What causes centronuclear myopathy 1 (CNM1)?

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

CNM1

CNM1 is caused by mutations in the dynamin 2 gene (DNM2). [37, 38]  Dynamins are large GTPases that are involved in organelle fission events. Dynamin 2 has been implicated in endocytosis, and a likely hypothesis is that endocytotic function is disrupted due to mutations in dynamin 2. Other actions of dynamin that may play a role in disease pathogenesis include actin assembly, cytokinesis, and regulation of centrosomal function. Dynamin 2 mutations can also cause a CMT 2 phenotype with axonal neuropathy and clinical features that overlap with autosomal dominant centronuclear myopathy.

The mutations in DNM2 account for about 50% of cases but only 15% of pediatric cases. [39, 40]  Most patients have a mild phenotype with onset in adolescence or adulthood with axial/neck flexor as well as distal more than proximal limb weakness and slow progression. Other features can include facial weakness, ptosis, ophthalmoplegia, and contractures, especially of the ankles.

However, a more severe phenotype has been described at birth with hypotonia and a poor suck. There is often also facial weakness, high-arched palate, ptosis, ophthalmoplegia, joint hyperlaxity, and contractures.

One remarkable factor is that weakness is distal more than proximal, resulting in delayed major motor milestones, but ambulation is usually obtained and there is often slow improvement to young adulthood. Intermediate cases have also been described. [41]


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