Résumé :
|
Communication n° 335 Malignant hyperthermia susceptibility (MHS) is a sub clinical pharmacogenetic disorder caused by an impairment of skeletal muscle calcium homeostasis in response to triggering agents. MHS involve two calcium channels located at the level of the triadic junction, the ryanodine receptor present in the membrane of the sarcoplasmic reticulum, and the dihydropyridine receptor present in the plasmic membrane. While IVCT is the gold standard to define MHS, molecular analysis is increasingly used for diagnosis of MHS. Mutations associated with MHS have been reported in two genes, RYR1 and CACNA1S. Mutations in RYR1 are also responsible for central core disease (CCD), a myopathy that can be associated with a positive IVCT response. We report here correlation studies between molecular, pharmacological, histological and functional data in 179 families. Extensive molecular analysis allowed to identify a variant in 60% of the confirmed MHS families and resulted in the characterization of 11 new variations in the RYR1 gene. Most mutations clustered to MH1 and MH2 domains of RYR1. Functional analysis allowed assigning a causative role for seven MHS mutations. Use of genetic data for determination of the MHS status led to a 99.5% sensitivity for IVCT. Apparently false IVCT positive MHS diagnosis was analyzed not only in term of specificity of IVCT but also raised the question of the presence of a second MHS trait in families and of the genetic heterogeneity of the disease. Histological analysis evidenced the presence of cores in more than 20% of the muscles biopsies originating from 242 MHS patients who did not present with clinical symptoms. This indicated that these patients must be considered as MHS patients with cores and clearly differentiated from CCD patients with MHS.
|