles was interpreted as infiltration of fatty tissue. This type of density change was further classified into diffuse, streaked, cobblestone and salt-and-pepper patterns according to the spacial distribution of low-density areas. 3. Selectivity pattern: As the chronological sequence of DMD muscle degeneration is usually different among individual muscles, it may be seen, in some stages, that some of the synergistic muscles are still only slightly involved, while the others are quite severely atrophied with evident fat infiltration. In certain stages of the disease, most of the patients show relative preservation of particular muscles although they assumed a rounded shape. The most resistent muscle was musculus gracilis, followed by the musculus sartorius, musculus semitendinosus (and/or musculus semimembranosus) in that order. According to the severity of the CT changes, 86 of the 91 patients were classed into five stages from A1 to A5. Morphological stages (A1-A5) were well correlated to the functional disability stages by Ueda with a correlation factor of r=0.88. (J.P.N.)

  1. Nanotherapy for Duchenne muscular dystrophy.

    Science.gov (United States)

    Nance, Michael E; Hakim, Chady H; Yang, N Nora; Duan, Dongsheng

    2018-03-01

    Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials. Recent regulatory approval of Ataluren (a nonsense mutation read-through chemical) in Europe and Exondys51 (an exon-skipping antisense oligonucleotide drug) in the United States shall offer critical insight in how to move DMD nanotherapy to human patients. Progress in novel, optimized nano-delivery systems may further improve emerging molecular therapeutic modalities for DMD. Despite these progresses, DMD nanotherapy faces a number of unique challenges. Specifically, the dystrophin gene is one of the largest genes in the genome while nanoparticles have an inherent size limitation per definition. Furthermore, muscle is the largest tissue in the body and accounts for 40% of the body mass. How to achieve efficient bodywide muscle targeting in human patients with nanomedication remains a significant translational hurdle. New creative approaches in the design of the miniature micro-dystrophin gene, engineering of muscle-specific synthetic AAV capsids, and novel nanoparticle-mediated exon-skipping are likely to result in major breakthroughs in DMD therapy. WIREs Nanomed Nanobiotechnol 2018, 10:e1472. doi: 10.1002/wnan.1472 This article is categorized under: Biology-Inspired Nanomaterials > Protein and Virus-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies. © 2017 Wiley Periodicals, Inc.

  2. Magnetic resonance imaging of children with Duchenne muscular dystrophy

    International Nuclear Information System (INIS)

    Schreiber, A.; Smith, W.L.; Franken, E.A.; Dunn, V.; Ehrhardt, J.; Ionasescu, V.; Zellweger, H.

    1987-01-01

    Eight children representing a spectrum of clinical states of biopsy-proven Duchenne muscular dystrophy (DMD) underwent magnetic resonance (MR) scans to assess the degree of muscular involvement and disease progression. Five muscle groups (neck, shoulder girdle, pelvic girdle, thigh and calf) were evaluated. In each case, involved muscles were clearly demarcated. Image estimates of disease severity by degree of muscle involvement correlated well with clinical staging. In our experience MR is useful for assessment of disease stage, selection of appropriate muscles for biopsy and planning for courses of physical and rehabilitation therapy. (orig.)

  3. Congenital toxoplasmosis

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/001360.htm Congenital toxoplasmosis To use the sharing features on this page, please enable JavaScript. Congenital toxoplasmosis is a group of symptoms that occur when ...

  4. Congenital Hypothyroidism

    Science.gov (United States)

    ... Disease Featured Resource Find an Endocrinologist Search Congenital Hypothyroidism March 2012 Download PDFs English Espanol Editors Rosalind S. ... Resources MedlinePlus (NIH) Mayo Clinic What is congenital hypothyroidism? Newborn babies who are unable to make enough ...

