P.296 - Congenital myopathy with protein aggregates and nemaline bodies related to CFL2 mutations

Abstract

Congenital myopathy (CM) caused by mutations in cofilin-2 gene (CFL2) is a rare neuromuscular disorder. The few reported cases show phenotypic heterogeneity ranging from early onset and rapid progressive form to milder myopathy characterized by limb girdle and axial muscles weakness. Muscle histology is also heterogeneous showing features of nemaline or myofibrillar myopathy or the coexistence of both histopathological changes. CFL2- null mutations result in more severe disease variants than those related to missense mutations although the precise mechanism through which cofilin-2 abnormality results in nemaline myopathy remains elusive. We report on three new cases, from two unrelated families, of severe CMs related to novel homozygous (p.D86H) or compound heterozygous (p.D79Y and p.S94LfsX6) mutations in CFL2.All babies presented severe neonatal generalized muscle weakness needing continuous respiratory and nutritional support since birth. One baby died at the age of 3 months; his sister and the other proband are still alive at the age of 1 year and 7 years respectively. Muscle biopsies showed severe myopathic changes, with fiber splitting, internal nuclei, many rod bodies and sarcoplasmic protein aggregates that mainly look like actin filaments. In the older baby dystrophic features such as fatty infiltration and fibrosis were also observed and CFL2 protein is reduced thus suggesting that the p.D86H mutationresults in a misfolding or destabilization of the protein's tertiarystructure, which leads to cofilin-2 degradation.