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.
The prevalence of TK2-MDS is unknown. Approximately 45 cases have been described.
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.
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.
Other Names for This Condition
- mitochondrial DNA depletion syndrome 2 (myopathic type)
- TK2-related mitochondrial DNA depletion myopathy
Additional Information & Resources
Genetic Testing Information
Research Studies from ClinicalTrials.gov
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed
- 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. Citation on PubMed or Free article on PubMed Central