P.76 - Reducing body myopathy as a new phenotype of Filamin C mutation

Abstract

This 8 years old girl was born at 37SA to Moroccan parents who are first cousins, with no familial medical history. She developed at 10 months a psychomotor retardation with short and stiff neck, a progressive malignant scoliosis with axial and proximal muscle weakness, pelvic stiffness and shoulder girdles. She presents asymmetric hypertrophic cardiomyopathy. CK were slithly elevated (473 UI/L, N < 170). Brain MRI was normal. Muscle biopsy showed fascicular hypertrophic type I and II fibers with reducing bodies, and a predominancy of type I fibers and numerous type II atrophic fibers. Genetic analysis for FHL1, LMNA, RYR1 and genes encoded for selenoprotein revealed no mutation. Genomic DNA sample was analyzed using a Next Generation Sequencing approach based on a panel of 48 cardiomyopathy-causing genes involved in cardiac and muscular diseases. A missense variation (NM_1458.4:c.3503G > A, p.Gly1168Asp) affecting FLNC, encoding filamin-C also known as actin-binding-like protein (ABPL) or filamin-2 (FLN2) was identified. This variation affects a highly conserved aminoacid located in the 10th repetitive immunoglobulin-like domain (R10) of the protein. The variation is not yet reported in molecular databases such as dbSNP, Exome Variant Server or ExAC. All tested softwares to predict the effect of the variation (GVGD, Mutation Taster, PolyPhen2, SIFT and UMD Predictor) suggest that this variation is likely pathogen. Proband's parents were tested for this variation and neither of whom carries the variation suggesting a de novo mutation. Immunolabelling of filamin C was performed on muscular cross sections of the proband, revealing large filamin C aggregates in muscular fibers. Reducing body myopathies are usually observed in FHL1 mutations. The first case of filamin C mutation revealed by reducing body myopathy is here reported.