Résumé :
|
RYR1 has been associated with central core disease, in addition to multiminicore disease and malignant hyperthermia (MH). However, the frequency of RYR1 mutations in central core disease and its genotype-phenotype correlation was not clear. Our recent study showed that virtually all central core disease cases are due to RYR1 mutations. Furthermore, almost all cases with "typical cores", with well demarcated rims that are usually single and centrally-located, have mutations in the C-terminal region of RYR1; in contrast, the cases with "atypical cores", with ambiguous margin that are sometimes present in multiplicity and/or peripherally-located, harbor mutations in the non-C-terminal region. All of the latter cases were identified as MH susceptible by calcium-induced calcium rate (CICR) test. In contrast, two cases with typical cores for which CICR test was performed showed normal or even decreased CICR, indicating that typical central core disease is not associated with MH susceptibility while non-typical central core disease is. Among cases with non-C-terminal mutations, 50% showed non-typical cores and/or multiminicores while the remaining did not show any core on muscle pathology. These results suggest that C-terminal mutations and non-C-terminal mutations may make the channel hypoactive and hyperactive, respectively. Interestingly, nearly all muscle fibers are type 1 in all cases with typical cores due to C-terminal mutations. This led us to screen for RYR1 mutations in cases with congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) on the hypothesis that CNMDU1 may also be due to C-terminal mutations as in typical central core disease. As expected, four out of ten patients with CNMDU1 had mutations in the C-terminal region of RYR1. Although we still do not know the etiology of cores, type 1 fiber conversion may be a phenomenon more upstream than core formation in the pathogenesis of C-terminal mutations.
|