Publications by authors named "Michel Fardeau"

77 Publications

The clinical, histologic, and genotypic spectrum of -related myopathy: A case series.

Neurology 2020 09 13;95(11):e1512-e1527. Epub 2020 Aug 13.

From the Basic and Translational Myology Lab (R.N.V.-Q., V.G., A.F.), UMR8251, Université de Paris/CNRS; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (R.N.V.-Q., B. Eymard, N.B.R., A.F.) and Neuromuscular Morphology Unit (N.B.R., M.F.), Institut de Myologie, Pitié-Salpêtrière Hospital, AP-HP, Paris, France; Department of Paediatric Neurology (M.v.d.H.), Medinzinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany; AP-HP (C.M., P.R.), Centre de Génétique Moléculaire et Chromosomique, UF Cardiogénétique et Myogénétique Moléculaire et Cellulaire, GH Pitié-Salpêtrière, Paris; Department of Neurology (V.G.), University Hospital of Montpellier, France; Neuromuscular and Neurogenetic Disorders of Childhood Section (S.D.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Unit of Neuromuscular and Neurodegenerative Disorders (E.B.), Bambino Gesu' Children's Research Hospital, Rome, Italy; Departamento de Neurología Pediátrica (C.C.), Clínica Las Condes, Santiago, Chile; Paediatrics Department (D.C.), Hôpital de Hautepierre, Strasbourg, France; Neuromuscular Unit (J.C.), Neuropaediatrics Department, Institut de Recerca Hospital Universitari Sant Joan de Deu, Barcelona; Center for the Biomedical Research on Rare Diseases (CIBERER) (J.C.), ISCIII; Department of Neurology (M.L.C.), Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos; Department of Medicine (M.L.C.), Universidad Complutense de Madrid, Spain; Department of Neurology (M.d.V.), Amsterdam University Medical Centre, Amsterdam Neuroscience, the Netherlands; Department of Pediatric Neurology (I.D.), Necker Enfants Malades Hospital, Paris Descartes University, France; Department of Child Neurology (N.G.), University Hospitals Leuven, Belgium; Department of Pediatric Neurology (A.K.), Center for Chronically Sick Children, Institute of Cell Biology and Neurobiology, Charité-Universitätsmedizin Berlin, Germany; Department of Neuropediatrics (E.L.), CHRU de Tours, Université François Rabelais de Tours, UMR INSERM U1253, Tours, France; Department of Neuropediatrics (J.L.), University Children's Hospital of Basel (UKBB), Switzerland; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (E.M.), Neurology Department, Raymond-Poincaré Hospital, AP-HP, Garches; Centre de Référence des Maladies Neuromusculaires Nord/Est/Ile de France (M.M.), Service de Neuropédiatrie, Hôpital Trousseau, Paris, France; Department of Biomedical and Neuromotor Sciences (L.M.), University of Bologna, Italy; Réanimation Médicale, Physiologie-Explorations Fonctionnelles et Centre d'Investigation Clinique, UMR 1429 (D.O.), INSERM-UMR, 1179, UVSQ (D.O.), and Neuromuscular Unit, Department of Pediatric Neurology, Intensive Care and Rehabilitation, AP-HP, UVSQ Paris Saclay (B. Estournet, S.Q.-R.), Hôpital Raymond Poincaré, Garches, France; Department of Neurology (U.R.), Medizinische Fakultät Carl Gustav Carus Technische Universität Dresden, German; Division of Pediatric Neurology, Department of Pediatrics (M.A.S.), College of Medicine, King Saud University, Riyadh, Saudi Arabia; Friedrich-Baur-Institut (B.S.-W.), Department of Neurology, Ludwig-Maximilians-University of Munich; Department of Pediatric Neurology (M.S.), University of Tübingen, Germany; The John Walton Muscular Dystrophy Research Centre (V.S.), Institute of Genetic Medicine, Newcastle University, Newcastle Hospitals NHS Foundation Trust, UK; Department of Child Neurology (H.T.), Hacettepe University, School of Medicine, Ankara, Turkey; Centre de Compétence Neuromusculaire (J.A.U.), Hôpital Marin, Hendaye, France; Department of Neurology (A.v.d.K.), Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, the Netherlands; Pediatrics and Adolescent Medicine, Division of Pediatric Neurology (E.W.), University Medical Center Göttingen, Georg-August University Göttingen, Germany; Neuromuscular and Neurogenetic Disorders of Childhood Section (C.G.B.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; and Department of Pediatric Neurology (U.S.), Developmental Neurology and Social Pediatrics, University of Essen, Germany.

Objective: To clarify the prevalence, long-term natural history, and severity determinants of -related myopathy (SEPN1-RM), we analyzed a large international case series.

Methods: Retrospective clinical, histologic, and genetic analysis of 132 pediatric and adult patients (2-58 years) followed up for several decades.

Results: The clinical phenotype was marked by severe axial muscle weakness, spinal rigidity, and scoliosis (86.1%, from 8.9 ± 4 years), with relatively preserved limb strength and previously unreported ophthalmoparesis in severe cases. All patients developed respiratory failure (from 10.1±6 years), 81.7% requiring ventilation while ambulant. Histopathologically, 79 muscle biopsies showed large variability, partly determined by site of biopsy and age. Multi-minicores were the most common lesion (59.5%), often associated with mild dystrophic features and occasionally with eosinophilic inclusions. Identification of 65 mutations, including 32 novel ones and the first pathogenic copy number variation, unveiled exon 1 as the main mutational hotspot and revealed the first genotype-phenotype correlations, bi-allelic null mutations being significantly associated with disease severity ( = 0.017). SEPN1-RM was more severe and progressive than previously thought, leading to loss of ambulation in 10% of cases, systematic functional decline from the end of the third decade, and reduced lifespan even in mild cases. The main prognosis determinants were scoliosis/respiratory management, mutations, and body mass abnormalities, which correlated with disease severity. We propose a set of severity criteria, provide quantitative data for outcome identification, and establish a need for age stratification.

