title: Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing.
abstract: Recessive nebulin (NEB) mutations are a common cause of nemaline myopathy (NM), typically characterized by generalized weakness of early-onset and nemaline rods on muscle biopsy. Exceptional adult cases with additional cores and an isolated distal weakness have been reported. The large NEB gene with 183 exons has been an obstacle for the genetic work-up. Here we report a childhood-onset case with distal weakness and a core-rod myopathy, associated with recessive NEB mutations identified by next generation sequencing (NGS). This 6-year-old boy presented with a history of gross-motor difficulties following a normal early development. He had distal leg weakness with bilateral foot drop, as well as axial muscle weakness, scoliosis and spinal rigidity; additionally he required nocturnal respiratory support. Muscle magnetic resonance (MR) imaging showed distal involvement in the medial and anterior compartment of the lower leg. A muscle biopsy featured both rods and cores. Initial targeted testing identified a heterozygous Nebulin exon 55 deletion. Further analysis using NGS revealed a frameshifting 4 bp duplication, c.24372_24375dup (P.Val8126fs), on the opposite allele. This case illustrates that NEB mutations can cause childhood onset distal NM, with additional cores on muscle biopsy and proves the diagnostic utility of NGS for myopathies, particularly when large genes are implicated.
authors: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK.
authors: Mariacristina
authors: M
authors: Scoto
authors: Thomas
authors: T
authors: Cullup
authors: Sebahattin
authors: S
authors: Cirak
authors: Shu
authors: S
authors: Yau
authors: Adnan Y
authors: AY
authors: Manzur
authors: Lucy
authors: L
authors: Feng
authors: Thomas S
authors: TS
authors: Jacques
authors: Glenn
authors: G
authors: Anderson
authors: Stephen
authors: S
authors: Abbs
authors: Caroline
authors: C
authors: Sewry
authors: Heinz
authors: H
authors: Jungbluth
authors: Francesco
authors: F
authors: Muntoni
mesh_terms: D000328:Adult; D017668:Age of Onset; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D049310:Distal Myopathies / Q000235:genetics* / Q000473:pathology*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007231:Infant, Newborn; D008279:Magnetic Resonance Imaging; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics*; D010641:Phenotype
chemical_list: D009124:Muscle Proteins; C035620:nebulin