Filamentous tangles with nemaline rods in MYH2 myopathy: a novel phenotype

Acta Neuropathologica Communications

Gaofeng Cui¹  Georges Mer¹  Margherita Milone²  Anthony J. Windebank²  Michael J. Polzin²  Nicolas N. Madigan²  Christopher J. Klein²  Teerin Liewluck²  Mohammad H. Alsharabati³ 

[1] Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 1st St SW, 55905, Rochester, MN, USA;Department of Neurology, Mayo Clinic, 200 1st St SW, 55905, Rochester, MN, USA;Department of Neurology, UnityPoint Health, 1221 Pleasant St Suite 300, 50309, Des Moines, IA, USA;

关键词: Congenital myopathy;    MYH2;    MyHC-IIA;    Myosin heavy chain IIA;    Nemaline rods;    Sarcomeric protein aggregation;    Ophthalmoplegia;    Rimmed vacuoles;    Type 2A fiber atrophy;    Type 2A fiber loss;   

DOI  :  10.1186/s40478-021-01168-9

来源: Springer

【 摘 要 】

The MYH2 gene encodes the skeletal muscle myosin heavy chain IIA (MyHC-IIA) isoform, which is expressed in the fast twitch type 2A fibers. Autosomal dominant or recessive pathogenic variants in MYH2 lead to congenital myopathy clinically featured by ophthalmoparesis and predominantly proximal weakness. MYH2-myopathy is pathologically characterized by loss and atrophy of type 2A fibers. Additional myopathological abnormalities have included rimmed vacuoles containing small p62 positive inclusions, 15–20 nm tubulofilaments, minicores and dystrophic changes. We report an adult patient with late-pediatric onset MYH2-myopathy caused by two heterozygous pathogenic variants: c.3331C>T, p.Gln1111* predicted to result in truncation of the proximal tail region of MyHC-IIA, and c.1546T>G, p.Phe516Val, affecting a highly conserved amino acid within the highly conserved catalytic motor head relay loop. This missense variant is predicted to result in a less compact loop domain and in turn could affect the protein affinity state. The patient’s genotype is accompanied by a novel myopathological phenotype characterized by centralized large myofilamentous tangles associated with clusters of nemaline rods, and ring fibers, in addition to the previously reported rimmed vacuoles, paucity and atrophy of type 2A fibers. Electron microscopy demonstrated wide areas of disorganized myofibrils which were oriented in various planes of direction and entrapped multiple nemaline rods, as corresponding to the large tangles with rods seen on light microscopy. Nemaline rods were rarely observed also in nuclei. We speculate that the mutated MyHC-IIA may influence myofibril disorganization. While nemaline rods have been described in myopathies caused by pathogenic variants in genes encoding several sarcomeric proteins, to our knowledge, nemaline rods have not been previously described in MYH2-myopathy.

【 授权许可】

CC BY