MEDG550/Student Activities/Myotubular Myopathy

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Myotubular myopathy (MTM), also known as X-linked Myotubular Myopathy (XLMTM) is a rare inherited neuromuscular condition that is present at birth in males[1]. MTM primarily affects the skeletal muscle[1]. Skeletal muscles are the voluntary muscles of the human body, meaning they move and work as needed. Examples of skeletal muscles include leg and arm muscles, back muscles used to maintain posture, breathing muscle known as diaphragm, and muscles used to chew and swallow. MTM is characterized by muscle weakness, low muscle tone and breathing complications[1].

MTM belongs to a larger group of conditions known as centronuclear myopathies[1][2]. Centronuclear myopathy is an umbrella term for different types of inherited myopathies with variable age of onset, symptoms, and inheritance patterns in families[1]. MTM is the most common and severe type of centronuclear myopathies[1]. The severity of MTM varies between individuals. Most severely affected males do not survive the first year of life due to weakness in their breathing muscles[3][4]. Mildly affected males can survive into later childhood or adulthood[5][6][7].

Prevalence

Estimated prevalence of MTM is 1 in every 50,000 male births in the general population[2].

Genetic Cause

Genes are part of our genetic material and encode for proteins which provide instructions for cells to grow and function. Genetic conditions are caused by changes in the spelling of the genes, known as gene changes. Gene changes can have different consequences depending on which part of the gene is changed. Generally, gene changes results in the gene to turn off and result in absence of the protein or partially functional protein product which may cause disease symptoms.

MTM is a genetic condition caused by gene changes in a gene called MTM1, which encodes the myotubularin protein[8].  MTM1 is one of the genes responsible for normal muscle development and function. [9][10][11]. When there is a gene change in the MTM1 gene, muscle weakness and other symptoms of MTM become apparent[12][13][14].

Inheritance

Genes are stored in structures called chromosomes. Each of our cells have a pair of sex chromosomes, which are known as X and Y chromosomes. Females have two X chromosomes, whereas males have one X and one Y chromosome. Females randomly pass on one of their X chromosomes, and males pass on either their X or Y chromosome to their children. MTM1 is found on the X-chromosome meaning females have two copies and males have one copy of the MTM1 gene.

Female can be carriers of MTM, meaning one of their MTM1 copy is the "faulty" copy with the gene change and the other copy is normal "working" copy. Carrier females are usually asymptomatic as they have two copies of the gene and working copy can compensate for the faulty copy[12][15][16]. However, some females can show mild symptoms of muscle weakness[12][15][16][17][18]. Males are affected in MTM as they only have one copy of the gene.

MTM is inherited in a X-linked recessive pattern. Carrier females can pass on their normal or affected X chromosome to their kids and there is a 50% chance of passing either X chromosome. There is a 1/2 (50%) chance her daughter will be a carrier. There is also a 1/2 (50%) chance her son will be affected.

MTM is inherited in families in an X-linked recessive pattern, which means affected males inherited this condition from their carrier mothers[19]. A carrier female has 50% chance of passing on her faulty copy to each of her children. If she passes her faulty copy to her daughter, she will also be a carrier of MTM. If she passes her faulty copy to her son, he will develop MTM since he only has the faulty copy of the MTM1 gene.

Overall, in every pregnancy a carrier females has:

  • 25% chance of having a carrier daughter
  • 25% chance of having an affected son
  • 50% chance of having unaffected son or daughter

Alternatively, a gene change can occur spontaneously in the MTM1 gene of a child[20]. This is known as a de novo gene change and can result in MTM even though it is not inherited from a carrier mother[20].

Clinical Features and Symptoms

Clinical features of MTM can present during pregnancy or after birth depending on the severity.

Prenatal Features

There are some prenatal features of MTM that are often observed during pregnancy. Prenatal complications can include the following:

  • Increased amount of amnionic fluid, also known as polyhydramnios [1][21]
  • Premature delivery (before 37 weeks)[4]
  • Lack of oxygen and blood flow to the brain during birth, also known as birth asphyxia[5][22]
  • Reduced baby movements such as kicking, rolling and fluttering[1]

Additionally, reoccurring miscarriages and deaths of newborn male babies is commonly seen in families[1][2].  

