What causes centronuclear myopathy X (CNMX)?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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CNMX is due to mutations in myotubularin (MTM1). [47]  Point mutations (missense, nonsense, and splice site), as well as small or large insertions and deletions, have been found throughout the gene. A clear genotype-phenotype correlation does not exist, but most nonsense and splice site, as well as some missense mutations in conserved residues, result in a severe phenotype, and many missense mutations or deletions have a mild phenotype. Myotubularin is ubiquitously expressed in the nucleus of most cells.

Myotubularin is a lipid phosphatase whose main action is to dephosphorylate phosphoinositide-3-phosphate. Phosphoinositides are specialized lipids that target localization of proteins to various subcellular organelles and are important in membrane trafficking.

Myotubularin interacts with proteins with the SET domain that are important in epigenetic mechanisms of gene regulation. Myotubularin may serve as a link between genetic regulatory proteins and signaling pathways involved in vesicular trafficking of substrate necessary for myoblast fusion.

In myotubularin knockout mice, muscle development occurs normally, but a myopathy develops suggesting that the absence of myotubularin affects muscle maintenance, not muscle formation.

In the pediatric population, mutations in MTM1 account for about 50% of CNM cases.  Affected males often present in utero with with decreased fetal movements and polyhydramnios. At birth, severe weakness and hypotonia, feeding difficulty, and respiratory distress are present.

There is often noticeable ptosis, facial weakness, and ophthalmoplegia. Skeletal features include pectus carinatum, micrognathia, knee and hip contractures, elongated birth length, narrow face, slender/long digits, and macrocephaly.

Systemically, these boys may have cryptorchidism, pyloric stenosis, gallstones, hepatic dysfunction, spherocytosis, renal calcinosis, and bleeding diathesis.

Currently, the prognosis is poor with 54%–65% of patients dying before 18 months of age. [48, 49]  Additionally, 90% required ventilatory support at birth. Fifty-seven percent of survivors older than 1 year need 24-hour ventilator support [50] ; however, these survivors have nonprogressive weakness and can live into adulthood. However, at the time of writing this article, there is a current viral vector-based gene replacement therapy in clinical trials.

Of note, most carriers are asymptomatic, but mild facial and limb weakness may be present. Progression may result in gait difficulty and kyphoscoliosis. Skewed X-inactivation may result in a carrier who presents severely with infant-onset weakness, feeding difficulty, and skeletal deformities.

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