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

    Directory of Open Access Journals (Sweden)

    Michelle F Goody

    Full Text Available 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

  6. Sarcopenia and sarcopenic obesity in patients with muscular dystrophy

    Directory of Open Access Journals (Sweden)

    Luciano eMerlini

    2014-10-01

    Full Text Available Aging sarcopenia and muscular dystrophy 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 muscular dystrophy 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, and for physical performance gait speed. The study involved 14 adult patients with different types of muscular dystrophy. We were able to demonstrate that all patient were sarcopenic-obese. We showed in fact that all were sarcopenic based on appendicular lean, fat & bone free, mass index (ALMI. In addition all resulted obese according to the % of body fat determined by DXA in contrast with 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 hand held dynamometry, 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 suggest the relevance of a proper evaluation of body composition in muscular dystrophy and we propose to use, both in research and practice, the measurement techniques that has already been demonstrated effective in aging sarcopenia.

  7. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy.

    Science.gov (United States)

    Guiraud, Simon; Chen, Huijia; Burns, David T; Davies, Kay E

    2015-12-01

    What is the topic of this review? This review highlights recent progress in genetically based therapies targeting the primary defect of Duchenne muscular dystrophy. What advances does it highlight? Over the last two decades, considerable progress has been made in understanding the mechanisms underlying Duchenne muscular dystrophy, leading to the development of genetic therapies. These include manipulation of the expression of the gene or related genes, the splicing of the gene and its translation, and replacement of the gene using viral approaches. Duchenne muscular dystrophy is a lethal X-linked disorder caused by mutations in the dystrophin gene. In the absence of the dystrophin protein, the link between the cytoskeleton and extracellular matrix is destroyed, and this severely compromises the strength, flexibility and stability of muscle fibres. The devastating consequence is progressive muscle wasting and premature death in Duchenne muscular dystrophy patients. There is currently no cure, and despite exhaustive palliative care, patients are restricted to a wheelchair by the age of 12 years and usually succumb to cardiac or respiratory complications in their late 20s. This review provides an update on the current genetically based therapies and clinical trials that target or compensate for the primary defect of this disease. These include dystrophin gene-replacement strategies, genetic modification techniques to restore dystrophin expression, and modulation of the dystrophin homologue, utrophin, as a surrogate to re-establish muscle function. © 2015 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

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

    Directory of Open Access Journals (Sweden)

    Sandra J Feeney

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

  9. [Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy].

    Science.gov (United States)

    Silva, Helga Cristina Almeida da; Hiray, Marcia; Vainzof, Mariz; Schmidt, Beny; Oliveira, Acary Souza Bulle; Amaral, José Luiz Gomes do

    2017-05-31

    Duchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia. Male patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels - CK), with CK values of 7,779-29,040IU.L -1 (normal 174IU.L -1 ). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy. On preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia. Copyright © 2017 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.

  10. Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

    Science.gov (United States)

    Parvatiyar, Michelle S; Marshall, Jamie L; Nguyen, Reginald T; Jordan, Maria C; Richardson, Vanitra A; Roos, Kenneth P; Crosbie-Watson, Rachelle H

    2015-12-23

    Duchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy. SSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix. SSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  11. Relevant aspects of golden retriever muscular dystrophy for the study of Duchenne muscular dystrophy in humans

    Directory of Open Access Journals (Sweden)

    Julieta Rodini Engrácia de Moraes

    2017-09-01

    Full Text Available ABSTRACT: Golden Retriever muscular dystrophy (GRMD is the most representative model for studying Duchenne muscular dystrophy (DMD in humans, owing its phenotypic expression. DMD is a recessive disorder linked to the X chromosome in which the loss of dystrophin induces progressive weakness and degeneration of the skeletal and cardiac muscles, which lead to replacement by connective and adipose tissues. Onset of clinical signs occurs between 2 and 5 years of age, and many patients die from heart or respiratory failure. The main studies concerning dystrophic Golden Retrievers (DGR sought to elucidate the pathophysiology of the disease and its clinical implications to develop therapies and alternative treatments to improve the quality of life and increase longevity of DMD patients. This review presents an overview of relevant contributions of the DGR model for elucidating DMD in humans.

