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

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:9

Enthalten in:

Acta neuropathologica communications - 9(2021), 1 vom: 29. Apr., Seite 79

Sprache:

Englisch

Beteiligte Personen:

Madigan, Nicolas N [VerfasserIn]
Polzin, Michael J [VerfasserIn]
Cui, Gaofeng [VerfasserIn]
Liewluck, Teerin [VerfasserIn]
Alsharabati, Mohammad H [VerfasserIn]
Klein, Christopher J [VerfasserIn]
Windebank, Anthony J [VerfasserIn]
Mer, Georges [VerfasserIn]
Milone, Margherita [VerfasserIn]

Links:

Volltext

Themen:

Case Reports
Congenital myopathy
EC 3.6.4.1
Journal Article
MYH2
MyHC-IIA
Myosin Heavy Chains
Myosin heavy chain IIA
Nemaline rods
Ophthalmoplegia
Research Support, Non-U.S. Gov't
Rimmed vacuoles
Sarcomeric protein aggregation
Type 2A fiber atrophy
Type 2A fiber loss

Anmerkungen:

Date Completed 03.12.2021

Date Revised 14.12.2021

published: Electronic

Citation Status MEDLINE

doi:

10.1186/s40478-021-01168-9

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM324798075