The phenotype and genotype of congenital myopathies based on a large pediatric cohort

Abstract Background Congenital myopathies (CMs) are a clinically and genetically heterogeneous group of hereditary muscular disorders. The distribution of genetic and histologic subtypes has been addressed in only a few cohorts and the relationship between phenotypes and genotypes is only partially understood. Methods Retrospective cross-sectional data collection study conducted at a single center. The clinical, histopathological and molecular characterization of 104 patients with CM is reported. Results The most common histopathological subtype was core myopathy (42%). Patients with severe endomysial fibrosis were more commonly unable to walk than patients with only a mild grade (56% vs 16%). Inability to walk was also more prevalent in patients with severe fatty replacement (44% vs 19%). The genetic etiology was more frequently identified among those patients with “specific” histologic findings (74% vs 62%). A definite molecular diagnosis was reached in 65/104 patients (62%), with RYR1 (24/104) and TTN (8/104) as the most frequent causative genes. Neonatal onset occurred in 56%. Independent ambulation was achieved by 74%. Patients who walked late were more likely to become wheelchair-dependent. Respiratory support was needed in 1/3 patients. Gastrostomy placement was required in 15%. Cardiac involvement was observed in 3%, scoliosis in 43%, and intellectual disability in 6%. Conclusions This study provides an updated picture of the clinical, histopathological and molecular landscape of CMs. Independently of the causative gene, fibrosis and fatty replacement in muscle biopsy is significantly associated with clinical severity. Mutations in TTN are responsible for a higher proportion of cases than previously thought.