{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:13:08Z","timestamp":1790709188194,"version":"4.1.0"},"reference-count":51,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2022,3,1]],"date-time":"2022-03-01T00:00:00Z","timestamp":1646092800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JND"],"published-print":{"date-parts":[[2022,3,1]]},"abstract":"<jats:p>Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: &lt;\u200a2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.<\/jats:p>","DOI":"10.3233\/jnd-210786","type":"journal-article","created":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T12:08:07Z","timestamp":1643371687000},"page":"225-235","source":"Crossref","is-referenced-by-count":38,"title":["Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies"],"prefix":"10.1177","volume":"9","author":[{"given":"Andres","family":"Berardo","sequence":"first","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Dom\u00ednguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Neurology Department, Neuromuscular Unit, Research Institute (\u2018imas12\u2019), University Hospital, 12 de Octubre, Spanish Network for Biomedical Research in Rare Diseases (CIBERER), Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Engelstad","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Hirano","sequence":"additional","affiliation":[{"name":"Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","reference":[{"issue":"6","key":"10.3233\/JND-210786_ref1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1006\/scdb.2001.0279","article-title":"Defects of intergenomic communication: autosomal disorders that cause multiple deletions and depletion of mitochondrial DNA","volume":"12","author":"Hirano","year":"2001","journal-title":"Semin Cell Dev Biol"},{"issue":"3","key":"10.3233\/JND-210786_ref3","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/ana.25550","article-title":"SSBP1 mutations in dominant optic atrophy with variable retinal degeneration","volume":"86","author":"Jurkute","year":"2019","journal-title":"Ann Neurol"},{"issue":"2","key":"10.3233\/JND-210786_ref4","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1038\/ng.2501","article-title":"Loss-of-function mutations in MGME1 impair mtDNA replication and cause multisystemic mitochondrial disease","volume":"45","author":"Kornblum","year":"2013","journal-title":"Nat Genet"},{"issue":"6","key":"10.3233\/JND-210786_ref5","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1086\/504303","article-title":"Mutant POLG2 disrupts DNA polymerase gamma subunits and causes progressive external ophthalmoplegia","volume":"78","author":"Longley","year":"2006","journal-title":"Am J Hum Genet"},{"issue":"1","key":"10.3233\/JND-210786_ref6","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ajhg.2015.05.013","article-title":"RNASEH1 Mutations Impair mtDNA Replication and Cause Adult-Onset Mitochondrial Encephalomyopathy","volume":"97","author":"Reyes","year":"2015","journal-title":"Am J Hum Genet"},{"issue":"3","key":"10.3233\/JND-210786_ref7","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1038\/90058","article-title":"Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria","volume":"28","author":"Spelbrink","year":"2001","journal-title":"Nat Genet"},{"issue":"3","key":"10.3233\/JND-210786_ref8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/90034","article-title":"Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions","volume":"28","author":"Van Goethem","year":"2001","journal-title":"Nat Genet"},{"issue":"6","key":"10.3233\/JND-210786_ref9","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/ng2040","article-title":"Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion","volume":"39","author":"Bourdon","year":"2007","journal-title":"Nat Genet"},{"issue":"3","key":"10.3233\/JND-210786_ref10","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/ng746","article-title":"The deoxyguanosine kinase gene is mutated in individuals with depleted hepatocerebral mitochondrial DNA","volume":"29","author":"Mandel","year":"2001","journal-title":"Nat Genet"},{"issue":"5402","key":"10.3233\/JND-210786_ref11","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1126\/science.283.5402.689","article-title":"Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder","volume":"283","author":"Nishino","year":"1999","journal-title":"Science"},{"issue":"3","key":"10.3233\/JND-210786_ref12","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/ng751","article-title":"Mutant mitochondrial thymidine kinase in mitochondrial DNA depletion myopathy","volume":"29","author":"Saada","year":"2001","journal-title":"Nat