O.22 Autosomal dominant Core Congenital Myopathy caused by a mutation in the MYH7 gene

Abstract

Autosomal dominant (AD) Central core disease (CCD) named currently congenital myopathy with core is an inherited disorder characterised by the presence of cores which are well-limited rounded areas devoid of any oxidative staining. The cores extend almost along the full length of the fibres; these areas correspond to sarcomeric disorganisation, Z line streaming and absence of mitochondria. Genetic studies of AD-CCD families demonstrated the presence of heterozygous mutations in the RYR1 gene in the large majority of families. However, this gene was excluded in some families, suggesting a genetic heterogeneity of AD-Core myopathies (Romero et al., 2005). To enlarge the genetic spectrum of autosomal dominant congenital myopathies with cores demonstrating mutations in a second gene. AD-CCD family with three affected members: the mother and two of three siblings. The symptoms began during the early childhood with delayed motor development. Later they develop proximal weakness, hypertrophy of calves, scapular winging and significant weakness (amyotrophic) of quadriceps and tibialis anterior. No cardiac or ocular involvement was noted. The muscle biopsies sections showed a particular pattern: relatively large and eccentric cores (placed near the subsarcolemmal regions) associated with type 1 predominance and fibre type disproportion in a patient. The large majority of the cores have abrupt borders. Electron microscopy confirmed the presence of multiple large disorganised sarcomeric areas as characteristic unstructured and structured cores. Moreover, some fibres contain focal disorganised areas. Exome sequencing analysis identified a heterozygous missense mutation L1723P in MYH7 segregating with the disease and affecting a conserved residue in the tail domain. With this study we describe MYH7 as a second causative gene for AD-CCD in addition to RYR1 . Our study enlarges the genetic spectrum of AD-CCD myopathies.