Differential Diagnosis

Diagnosing XLMTM can be challenging due to its similarities with other neuromuscular disorders, such as:1*

  • Spinal muscular atrophy type 1 (SMA type 1)
  • Myotonic dystrophy type 1 (DM1; neonatal and later onset)
  • Prader-Willi syndrome (PWS)
  • Congenital facioscapulohumeral muscular dystrophy (FSHD)2
  • Congenital myasthenia syndromes (CMS)3

*This is not an all-inclusive list of possible neuromuscular disorders with similarities to XLMTM.

However, several distinguishing features facilitate differential diagnosis.1,4,5

Features shared by XLMTM and other neuromuscular disorders4,5

  • Neonatal hypotonia
  • Respiratory insufficiency

 

Distinguishing features of XLMTM1,4,5

  • Facial weakness
  • Dolichocephaly (length and head circumference greater than 90th percentile)
  • Ophthalmoparesis (muscle weakness in the eyes), often associated with ptosis (drooping eyelids)
    Long fingers and toes
  • Bulbar weakness leading to insufficient sucking and swallowing
  • “Frog leg” position with abducted hips and flexed knees
  • Areflexia (abnormal or absent reflexes)

Download the Differential Diagnosis Brochure

As a multisystem disorder, XLMTM presents with varied clinical manifestations that fall on a spectrum of severity.5

Key clinical hallmarks in males with severe XLMTM1,4-12

    1. Early onset, severe respiratory failure
      Most patients require ventilatory support at birth. Approximately 50% die of respiratory failure before 18 months of age.
    2. Profound neonatal hypotonia
      Decreased muscle tone may be profound at birth and can impair motor milestone achievement.
    3. Facial weakness
      Weakness in the facial muscles is often profound.
    4. Dolichocephaly
      A distinctively long and narrow head may measure above the 90th percentile in anterior-posterior length.
    5. Ophthalmoparesis, often associated with ptosis
      Weakness of the extraocular muscles is common and often associated with drooping of the upper eyelids known as ptosis.
    6. Long fingers and toes
      Noticeably long fingers and toes.
    7. Bulbar weakness leading to insufficient sucking and swallowing
      Dysphagia and pharyngeal hypotonia due to bulbar weakness leads to insufficient sucking and swallowing, likely requiring a gastrostomy tube.
    8. Areflexia (abnormal or absent reflexes)
      Reflexes, including anti-gravity movements, may be abnormal or absent at birth.
    9. Diminished muscle bulk
      Decreased muscle mass.
    10. Decreased fetal movement and polyhydramnios during gestation
      Decreased fetal movement and excessive amniotic fluid are reported in approximately half of XLMTM pregnancies.
    11. Undescended testes10
      Affected boys often have undescended testes (cryptorchidism).
    12. Hepatobiliary disease5,11,12,13
      Intrahepatic cholestasis is a recently recognized condition of clinical significance. Some patients have a history of raised serum liver enzymes, bilirubin, and bile acids, and can present with jaundice, gallstones, pruritus and/or an enlarged liver. This hepatobiliary disease or cholestatic tendency is distinct from hepatic peliosis, another non-muscle related manifestation that affects 5–10% of XLMTM patients and can cause serious liver bleeding/hemorrhage.

Secondary complications of generalized hypotonia:8,9,14-16

  • Inability to manage salivary secretions
  • Feeding difficulties characterized by swallowing, suckling, and chewing difficulties, resulting in gastrostomy tube placement in >80% of patients
  • Thin or easily fractured bones
  • Delayed speech development
  • Scoliosis in >70% of patients, which can worsen over time and further impair breathing, requiring surgery
  • Abnormal bone development

Effects on cognition:

Cognitive function is not thought to be affected. However, many individuals will require specialized education services and assistance with neurodevelopmental needs. Patients with XLMTM who experienced perinatal hypoxic events that affected the central nervous system, such as ischemic encephalopathy, may experience learning or cognitive impairments.5,8,17

