Résumé :
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Communication n° 402. Central Core Disease (CCD) was the first congenital muscle disorder described based on structural changes of the muscle fibres (Shy & Magee, 1956; Greenfield et al, 1958). It is generally considered as one of the more frequent congenital myopathies. The clinical phenotype was classically described as relatively benign and non-progressive: mild hypotonia during early childhood with delayed motor milestones, diffuse and moderate muscle weakness and frequent skeletal deformities. The majority of the RYR1 gene mutations are located in the C-terminal domain of the protein. We studied 3 unrelated families with numerous patients affected by Central Core Disease and autosomal dominant inheritance. In generally, the clinical phenotype of patients from the first and second generation corresponding with the classical presentation of CCD, by contrast, patients of the thirst generation developed a phenotype more severe than the parents and the grandparents presenting with severe symptoms at birth (severe hypotonia and hypotrophy, congenital dislocation of the hips, skeletal and feet deformities, etc.) and a severe evolution during childhood (kyphoscoliosis, respiratory difficulties). The IVCT demonstrated were positive for malignant hyperthermia susceptibility in the two studied families. Histochemical and ultrastructural studies of muscle showed different patterns of core lesions: unique central or eccentric cores and single or multiple peripheral cores. Molecular genetic investigations led to the identification of mutations in the Ryanodine Receptor (RYR1) gene in all affected patients from 2 families, these mutations were located in the C-terminal domain of the protein. In the thirst family was demonstrated a linked to RyR1 locus We reported three families showing an important difference in the clinical severity demonstrating a aggravation among the generations. Future studies of physiopathological mechanism of RyR1 mutations and to analyse the eventual responsibility of the genetic environment from the non-affected parents will certainly provide further understanding into this particular group of CCD families.
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