Conclusion: Our results inform clinical practice, improving diagnosis and management, and represent a major breakthrough for clinical trial readiness in this not so rare disease.
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http://dx.doi.org/10.1212/WNL.0000000000010327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713742PMC
September 2020

Clinical, histological, and genetic characterization of PYROXD1-related myopathy.

Acta Neuropathol Commun 2019 08 27;7(1):138. Epub 2019 Aug 27.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1 rue Laurent Fries, 67404, Illkirch, France.

Recessive mutations in PYROXD1, encoding an oxidoreductase, were recently reported in families with congenital myopathy or limb-girdle muscular dystrophy. Here we describe three novel PYROXD1 families at the clinical, histological, and genetic level. Histological analyses on muscle biopsies from all families revealed fiber size variability, endomysial fibrosis, and muscle fibers with multiple internal nuclei and cores. Further characterization of the structural muscle defects uncovered aggregations of myofibrillar proteins, and provided evidence for enhanced oxidative stress. Sequencing identified homozygous or compound heterozygous PYROXD1 mutations including the first deep intronic mutation reinforcing a cryptic donor splice site and resulting in mRNA instability through exonisation of an intronic segment. Overall, this work expands the PYROXD1 mutation spectrum, defines and specifies the histopathological hallmarks of the disorder, and indicates that oxidative stress contributes to the pathomechanism. Comparison of all new and published cases uncovered a genotype/phenotype correlation with a more severe and early-onset phenotypic presentation of patients harboring splice mutations resulting in reduced PYROXD1 protein levels compared with patients carrying missense mutations.
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http://dx.doi.org/10.1186/s40478-019-0781-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710884PMC
August 2019

ACTN2 mutations cause "Multiple structured Core Disease" (MsCD).

Acta Neuropathol 2019 03 30;137(3):501-519. Epub 2019 Jan 30.

Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 1, rue Laurent Fries, BP 10142, 67404, Illkirch, France.

The identification of genes implicated in myopathies is essential for diagnosis and for revealing novel therapeutic targets. Here we characterize a novel subclass of congenital myopathy at the morphological, molecular, and functional level. Through exome sequencing, we identified de novo ACTN2 mutations, a missense and a deletion, in two unrelated patients presenting with progressive early-onset muscle weakness and respiratory involvement. Morphological and ultrastructural analyses of muscle biopsies revealed a distinctive pattern with the presence of muscle fibers containing small structured cores and jagged Z-lines. Deeper analysis of the missense mutation revealed mutant alpha-actinin-2 properly localized to the Z-line in differentiating myotubes and its level was not altered in muscle biopsy. Modelling of the disease in zebrafish and mice by exogenous expression of mutated alpha-actinin-2 recapitulated the abnormal muscle function and structure seen in the patients. Motor deficits were noted in zebrafish, and muscle force was impaired in isolated muscles from AAV-transduced mice. In both models, sarcomeric disorganization was evident, while expression of wild-type alpha-actinin-2 did not result in muscle anomalies. The murine muscles injected with mutant ACTN2 displayed cores and Z-line defects. Dominant ACTN2 mutations were previously associated with cardiomyopathies, and our data demonstrate that specific mutations in the well-known Z-line regulator alpha-actinin-2 can cause a skeletal muscle disorder.
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http://dx.doi.org/10.1007/s00401-019-01963-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545377PMC
March 2019

Sarcomeric disorganization and nemaline bodies in muscle biopsies of patients with EXOSC3-related type 1 pontocerebellar hypoplasia.

Muscle Nerve 2019 01 16;59(1):137-141. Epub 2018 Dec 16.

Unité de Morphologie Neuromusculaire, Institut de Myologie, Sorbonne University, INSERM UMR 974, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, 75013, Paris, France.

Introduction: Mutations in the EXOSC3 gene are responsible for type 1 pontocerebellar hypoplasia, an autosomal recessive congenital disorder characterized by cerebellar atrophy, developmental delay, and anterior horn motor neuron degeneration. Muscle biopsies of these patients often show characteristics resembling classic spinal muscle atrophy, but to date, no distinct features have been identified.

Methods: Clinical data and muscle biopsy findings of 3 unrelated patients with EXOSC3 mutations are described.

Results: All patients presented as a severe congenital cognitive and neuromuscular phenotype with short survival, harboring the same point mutation (c.92G>C; p.Gly31Ala). Muscle biopsies consistently showed variable degrees of sarcomeric disorganization with myofibrillar remnants, Z-line thickening, and small nemaline bodies.

Conclusions: In this uniform genetic cohort of patients with EXOSC3 mutations, sarcomeric disruption and rod structures were prominent features of muscle biopsies. In the context of neonatal hypotonia, ultrastructural studies might provide early clues for the diagnosis of EXOSC3-related pontocerebellar hypoplasia. Muscle Nerve 59:137-141, 2019.
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http://dx.doi.org/10.1002/mus.26305DOI Listing
January 2019

Genetic Mutations and Demographic, Clinical, and Morphological Aspects of Myofibrillar Myopathy in a French Cohort.

