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TK2-related mitochondrial DNA depletion syndrome, myopathic form

Reviewed September 2013

What is TK2-related mitochondrial DNA depletion syndrome, myopathic form?

TK2-related mitochondrial DNA depletion syndrome, myopathic form (TK2-MDS) is an inherited condition that causes progressive muscle weakness (myopathy).

The signs and symptoms of TK2-MDS typically begin in early childhood. Development is usually normal early in life, but as muscle weakness progresses, people with TK2-MDS lose motor skills such as standing, walking, eating, and talking. Some affected individuals have increasing weakness in the muscles that control eye movement, leading to droopy eyelids (progressive external ophthalmoplegia).

Most often in TK2-MDS, the muscles are the only affected tissues; however, the liver may be enlarged (hepatomegaly), seizures can occur, and hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) may be present. Intelligence is usually not affected.

As the disorder worsens, the muscles that control breathing become weakened and affected individuals frequently have to rely on mechanical ventilation. Respiratory failure is the most common cause of death in people with TK2-MDS, often occurring in childhood. Rarely, the disorder progresses slowly and affected individuals survive into adolescence or adulthood.

How common is TK2-related mitochondrial DNA depletion syndrome, myopathic form?

The prevalence of TK2-MDS is unknown. Approximately 45 cases have been described.

What genes are related to TK2-related mitochondrial DNA depletion syndrome, myopathic form?

As the condition name suggests, mutations in the TK2 gene cause TK2-MDS. The TK2 gene provides instructions for making an enzyme called thymidine kinase 2 that functions within cell structures called mitochondria, which are found in all tissues. Mitochondria are involved in a wide variety of cellular activities, including energy production; chemical signaling; and regulation of cell growth, cell division, and cell death. Mitochondria contain their own genetic material, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. Thymidine kinase 2 is involved in the production and maintenance of mtDNA. Specifically, this enzyme plays a role in recycling mtDNA building blocks (nucleotides) so that errors in mtDNA sequencing can be repaired and new mtDNA molecules can be produced.

Mutations in the TK2 gene reduce the production or activity of thymidine kinase 2. A decrease in enzyme activity impairs recycling of mtDNA nucleotides, causing a shortage of nucleotides available for the repair and production of mtDNA molecules. A reduction in the amount of mtDNA (known as mtDNA depletion) impairs mitochondrial function. Greater mtDNA depletion tends to cause more severe signs and symptoms. The muscle cells of people with TK2-MDS have very low amounts of mtDNA, ranging from 5 to 30 percent of normal. Other tissues can have 60 percent of normal to normal amounts of mtDNA.

It is unclear why TK2 gene mutations typically affect only muscle tissue, but the high energy demands of muscle cells may make them the most susceptible to cell death when mtDNA is lost and less energy is produced in cells. The brain and the liver also have high energy demands, which may explain why these organs are affected in severe cases of TK2-MDS.

Related Gene(s)

Changes in this gene are associated with TK2-related mitochondrial DNA depletion syndrome, myopathic form.

  • TK2

How do people inherit TK2-related mitochondrial DNA depletion syndrome, myopathic form?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of TK2-related mitochondrial DNA depletion syndrome, myopathic form?

These resources address the diagnosis or management of TK2-related mitochondrial DNA depletion syndrome, myopathic form, and may include treatment providers.

  • Cincinnati Children's Hospital: Mitochondrial Diseases Program (http://www.cincinnatichildrens.org/service/m/mitochondrial-disorders/patients/)
  • Gene Review: TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form (http://www.ncbi.nlm.nih.gov/books/NBK114628/)

You might also find information on the diagnosis or management of TK2-related mitochondrial DNA depletion syndrome, myopathic form, in Educational resources (http://www.ghr.nlm.nih.gov/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook.

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about TK2-related mitochondrial DNA depletion syndrome, myopathic form?

You may find the following resources about TK2-related mitochondrial DNA depletion syndrome, myopathic form, helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for TK2-related mitochondrial DNA depletion syndrome, myopathic form?

