What causes nemaline myopathy 4 (NEM4)?

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

NEM4 is due to an autosomal dominant mutation in the gene for β-tropomyosin (TPM2). It is a rare cause of nemaline myopathy. Abnormal tropomyosin-actin interactions resulting in reduction in force generation, increased activation of myosin ATPase, and destabilization of the coiled-coil structure have been reported.

Mutations have also been associated with distal arthrogryposis and pterygia suggesting that β-tropomyosin may have a unique role during fetal development, particularly in distal muscles.

Presentation is from infancy to childhood with hypotonia and moderate-to-severe proximal weakness with minimal or no progression. Major motor milestones are delayed, but independent ambulation is usually achieved, although a wheelchair may be needed in later life.

Other problems can include feeding difficulties as an infant, facial weakness, long narrow face, high arched palate, kyphoscoliosis, and respiratory failure.

One consanguineous family with autosomal recessive inheritance has been described with a TPM2 mutation and Escobar syndrome [18]  (thick skin folds keeping joints in a fixed position). Presentation was at birth with hypotonia, pterygia, and arthrogryposis.

A mutation in TPM2 has also been described in cap myopathy. [19]  This disease has only been described in 5 sporadic cases and in one family with dominant inheritance. Presentation is either congenital or childhood onset of hypotonia with facial and slowly progressive proximal weakness. Respiratory failure may result in death in teenage years. Other features include a long narrow face and scoliosis. About 50% of muscle fibers showed a crescent-shaped peripheral cap that was granular in appearance on the modified GT stain and reacted strongly to NADH, phosphorylase, and periodic acid-Schiff, but not to myosin ATPase. On electron microscopy (EM), the caps were filled with abnormally arranged myofibrils, which lacked thick filaments.

Distal arthrogryposis has also been described as due to a mutation in TPM2.20 Presentation is at birth with flexion contractures of hands and feet.


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