Genet Test Mol Biomarkers 2018 Jun;22(6):374-383

2 Laboratoire de Pathologie Musculaire Risler, Groupe Hospitalier Pitié-Salpêtrière , Paris, France .

Background: Protein aggregate myopathies (PAM) represent a group of familial or sporadic neuromuscular conditions with marked clinical and genetic heterogeneity that occur in children and adults. Familial PAM includes myofibrillar myopathies defined by the presence of desmin-positive protein aggregates and degenerative intermyofibrillar network changes. PAM is often caused by dysfunctional genes, such as DES, PLEC 1, CRYAB, FLNC, MYOT, ZASP, BAG3, FHL1, and DNAJB6.

Objective: To retrospectively analyze genetic mutations and demographic, clinical, and morphological aspects of PAM in a French population.

Methods: Forty-eight PAM patients (29 men, 19 women) were divided into two groups, those with genetically (GIM) and nongenetically identified (NGIM) mutations associated with myofibrillar myopathy.

Results: Age of myopathy onset ranged from 13 to 68 years. GIM group mutations (81.25%) included DES (14), ZASP (8), FLNC (4), MYOT (4), BAG3 (1), CRYAB (2), and DNAJB6 (6). The MYOT subgroup displayed a significantly older onset age (p = 0.029). Autosomal dominant inheritance was found in 74.3% of GIM and 44.4% of NGIM subjects. Overall, 22.9% had Maghrebian heritage, 72.9% Caucasian, and 4.2% Asian. The most common clinical sign was distal muscle weakness (66%) followed by simultaneous distal and proximal weakness in 49%. Eleven patients had contractures, one had a rigid spine, and five had respiratory dysfunction. GIM subjects had greater cardiac involvement (51.7%) versus the NGIM group (33.3%). The average serum creatine kinase level was 393 U/L in GIM and 382 U/L in NGIM subjects. Morphological analysis showed significant differences among GIM subgroups, including the number of vacuoles and regenerated fibers (ZASP), group atrophy (ZASP), and rubbed out fibers (MYOT). Ultrastructural findings showed significant differences in intranuclear rods, Z-disc thickness, and intranuclear inclusions between gene mutation subgroups. Paracrystalline inclusions were present in three patients (DNAJB6). The most frequent mutation in was in DES, followed by ZASP.

Conclusions: GIM and NGIM PAM subjects showed similar results, suggesting that any unknown genes, which cause this disease have characteristics similar to those already described. Considering the complexity of clinical, morphological, and genetic data related to PAM, particularly myofibrillar myopathies, physicians should be careful when diagnosing patients with sporadic PAM.
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http://dx.doi.org/10.1089/gtmb.2018.0004DOI Listing
June 2018

[About the technique of muscle biopsy (IV). The advent of histochemistry and cytoenzymology in the analysis of muscle biopsies. A short and personal historical overview].

Authors:
Michel Fardeau

Med Sci (Paris) 2017 Nov 15;33 Hors série n°1:7-10. Epub 2017 Nov 15.

Professeur honoraire au CNAM, Fondateur de la Société Française de Myologie, Paris, France.

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http://dx.doi.org/10.1051/medsci/201733s102DOI Listing
November 2017

Mutations in GFPT1-related congenital myasthenic syndromes are associated with synaptic morphological defects and underlie a tubular aggregate myopathy with synaptopathy.

J Neurol 2017 Aug 15;264(8):1791-1803. Epub 2017 Jul 15.

Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Université Paris 06 UMR S 1127, Hôpital de la Pitié-Salpêtrière, 47-83 boulevard de l'Hôpital, 75013, Paris, France.

Mutations in GFPT1 (glutamine-fructose-6-phosphate transaminase 1), a gene encoding an enzyme involved in glycosylation of ubiquitous proteins, cause a limb-girdle congenital myasthenic syndrome (LG-CMS) with tubular aggregates (TAs) characterized predominantly by affection of the proximal skeletal muscles and presence of highly organized and remodeled sarcoplasmic tubules in patients' muscle biopsies. We report here the first long-term clinical follow-up of 11 French individuals suffering from LG-CMS with TAs due to GFPT1 mutations, of which nine are new. Our retrospective clinical evaluation stresses an evolution toward a myopathic weakness that occurs concomitantly to ineffectiveness of usual CMS treatments. Analysis of neuromuscular biopsies from three unrelated individuals demonstrates that the maintenance of neuromuscular junctions (NMJs) is dramatically impaired with loss of post-synaptic junctional folds and evidence of denervation-reinnervation processes affecting the three main NMJ components. Moreover, molecular analyses of the human muscle biopsies confirm glycosylation defects of proteins with reduced O-glycosylation and show reduced sialylation of transmembrane proteins in extra-junctional area. Altogether, these results pave the way for understanding the etiology of this rare neuromuscular disorder that may be considered as a "tubular aggregates myopathy with synaptopathy".
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http://dx.doi.org/10.1007/s00415-017-8569-xDOI Listing
August 2017

Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues.

Acta Neuropathol 2017 Dec 6;134(6):889-904. Epub 2017 Jul 6.

Laboratoire Diagnostic Génétique, Faculté de Médecine, CHRU, Nouvel Hôpital Civil, 1 place de l'Hôpital, 67091, Strasbourg, France.

