Résumé :
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Charcot-Marie-Tooth neuropathies (CMT), also known as hereditary motor and sensory neuropathies (HMSN), are a group of genetically and clinically heterogeneous diseases of the peripheral nervous system. 40 genes and more than 60 loci have been identified to date. The French CMT diagnosis network has defined 6 types of strategies for molecular exploration, linked to 6 phenotypic sub-types of CMT. We focused our study on type 2 CMT (axonal) which phenotypic presentation is characterised by relative preservation of nerve conduction velocity (>38m/s in the median nerve), with decrease in compound motor action potentials providing evidence of axonal loss. We studied in particular MFN2 (Mitofusine 2) and GDAP1 (Ganglioside Induced Differentiation-Associated Protein 1) genes because of several points of particular interest. First, their mutational spectrum is large and only recently described, making molecular interpretation of news variants and subsequent genetic counselling difficult. Second they are both implicated in mitochondrial dynamic. Third their place within the exploration strategy diagram is not completely solved to date. We aimed to estimate the frequency of mutations in MFN2 and GDAP1 genes in a big cohort of CMT patients collected in France and to evaluate the potential pathogenicity of new mutations. The frequency of mutation in MFN2 gene is about 11% (25/226) and in GDAP1 gene is about 6.7% (9/135) in our study. Indeed, 75% (6/8) of GDAP1 sequence variations and 72% (18/25) of MFN2 sequence variations, we found weren’t reported to date and raised to a lot of difficulties in genetic counselling. We report in particular and discuss a missense mutation in GDAP1 that seems to segregate with the disease in both dominant and recessive mode of inheritance.
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