Genet"},{"issue":"2","key":"10.3233\/JND-210786_ref13","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1016\/S0014-5793(98)01711-6","article-title":"Human thymidine kinase molecular cloning and characterisation of the enzyme activity with antiviral and cytostatic nucleoside substrates","volume":"443","author":"Wang","year":"1999","journal-title":"FEBS Lett"},{"key":"10.3233\/JND-210786_ref14","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/978-1-4615-7703-4_53","article-title":"Expression and substrate specificities of human thymidine kinase 1, thymidine kinase 2 and deoxycytidine kinase","volume":"309b","author":"Eriksson","year":"1991","journal-title":"Adv Exp Med Biol"},{"issue":"8740","key":"10.3233\/JND-210786_ref15","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/0140-6736(91)91294-5","article-title":"Depletion of muscle mitochondrial DNA in AIDS patients with zidovudine-induced myopathy","volume":"337","author":"Arnaudo","year":"1991","journal-title":"Lancet"},{"issue":"16","key":"10.3233\/JND-210786_ref16","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1093\/hmg\/ddn143","article-title":"Thymidine kinase 2 (H126N) knockin mice show the essential role of balanced deoxynucleotide pools for mitochondrial DNA maintenance","volume":"17","author":"Akman","year":"2008","journal-title":"Hum Mol Genet"},{"issue":"15","key":"10.3233\/JND-210786_ref17","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1093\/hmg\/ddn133","article-title":"Progressive loss of mitochondrial DNA in thymidine kinase 2-deficient mice","volume":"17","author":"Zhou","year":"2008","journal-title":"Hum Mol Genet"},{"issue":"1","key":"10.3233\/JND-210786_ref18","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1093\/hmg\/ddq453","article-title":"Onset and organ specificity of Tk2 deficiency depends on Tk1 down-regulation and transcriptional compensation","volume":"20","author":"Dorado","year":"2011","journal-title":"Hum Mol Genet"},{"issue":"8","key":"10.3233\/JND-210786_ref19","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.15252\/emmm.201404092","article-title":"Deoxypyrimidine monophosphate bypass therapy for thymidine kinase 2 deficiency","volume":"6","author":"Garone","year":"2014","journal-title":"EMBO Mol Med"},{"issue":"48","key":"10.3233\/JND-210786_ref20","doi-asserted-by":"crossref","first-page":"33137","DOI":"10.1074\/jbc.M114.610808","article-title":"The human SLC25A33 and SLC25A36 genes of solute carrier family 25 encode two mitochondrial pyrimidine nucleotide transporters","volume":"289","author":"Di Noia","year":"2014","journal-title":"J Biol Chem"},{"issue":"17","key":"10.3233\/JND-210786_ref21","doi-asserted-by":"crossref","first-page":"2226","DOI":"10.1016\/j.yexcr.2012.05.028","article-title":"The pyrimidine nucleotide carrier PNC1 and mitochondrial trafficking of thymidine phosphates in cultured human cells","volume":"318","author":"Franzolin","year":"2012","journal-title":"Exp Cell Res"},{"issue":"2-3","key":"10.3233\/JND-210786_ref22","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.mam.2012.05.005","article-title":"The mitochondrial transporter family SLC identification, properties and physiopathology","volume":"34","author":"Palmieri","year":"2013","journal-title":"Mol Aspects Med"},{"issue":"4-6","key":"10.3233\/JND-210786_ref23","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/15257771003729591","article-title":"Enzymatic regulation of cytosolic thymidine kinase 1 and mitochondrial thymidine kinase a mini review","volume":"29","author":"Munch-Petersen","year":"2010","journal-title":"Nucleosides, Nucleotides & Nucleic Acids"},{"key":"10.3233\/JND-210786_ref24","first-page":"356","article-title":"Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency","volume":"46","author":"Lopez-Gomez","year":"2019","journal-title":"EBio Medicine"},{"issue":"1","key":"10.3233\/JND-210786_ref25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1096-7192(03)00063-5","article-title":"mtDNA depletion myopathy: elucidation of the tissue specificity in the mitochondrial thymidine kinase (TK2) deficiency","volume":"79","author":"Saada","year":"2003","journal-title":"Mol Genet Metab"},{"issue":"8","key":"10.3233\/JND-210786_ref27","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1136\/jmedgenet-2017-105012","article-title":"Retrospective natural history of thymidine kinase 2 deficiency","volume":"55","author":"Garone","year":"2018","journal-title":"J Med Genet"},{"issue":"2","key":"10.3233\/JND-210786_ref28","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.ymgme.2018.04.012","article-title":"Clinical and molecular spectrum of thymidine kinase 2-related mtDNA maintenance defect","volume":"124","author":"Wang","year":"2018","journal-title":"Mol