First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC

Abstract

Filamin C (encoded by the FLNC gene) is a large actin‐cross‐linking protein involved in shaping the actin cytoskeleton in response to signaling events both at the sarcolemma and at myofibrillar Z‐discs of cross‐striated muscle cells. Multiple mutations in FLNC are associated with myofibrillar myopathies of autosomal‐dominant inheritance. Here, we describe for the first time a boy with congenital onset of generalized muscular hypotonia and muscular weakness, delayed motor development but no cardiac involvement associated with a homozygous FLNC mutation c.1325C>G (p.Pro442Arg). We performed ultramorphological, proteomic, and functional investigations as well as immunological studies of known marker proteins for dominant filaminopathies. We show that the mutant protein is expressed in similar quantities as the wild‐type variant in control skeletal muscle fibers. The proteomic signature of quadriceps muscle is altered and ultrastructural perturbations are evident. Moreover, filaminopathy marker proteins are comparable both in our homozygous and a dominant control case (c.5161delG). Biochemical investigations demonstrate that the recombinant mutant protein is less stable and more prone to degradation by proteolytic enzymes than the wild‐type variant. The unusual congenital presentation of the disease clearly demonstrates that homozygosity for mutations in FLNC severely aggravates the phenotype.

Target formation in muscle fibres indicates reinnervation – A proteomic study in muscle samples from peripheral neuropathies

“…Data analysis was carried out as described 21 . In brief, raw files were converted into mgf format using Proteome Discoverer 1.4 (Thermo Fischer Scientific, Germany) and then searched against a database containing the Swiss‐Prot part of UniProt KB 22 for homo sapiens (version 2017_11, 20,243 entries).…”

“…Data analysis was carried out as described. 21 In brief, raw files were converted into mgf format using Proteome Discoverer 1.4…”

Rare clinical phenotype of filaminopathy presenting as restrictive cardiomyopathy and myopathy in childhood

“…In previously reported cases of DM and MFM, the disease manifestation mainly occurred later in life, with the first symptoms becoming evident in the third-fifth decades of life [ 25 , 26 ]. The only exception is the congenital form of myopathy caused by a homozygous FLNC mutation and characterized by generalized muscle weakness and the absence of cardiomyopathy signs [ 27 ]. In most cases of FLNC- associated RCM, clinical manifestation occurred in adulthood and was not combined with overt MFM or DM [ 33 ], 52].…”

Expanding the clinical and molecular spectrum of ATP6V1A related metabolic cutis laxa

“…Histological studies on the quadriceps biopsy derived from index patient B‐II‐1 were carried out as described before. 25 Immunofluorescence studies on the same biopsy were performed following a recently published protocol 26 utilizing a LAMP2 antibody (monoclonal mouse H4B4; kindly provided by Prof. M. Vorgerd).…”