A.P.3

Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogenous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with respiratory and/or extraskeletal involvement. We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives ( n  = 43) and particularly focused on the associated extraskeletal symptoms. We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with a mild phenotype and an axonal sensorimotor polyneuropathy. We detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, hearing loss in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene, dysphonia with a DES mutation and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%). We conclude that extraskeletal symptoms frequently occur in MFM, particularly polyneuropathy, deafness, cardiac and respiratory involvement. In case of muscle weakness and extraskeletal symptoms the presence of a MFM should be considered. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim.