Molecular Genetics of Nemaline Myopathy

Sarah A Sandaradura, University of Sydney, Sydney, New South Wales, Australia
Kathryn N North, Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, Children's Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia

Published online: December 2012

DOI: 10.1002/9780470015902.a0024341

Nemaline myopathy (NM) is a rare neuromuscular condition characterised by muscle weakness, hypotonia, depressed or absent deep tendon reflexes and nemaline bodies (rods) on skeletal muscle biopsy. There are six clinical subtypes, ranging from a severe congenital form to a milder phenotype with onset in childhood or adulthood. Pathogenic mutations have been described to date in 8 genes, the majority of which encode protein components of the muscle thin filament, and there is evidence of further genetic heterogeneity. Genotype–phenotype correlation is limited. Inheritance may be autosomal dominant or autosomal recessive and de novo dominant mutations are common. The most common genetic causes are autosomal recessive mutations in NEB and de novo autosomal dominant mutations in ACTA1. There is significant overlap between subtypes and variability in severity of manifestations. Animal models have assisted understanding of pathogenesis.

Key Concepts:

  • NM is one of the most common forms of congenital myopathy.
  • Typical clinical features include weakness, hypotonia and depressed or absent deep tendon reflexes.
  • Inheritance may be autosomal recessive, autosomal dominant or sporadic (new dominant).
  • Mutations in 8 genes have been associated with NM, and there is evidence of further genetic heterogeneity.
  • Autosomal dominant mutations in ACTA1 and autosomal recessive mutations in NEB are the most common known genetic causes.
  • Current understanding of genotype–phenotype correlation is limited.
  • Molecular genetic testing and prenatal diagnosis are available clinically.
  • Clinical and histological features assist prioritisation of molecular genetic testing.
  • New technology, such as exome sequencing, will aid gene discovery and molecular diagnosis in NM.

Keywords: nemaline myopathy; congenital myopathy; muscle weakness, genetics; nemaline rod

Figure 1. Clinical features in NM. Clinical photographs of a 3-year-old boy with NM due to a new dominant mutation in ACTA1, showing hypotonia, a narrow face with facial muscle weakness, generalised muscle weakness and a cervical kyphosis with wasting around the shoulder girdle.
Figure 2. Histopathological findings of skeletal muscle biopsy specimens. (a, b) Light microscopy on skeletal muscle biopsy (quadriceps) from a patient with NM (400× magnification). (a) H&E staining showing fibre size variation and eosinophilic inclusions (arrows). No fibrosis and nuclei are peripheral. (b) Gomori trichrome stain showing clusters of rods and granules (basophilic in this image), located peripherally and centrally. (c, d) Electron microscopic findings in the same patient. (c) Intrasarcoplasmic rods and granules. (d) Rod, showing internal lattice.
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 Further Reading
    North K (2008) What's new in congenital myopathies? Neuromuscular Disorders 18: 433–442.
    book North K and Ryan MM (2012) "Nemaline Myopathy". In: Pagon RA, Bird TD, Dolan CR and Stephens K (eds) GeneReviews. Seattle (WA): University of Washington, Seattle.
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    Wang CH, Dowling JJ, North K et al. (2012) Consensus statement on standard of care for congenital myopathies. Journal of Child Neurology 27: 363–382.

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Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease
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Article Title: Molecular Genetics of Nemaline Myopathy
 
How to Cite close
Sandaradura, Sarah A, and North, Kathryn N(Dec 2012) Molecular Genetics of Nemaline Myopathy. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024341]