  12. Reflex sympathetic dystrophy in hemiplegia.

    Science.gov (United States)

    Gokkaya, Nilufer Kutay Ordu; Aras, Meltem; Yesiltepe, Elcin; Koseoglu, Fusun

    2006-12-01

    There is a high incidence of reflex sympathetic dystrophy of the upper limbs in patients with hemiplegia, and its painful and functional consequences present a problem to specialists in physical medicine and rehabilitation. This study was designed to assess the role of several factors in the occurrence of reflex sympathetic dystrophy in patients with hemiplegia. Ninety-five consecutive stroke patients (63 male and 32 female, mean age 59+/-12 years) admitted to our hospital were evaluated. Of the study group, 29 patients (30.5%) were found to develop reflex sympathetic dystrophy. There were no significant differences between the hemiplegic patient groups with or without reflex sympathetic dystrophy regarding age, gender, etiology, side of involvement, disease duration and the presence of comorbidities. The recovery stages of hemiplegia, as shown by Brunnstrom functional classification, were significantly different between the two groups; patients in lower recovery stages tended to develop reflex sympathetic dystrophy more frequently (Preflex sympathetic dystrophy. Glenohumeral subluxation was present in 37 patients (38.9%) in our study group and the presence of this complication was related to the occurrence of reflex sympathetic dystrophy. The presence of glenohumeral subluxation was significantly higher in patients with reflex sympathetic dystrophy (21/29, 72.4%) when compared to the patients without reflex sympathetic dystrophy (16/66, 24.2%) (Preflex sympathetic dystrophy. These results suggest that lower recovery stages, reduced tonus and glenohumeral subluxation significantly contribute to the occurrence of reflex sympathetic dystrophy in the hemiplegic patient. We believe that preventive and treatment measures should consider these factors as they seem to have in common a higher risk of traumatizing the paralyzed upper limb and causing reflex sympathetic dystrophy.

  13. CT findings of muscular dystrophy; Limb girdle type (LG), myotonic type (MYD) and Duchenne type (DMD)

    Energy Technology Data Exchange (ETDEWEB)

    Saitoh, Hiroshi (Tokushima Univ. (Japan). School of Medicine)

    1991-07-01

    CT scans of muscles in patients with limb girdle type (LG), myotonic type (MYD) and Duchenne type (DMD) dystrophies were obtained at five different body levels: the neck, L3 vertebral body, pelvic girdle, thigh and lower leg. CT numbers, cross sectional areas (CSA) and %CSA of muscle or fat were evaluated in each muscle. The characteristic CT patterns for each type of muscular dystrophy were obtained. Compared with DMD, the gracilis and soleus were more severely damaged in LG and the biceps femoris remained relatively preserved among the hamstrings. In addition, the multifidus of the neck and sternocleidomastoid also were more severely damaged in MYD. This study suggests that CT scan will be useful in the differential diagnosis of these types of muscular dystrophy as well as in planning appropriate rehabilitation and detecting damaged muscles. (author).

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

    OpenAIRE

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

    2012-01-01

    Rimmed vacuoles in myofibers are thought to be due to the accumulation of autophagic vacuoles, and can be characteristic in certain myopathies with protein inclusions in myofibers. In this study, we performed a detailed clinical, molecular, and pathological characterization of Becker muscular dystrophy patients who have rimmed vacuoles in muscles. Among 65 Becker muscular dystrophy patients, we identified 12 patients who have rimmed vacuoles and 11 patients who have deletions in exons 45-48 i...

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

    Energy Technology Data Exchange (ETDEWEB)

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

    1995-08-28

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

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

    OpenAIRE

    Suneja, B; Suneja, ES; Adlakha, VK; Chandna, P

    2015-01-01

    ABSTRACT Duchenne muscular dystrophy (DMD) is an recessive X-linked mediated, musculoskeletal disorder that affects only males. It is the most common and severe form of muscular dystrophy where there is failure to manufacture dystrophin. Clinically, it is characterized by progressive muscle wasting eventually leading to premature death. This case report describes the genetic, oral and systemic findings in two cases of DMD in male siblings. How to cite this article: Suneja B, Suneja ES, Adlakh...

  17. A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups

    Science.gov (United States)

    Randolph, Matthew E.; Pavlath, Grace K.

