Phenotypic characterization of dominantly inherited distal nebulin myopathy

ABSTRACT Nebulin is a large mammalian protein crucial for skeletal muscle sarcomere function. While NEB variants typically cause recessively inherited muscle disorders, a dominantly inherited distal myopathy due to a large multi-exon deletion in NEB was described in 2019 in a single family. We identified 6 unrelated South African families with dominantly inherited distal myopathy associated with a large heterozygous deletion involving exons 14-77 of NEB and collected phenotypic data from 17 affected individuals. The median age at onset was 14 years (range 1 to 48 years), and the phenotype appeared to be mild compared to recessively inherited forms. Distal lower limb onset was most common, and on examination ankle dorsiflexors and toe extensors were the weakest muscle groups in almost all participants. Other frequently involved muscles included finger extensors, flexors, and abductors, and neck flexors. MRI in 3 affected participants showed increased T1 signal intensity in the tibialis anterior muscle, and muscle biopsy (4 participants) revealed non-specific myopathic features. Interestingly, sensory complaints were reported by 7 (41%) participants, but electrodiagnostic abnormalities were heterogeneous and non-specific, and confined to 3 participants from two families. The pathogenic mechanism underlying heterozygous NEB variants remains incompletely understood, and further functional and ultrastructural studies are required.