Résumé :
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Background: Congenital fibre type disproportion (CFTD) is a subtype of congenital myopathy in which consistent type 1 fibre hypotrophy, compared to type 2 fibres, is the main histological abnormality. Recessive mutations in RYR1 have been associated with several histological patterns, including core myopathies and increased nuclear internalization but not with the pattern associated with CFTD. We present an affected boy, born to healthy non-consanguineous parents, who had slowly progressive severe congenital generalized hypotonia and weakness. He sat unsupported at age 1 year but never walked and he had a myopathic face with ptosis and ophthalmoplegia. Nocturnal non-invasive ventilation and a gastrostomy were required from age 2 years. He died at age 3 years from respiratory failure. Quadriceps muscle biopsies taken at ages 6 months and 3 years showed marked hypotrophy of type 1 fibres and marked type 2 fibre hypertrophy but no other notable abnormalities on standard or electron microscopy. In sequencing the RYR1 gene from cDNA (generated from skeletal muscle) there was homozygosity for a novel missense change (c.6104A>T, p.His2035Leu) that was present in genomic DNA in the heterozygous state. Careful analysis revealed low levels of a second transcript in cDNA, that contained a nonsense mutation (c.738T>G, p.Try246Stop). Family studies showed that the Stop mutation was paternally inherited. There was loss of the transcript from this allele in muscle-derived cDNA in the father also, consistent with nonsense-mediated decay. Western blotting showed reduced levels of RYR1 in the proband and his father. Conclusion: Compound heterozygosity for the p.His2035Leu mutation, together with a nonsense (silencing) mutation in RYR1 results in a severe congenital myopathy and typical histological changes of CFTD with an extreme difference in the sizes of type 1 and type 2 fibres. RYR1 is the fourth gene to be associated with CFTD.
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