Molecular Genetics of Nemaline Myopathy

Abstract

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 filam ent , 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.