X-linked myotubular myopathy (XLMTM), a severe congenital myopathy, is caused by mutations in the MTM1 gene located on the X chromosome. A majority of affected males die in the early postnatal period, whereas female carriers are believed to be usually asymptomatic. Nevertheless, several affected females have been reported. To assess the phenotypic and pathological spectra of carrier females and to delineate diagnostic clues, we characterized 17 new unrelated affected females and performed a detailed comparison with previously reported cases at the clinical, muscle imaging, histological, ultrastructural and molecular levels. Taken together, the analysis of this large cohort of 43 cases highlights a wide spectrum of clinical severity ranging from severe neonatal and generalized weakness, similar to XLMTM male, to milder adult forms. Several females show a decline in respiratory function. Asymmetric weakness is a noteworthy frequent specific feature potentially correlated to an increased prevalence of highly skewed X inactivation. Asymmetry of growth was also noted. Other diagnostic clues include facial weakness, ptosis and ophthalmoplegia, skeletal and joint abnormalities, and histopathological signs that are hallmarks of centronuclear myopathy such as centralized nuclei and necklace fibers. The histopathological findings also demonstrate a general disorganization of muscle structure in addition to these specific hallmarks. Thus, MTM1 mutations in carrier females define a specific myopathy, which may be independent of the presence of an XLMTM male in the family. As several of the reported affected females carry large heterozygous MTM1 deletions not detectable by Sanger sequencing, and as milder phenotypes present as adult-onset limb-girdle myopathy, the prevalence of this myopathy is likely to be greatly underestimated. This report should aid diagnosis and thus the clinical management and genetic counseling of MTM1 carrier females. Furthermore, the clinical and pathological history of this cohort may be useful for therapeutic projects in males with XLMTM, as it illustrates the spectrum of possible evolution of the disease in patients surviving long term.
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http://dx.doi.org/10.1007/s00401-017-1748-0DOI Listing
December 2017

Recessive MYPN mutations cause cap myopathy with occasional nemaline rods.

Ann Neurol 2017 Mar 20;81(3):467-473. Epub 2017 Mar 20.

Institute of Genetics and Molecular and Cellular Biology, Illkirch, France.

Congenital myopathies are phenotypically and genetically heterogeneous. We describe homozygous truncating mutations in MYPN in 2 unrelated families with a slowly progressive congenital cap myopathy. MYPN encodes the Z-line protein myopalladin implicated in sarcomere integrity. Functional experiments demonstrate that the mutations lead to mRNA defects and to a strong reduction in full-length protein expression. Myopalladin signals accumulate in the caps together with alpha-actinin. Dominant MYPN mutations were previously reported in cardiomyopathies. Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance. Ann Neurol 2017;81:467-473.
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http://dx.doi.org/10.1002/ana.24900DOI Listing
March 2017

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy.

Acta Neuropathol 2017 04 23;133(4):517-533. Epub 2016 Dec 23.

Centre National de Génotypage, Institut de Génomique, CEA, Evry, France.

Muscle contraction upon nerve stimulation relies on excitation-contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Ca1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.
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http://dx.doi.org/10.1007/s00401-016-1656-8DOI Listing
April 2017

Natural history of LGMD2A for delineating outcome measures in clinical trials.

Ann Clin Transl Neurol 2016 04 4;3(4):248-65. Epub 2016 Mar 4.

Hôpital Marin Centre Neuromusculaire GNMH Hendaye France.

Objective: Limb-girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium-dependent cysteine protease of the skeletal muscle.

Methods: In this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14-65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients.

Results: Our study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis.

Interpretation: All the generated data will help to determine the endpoints for further clinical studies.
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http://dx.doi.org/10.1002/acn3.287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818744PMC
April 2016

[About the technique of muscle biopsy - A historical flash-back on the technique of muscle biopsie].

Authors:
Michel Fardeau

Med Sci (Paris) 2015 Nov 6;31 Spec No 3:7-10. Epub 2015 Nov 6.

Professeur honoraire au CNAM, Fondateur de la Société Française de Myologie, Paris, France.

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http://dx.doi.org/10.1051/medsci/201531s302DOI Listing
November 2015

PABPN1 (GCN)11 as a Dominant Allele in Oculopharyngeal Muscular Dystrophy -Consequences in Clinical Diagnosis and Genetic Counselling.

J Neuromuscul Dis 2015 Jun;2(2):175-180

APHP, Centre de Référence des Maladies Neuromusculaires Paris Est, Unité de Morphologie Neuromusculaire, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, -83, bld de l'hôpital, Paris cedex 13, France.

Oculopharyngeal muscular dystrophy (OPMD) is mainly characterized by ptosis and dysphagia. The genetic cause is a short expansion of a (GCN)10 repeat encoding for polyalanine in the poly(A) binding protein nuclear 1 (PABPN1) gene to (GCN)12-17 repeats. The (GCN)11/Ala11 allele has so far been described to be either a polymorphism or a recessive allele with no effect on the phenotype in the heterozygous state. Here we report the clinical and histopathological phenotype of a patient carrying a single (GCN)11/Ala11 heterozygous allele and presenting an atypical form of OPMD with dysphagia and late and mild oculomotor symptoms. Intranuclear inclusions were observed in his muscle biopsy. This suggests a dominant mode of expression of the (GCN)11/Ala11 allele associated with a partial penetrance of OPMD.
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http://dx.doi.org/10.3233/JND-140060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5271460PMC
June 2015

Cylindrical spirals associated with severe congenital muscle weakness and epileptic encephalopathy.