Clinical Features

There is a spectrum of clinical features that vary from severe to mild symptoms. Most common features of MTM are:

  • General muscle weakness including facial and eye muscles[1]
  • Floppiness, also known as low muscle tone[1]
  • Difficulties in feeding, sucking, swallowing, and breathing due to decreased tone of the muscles associated with eating and breathing[1]
  • Delayed developmental milestones such as sitting up and walking independently[23]  
  • Distinct facial features such as long face, large head, high arched palate, long fingers and toes and droopy eyelids[1]

Approximately 80% of the affected males have severe presentation and depend highly on technological aids for breathing, feeding and wheelchair assistance[7]. Many fail to achieve independent breathing and depend on ventilatory support completely or partially throughout lifetime[1][7]. Additionally, majority of the patients require feeding supports such as a gastrostomy tube (G-tube) and most patients are not able to walk independently and depend on aids such as wheelchair[7][23]. Approximately 20% of the affected males have milder presentation and can walk independently and do not require complete ventilatory support in childhood[7][24][25].

Additional features can include:

  • Curvature of the spine, also known as scoliosis[7]
  • Undescended testes[1][7]
  • Constipation[7]
  • Liver complications[7][4]
  • Learning disability[7]
  • Skeletal problems with hips and knees[1]

Disease course and muscle weakness is mostly stable in affected individuals with low hospitalization and emergency room visits after the first year of life[7][23].

Diagnosis

There are two methods for diagnosing MTM:

Muscle Biopsy

Muscle biopsy is an invasive procedure used to remove a small piece of tissue from your muscle to diagnose diseases involving the skeletal muscle. Removed muscle tissues are further analyzed under the microscope for their shape, size and structure. Muscle biopsy in combination with clinical features can be diagnostic for MTM[26].

Genetic Testing

DNA sequencing of the MTM1 gene is routinely done to confirm the diagnosis at the molecular level[26]. Genetic testing can be done by blood or saliva samples and searches the MTM1 gene for any gene changes that might be causing MTM symptoms.  

Treatment and Management

There are currently no treatments available for MTM[7]. However, the condition is managed at an individual level with a multidisciplinary approach to maximize functional abilities of the child[27]. Child’s health is managed by neurologists, pulmonologists, orthopedists, eye specialists, pediatricians, physiotherapists, and other health care workers as needed[27]. Breathing, feeding, and ambulatory aids are major components of disease management[7][27].

There are currently ongoing gene therapy clinical trials for MTM[28][29]. Gene therapy is a one-time administration of a working and functional MTM1 gene into the blood via a carrier[29]. Virus cells that are known not to cause disease are called vectors and used as a carrier of the working MTM1 gene into the body. When the MTM1 gene is administered, it is able to make the myotubularin protein. Other therapeutic strategies are also being investigated by researchers[28].

Genetic Counselling

Patients and families with a diagnosis of MTM can benefit from seeing a genetic counsellor. If you have a family or personal history of MTM, a genetic counsellor can discuss the medical and psychological implications of MTM in detail. Genetic counsellors can also assess your family and personal history to evaluate your risk, order genetic testing for diagnosis if needed and discuss chances of having another affected child.

If you are known carrier of MTM and/or have an affected child with MTM, genetic counsellors can discuss the risks of your future children inheriting this gene change. Additionally, preconception or prenatal counselling could be beneficial to learn more about preconception and prenatal testing options that would be available to you. Preconception preimplantation genetic testing can be done as part of in-vitro fertilization (IVF) treatment to select and implement embryos that do not have a gene change in the MTM1 gene. During pregnancy, prenatal diagnostic testing such as amniocentesis or chorionic villus sampling (CVS) can be considered to test the baby for any changes in the MTM1 gene. A genetic counsellor can discuss the benefits and risks of these treatment and testing options further with you.

Psychological Considerations

MTM has a high disease burden on affected individuals and their families. On average students with MTM missed school more than other students and their parents missed more work days than other parents[7]. Parents usually require training, skills, and resources to manage eating and breathing difficulties of their child[7]. These factors can have social, physical and psychological impact on families and they may benefit from additional support.

Patient Resources

Myotubular Trust - https://myotubulartrust.org

MTM-CNM Family Connections - http://www.mtm-cnm.org/resources.html

Joshua Frase Foundation/Registry - https://joshuafrase.org

Muscular Dystrophy Association - https://www.mda.org

Clinical Trials

The European Union Clinical Trials Register – https://www.clinicaltrialsregister.eu/ctr-search/search

