What causes nemaline myopathy 8 (NEM8)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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NEM8 is due to an autosomal recessive mutation in the gene for Kelch-like family member 40 (KLHL40). [24]  This is a common form of severe nemaline rod myopathy, accounting for 20% of all cases screened and 28% of patients in the Japanese population [24] . KLHL40 is a member of the Kelch-repeat-containing protein superfamily. Members of this family have a wide range of functions, which generally involve protein-protein interactions. KLHL40 is more abundant in fetal skeletal muscle than in adult muscle and localizes to the A-band. Muscle pathology from affected patients showed numerous small rods, many requiring EM for visualization. KLHL40 immunostaining is reduced or absent in muscle of patients harboring a mutation. Knockdown of KLHL40 in Zebrafish resulted in disruption of myofibers, widened Z-disks, aggregates containing a-actinin (Z-disk protein), and loss of movement. It is thought to likely play a role in muscle development and function. [24]

Patients present at birth with severe symptoms. The majority have fetal akinesia or hypokinesia. Respiratory failure, facial weakness, facial dysmorphism, dysphagia, contractures, and diffuse weakness occur in more than 90%. In one series, ventilation was needed in 38% and gastrostomy tube was needed in 54%. Other features included ophthalmoparesis and pathological fractures. Overall, many patients died within the first 6 months of birth, although some lived into the second decade. [24]

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