What causes nemaline myopathy 3 (NEM3)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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Answer

NEM3 is due to autosomal dominant, autosomal recessive, or sporadic de novo mutations in alpha-actin (ACTA1). It is likely the second most common cause of nemaline myopathy (20%–30%), and overrepresents the severe phenotype. Alpha-actin is present in skeletal muscle but not cardiac muscle. Overall, this protein makes up 10%–20% of all muscle protein. [13]  The actin monomer, G-actin (has binding site for myosin) polymerizes to form F-actin. Two strands of F-actin combine in a double helix as part of the thin filament. F-actin binds to other thin filament proteins including nebulin, tropomyosins, and troponins and most importantly binds myosin during muscle contraction.

Most mutations are missense and spread throughout the gene. Autosomal dominant mutations exert a dominant negative effect and autosomal recessive mutations that result in no functional actin both cause cytoplasmic rods, suggesting that multiple mechanisms are responsible for disease manifestations. ACTA1 mutations may have one or more effects: increase or decrease of 1) polymerization into F-actin, 2) the sliding speed of actin filaments, 3) calcium regulation, or 4) the strength of binding to α-actinin. [14]

In autosomal dominant disease, there are likely abnormalities in folding, polymerization, or aggregation of mutant actin, whereas in autosomal recessive disease, altered ratios of sarcomeric proteins during development or turnover of the thin filament are sufficient to form rods. Therefore, nemaline rods may result from either changes in normal stoichiometry of sarcomeric proteins or due to the presence of mutant α-actinin.

The degree of sarcomeric disruption, as seen on electron microscopy, correlates with disease severity such that, in general, the most severely affected patients have the most myofibrillar disorganization.

Autosomal dominant cases are usually mild, and recessive cases are usually severe. In a large series of 109 patients with nemaline myopathy 26% had a mutation in ACTA1. [15]  More than 50% of patients had the severe congenital form of nemaline myopathy, although rare adult-onset cases have been described.

In a large series reporting previously published reports and unpublished data from the authors, [14]  177 different mutations were described, 157 being missense and 133 being de novo. Mutations occurred in 29% of the amino acid residues throughout α-actin.

Mutations in ACTA1 can also cause nemaline myopathy with intranuclear rods.15 Cases are most often sporadic but can be autosomal dominant. Presentation is likely similar to the typical nemaline myopathy, with 43% of cases having a severe congenital form, although adult-onset cases have been described. Other diseases described due to ACTA1 mutations include (1) actin filament aggregate myopathy [16]  usually causing severe disease, (2) myopathy with core-like areas [17] , and (3) congenital fiber type disproportion (see below).


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