CONGENITAL MYOPATHIES: NEMALINE AND TITINOPATHIES: P.230Clinical, genetic and pathological characterization of a wide cohort of UK patients with NEB gene related nemaline myopathy

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.