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Thymidine kinase 2 (TK2) is a mitochondrial enzyme participating in the salvage of deoxyribonucleotides needed for mitochondrial DNA (mtDNA) replication. TK2 catalyzes the first and rate-limiting step of the deoxypyrimidine salvage pathway. Mutations in TK2 were typically associated with a severe myopathic form of mtDNA depletion syndrome (MDS) characterized by a dramatic decrease in mtDNA copy number in muscle that manifests during infancy and leads to the early death of most patients.1 Recently, several patients have been diagnosed with a late-onset or slow-progressing form of the disease manifesting as a milder myopathy with mtDNA multiple deletions.2–5 Here we describe 7 adult cases presenting with a mild myopathy compatible with a relatively normal life for decades and associated with multiple mtDNA deletions and no marked depletion in skeletal muscle. TK2 activity was drastically reduced in cultured fibroblasts of 2 of these patients, suggesting that redundant or complementary biochemical mechanisms could bypass the defect in some individuals, in contrast with severely affected infantile patients.
Acknowledgments
Acknowledgment: The authors thank Michael Terry for English language assistance and Laura Rufian and Sara Jiménez for technical support.
Footnotes
Supplemental data at Neurology.org
Author contributions: Drs. J. Díaz-Manera, E. Cancho, B. San Millan, A. Hernandez-Lain, and J.S. Rodríguez-Vico managed patient care and designed the clinical study. Drs. B. San Millan and A. Hernandez-Lain performed the histopathologic analysis of patient samples. Drs. Y. Cámara, M.J. Melià, A. Blázquez, A. Delmiro, E. López-Gallardo, B. Bornstein, G. Garrabou, C. Morén, E. Gallardo, and L. Carreño-Gago performed the biochemical, genetic, and molecular analysis. Drs. M.A. Martín, E. Gallardo, Y. Cámara, R. Martí, and E. García-Arumí designed, directed, and supervised biochemical and molecular studies. Drs. Y. Cámara, R. Martí, and E. García-Arumí wrote and edited the manuscript.
Study funding: Drs. E. García-Arumí, M.A. Martín, R. Martí, and B. Bornstein have received funding from the Spanish Instituto de Salud Carlos III (grant PI12/02149 to E.G.-A., PI12/01683 to M.A.M., PI12/00322 to R.M., and PI12/01795 to B.B.). Dr. Y. Cámara has received a postdoctoral grant (grant DdT1 2013) from the French Muscular Dystrophy Association-Téléthon (AFMTéléthon).
Disclosure: Y. Cámara has received a postdoctoral grant (grant DdT1 2013) from the French Muscular Dystrophy Association-Téléthon (AFMTéléthon). L. Carreño-Gago reports no disclosures relevant to the manuscript. M. Martín has received funding from the Spanish Instituto de Salud Carlos III (grants PI12/01683). M. Melià, A. Blázquez, A. Delmiro, G. Garrabou, C. Morén, J. Díaz-Manera, and E. Gallardo report no disclosures relevant to the manuscript. B. Bornstein has received funding from the Spanish Instituto de Salud Carlos III (grant PI12/01795). E. López-Gallardo, A. Hernandez-Lain, B. San Millan, E. Cancho, and J. Rodríguez-Vico report no disclosures relevant to the manuscript. R. Martí has received funding from the Spanish Instituto de Salud Carlos III (grant PI12/00322). E. García-Arumí has received funding from the Spanish Instituto de Salud Carlos III (grant PI12/02149). Go to Neurology.org for full disclosures.
- Received November 4, 2014.
- Accepted in final form January 29, 2015.
- © 2015 American Academy of Neurology
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