C.P.3 Genetic and clinical heterogeneity of RYR1-related myopathies in a cohort of 60 Dutch families with identification of 40 novel mutations

Abstract

RYR1-related myopathies have a very variable phenotype. Sequential analysis of RYR1 in the Netherlands has been performed since 2008. Our goal was to better define the phenotype or RYR1-related myopathies and to report several new mutations. We have therefore collected the results of genetic analysis clinical findings and in all patients in whom one or more RYR1 mutations were detected between 2008 and 2012. In this period, mutation analysis was performed in approximately 250 patients. In 79 patients belonging to 60 families one or more RYR1 mutations were found. In total, 55 mutations, of which 40 were novel mutations. The phenotype of these RYR1-related myopathies was very variable, including the well-known phenotypes central core disease, multiminicore disease, centronuclear myopathy, malignant hyperthermia, but also less well-defined presentations such as exercise-induced hyperCKemia, exercise-induced myalgia, heat-induced myalgia, statin-induced hyperCKemia, and viral-infection-induced hyperCKemia. Furthermore, cardiac and pulmonary manifestations were infrequently encountered while screening took only place in a minority of patients. Next, the muscle biopsies showed remarkable mitochondrial or inflammatory changes in few patients. In one patient, we could show the evolvement of pathological features in four subsequent biopsies in a period of 11years. Finally, complex inheritance patterns, with several mutations and AR and AD inheritance pattern of specific traits were encountered in some families. We conclude that RYR1-related myopathies are not rare in the Netherlands with many new mutations, some of which the pathogenicity remained unclear. In addition, RYR1-related myopathies are both clinically, histologically and genetically more diverse than previously reported. Future research should focus on functional studies of the ryanodine receptor to elucidate the pathogenicity of these mutations.