Résumé :
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Communication n° 699 Background: Congenital myasthenic syndromes (CMS) are a heterogeneous group of hereditary disorders due to defects in the neuromuscular transmission. According to the site of the primary defect, these syndromes are classified as presynaptic, synaptic or postsynaptic. The latter category, particularly CMS due to mutations in the epsilon subunit gene (CHRNE) of acetylcholine receptor (AChR), accounts for the majority of cases of CMS. Mutations in the rapsyn gene (RAPSN) are probably the second most important causes for CMS in patients of European ethnic origin. Rapsyn plays an important role in concentrating acetylcholine receptors in the postsynaptic membrane and linking them to the cytoskeleton through dystroglycan. Such function is submitted to the influence of agrin and MuSK. Mutations in RAPSN induce a reduction of rapsyn and consequently of the AChR itself at the neuromuscular junction. To date, half of published cases with the RAPSN mutations bear the homozygous N88K missense mutation. However, the other half of the cases bear the N88K on one allele and a second mutation on the other allele. Genotype-phenotype correlation remains unclear. Patients and methods: As part of the activity of the French CMS network, 121 individuals from unrelated families with suspected or confirmed CMS were analyzed for mutations on the RAPSN gene. Clinical data, including EMG examination, was collected for all patients. We looked for genotype-phenotype correlations in these patients regarding severity of the disease, disease progression and response to treatment. Results: Ten patients were found to bear RAPSN mutations. Three patients were homozygous for N88K. All of them had a mild disease form. Six patients were heteroallelic for N88K and another mutation. Among them, four patients had severe signs including respiratory distress episodes. One Finally, one patient was found to carry two allelic mutations without N88K and presented with severe initial signs. All patients responded well to anticholinesterase medications. Conclusion: Mutations in RAPSN are one of the most important causes for CMS in France. The N88K mutation is the most predominant mutation identified. A founder effect among the Indo-European population has been evidenced, although other founders may co-exist. We also present here the first case of CMS caused by two mutations in RAPSN other than N88K. Genotype-phenotype correlation is not clear although homozygosity to N88K seems to be of milder severity.
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