    2015-01-01

    The human body contains approximately 640 individual skeletal muscles. Despite the fact that all of these muscles are composed of striated muscle tissue, the biology of these muscles and their associated muscle stem cell populations are quite diverse. Skeletal muscles are affected differentially by various muscular dystrophies (MDs), such that certain genetic mutations specifically alter muscle function in only a subset of muscles. Additionally, defective muscle stem cells have been implicated in the pathology of some MDs. The biology of muscle stem cells varies depending on the muscles with which they are associated. Here we review the biology of skeletal muscle stem cell populations of eight different muscle groups. Understanding the biological variation of skeletal muscles and their resident stem cells could provide valuable insight into mechanisms underlying the susceptibility of certain muscles to myopathic disease. PMID:26500547

  18. Computed tomography of the skeletal muscles in neuromuscular diseases

    International Nuclear Information System (INIS)

    Nagao, Hideo; Takahashi, Mitsugi; Habara, Shinji; Nagai, Yoshinao; Matsuda, Hiroshi

    1986-01-01

    Computed tomographic (CT) scans of the shoulder girdle, upper arm, waist, pelvic girdle, thigh, and lower leg were obtained in a total of 21 patients with neuromuscular diseases, including 10 with Duchenne muscle dystrophy (DMD), 3 with Fukushima type congenital muscular dystrophy (FCMD), 3 with Werdnig-Hoffmann's disease (WH), 3 with autosomal recessive muscular dystrophy in childhood (childhood MC), one with nemaline myopathy (NM), and one with myositis ossificans circumscripta (MOC). Age-dependent changes in CT findings were examined in the 10 DMD patients ranging in age from 3 to 15 years. Each muscle of the shoulder girdle and upper arm was seen as a low density area on CT in patients 9 years of age when the arms are difficult to elevate. Changes in the m. quadriceps femoris occurring in all the patients were visible earlist on CT, followed by those in the m. gluteus maximus, m. gastrocnemius, and m. soleus. CT scans of the thigh was thus considered most useful in diagnosing DMD. CT scans of the lower leg showed low density areas in the m. gastrocnemius and m. soleus in both WH and FCMD patients, while a low density area seen in the m. gluteus maximum on CT was restricted to FCMD patients. This suggests the potential of CT in the differentiation of WH from FCMD. In patients with childhood ARMD, there were various CT findings including normal and extremely low density areas. CT findings in NM patients were similar to those in DMD patients. High density areas were seen along the fascia of the trunk in MOC patients. (Namekawa, K.)

  19. Gait propulsion in patients with facioscapulohumeral muscular dystrophy and ankle plantarflexor weakness

    NARCIS (Netherlands)

    Rijken, N.H.M.; Engelen, B.G.M. van; Rooy, J.W.J. de; Weerdesteyn, V.G.M.; Geurts, A.C.H.

    2015-01-01

    Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot

  20. Effects of Sildenafil on Cerebrovascular Reactivity in Patients with Becker Muscular Dystrophy

    DEFF Research Database (Denmark)

    Lindberg, Ulrich; Witting, Nanna; Jørgensen, Stine Lundgaard

    2017-01-01

    Patients suffering from Becker muscular dystrophy (BMD) have dysfunctional dystrophin proteins and are deficient in neuronal nitric oxide synthase (nNOS) in muscles. This causes functional ischemia and contributes to muscle wasting. Similar functional ischemia may be present in brains of patients...

  1. Laminin α2 chain-deficiency is associated with microRNA deregulation in skeletal muscle and plasma

    Directory of Open Access Journals (Sweden)

    Johan eHolmberg

    2014-07-01

    Full Text Available MicroRNAs (miRNAs are widespread regulators of gene expression, but little is known of their potential roles in congenital muscular dystrophy type 1A (MDC1A. MDC1A is a severe form of muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. To gain insight into the pathophysiological roles of miRNAs associated with MDC1A pathology, laminin α2 chain-deficient mice were evaluated by quantitative PCR. We demonstrate that expression of muscle-specific miR-1, miR-133a, and miR-206 is deregulated in laminin α2 chain-deficient muscle. Furthermore, expression of miR-223 and miR-21, associated with immune cell infiltration and fibrosis, respectively, is altered. Finally, we show that plasma levels of muscle-specific miRNAs are markedly elevated in laminin α2 chain-deficient mice and partially normalized in response to proteasome inhibition therapy. Altogether, our data suggest important roles for miRNAs in MDC1A pathology and we propose plasma levels of muscle-specific miRNAs as promising biomarkers for the progression of MDC1A.