Recessive X-linked diseases, like XLMTM, rarely cause symptoms in heterozygous females because one normal allele sufficiently compensates for the other missing or mutated copy.18 However, although female carriers of mutated or dysfunctional MTM1 are typically asymptomatic, there is growing awareness of clinical presentations in affected girls and women.10,18 Evidence suggests that up to 50% of female carriers may exhibit symptoms to varying degrees.17

 

Much like with affected males, signs and symptoms can exist on a spectrum of mild, moderate, and severe presentations. There are also two overarching groups (non-manifesting carriers and manifesting carriers) who exhibit different degrees of clinical symptoms.19-21

Range of XLMTM severity in females

Non-manifesting carriers:21

  • Fatigue
  • Intolerance to physical activity
  • Myalgia
  • Cramps
  • No muscle weakness
  • Independent ambulation

Manifesting carriers:21

Mild21

  • Muscle weakness
  • Independent ambulation
  • Weakness becomes more apparent during adulthood5
  • May progress to respiratory decline requiring ventilatory support5

Moderate10,21

  • Asymmetrical muscle weakness in the extremities
  • Assisted ambulation
  • Impaired motor function
  • Debilitating myalgias and muscle fatigue

Severe10,21

  • Onset as an infant5
  • Severe, generalized weakness during childhood5
  • Motor impairment 
  • Wheelchair dependence 
  • Respiratory support

Confirming clinical suspicions

Histopathologic features from biopsy samples and genetic testing can rule out other possible causes of muscle weakness.5

Muscle biopsies exhibit recognizable XLMTM pathophysiology, particularly severe variations in muscle fiber size.11

 

The triad of characteristic features includes:11

  • Very small, round fibers
  • Greater number of fibers with large centrally placed nuclei
  • Abnormal aggregation of mitochondria and other organelles

Biopsy of healthy muscle fiber (left) and muscle fiber from a patient with XLMTM (right). Nuclei are shown in purple and muscle fibers in pink; labels indicate enlarged central nuclei characteristic of CNM compared with peripheral nuclei in healthy muscle tissue.

 

*XLMTM histology image courtesy of Dr. Michael Lawlor, MD/PhD, Director, Congenital Muscle Disease Tissue Repository, Medical College of Wisconsin.

Molecular genetic testing is the definitive method for diagnosing XLMTM.1,5,22 The preferred test is based on phenotypic and laboratory findings, and whether suspected XLMTM is easily distinguishable from other central myopathies.5

Gene-targeted testing5

Gene-targeted testing is advised when phenotypic and laboratory findings suggest XLMTM.

 

  • Multigene panel of MTM1 and other genes of interest that analyzes sequence, deletion/duplication, etc.
  • Single-gene testing for male patients with a positive family history or severely affected male infants with physical features consistent with XLMTM. This type of test is primarily used in these select circumstances.

Comprehensive genomic testing5

Comprehensive genomic testing is advised when myopathy presentation is indistinguishable from other inherited disorders.

 

  • Exome sequencing
  • Genome sequencing
  • Exome array may be used as a backup for exome sequencing, but it is not always clinically available. This approach can identify deletions or duplications in multiple exons that are not detected by sequence analysis.

CPT codes for select molecular genetic tests23,24†

MTM1 sequencing analysis81406
MTM1 deletion/duplication analysis81405
Gene sequencing panels, arrays, and next-generation sequencing (NGS)81479
Congenital myopathy panel (includes MTM1)81443

†Information current as of September 2025. Please consult the latest CPT code book, test kit, or laboratory/organizational guidance before ordering molecular genetic tests. This information is not intended to replace clinical judgment.

Learn more about testing options and how to order from the GTR: Genetic Testing Registry

Patients with XLMTM frequently require early and intensive healthcare interventions.