Muscle Nerve 2015 Nov 18;52(5):895-9. Epub 2015 Jun 18.

UPMC Université Paris 06, Institut National de la Santé et de la Recherche Médicale UMR 974, CNRS FRE3617, Center for Research in Myology, GH Pitié-Salpêtrière, Sorbonne Universités, 47 Boulevard de l'Hôpital, 75013, Paris, France.

Introduction: Cylindrical spirals are characteristic muscular inclusions consisting of spiraling double-laminated membranes. They are found in heterogeneous clinical conditions.

Methods: We obtained muscle biopsies from 2 young sisters with severe congenital hypotonia, muscle weakness, and epileptic encephalopathy, and identified cylindrical spirals.

Results: We found an association between congenital encephalomyopathy and cylindrical spirals.

Conclusions: In this morphological and ultrastructural study, we speculate on the origin of these peculiar structures.
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http://dx.doi.org/10.1002/mus.24699DOI Listing
November 2015

Endplate denervation correlates with Nogo-A muscle expression in amyotrophic lateral sclerosis patients.

Ann Clin Transl Neurol 2015 Apr 16;2(4):362-72. Epub 2015 Feb 16.

Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM F-75013, Paris, France ; APHP, Hôpital Pitié-Salpêtrière, Centre de référence de pathologie neuromusculaire Paris-Est, Institut de Myologie Paris, France.

Objective: Data from mouse models of amyotrophic lateral sclerosis (ALS) suggest early morphological changes in neuromuscular junctions (NMJs), with loss of nerve-muscle contact. Overexpression of the neurite outgrowth inhibitor Nogo-A in muscle may play a role in this loss of endplate innervation.

Methods: We used confocal and electron microscopy to study the structure of the NMJs in muscle samples collected from nine ALS patients (five early-stage patients and four long-term survivors). We correlated the morphological results with clinical and electrophysiological data, and with Nogo-A muscle expression level.

Results: Surface electromyography assessment of neuromuscular transmission was abnormal in 3/9 ALS patients. The postsynaptic apparatus was morphologically altered for almost all NMJs (n = 430) analyzed using confocal microscopy. 19.7% of the NMJs were completely denervated (fragmented synaptic gutters and absence of nerve terminal profile). The terminal axonal arborization was usually sparsely branched and 56.8% of innervated NMJs showed a typical reinnervation pattern. Terminal Schwann cell (TSC) morphology was altered with extensive cytoplasmic processes. A marked intrusion of TSCs in the synaptic cleft was seen in some cases, strikingly reducing the synaptic surface available for neuromuscular transmission. Finally, high-level expression of Nogo-A in muscle was significantly associated with higher extent of NMJ denervation and negative functional outcome.

Interpretation: Our results support the hypothesis that morphological alterations of NMJs are present from early-stage disease and may significantly contribute to functional motor impairment in ALS patients. Muscle expression of Nogo-A is associated with NMJ denervation and thus constitutes a therapeutic target to slow disease progression.
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http://dx.doi.org/10.1002/acn3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402082PMC
April 2015

[Not Available].

Authors:
Michel Fardeau

Bull Acad Natl Med 2015 Jan;199(1):19-20

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January 2015

Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1.

J Med Genet 2014 Dec 17;51(12):824-33. Epub 2014 Oct 17.

Department of Translational Medicine and Neurogenetics, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France University of Strasbourg, Illkirch, France Collège de France, Chaire de Génétique Humaine, Illkirch, France.

Background: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double-walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene.

Methods: The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum.

Results: We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EF-hand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adult-onset myalgia without muscle weakness and normal CK levels.

Conclusions: The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.
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http://dx.doi.org/10.1136/jmedgenet-2014-102623DOI Listing
December 2014

Adult-onset autosomal dominant centronuclear myopathy due to BIN1 mutations.

Brain 2014 Dec 25;137(Pt 12):3160-70. Epub 2014 Sep 25.

1 IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), 67404 Illkirch, France 2 Inserm, U964, 67404 Illkirch, France 3 CNRS, UMR7104, 67404 Illkirch, France 4 Université de Strasbourg, 67404 Illkirch, France 5 Collège de France, Chaire de Génétique Humaine, 67404 Illkirch, France

Centronuclear myopathies are congenital muscle disorders characterized by type I myofibre predominance and an increased number of muscle fibres with nuclear centralization. The severe neonatal X-linked form is due to mutations in MTM1, autosomal recessive centronuclear myopathy with neonatal or childhood onset results from mutations in BIN1 (amphiphysin 2), and dominant cases were previously associated to mutations in DNM2 (dynamin 2). Our aim was to determine the genetic basis and physiopathology of patients with mild dominant centronuclear myopathy without mutations in DNM2. We hence established and characterized a homogeneous cohort of nine patients from five families with a progressive adult-onset centronuclear myopathy without facial weakness, including three sporadic cases and two families with dominant disease inheritance. All patients had similar histological and ultrastructural features involving type I fibre predominance and hypotrophy, as well as prominent nuclear centralization and clustering. We identified heterozygous BIN1 mutations in all patients and the molecular diagnosis was complemented by functional analyses. Two mutations in the N-terminal amphipathic helix strongly decreased the membrane-deforming properties of amphiphysin 2 and three stop-loss mutations resulted in a stable protein containing 52 supernumerary amino acids. Immunolabelling experiments revealed abnormal central accumulation of dynamin 2, caveolin-3, and the autophagic marker p62, and general membrane alterations of the triad, the sarcolemma, and the basal lamina as potential pathological mechanisms. In conclusion, we identified BIN1 as the second gene for dominant centronuclear myopathy. Our data provide the evidence that specific BIN1 mutations can cause either recessive or dominant centronuclear myopathy and that both disorders involve different pathomechanisms.
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http://dx.doi.org/10.1093/brain/awu272DOI Listing
December 2014

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

Neuromuscul Disord 2014 Nov 28;24(11):993-8. Epub 2014 Jun 28.