  2. CONGENITAL ANTERIOR TIBIOFEMURAL SUBLUXATION

    Directory of Open Access Journals (Sweden)

    A. Shahla

    2008-06-01

    Full Text Available Congenital anterior tibiofemoral subluxation is an extremely rare disorder. All reported cases accompanied by other abnormalities and syndromes. A 16-year-old high school girl referred to us with bilateral anterior tibiofemoral subluxation as the knees were extended and reduced at more than 30 degrees flexion. Deformities were due to tightness of the iliotibial band and biceps femuris muscles and corrected by surgical release. Associated disorders included bilateral anterior shoulders dislocation, short metacarpals and metatarsals, and right calcaneuvalgus deformity.

  3. Sleep disturbances in myotonic dystrophy type 2.

    Science.gov (United States)

    Shepard, Paul; Lam, Erek M; St Louis, Erik K; Dominik, Jacob

    2012-01-01

    Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep-disordered breathing, hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (5 women, 3 men) with DM2 were identified. Excessive daytime sleepiness was seen in 6 patients (75%), insomnia in 5 (62.5%), and excessive fatigue in 4 (50%). Obstructive sleep apnea was diagnosed in 3 of 5 patients (60%) studied with PSG. Respiratory muscle weakness was present in all 6 patients (100%) who received pulmonary function testing. Four of 8 (50%) met criteria for diagnosis of restless legs syndrome. The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2. Copyright © 2012 S. Karger AG, Basel.

  4. siRNA-mediated Allele-specific Silencing of a COL6A3 Mutation in a Cellular Model of Dominant Ullrich Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Véronique Bolduc

    2014-01-01

    Full Text Available Congenital muscular dystrophy type Ullrich (UCMD is a severe disorder of early childhood onset for which currently there is no effective treatment. UCMD commonly is caused by dominant-negative mutations in the genes coding for collagen type VI, a major microfibrillar component of the extracellular matrix surrounding the muscle fibers. To explore RNA interference (RNAi as a potential therapy for UCMD, we designed a series of small interfering RNA (siRNA oligos that specifically target the most common mutations resulting in skipping of exon 16 in the COL6A3 gene and tested them in UCMD-derived dermal fibroblasts. Transcript analysis by semiquantitative and quantitative reverse transcriptase PCR showed that two of these siRNAs were the most allele-specific, i.e., they efficiently knocked down the expression from the mutant allele, without affecting the normal allele. In HEK293T cells, these siRNAs selectively suppressed protein expression from a reporter construct carrying the mutation, with no or minimal suppression of the wild-type (WT construct, suggesting that collagen VI protein levels are as also reduced in an allele-specific manner. Furthermore, we found that treating UCMD fibroblasts with these siRNAs considerably improved the quantity and quality of the collagen VI matrix, as assessed by confocal microscopy. Our current study establishes RNAi as a promising molecular approach for treating dominant COL6-related dystrophies.

  5. Sleep Disordered Breathing in Duchenne Muscular Dystrophy.

    Science.gov (United States)

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

    2017-05-01

    This review aims to explain the inevitable imbalance between respiratory load, drive, and muscular force that occurs in the natural aging of Duchenne muscular dystrophy and that predisposes these patients to sleep disordered breathing (SDB). In DMD, SDB is characterized by oxygen desaturation, apneas, hypercapnia, and hypoventilation during sleep and ultimately develops into respiratory failure during wakefulness. It can be present in all age groups. Young patients risk obstructive apneas because of weight gain, secondary to progressive physical inactivity and prolonged corticosteroid therapy; older patients hypoventilate and desaturate because of respiratory muscle weakness, in particular the diaphragm. These conditions are further exacerbated during REM sleep, the phase of maximal muscle hypotonia during which the diaphragm has to provide most of the ventilation. Evidence is given to the daytime predictors of early symptoms of SDB, important indicators for the proper time to initiate mechanical ventilation.

