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.
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Acknowledgements
Thomas Cullup and Heinz Jungbluth were supported by a grant from the Guy’s and St Thomas’ Charitable Foundation (Grant number 070404). The authors acknowledge the use of BRC Core Facilities provided by the financial support from the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. The authors thank the support of the National Commissioning Group to the Dubowitz Neuromuscular Centre for congenital muscular dystrophies and congenital myopathies, and the MRC Neuromuscular Centre Biobank. Francesco Muntoni is funded by Great Ormond Street Hospital Children’s Charity. The authors also wish to thank Vilma-Lotta Lehtokari and Carina Wallgren-Pettersson for kindly donating Nebulin exon 55 deletion control samples.
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Scoto, M., Cullup, T., Cirak, S. et al. Nebulin (NEB) mutations in a childhood onset distal myopathy with rods and cores uncovered by next generation sequencing. Eur J Hum Genet 21, 1249–1252 (2013). https://doi.org/10.1038/ejhg.2013.31
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DOI: https://doi.org/10.1038/ejhg.2013.31
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