XLMTM mechanism of disease

Skeletal muscle structure and function are affected by dysfunctional or absent myotubularin protein

Dysfunctional or absent myotubularin protein results in disorganized and defective muscle fibers. This leads to profound muscle weakness and hypotonia, impacting respiratory and neuromuscular motor function.1-4 Myotubularin is a phosphatase involved in several cellular processes required for skeletal muscle maintenance and function, including5-9:

  • Muscle growth and differentiation
  • Cellular organization and structure
  • Cellular function

Normal neuromuscular junction


In healthy muscle cells, myotubularin protein associates with the muscle triad, which is a structure composed of T tubules and the terminal sarcoplasmic reticulum.3 The triad mediates excitation-contraction (EC) coupling, a process in which electrical stimuli at the neuromuscular junction (NMJ) are translated into muscle contractions.5


In humans and animal models, defective myotubularin protein in skeletal muscle cells results in impaired EC coupling and mislocalization of cellular organelles. Skeletal muscle impairment, specifically EC coupling, is believed to be a primary cause of profound muscle weakness associated with X-linked myotubular myopathy (XLMTM).4

XLMTM pathology has the potential to be recovered

Unlike other neuromuscular disorders, such as Duchenne muscular dystrophy (DMD) or spinal muscular atrophy (SMA), muscle fiber necrosis leading to atrophy is usually absent in XLMTM.10-12 Because the muscle fibers have not atrophied, the skeletal muscle defect in XLMTM is unique in its capacity to be restored by repairing function of the triad and recovering contractile force.3,13-16 Future therapies can potentially address the pathology of XLMTM.

XLMTM presents with a range of signs and symptoms and has a substantial impact on the lives of patients and their families.


1. Al-Qusairi L, et al. Proc Natl Acad Sci U S A. 2009;106(44):18763-18768. 2. Dowling JJ, et al. PLoS Genet. 2009;5(2):e1000372. 3. Buj-Bello A, et al. Hum Mol Genet. 2008;17(14):2132-2143. 4. Zanoteli E. Expert Opin Orphan Drugs. 2018;6(6):375-384. 5. Dowling JJ, et al. In: Adam MP, et al, eds. GeneReviews®. 2002. 6. Buj-Bello A, et al. Proc Natl Acad Sci U S A. 2002;99(23):15060-15065. 7. Di Paolo G, et al. Nature. 2006;443:651-657. 8. Hnia K, et al. J Clin Invest. 2011;121(1):70-85. 9. Amoasii L, et al. J Cell Sci. 2013;126(Pt 8):1806-1819. 10. Lawlor MW, et al. J Neuropathol Exp Neurol. 2016;75(2):102-110. 11. North KN, et al. Neuromuscul Disord. 2014;24(2):97-116. 12. Guan X, et al. Methods. 2016;99:91-98. 13. Mack DL, et al. Mol Ther. 2017;25(4):839-854. 14. Maani N, et al. Nat Commun. 2018;9(1):4849. 15. Childers MK, et al. Sci Transl Med. 2014;6(220):220ra10. 16. Elverman M, et al. Muscle Nerve. 2017;56(5):943-953.


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