  6. Computed tomography of muscles in neuromuscular disease

    International Nuclear Information System (INIS)

    Serratrice, G.

    1986-01-01

    137 patients with neuromuscular diseases were studied by CT scan. Four levels were chosen: mid-calf, mid-thigh, pelvic girdle, and spinal muscles. The scans were compared with normal control scans taken from the same sites. The patients were divided into those with myogenic diseases and those with neurogenic diseases. Of the 102 patients with myogenic changes, 17 had X-linked dystrophy, 13 had facio-scapulo-humeral dystrophy, 22 had limb girdle dystrophy, 19 had myotonic dystrophy, 14 had inflammatory muscle diseases, and 17 had miscellaneous muscular diseases. Of the 35 patients with neurogenic changes, 8 had amyotrophic lateral sclerosis (ALS), 16 had chronic spinal amyotrophies, 9 had peripheral neuropathies, and 2 had Friedreich's disease. The analysis of muscles changes (volume, outline, density) was established on the following muscles: tibialis anterior, peroneus, soleus, gastrocnemius mediale, gastrocnemius laterale, quadriceps, semitendinosus, semimembranosus, sartorius, adductor, gracilis, gluteus, spine extensors, and psoas

  7. Bones, Muscles, and Joints: The Musculoskeletal System

    Science.gov (United States)

    ... Facts Dealing With Broken Bones Proximal Biceps Tendonitis Hamstring Strain Muscular Dystrophy Stress Fractures Scoliosis Juvenile Idiopathic Arthritis (JIA) Strains and Sprains Broken Bones Bones, Muscles, and Joints Achilles Tendonitis View more Partner Message ...

  8. Understanding the process of fibrosis in Duchenne muscular dystrophy.

    Science.gov (United States)

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

    2014-01-01

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

  9. Understanding the Process of Fibrosis in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Yacine Kharraz

    2014-01-01

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

  10. Ritodrine-induced rhabdomyolysis, infantile myotonic dystrophy, and maternal myotonic dystrophy unveiled.

    Science.gov (United States)

    Ogoyama, Manabu; Takahashi, Hironori; Kobayashi, Yukako; Usui, Rie; Matsubara, Shigeki

    2017-02-01

    A primiparous pregnant woman in remission of myositis suffered very acute-onset ritodrine-induced rhabdomyolysis. At 29 gestational weeks, ritodrine was administered for threatened preterm labor. Just 3 h later, she complained of severe limb muscle pain, with serum creatinine phosphokinase elevated to 32 019 U/L and myoglobinuria. The muscle pain disappeared immediately after ceasing administration of ritodrine. At 31 weeks, premature rupture of the membranes occurred, necessitating cesarean section, yielding a baby with weak tonus, and the presence of infantile muscle diseases was suspected. Genetic analysis of the infant confirmed myotonic dystrophy (dystrophia myotonica, DM), which prompted us to perform maternal genetic analysis, confirming maternal DM. Ritodrine can induce rhabdomyolysis even in the prodromal phase with a mild phenotype of DM. A literature review suggested that ritodrine-induced rhabdomyolysis may be likely to occur more acutely after ritodrine administration in DM compared with non-DM mothers. © 2016 Japan Society of Obstetrics and Gynecology.

