TY  - JOUR
A1  - Mair, Dorothea
A1  - Biskup, Saskia
A1  - Kress, Wolfram
A1  - Abicht, Angela
A1  - Brück, Wolfgang
A1  - Zechel, Sabrina
A1  - Knop, Karl Christian
A1  - Koenig, Fatima Barbara
A1  - Tey, Shelisa
A1  - Nikolin, Stefan
A1  - Eggermann, Katja
A1  - Kurth, Ingo
A1  - Ferbert, Andreas
A1  - Weis, Joachim
T1  - Differential diagnosis of vacuolar myopathies in the NGS era
JF  - Brain Pathology
N2  - Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
KW  - autophagy
KW  - FSHD
KW  - glycogenin 1
KW  - muscular dystrophy
KW  - myofibrillar myopathy
KW  - next generation sequencing (NGS)
KW  - Pompe disease
KW  - sarcotubular myopathy
KW  - TRIM32
KW  - vacuolar myopathy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216048
VL  - 30
IS  - 5
SP  - 877
EP  - 896
ER  - 
TY  - JOUR
A1  - Kölbel, Heike
A1  - Roos, Andreas
A1  - van der Ven, Peter F. M.
A1  - Evangelista, Teresinha
A1  - Nolte, Kay
A1  - Johnson, Katherine
A1  - Töpf, Ana
A1  - Wilson, Michael
A1  - Kress, Wolfram
A1  - Sickmann, Albert
A1  - Straub, Volker
A1  - Kollipara, Laxmikanth
A1  - Weis, Joachim
A1  - Fürst, Dieter O.
A1  - Schara, Ulrike
T1  - First clinical and myopathological description of a myofibrillar myopathy with congenital onset and homozygous mutation in FLNC
JF  - Human Mutation
N2  - 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.
KW  - congenital myopathy
KW  - filamin C
KW  - myofibrillar myopathy
KW  - proteomic signature
KW  - recessive inheritance
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215481
VL  - 41
IS  - 9
SP  - 1600
EP  - 1614
ER  -