  • mitochondrial DNA depletion syndrome 2 (myopathic type)
  • MTDPS2
  • TK2-related mitochondrial DNA depletion myopathy

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about TK2-related mitochondrial DNA depletion syndrome, myopathic form?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding TK2-related mitochondrial DNA depletion syndrome, myopathic form?

autosomal ; autosomal recessive ; cell ; cell division ; depletion ; DNA ; enzyme ; gene ; kinase ; mitochondria ; motor ; ophthalmoplegia ; prevalence ; recessive ; respiratory ; sensorineural ; sensorineural hearing loss ; sequencing ; syndrome ; tissue

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Béhin A, Jardel C, Claeys KG, Fagart J, Louha M, Romero NB, Laforêt P, Eymard B, Lombès A. Adult cases of mitochondrial DNA depletion due to TK2 defect: an expanding spectrum. Neurology. 2012 Feb 28;78(9):644-8. doi: 10.1212/WNL.0b013e318248df2b. Epub 2012 Feb 15. (http://www.ncbi.nlm.nih.gov/pubmed/22345218?dopt=Abstract)
  • Blakely E, He L, Gardner JL, Hudson G, Walter J, Hughes I, Turnbull DM, Taylor RW. Novel mutations in the TK2 gene associated with fatal mitochondrial DNA depletion myopathy. Neuromuscul Disord. 2008 Jul;18(7):557-60. doi: 10.1016/j.nmd.2008.04.014. Epub 2008 May 27. (http://www.ncbi.nlm.nih.gov/pubmed/18508266?dopt=Abstract)
  • Götz A, Isohanni P, Pihko H, Paetau A, Herva R, Saarenpää-Heikkilä O, Valanne L, Marjavaara S, Suomalainen A. Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome. Brain. 2008 Nov;131(Pt 11):2841-50. doi: 10.1093/brain/awn236. Epub 2008 Sep 26. (http://www.ncbi.nlm.nih.gov/pubmed/18819985?dopt=Abstract)
  • Lesko N, Naess K, Wibom R, Solaroli N, Nennesmo I, von Döbeln U, Karlsson A, Larsson NG. Two novel mutations in thymidine kinase-2 cause early onset fatal encephalomyopathy and severe mtDNA depletion. Neuromuscul Disord. 2010 Mar;20(3):198-203. doi: 10.1016/j.nmd.2009.11.013. Epub 2010 Jan 18. (http://www.ncbi.nlm.nih.gov/pubmed/20083405?dopt=Abstract)
  • Martí R, Nascimento A, Colomer J, Lara MC, López-Gallardo E, Ruiz-Pesini E, Montoya J, Andreu AL, Briones P, Pineda M. Hearing loss in a patient with the myopathic form of mitochondrial DNA depletion syndrome and a novel mutation in the TK2 gene. Pediatr Res. 2010 Aug;68(2):151-4. doi: 10.1203/00006450-201011001-00294. Erratum in: Pediatr Res. 2010 Nov;68(5):451. (http://www.ncbi.nlm.nih.gov/pubmed/20421844?dopt=Abstract)
  • OMIM: MITOCHONDRIAL DNA DEPLETION SYNDROME 2 (MYOPATHIC TYPE) (http://omim.org/entry/609560)
  • Oskoui M, Davidzon G, Pascual J, Erazo R, Gurgel-Giannetti J, Krishna S, Bonilla E, De Vivo DC, Shanske S, DiMauro S. Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene. Arch Neurol. 2006 Aug;63(8):1122-6. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16908738?dopt=Abstract)
  • Paradas C, Gutiérrez Ríos P, Rivas E, Carbonell P, Hirano M, DiMauro S. TK2 mutation presenting as indolent myopathy. Neurology. 2013 Jan 29;80(5):504-6. doi: 10.1212/WNL.0b013e31827f0ff7. Epub 2013 Jan 9. (http://www.ncbi.nlm.nih.gov/pubmed/23303857?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: September 2013
Published: April 21, 2014