  11. The Dystrophin-Glycoprotein Complex in the Prevention of Muscle Damage

    Directory of Open Access Journals (Sweden)

    Jessica D. Gumerson

    2011-01-01

    Full Text Available Muscular dystrophies are genetically diverse but share common phenotypic features of muscle weakness, degeneration, and progressive decline in muscle function. Previous work has focused on understanding how disruptions in the dystrophin-glycoprotein complex result in muscular dystrophy, supporting a hypothesis that the muscle sarcolemma is fragile and susceptible to contraction-induced injury in multiple forms of dystrophy. Although benign in healthy muscle, contractions in dystrophic muscle may contribute to a higher degree of muscle damage which eventually overwhelms muscle regeneration capacity. While increased susceptibility of muscle to mechanical injury is thought to be an important contributor to disease pathology, it is becoming clear that not all DGC-associated diseases share this supposed hallmark feature. This paper outlines experimental support for a function of the DGC in preventing muscle damage and examines the evidence that supports novel functions for this complex in muscle that when impaired, may contribute to the pathogenesis of muscular dystrophy.

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

    Science.gov (United States)

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

    2015-06-01

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

  13. Congenital tuberculosis

    African Journals Online (AJOL)

    Prof Ezechukwu

    2012-06-20

    Jun 20, 2012 ... Key words: Congenital tuberculo- sis, case report, miliary tuberculosis. Introduction. Congenital tuberculosis defines tuberculosis in infants of .... tary TB and otitis media, resulting in seizures, deafness, and death. It is therefore not surprising that the index case who presented at twelve weeks of age, had ...

  14. Congenital Myasthenia

    Science.gov (United States)

    ... Symptoms of congenital myasthenia usually appear in the first few years of childhood, but may not be noticeable until much later, ... Symptoms of congenital myasthenia usually appear in the first few years of childhood, but may not be noticeable until much later, ...

  15. Congenital ganglioglioma.

    Science.gov (United States)

    Karthikeyan, Gengaimuthu; Subburam, Paiyanan; Ravishankar, Soundian Soundian

    2002-03-01

    Congenital neoplasms of brain presenting at birth are extremely uncommon. We report a case of congenital ganglioglioma presenting at birth with hydrocephalus. Ventriculoperitoneal shunt and surgical debulking of the tumour along with histopathological confirmation were done at 6 months of age. On follow-up at 18 months, the child's hydrocephalus is static and his assessed developmental age is 10-12 months.

  16. Cone rod dystrophies

    Directory of Open Access Journals (Sweden)

    Hamel Christian P

    2007-02-01

    Full Text Available Abstract Cone rod dystrophies (CRDs (prevalence 1/40,000 are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP, also called the rod cone dystrophies (RCDs resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7. Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far. The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs, CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs, and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs. It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is

  17. Duchenne muscular dystrophy with associated growth hormone deficiency

    International Nuclear Information System (INIS)

    Ghafoor, T.; Mahmood, A.; Shams, S.

    2003-01-01

    A patient with duchenne muscular dystrophy (DMD) and growth hormone (GH) deficiency is described who had no clinical evidence of muscular weakness before initiation of GH replacement therapy. Treatment with human GH resulted in appearance of symptoms of easy fatigability and muscle weakness. Thorough investigations including serum creating phosphokinase (CK) levels in recommended in every patient with GH deficiency before starting GH replacement therapy. (author)

  18. Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report

    OpenAIRE

    Nair, Velu; Das, Satyaranjan; Sharma, Ajay; Sharma, Sanjeevan; Kaur, Jasmeet; Mishra, DK

    2011-01-01

    Abstract Introduction Diamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental. Case presentation We report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemi...

  19. Emerging genetic therapies to treat Duchenne muscular dystrophy

    Science.gov (United States)

    Nelson, Stanley F.; Crosbie, Rachelle H.; Miceli, M. Carrie; Spencer, Melissa J.

    2010-01-01

    Purpose of review Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations. The purpose of this review is to highlight two emerging therapies designed to repair the primary genetic defect, called `exon skipping' and `nonsense codon suppression'. Recent findings A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops. Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo. Both approaches have concluded phase I trials with no serious adverse events. Summary These novel therapies that act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans. Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy. PMID:19745732

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

    Directory of Open Access Journals (Sweden)

    Francesca Sciandra

    2015-01-01

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

  1. Reflex Sympathetic Dystrophy in Children

    Directory of Open Access Journals (Sweden)