References

 

1. North KN, Wang CH, Clarke N, et al. Approach to the diagnosis of congenital myopathies. Neuromuscul Disord. 2014;24(2):97-116. doi:10.1016/j.nmd.2013.11.00 2. Preston MK, Wang LH. Facioscapulohumeral muscular dystrophy. In: Adam MP, Bick S, Mirzaa GM, et al., eds. GeneReviews® [Internet]. Updated July 10, 2025. Accessed November 17, 2025. https://www.ncbi.nlm.nih.gov/books/NBK1443/ 3. Abicht A, Müller JS, Lochmüller H. Congenital Myasthenic Syndromes Overview. In: Adam MP, Bick S, Mirzaa GM, et al., eds. GeneReviews® [Internet]. Updated Dec 23, 2021. Accessed 22 Jan 2026. https://www.ncbi.nlm.nih.gov/books/NBK1168/ 4. Younger DS. Congenital myopathies. Handb Clin Neurol. 2023;195:533-561. doi:10.1016/B978-0-323-98818-6.00027-3 5. 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/ 6. Graham RJ, Muntoni F, Hughes I, et al. Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis. Arch Dis Child. 2020;105(4):332-338. doi:10.1136/archdischild-2019-317910 7. Martin C, Servais L. X-linked myotubular myopathy: an untreated treatable disease. Expert Opin Biol Ther. 2025;25(4):379-394. doi: 10.1080/14712598.2025.2473430 8. Amburgey K, Tsuchiya E, de Chastonay S, et al. A natural history study of X-linked myotubular myopathy. Neurology. 2017;89(13):1355-1364. doi:10.1212/WNL.0000000000004415 9. Annoussamy M, Lilien C. Gidaro T, et al. X-linked myotubular myopathy: A prospective international natural history study. Neurology. 2019;92(16):e1852-e1867. doi:10.1212/WNL.0000000000007319 10. Woo H, Lee S, Han JY, et al. Clinical characteristics and neurologic outcomes of X-linked myotubular myopathy. Ann Child Neurol. 2022;30(3):127-133. doi: 10.26815/acn.2022.00171 11. Lawlor MW, Dowling JJ. X-linked myotubular myopathy. Neuromuscul Disord. 2021;31(10):1004-1012. doi:10.1016/j.nmd.2021.08.003 12. 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 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. McEntagart M. Parsons G, Buj-Bello A, et al. Genotype-phenotype correlations in X-linked myotubular myopathy. Neuromuscul Disord. 2002;12(10):939-946. doi:10.1016/ s0960-8966(02)00153-0 15. Wang CH, Dowling JJ, North K, et al. Consensus statement on standard of care for congenital myopathies. J Child Neurol. 2012;7(3):363-382. doi:10.1177/0883073812436605 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. Cumbo F, Tosi M, Mizzoni I, et al. Cognitive, adaptive and perseverative aspects characterization of children with XLMTM: An explorative study. Eur J Paediatr Neurol. 2024;51:58-61. doi: 10.1016/j.ejpn.2024.05.013 18. Souza LS, Almeida CF, Yamamoto GL, et al. Manifesting carriers of X-linked myotubular myopathy: Genetic modifiers modulating the phenotype. Neural Genet. 2020;6(5):e513. doi:10.1212/ NXG.0000000000000513 19. 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 20. 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 21. Chausova P, Murtazina A, Stepanova A, et al. X-linked myotubular myopathy in a female patient with a pathogenic variant in the MTM1 gene. Int J Mol Sci. 2023;24(9):8409. doi:10.3390/ijms24098409 22. 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 23. Genetic testing for centronuclear and myotubular myopathy. The University of Chicago Genetic Services Laboratories. Accessed September 4, 2025. https://dnatesting.uchicago.edu/sites/default/files/Centronuclear Myopathy Information Sheet 4-18-17.pdf 24. Congenital myopathy panel. The University of Chicago Genetic Services Laboratories. Accessed November 17, 2025. https://dnatesting.uchicago.edu/tests/congenital-myopathy-panel