Résumé :
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The congenital myopathies are a diverse group of entities, with considerable genetic heterogeneity. The genetic heterogeneity includes mutations in multiple different genes causing similar pathological phenotypes, and multiple different pathological phenotypes arising from mutations in the same gene. Novel genes continue to be identified for the congenital myopathies; further disease phenotypes continue to be associated with already-known genes, and further genes remain to be found. Some interesting aspects of the genetics of the congenital myopathies include the high new mutation rates in some genes such as skeletal muscle a-actin (ACTA1) and the ryanodine receptor (RYR1), dominant and recessive disease from different mutations in the same gene eg ACTA1, RYR1 and slow a-tropomyosin (TPM3), somatic mosaicism in mildly affected parents and epigenetic silencing of normal alleles unmasking recessive disease. The pathobiology of most congenital myopathies remains unclear. With ACTA1, we have demonstrated that complete lack of skeletal muscle a-actin is a recessive disease where cardiac a-actin partially replaces skeletal muscle a-actin, but nemaline bodies form even in the absence of any mutant protein. Having identified many, perhaps most, of the disease genes, the main aim must now be to develop effective therapies for the congenital myopathies. Investigation of experimental therapies for the congenital myopathies is lagging behind the strides being taken in developing therapies for Duchenne muscular dystrophy. However, it should be possible for those interested in developing therapies for the congenital myopathies to piggy-back on results already achieved in experimental therapies for Duchenne. One particular difficulty facing the congenital myopathies is the size of some of the proteins involved, such as nebulin and titin which are larger even than dystrophin; titin is the largest protein known. Different approaches will probably be applicable to different proteins and even, as with dystrophin, to different mutations within the proteins.
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