    Adnan Ayvaz

    2013-10-01

    Full Text Available    Reflex sympathetic dystrophy (chronic regional pain syndrome isn’t frequently encountered in practical pediatrics and childhood. Reflex sympathetic dystrophy syndrome (RSD is a disorder characterized by widespread localized pain, often along with swelling, discoloration, trophic changes and autonomic abnormalities such as vasomotor disorders. Its etio-pathogenesis hasn’t been completely determined.The disease can form in an area innerved by a partially damaged nerve and usually follows minor injury or trauma. In this paper, two girl patients with reflex sympathetic dystrophy are discussed along with the laboratory and clinic finding by accompaniment the literature as it is rarely seen in childhood.

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

    Science.gov (United States)

    2015-02-11

    such as duchenne muscular dystrophy) results in impaired regeneration, increased atrophy and fibrosis of skeletal muscle [24-27]. It has also been...2005; 122:289-301. 24. Cohn RDCampbell KP. Molecular basis of muscular dystrophies. Muscle Nerve 2000; 23:1456-1471. 25. Morgan JEZammit PS. Direct...effects of the pathogenic mutation on satellite cell function in muscular dystrophy. Exp Cell Res 2010; 316:3100-3108. 26. Conboy IMRando TA

  3. Myopathy in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

    Science.gov (United States)

    Watanabe, Mitsuru; Ochi, Hirofumi; Arahata, Hajime; Matsuo, Tomohito; Nagafuchi, Seiho; Ohyagi, Yasumasa; Kira, Jun-Ichi

    2012-06-01

    Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by monogenic mutations in the autoimmune regulator (AIRE) gene. No attention has been paid to muscle manifestations in this disorder. We aimed to uncover whether progressive myopathy is a component of this disorder. A case description and literature search for APECED cases presenting with myopathy and analysis of AIRE gene expression in biopsied muscles from 4 healthy volunteers and the patient by reverse transcriptase polymerase chain reaction. A 52-year-old woman with APECED caused by AIRE gene mutations developed progressive myopathy involving proximal limb and paraspinal muscles. Muscle biopsy specimens showed myopathic changes without inflammatory cell infiltrate. We detected AIRE gene expression in all muscle tissues examined. An extensive literature search uncovered 5 cases of APECED with myopathy, all of whom had similar features. Progressive myopathy involvement could be a hitherto unknown manifestation of APECED. Copyright © 2012 Wiley Periodicals, Inc.

  4. Drug Discovery of Therapies for Duchenne Muscular Dystrophy.

    Science.gov (United States)

    Blat, Yuval; Blat, Shachar

    2015-12-01

    Duchenne muscular dystrophy (DMD) is a genetic, lethal, muscle disorder caused by the loss of the muscle protein, dystrophin, leading to progressive loss of muscle fibers and muscle weakness. Drug discovery efforts targeting DMD have used two main approaches: (1) the restoration of dystrophin expression or the expression of a compensatory protein, and (2) the mitigation of downstream pathological mechanisms, including dysregulated calcium homeostasis, oxidative stress, inflammation, fibrosis, and muscle ischemia. The aim of this review is to introduce the disease, its pathophysiology, and the available research tools to a drug discovery audience. This review will also detail the most promising therapies that are currently being tested in clinical trials or in advanced preclinical models. © 2015 Society for Laboratory Automation and Screening.

  5. Pattern Dystrophy of the Macula in a Case of Steinert Disease

    Directory of Open Access Journals (Sweden)

    Filipe Esteves

    2013-09-01

    Full Text Available Introduction: Myotonic dystrophies are typically associated with ocular complications like ptosis, weakness of the ocular muscle and cataracts, but also with less recognized retinal changes. Case Report: A 41-year-old female with type 1 myotonic dystrophy complained of progressive vision loss. Slit lamp examination revealed the presence of typical bilateral polychromatic cataract with posterior subcapsular component. Dilated fundus examination was remarkable for bilateral macular depigmented changes. Multimodal imaging analysis of the macula suggested the presence of a butterfly-shaped pattern dystrophy. Discussion: In cases of myotonic dystrophies it is of great relevance to anal