C.P.4.12 Molecular determinants of dominant and recessive forms of structural congenital myopathies with cores

Structural congenital myopathies comprise a number of different entities that include central and multiminicore diseases associated with mutations in the RYR1 gene. We have studied a panel of 229 unrelated patients presenting with core myopathies ranging from congenital onset with severe phenotype to milder non or slowly progressive forms. RYR1-related diseases including malignant hyperthermia (MH) with cores, exertional heat stress syndrome and centronuclear myopathies were excluded. Muscle biopsies were characterized by core lesions showing highly variable localisation, size, length and number within the muscle fibres suggesting a continuum from classical unique central cores to multiple small diffuse cores. 156 cases were sporadic while 59 and 13 patients had a familial history of dominant or recessive core myopathy, respectively. Mutation analysis was performed by screening of C-terminal exons 92 to 106 or by entire cDNA sequencing (52 patients) of the RYR1 gene. A dominant mutation was identified in 61 cases, two recessive mutations in 27 cases and one mutation in 20 cases with unknown status (AR or AD). Dominant RYR1 mutations were missense and in-frame mutations mostly localized in the C-terminal calcium channel domain. By contrast the 54 RYR1 mutations identified in recessive core myopathies were distributed along the all gene with 23% of them leading to haploinsufficiency (HI). Three patients presenting with a severe neonatal phenotype were compound heterozygous for 2 HI mutations associated with a strong RYR1 depletion. Eight patients were compound heterozygous for 1 HI mutation and one missense mutation. The variability observed in phenotype severity was likely to be related to the nature of the missense mutation associated with a hemizygous expression of mutant RYR1 protein. 14 patients were homozygous (n = 2) or compound heterozygous (n = 12) for missense mutations that included a high frequency of mutations reported as responsible for MH when present at an heterozygous level.