Institut de Myologie, UPMC Université, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.

We report on a 5-year-old girl who presented with an association of symptoms reminiscent of an Ullrich-like congenital muscular dystrophy including congenital hypotonia, proximal joint contractures, hyperlaxity of distal joints, normal cognitive development, and kyphoscoliosis. There was an excess of neuromuscular spindles on the skeletal muscle biopsy. This very peculiar feature on muscle biopsy has been reported only in patients with mutations in the HRAS gene. Sequence analysis of the subject's HRAS gene from blood leukocytes and skeletal muscle revealed a previously described heterozygous missense mutation (c.187G>A, p. Glu63Lys). The present report thus extends the differential diagnosis of congenital muscular dystrophy with major "retractile" phenotypes and adds congenital muscular dystrophy to the clinical spectrum of HRAS-related disorders.
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http://dx.doi.org/10.1016/j.nmd.2014.06.437DOI Listing
November 2014

Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene.

J Neurol Neurosurg Psychiatry 2014 Oct 14;85(10):1149-52. Epub 2014 May 14.

Department of Translational Medicine and Neurogenetics, IGBMC, Illkirch, France Inserm, U964, Illkirch, France CNRS, UMR7104, Illkirch, France Université de Strasbourg, Illkirch, France Collège de France, chaire de génétique humaine, Illkirch, France.

Background: Autosomal dominant (AD) central core disease (CCD) is a congenital myopathy characterised by the presence of cores in the muscle fibres which correspond to broad areas of myofibrils disorganisation, Z-line streaming and lack of mitochondria. Heterozygous mutations in the RYR1 gene were observed in the large majority of AD-CCD families; however, this gene was excluded in some of AD-CCD families.

Objective: To enlarge the genetic spectrum of AD-CCD demonstrating mutations in an additional gene.

Patients And Methods: Four affected AD family members over three generations, three of whom were alive and participate in the study: the mother and two of three siblings. The symptoms began during the early childhood with mild delayed motor development. Later they developed mainly tibialis anterior weakness, hypertrophy of calves and significant weakness (amyotrophic) of quadriceps. No cardiac or ocular involvement was noted.

Results: The muscle biopsies sections showed a particular pattern: eccentric cores in type 1 fibres, associated with type 1 predominance. Most cores have abrupt borders. Electron microscopy confirmed the presence of both unstructured and structured cores. Exome sequencing analysis identified a novel heterozygous missense mutation p.Leu1723Pro in MYH7 segregating with the disease and affecting a conserved residue in the myosin tail domain.

Conclusions: We describe MYH7 as an additional causative gene for AD-CCD. These findings have important implications for diagnosis and future investigations of AD-congenital myopathies with cores, without cardiomyopathy, but presenting a particular involvement of distal and quadriceps muscles.
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http://dx.doi.org/10.1136/jnnp-2013-306754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173876PMC
October 2014

Muscle histopathology in nebulin-related nemaline myopathy: ultrastrastructural findings correlated to disease severity and genotype.

Acta Neuropathol Commun 2014 Apr 12;2:44. Epub 2014 Apr 12.

Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.

Nemaline myopathy (NM) is a rare congenital myopathy characterised by hypotonia, muscle weakness, and often skeletal muscle deformities with the presence of nemaline bodies (rods) in the muscle biopsy. The nebulin (NEB) gene is the most commonly mutated and is thought to account for approximately 50% of genetically diagnosed cases of NM. We undertook a detailed muscle morphological analysis of 14 NEB-mutated NM patients with different clinical forms to define muscle pathological patterns and correlate them with clinical course and genotype. Three groups were identified according to clinical severity. Group 1 (n = 5) comprises severe/lethal NM and biopsy in the first days of life. Group 2 (n = 4) includes intermediate NM and biopsy in infancy. Group 3 (n = 5) comprises typical/mild NM and biopsy in childhood or early adult life. Biopsies underwent histoenzymological, immunohistochemical and ultrastructural analysis. Fibre type distribution patterns, rod characteristics, distribution and localization were investigated. Contractile performance was studied in muscle fibre preparations isolated from seven muscle biopsies from each of the three groups. G1 showed significant myofibrillar dissociation and smallness with scattered globular rods in one third of fibres; there was no type 1 predominance. G2 presented milder sarcomeric dissociation, dispersed or clustered nemaline bodies, and type 1 predominance/uniformity. In contrast, G3 had well-delimited clusters of subsarcolemmal elongated rods and type 1 uniformity without sarcomeric alterations. In accordance with the clinical and morphological data, functional studies revealed markedly low forces in muscle bundles from G1 and a better contractile performance in muscle bundles from biopsies of patients from G2, and G3.In conclusion NEB-mutated NM patients present a wide spectrum of morphological features. It is difficult to establish firm genotype phenotype correlation. Interestingly, there was a correlation between clinical severity on the one hand and the degree of sarcomeric dissociation and contractility efficiency on the other. By contrast the percentage of fibres occupied by rods, as well as the quantity and the sub sarcolemmal position of rods, appears to inversely correlate with severity. Based on our observations, we propose myofibrillar dissociation and changes in contractility as an important cause of muscle weakness in NEB-mutated NM patients.
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http://dx.doi.org/10.1186/2051-5960-2-44DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4234932PMC
April 2014

[Congenital myasthenic syndromes; French experience].

