Résumé :
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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. The combination of clinical, electrophysiological, morphological and molecular genetic studies allows referring a given CMS to mutation(s) in one of the 15 causative genes known to date. In this talk, we will highlight several aspects of this group of neuromuscular disorders, taking benefit from our experience concerning a population of more than 300 patients recruited by the neurologists and neuropediatricians of the French national network for CMS. About half of these patients have been identified for the defective gene. Using a candidate gene approach, variants in the genes encoding MuSK and agrin were identified for the first time. A novel homozygous mutation in MuSK was recently identified and presented as a poster in this meeting. In order to demonstrate that these variants were indeed responsible for the CMS phenotype, MuSK vectors or recombinant agrin proteins, either wild-type or bearing a mutation identified in patients, were tested for their ability to modify MuSK phosphorylation or AChR aggregation in cell cultures or to alter the NMJ structures in rodent muscles. Although the alterations of the agrin-MuSK-Dok7-AChR cascade in vitro were not always those expected, the NMJ structural changes in rodent muscle always recapitulated those observed in the patient muscle biopsies. Allelic quantification on DNAs of three patients with recessive CMS allowed the identification of novel multiexon deletions of the gene encoding rapsyn (RAPSN).Initial misdiagnosis is frequent in CMS patients. In our experience the most frequent mistake, particularly for DOK7 and COLQ CMS was congenital myopathy due to clinical presentation with prominent limb and axial muscle wasting, scoliosis, shadowing myasthenic variability and ambiguous histological pattern with structural abnormities. Other initial erroneous diagnoses were: metabolic myopathy if fatigability and/or lipid overload were found at biopsy, seronegative auto-immune myasthenia if onset after neonatal period. An extensive neuromuscular transmission study was performed in 67 patients. Electromyography was proven to be highly informative, allowing to ascertain CMS diagnosis in the congenital myopathy like forms and to strongly orientate towards the proper defective gene in most of cases. Finally, studies were conducted concerning long term prognosis of CMS, impact of pregnancy, puberty and menstrual cycle effect, and response to various therapies. Supported by Assistance Publique-Hpitaux de Paris (PHRC AOM 1036), Raux Inserm, ANR-Maladies Rares, Association Franse contre les Myopathies, and Comitxte Franco-Tunisien pour la Cooption Universitaire.
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