ClinicalTrials.gov – https://www.clinicaltrials.gov

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 Dowling, James J. (2015). Congenital and Other Structural Myopathies. Academic Press.
  2. ↑ 2.0 2.1 2.2 Jungbluth, Heinz (2008). "Centronuclear (myotubular) myopathy". Orphanet Journal of Rare Diseases. 3.
  3. ↑ McEntagart, M. (2002). "Genotype-phenotype correlations in X-linked myotubular myopathy". Neuromuscul Disord. 12.
  4. ↑ 4.0 4.1 4.2 Herman, Gail E. (February 1999). "Medical complications in long-term survivors with X-linked myotubular myopathy". The Journal of Pediatrics. 134.
  5. ↑ 5.0 5.1 Heckmatt, JZ (1985). "Congenital centronuclear (myotubular) myopathy: a clinical, pathological and genetic study in eight children". Brain. 108.
  6. ↑ Pierson, C.R (2007). "Myofiber size correlates with MTM1 mutation type and outcome in X-linked myotubular myopathy". Neuromuscul Disord. 17.
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 7.11 7.12 7.13 7.14 Amburgey, Kimberly (September 2017). "A natural history study of X-linked myotubular myopathy". Neurology. line feed character in |title= at position 36 (help)
  8. ↑ Laporte, Jocelyn (1996). "A gene mutated in X-linked myotubular myopathy defines a new putative tyrosine phosphatase family conserved in yeast". Nature Genetics. 13.
  9. ↑ Dowling, James J (2009). "Loss of myotubularin function results in T-tubule disorganization in zebrafish and human myotubular myopathy". PLoS Genet. 5.
  10. ↑ Buj-Bello, A (2008). "AAV-mediated intramuscular delivery of myotubularin corrects the myotubular myopathy phenotype in targeted murine muscle and suggests a function in plasma membrane homeostasis". Hum Mol Genet. 17. line feed character in |title= at position 61 (help)
  11. ↑ Qusairi-Al, L (2009). "T-tubule disorganization and defective excitation-contraction coupling in muscle fibers lacking myotubularin lipid phosphatase". Poc Natl Acad Sci USA. 106. line feed character in |title= at position 74 (help)
  12. ↑ 12.0 12.1 12.2 Dahl, N. (1995). "Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region". Am J Hum Genet. 56.
  13. ↑ Herman, Gail E (February 2002). "Characterization of mutations in fifty North American patients with X-linked myotubular myopathy". Human Mutation.
  14. ↑ Longo, G. (2016). "Mutation spectrum of the MTM1 gene in XLMTM patients: 10 years of experience in prenatal and postnatal diagnosis". Clinical Genetics.
  15. ↑ 15.0 15.1 Kristiansen, M. (2003). "X-inactivation patterns in carriers of X-linked myotubular myopathy". Neuromuscular Disorders. 13.
  16. ↑ 16.0 16.1 Tanner, S.M (1999). "Skewed X-inactivation in a manifesting carrier of X-linked myotubular myopathy and in her non-manifesting carrier mother". Human Genetics. 104.
  17. ↑ Jungbluth, H. (2003). "Early and severe presentation of X-linked myotubular myopathy in a girl with skewed X-inactivation". Neuromuscul Disord. 13.
  18. ↑ Penisson-Besnier, Isabelle (2007). "Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: A clinical and genetic study". Neuromuscul Disord. 17.
  19. ↑ Wallgren-Pettersson, C (September 1995). "The myotubular myopathies: differential diagnosis of the X linked recessive, autosomal dominant, and autosomal recessive forms and present state of DNA studies". J Med Genet.
  20. ↑ 20.0 20.1 Laporte, Jocelyn (April 2000). "MTM1 mutations in X-linked myotubular myopathy". Human Mutation. 15.
  21. ↑ Teeuw, AH (1993). "3 examples of fetal genetic neuromuscular disorders which lead to hydramnion". Ned Tijdschr Geneeskd. 137. line feed character in |title= at position 11 (help)
  22. ↑ Barth, PG (1998). "X-linked myotubular myopathy – A long-term follow up study". Eur J Ped Neurol. 1.
  23. ↑ 23.0 23.1 23.2 Beggs, Alan H. (April 2018). "A multicenter, retrospective medical record review of X‐linked myotubular myopathy: The recensus study". Muscle Nerve. 57.
  24. ↑ Biancalana, V (2003). "Characterisation of mutations in 77 patients with X-linked myotubular myopathy, including a family with a very mild phenotype". Hum Genet.
  25. ↑ Annoussamy, M. "X-linked myotubular myopathy: a prospective international natural history study". Neurology.
  26. ↑ 26.0 26.1 North, Kathryn N. (2014). "Approach to the diagnosis of congenital myopathies". Neuromuscular Disorders. 24.
  27. ↑ 27.0 27.1 27.2 Wang, Ching H. (2017). "Consensus Statement on Standard of Care for Congenital Myopathies". J Child Neurol.
  28. ↑ 28.0 28.1 Jungbluth, Heinz (April 2017). "Current and future therapeutic approaches to the congenital myopathies". Seminars in Cell & Developmental Biology. 64.
  29. ↑ 29.0 29.1 Shieh, P (October 2021). "O.1 ASPIRO gene therapy trial in X-linked myotubular myopathy (XLMTM): update on preliminary efficacy and safety findings". Neuromuscular Disorders. 31.
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