Bull Acad Natl Med 2014 Feb;198(2):257-70; discussion 270-1

Congenital myasthenic syndromes CMS) form a heterogeneous group of genetic diseases characterized by abnormal neuromuscular transmission. The associated muscular weakness is exacerbated by exertion and usually starts during infancy/childhood In 2002 a national Congenital Myasthenic Syndromes Network was created in France, composed of neurologists, neuropediatricians, pathologists, molecular geneticists and neurobiologists. The network has now identified nearly 300 cases of CMS, as well as three new culprit genes. Based on our personal experience and data from the most recent studies, we describe the 18 principal culprit genes so far identified, along with diagnostic pitfalls, the disease course, prognosis and treatment. The underlying genetic defect remains to be identified in nearly half of CMS patients.
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February 2014

Extensive morphological and immunohistochemical characterization in myotubular myopathy.

Brain Behav 2013 Jul 19;3(4):476-86. Epub 2013 Jun 19.

Unité de Morphologie Neuromusculaire, Institut de Myologie GHU La Pitié-Salpêtrière, Paris, France ; Groupe Hospitalier-Universitaire La Pitié-Salpêtrière, AP-HP, Centre de référence des maladies neuromusculaires Paris-Est, Paris, France ; UPMC-Paris6 UR76, INSERM UMR974, CNRS UMR 7215, Institut de Myologie GHU La Pitié-Salpêtrière, Paris, France.

The X-linked myotubular myopathy (XLMTM) also called X-linked centronuclear myopathy is a rare congenital myopathy due to mutations in the MTM 1 gene encoding myotubularin. The disease gives rise to a severe muscle weakness in males at birth. The main muscle morphological characteristics (significant number of small muscle fibers with centralized nuclei and type 1 fiber predominance) are usually documented, but the sequence of formation and maintenance of this particular morphological pattern has not been extensively characterized in humans. In this study, we perform a reevaluation of morphological changes in skeletal muscle biopsies in severe XLMTM. We correlate the pathologic features observed in the muscle biopsies of 15 newborns with MTM 1-mutations according to the "adjusted-age" at the time of muscle biopsy, focusing on sequential analysis in the early period of the life (from 34 weeks of gestation to 3 months of age). We found a similar morphological pattern throughout the period analyzed; the proportion of myofibers with central nuclei was high in all muscle biopsies, independently of the muscle type, the age of the newborns at time of biopsy and the specific MTM 1 mutation. We did not observe a period free of morphological abnormalities in human skeletal muscle as observed in myotubularin-deficient mouse models. In addition, this study demonstrated some features of delayed maturation of the muscle fibers without any increase in the number of satellite cells, associated with a marked disorganization of the muscle T-tubules and cytoskeletal network in the skeletal muscle fibers.
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http://dx.doi.org/10.1002/brb3.147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3869686PMC
July 2013

Peripheral nerve hyperexcitability with preterminal nerve and neuromuscular junction remodeling is a hallmark of Schwartz-Jampel syndrome.

Neuromuscul Disord 2013 Dec 4;23(12):998-1009. Epub 2013 Sep 4.

Inserm, U975, Centre de recherche de l'Institut du Cerveau et de la Moelle Épinière (CRICM), Groupe hospitalier Pitié-Salpêtrière, Paris, France; Université Pierre et Marie Curie Paris 6, UMRS975, Paris, France; CNRS, UMR7225, Paris, France; Ecole Pratique des Hautes Etudes, Paris, France.

Schwartz-Jampel syndrome (SJS) is a recessive disorder with muscle hyperactivity that results from hypomorphic mutations in the perlecan gene, a basement membrane proteoglycan. Analyses done on a mouse model have suggested that SJS is a congenital form of distal peripheral nerve hyperexcitability resulting from synaptic acetylcholinesterase deficiency, nerve terminal instability with preterminal amyelination, and subtle peripheral nerve changes. We investigated one adult patient with SJS to study this statement in humans. Perlecan deficiency due to hypomorphic mutations was observed in the patient biological samples. Electroneuromyography showed normal nerve conduction, neuromuscular transmission, and compound nerve action potentials while multiple measures of peripheral nerve excitability along the nerve trunk did not detect changes. Needle electromyography detected complex repetitive discharges without any evidence for neuromuscular transmission failure. The study of muscle biopsies containing neuromuscular junctions showed well-formed post-synaptic element, synaptic acetylcholinesterase deficiency, denervation of synaptic gutters with reinnervation by terminal sprouting, and long nonmyelinated preterminal nerve segments. These data support the notion of peripheral nerve hyperexcitability in SJS, which would originate distally from synergistic actions of peripheral nerve and neuromuscular junction changes as a result of perlecan deficiency.
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http://dx.doi.org/10.1016/j.nmd.2013.07.005DOI Listing
December 2013

Neuromuscular disease: muscle.

Authors:
Michel Fardeau

Curr Opin Neurol 2013 Oct;26(5):516-8

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http://dx.doi.org/10.1097/WCO.0b013e328365048dDOI Listing
October 2013

Skeletal muscle biopsy analysis in reducing body myopathy and other FHL1-related disorders.

