Résumé :
|
Congenital myasthenic syndromes (CMS) represent a heterogeneous group of diseases caused by genetic defects affecting neuromuscular transmission. CMS can present at any time from birth to adulthood, though usually within the first 2yr of life, and result in a spectrum of diseases ranging from wild weakness to severe disability with life-threatening episodes. The characterization of CMS comprises two complementary steps: establishing the diagnosis and identifying the pathophysiological type of CMS. A study oriented by the clinics, the EMG and the study of the neuromuscular junctions in muscle biopsies has identified several genes in which mutations cause the disease. New variants, especially in novel genes, have to be characterized by expressing them in cell culture systems or in rodent muscle to establish that they are indeed causing the CMS. Among the 210 index patients followed by the clinicians of the French CMS network, 98 have been traced to mutations in the genes coding for the collagenic tail of acetylcholinesterase COLQ (14); the acetylcholine receptor subunits CHRNA1 (2), CHRNB1 (1), CHRND (1) and CHRNE (45); rapsyn, RAPSN (19), the muscle-specific receptor tyrosine kinase MuSK, MUSK (3) and, recently identified, the MuSK-interacting protein dok-7, DOK7 (13). In our experience mutations in the choline acetyltransferase CHAT or in the muscle sodium channel SCN4A were never identified. Some mutations in given CMS genes appear to be more frequent in some areas and this is the case for North Africa. Among the 25 Maghrebian index patients followed by our network, 12 were mutated in the founder CHRNE1293insG mutation. The knowledge of the ethnic background can be instrumental in diagnosing CMS patients rapidly. Despite comprehensive characterization, the phenotypic expression of one given gene involved is variable, and the aetiology of many CMS remains to be discovered. Supported by APHP, Inserm, ANR Maladies Rares, CMCU and AFM.
|