P.82First clinical and neuropathological description of a myofibrillar myopathy with congenital onset based on a homozygous recessive FLNC mutation

Abstract

Filamin C encoded by the FLNC gene is a large actin-cross-linking protein involved in reorganization of actin cytoskeleton in response to signaling events and displaying structural functions at the Z-lines in muscle cells. FLNC-related disorders have been associated with myofibrillar myopathies of adult onset and dominant inheritance. Here, we describe the case of a boy of a consanguineous family with a congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development without cardiac involvement. We performed molecular genetic testing, histopathologic and morphological analyses (including electron microscopy), analysis of the proteomic signature and a FLNC folding assay. Two homozygous mutations (chr7:128478771 C>G; c.1325C>G; homozygous p.Pro442Arg in exon 8) in the FLNC-rod domain were found. The pathogenicity of these mutations could be confirmed by functional analysis. The heterozygous parents are clinically healthy. Based on the mode of inheritance and clinical details, we - for the first time - identified a patient with congenital autosomal recessive myopathy due to a homozygous variant in the FLNC. The disease course started in the neonatal period as a congenital myopathy with development of a distal myopathy in childhood without cardiac involvement, so far. Thus, our combined findings extend the currently recognized clinical and genetic spectrum of filaminopathies.