J Neuropathol Exp Neurol 2013 Sep;72(9):833-45

Unité de Morphologie Neuromusculaire, Institut de Myologie, Groupe Hospitalier Universitaire La Pitié-Salpêtrière, Paris, France.

FHL1 mutations have been associated with various disorders that include reducing body myopathy (RBM), Emery-Dreifuss-like muscular dystrophy, isolated hypertrophic cardiomyopathy, and some overlapping conditions. We report a detailed histochemical, immunohistochemical, electron microscopic, and immunoelectron microscopic analyses of muscle biopsies from 18 patients carrying mutations in FHL1: 14 RBM patients (Group 1), 3 Emery-Dreifuss muscular dystrophy patients (Group 2), and 1 patient with hypertrophic cardiomyopathy and muscular hypertrophy (Group 2). Group 1 muscle biopsies consistently showed RBs associated with cytoplasmic bodies. The RBs showed prominent FHL1 immunoreactivity whereas desmin, αB-crystallin, and myotilin immunoreactivity surrounded RBs. By electron microscopy, RBs were composed of electron-dense tubulofilamentous material that seemed to spread progressively between the myofibrils and around myonuclei. By immunoelectron microscopy, FHL1 protein was found exclusively inside RBs. Group 2 biopsies showed mild dystrophic abnormalities without RBs; only minor nonspecific myofibrillar abnormalities were observed under electron microscopy. Molecular analysis revealed missense mutations in the second FHL1 LIM domain in Group 1 patients and ins/del or missense mutations within the fourth FHL1 LIM domain in Group 2 patients. Our findings expand the morphologic features of RBM, clearly demonstrate the localization of FHL1 in RBs, and further illustrate major morphologic differences among different FHL1-related myopathies.
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http://dx.doi.org/10.1097/NEN.0b013e3182a23506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210222PMC
September 2013

Assessment of a symptomatic Duchenne muscular dystrophy carrier 20 years after myoblast transplantation from her asymptomatic identical twin sister.

Neuromuscul Disord 2013 Jul 31;23(7):575-9. Epub 2013 May 31.

Institut de Myologie, GH Pitié-Salpêtrière, Paris, France.

Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects.
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http://dx.doi.org/10.1016/j.nmd.2013.04.007DOI Listing
July 2013

Myofibrillar myopathies.

Handb Clin Neurol 2013 ;113:1337-42

Department of Neurology and Institute for Neuropathology, University Hospital RWTH Aachen, Aachen, Germany. Electronic address:

Myofibrillar myopathies (MFMs) are rare, inherited or sporadic, progressive neuromuscular disorders with considerable clinical and genetic heterogeneity. MFMs are defined morphologically by foci of myofibril dissolution that begins at the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of a large number of proteins including desmin. To date, mutations in six genes are known to cause MFMs, accounting for approximately half of the MFM patients identified. The causative genes encode mainly sarcomeric Z-disk(-related) proteins: desmin, αB-crystallin, myotilin, Z-band alternatively spliced PDZ motif containing protein (ZASP), filamin C and the antiapoptotic BCL2-associated athanogene 3 (Bag3). Although in most MFM patients the disease presents in adulthood and evolves slowly, some patients with desminopathy, αB-crystallinopathy or Bag3opathies have an infantile or juvenile disease onset. Cardiac involvement is very common in desminopathies and can sometimes be the initial or only symptom of the disease. Respiratory symptoms are noted during childhood in αB-crystallinopathies. Early severe cardiac and respiratory involvement is seen in Bag3opathies. Optical microscopic and immunohistochemical features are similar in MFMs; however, ultrastructural findings can be useful to differentiate between the distinct MFM subtypes. No curative treatment for MFMs is currently available. Careful follow-up, especially of cardiac and respiratory function, is important.
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http://dx.doi.org/10.1016/B978-0-444-59565-2.00005-8DOI Listing
March 2014

Diagnostic workup for neuromuscular diseases.

Handb Clin Neurol 2013 ;113:1291-7

Institute of Myology, INSERM U1016, Salpêtrière Hospital, Paris, France. Electronic address:

Clinical symptoms of neuromuscular diseases vary according to age and type of primary involvement (spinal motor neuron, nerve, neuromuscular junction or muscle). Tools at our disposal for diagnostic purposes are graduated based on the age of the patient and diagnostic suspicions generated by the clinical workup. Seven clinical presentations can be identified that all require technical facilities specifically dedicated to pediatric neuromuscular diseases: congenital hypomobility and arthrogryposis, paralytic hypotonia in infancy, motor delay and chronic walking difficulties after the age of 18 months, progressive walking difficulties after the age of 3 years, effort intolerance and acute rhabdomyolysis, acute motor symptoms or fatigability, and variability of symptoms. Electrophysiological investigation, particularly electromyography, is a valuable tool where neurogenic involvement or neuromuscular block is suspected. However, the technique is difficult to perform in children. Muscle biopsy is generally the key investigation and can be performed at any age. Molecular biology helps to improve diagnostic strategy. Muscle MRI, in combination with clinical evaluation, assists the selection of appropriate genetic tests and more generally the identification of genetically distinct forms of neuromuscular disorder. None of these are by any means routine investigations, and only a specialized multidisciplinary clinical approach can permit correct diagnosis and proper follow-up.
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http://dx.doi.org/10.1016/B978-0-444-59565-2.00001-0DOI Listing
March 2014