Abstract
Recessive NEB gene mutations are the most common cause of nemaline myopathy (NM), characterized by early onset generalized weakness and nemaline rods on muscle histopathology. Here we report a clinical, pathological, and genetic evaluation of 46 patients (42 families) with NEB-related NM referred for diagnosis to the Dubowitz Neuromuscular Centre. NEB gene analysis was performed by next generation sequencing. Review of available clinical data suggests a typical course in 26/38 patients, with onset at birth/first year of life, hypotonia and/or developmental delay. All 26 achieved independent ambulation and showed prominent axial weakness, 7 with severe foot drop. Scoliosis and/or kyphosis was observed in 13/26 patients. 9/25 needed overnight respiratory support, 10/24 had dysphagia (9 needing a PEG), and 10/20 variable speech involvement. Seven/38 patients showed more severe prenatal/neonatal onset, with early termination of pregnancy in one case and death < 6 months in 2. The remaining patients showed severe skeletal and respiratory weakness. Finally, 5/38 individuals had a later onset (>2 years of age) and followed a milder disease course. 32 patients were homozygous or compound heterozygotes for 2 NEB variants. Phasing of variants is in progress in 14 patients with 2 NEB variants. Altogether, we identified 53 variants, 16 frameshift, 10 stop and 10 splice site. Muscle biopsies were available in 16 patients. Frequent nemaline rods (14/16) and slow fibre predominance (9/16) were common findings. In 2 cases no rods were seen on light microscopy. The pathological spectrum also included increased central nuclei (2 cases), frequent cytoplasmic bodies (2 cases), and features of rod-core myopathy (2 cases). Although further deep phenotypic analysis is in progress, the available results confirm the wide clinical and pathological spectrum of NEB-related NM and further expand current knowledge on this rare condition.
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