P.9.15 Centronuclear myopathies: The experience of Italian Network for congenital myopathies

Abstract

Centronuclear myopathies (CNMs) are clinically and genetically heterogeneous diseases with common histological findings of centrally located nuclei in myofibers with predominance and hypotrophy of type 1 fibers. CNMs can be classified in 3 main forms: the X-linked myotubular myopathy (XLMTM), caused by mutations in the myotubularin gene (MTM1); the autosomal-dominant form caused by mutations in the dynamin 2 gene (DNM2); the autosomal-recessive form related to mutations in the amphiphysin 2 gene (BIN1). More recently mutations in ryanodine receptor 1 gene (RYR1) have also been associated to CNMs. We report the genetic findings of a cohort of 50 patients with clinical and histological diagnosis of CNM who have been referred in the last 2 decade to the main tertiary Italian centers for neuromuscular diseases. Most patients were screened for the 4 candidate genes although the flow-chart™ of genetic testing was addressed by gender, pattern of inheritance and age of onset and/or disease severity. The genetic defect was identified in 29 patients (58%): 14 were mutated in MTM1 (48%), 12 in DNM2 (42%), and 3 in RYR1(10%). No mutations in BIN1 were detected. A total of 21 different mutations were identified, 6 of which were not previously reported, including 5 in MTM1 and 1 in RYR1. All MTM1 patients had neonatal onset and all but 2 showed severe disease progression. Patients with mutations in DNM2 had variable age of onset and different degree of muscle weakness. The patient carrying recessive RYR1 mutations had severe congenital hypotonia and ophthalmoparesis, in contrast to heterozygous patients who had a milder phenotype. In conclusion our data confirm that (1) XLMTM represent the most severe phenotype (2) DNM2-related CNMs are associated to a wide spectrum of phenotypes (3) CNMs related to recessive RYR1 mutations can mimic XLMTM 4) 40% of our cohort is genetically uncharacterized further confirming the genetic heterogeneity of CNMs.