X-linked myotubular myopathy (XLMTM) is the most common and severe form of centronuclear myopathy (CNM)—a family of rare, inherited disorders characterized by profound muscle weakness.1-3

 

XLMTM may also be referred to as:2

 

  • Myotubular myopathy (MTM)
  • X-linked centronuclear myopathy (XLCNM)
  • X-MTM

 

XLMTM affects an estimated 1 in 40,000 - 50,000 newborn males.1,2

 

XLMTM most often affects males, but on occasion females can also be affected.1, 4, 5

 

Pathogenic variants in the MTM1 gene cause XLMTM2,6

Approximately 400 unique variants in the MTM1 gene, ranging from point mutations to insertions or deletions of varying sizes, are associated with XLMTM.7

 

XLMTM is an X-linked recessive inherited condition.2,6,8

Inheritance patterns where there is family history2,8

  • If a father has XLMTM, all his daughters will be carriers of a mutant MTM1 gene, but none of his sons will be affected.
  • If a mother is a carrier, her children have a 50% probability of being a carrier (daughters) or affected by XLMTM (sons).

Inheritance patterns for cases of a single occurrence in a family2

  • For a single occurrence in a family, there is an 80%-90% probability that the mother is a carrier.
  • In the 10%-20% of cases where the mother is not a carrier, the affected male has a de novo MTM1 mutation.

Myotubularin has a key role in muscle function

The MTM1 gene encodes myotubularin, a phosphatase enzyme involved in several cellular processes necessary for skeletal muscle maintenance and function, including:9,10

  • Muscle growth and differentiation
  • Cellular organization and structure
  • Cellular function
  • Contraction of muscle fibers

Myotubularin is also expressed in non-muscle tissues throughout the body, although its functions outside of skeletal muscle are not fully known.6,9,11

Pathogenic variants in the MTM1 gene can lead to absent or dysfunctional myotubularin, primarily affecting muscle strength and function, although non-muscle related clinical manifestations also occur.2,6,9

Loss of myotubularin in the liver is believed to have a role in the hepatobiliary disease or intrahepatic cholestasis that is a more recently recognized manifestation of XLMTM.11-13

Growing evidence of liver and other non-muscle manifestations.13-17 suggests that XLMTM should be considered a multisystemic disease.

MTM1 variants result in a spectrum of disease severity

Most pathogenic variants of MTM1 cause the typical severe form of the disease, but some, like missense mutations, may only partially disrupt myotubularin function and are associated with less severe presentation.2,6

A broad clinical classification based on ventilator dependence, motor development, and ambulatory status defines XLMTM subtypes as:2,17

  • Severe (classic) XLMTM (most common; 80% of cases) – requiring chronic respiratory, feeding, and ambulatory support
  • Moderate XLMTM – less severely delayed motor milestones and may have prolonged periods off ventilation
  • Mild XLMTM – ambulatory with minimally delayed motor development and survival into adulthood independent of ventilatory support

XLMTM can present with a range of signs and symptoms that have a substantial impact on the lives of patients and their families.

References


1. Vandersmissen I, Biancalana V, Servais L, et al. An integrated modelling methodology for estimating the prevalence of centronuclear myopathy. Neuromuscul Disord. 2018;28(9):766-777. doi:10.1016/j.nmd.2018.06.012 2. Dowling JJ, Lawlor MW, Das S. X-linked myotubular myopathy. In: Adam MP, Bick S, Mirzaa GM, et al., eds. GeneReviews® [Internet]. Updated August 23, 2018. Accessed November 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK1432 3. Pierson C. Gene therapy strategies for X-linked myotubular myopathy. Expert Opin Orphan Drugs. 2018;6(3):193-202. doi:10.1080/21678707.2018.1443807 4. Biancalana V, Scheidecker S, Miguet M, et al. Affected female carriers of MTM1 mutations display a wide spectrum of clinical and pathological involvement: delineating diagnostic clues. Acta Neuropathol. 2017;134:889-904. doi: 10.1007/s00401-017-1748-0 5. Reumers SFI, Braun F, Spillane JE, et al. Spectrum of clinical features in X-linked myotubular myopathy carriers: an international questionnaire study. Neurology. 2021;97(5):e501-e512. doi: 10.1212/WNL.0000000000012236 6. Lawlor MW, Dowling JJ. X-linked myotubular myopathy. Neuromuscul Disord. 2021;31(10):1004-1012. doi:10.1016/j.nmd.2021.08.003 7. Biancalana V, Beggs AH, Das S, et al. Clinical utility gene card for: Centronuclear and myotubular myopathies. Eur J Hum Genet. 2012;20{10). doi:10.1038/ejhg.2012.91 8. X-linked myotubular myopathy. National Organization for Rare Disorders (NORD). Updated April 13. 2016. Accessed November 17, 2025. https://rarediseases.org/rare-diseases/x-linked-myotubular-myopathy/ 9. Lawlor MW, Beggs AH, Buj-Bello A, et al. Skeletal muscle pathology in X-linked myotubular myopathy: review with cross-species comparisons. J Neuropathol Exp Neurol. 2016;75(2):102-110. doi:10.1093/jnen/nlv020 10. Zanoteli E. Centronuclear myopathy: advances in genetic understanding and potential for future treatments. Expert Opin Orphan Drugs. 2018;6(6):375-384. doi: 10.1080/21678707.2018.1480366 11. Molera C, Sarishvili T, Nascimento A, et al. Intrahepatic cholestasis is a clinically significant feature associated with natural history of X-linked myotubular myopathy (XLMTM): a case series and biopsy report. J Neuromuscul Dis. 2022;9(1);73-82. doi:10.3233/JND-210712 12. Karolczak S, Deshwar AR, Aristegui E, et al. Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy. J Clin Invest. 2023 Sep 15;133(18):e166275. doi: 10.1172/JCI166275 13. Dowling JJ, Müller-Felber W, Smith BK, et al. INCEPTUS natural history, run-in study for gene replacement clinical trial in X-linked myotubular myopathy. J Neuromuscul Dis. 2022;9(4):503-516. doi: 10.3233/JND-210781 14. D'Amico A, Longo A, Fattori F, et al. Hepatobiliary disease in XLMTM: a common comorbidity with potential impact on treatment strategies. Orphanet J Rare Dis. 2021;16(1):425. doi: 10.1186/s13023-021-02055-1 15. Neese JM, Yum S, Matesanz S, et al. Intracranial hemorrhage secondary to vitamin K deficiency in X-linked myotubular myopathy. Neuromuscul Disord. 2021;31(7):651-655. doi: 10.1016/j.nmd.2021.04.009 16. Beggs AH, Byrne BJ, De Chastonay S, et al. A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study. Muscle Nerve. 2018;57(4):550-560. doi: 10.1002/mus.26018 17. Gangfuss A, Schmitt D, Roos A, et al. Diagnosing X-linked myotubular myopathy - a German 20-year follow up experience. J Neuromuscul Dis. 2021;8(1):79-90. doi: 10.3233/JND-200539.