Genet Metab"},{"issue":"1","key":"10.3233\/JND-210786_ref29","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13023-019-1071-z","article-title":"Late-onset thymidine kinase 2 deficiency: a review of 18 cases","volume":"14","author":"Dom\u00ednguez-Gonz\u00e1lez","year":"2019","journal-title":"Orphanet J Rare Dis"},{"issue":"7","key":"10.3233\/JND-210786_ref30","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1001\/archneur.60.7.1007","article-title":"Mitochondrial myopathy of childhood associated with mitochondrial DNA depletion and a homozygous mutation (T77M) in the TK2 gene","volume":"60","author":"Mancuso","year":"2003","journal-title":"Arch Neurol"},{"issue":"8","key":"10.3233\/JND-210786_ref31","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1212\/01.WNL.0000028689.93049.9A","article-title":"Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA","volume":"59","author":"Mancuso","year":"2002","journal-title":"Neurology"},{"issue":"8","key":"10.3233\/JND-210786_ref32","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1001\/archneur.63.8.1122","article-title":"Clinical spectrum of mitochondrial DNA depletion due to mutations in the thymidine kinase 2 gene","volume":"63","author":"Oskoui","year":"2006","journal-title":"Arch Neurol"},{"issue":"3","key":"10.3233\/JND-210786_ref33","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0887-8994(96)00018-5","article-title":"Mitochondrial DNA depletion: prevalence in a pediatric population referred for neurologic evaluation","volume":"14","author":"Macmillan","year":"1996","journal-title":"Pediatr Neurol"},{"key":"10.3233\/JND-210786_ref34","doi-asserted-by":"crossref","unstructured":"R\u00f6tig A , Kumar D . Mitochondrial genetics and genomics in clinical medicine. In: Kumar D, Eng C, editors. Genomic Med. 2nd ed. United Kingdom: Oxford University Press; 2014. 131\u201347.","DOI":"10.1093\/med\/9780199896028.003.0009"},{"issue":"12","key":"10.3233\/JND-210786_ref35","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1016\/j.bbadis.2009.06.009","article-title":"Genetic causes of mitochondrial DNA depletion in humans","volume":"1792","author":"R\u00f6tig","year":"2009","journal-title":"Biochim Biophys Acta"},{"issue":"5","key":"10.3233\/JND-210786_ref36","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.jpeds.2007.01.044","article-title":"Mitochondrial DNA Depletion is a Prevalent Cause of Multiple Respiratory Chain Deficiency in Childhood","volume":"150","author":"Sarzi","year":"2007","journal-title":"J Pediatr"},{"issue":"4","key":"10.3233\/JND-210786_ref37","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1002\/humu.9135","article-title":"Mutation analysis in 16 patients with mtDNA depletion","volume":"21","author":"Carrozzo","year":"2003","journal-title":"Hum Mutat"},{"issue":"2","key":"10.3233\/JND-210786_ref38","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s10545-008-1038-z","article-title":"Clinical and molecular features of mitochondrial DNA depletion syndromes","volume":"32","author":"Spinazzola","year":"2009","journal-title":"J Inherit Metab Dis"},{"issue":"5","key":"10.3233\/JND-210786_ref39","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1017\/S1047951116001876","article-title":"Thymidine kinase 2 and alanyl-tRNA synthetase 2 deficiencies cause lethal mitochondrial cardiomyopathy: Case reports and review of the literature","volume":"27","author":"Mazurova","year":"2017","journal-title":"Cardiol Young"},{"issue":"2","key":"10.3233\/JND-210786_ref40","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1002\/ana.25506","article-title":"Deoxynucleoside therapy for thymidine kinase 2-deficient myopathy","volume":"86","author":"Dom\u00ednguez-Gonz\u00e1lez","year":"2019","journal-title":"Ann Neurol"},{"issue":"3","key":"10.3233\/JND-210786_ref41","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.nmd.2009.11.013","article-title":"Two novel mutations in thymidine kinase-2 cause early onset fatal encephalomyopathy and severe mtDNA depletion","volume":"20","author":"Lesko","year":"2010","journal-title":"Neuromuscul Disord"},{"issue":"Pt 11","key":"10.3233\/JND-210786_ref42","doi-asserted-by":"crossref","first-page":"2841","DOI":"10.1093\/brain\/awn236","article-title":"Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome","volume":"131","author":"G\u00f6tz","year":"2008","journal-title":"Brain"},{"issue":"4","key":"10.3233\/JND-210786_ref43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1055\/s-0037-1609039","article-title":"Phenotypic and Genotypic Heterogeneity of RRM2B Variants","volume":"49","author":"Finsterer","year":"2018","journal-title":"Neuropediatrics"},{"issue":"2","key":"10.3233\/JND-210786_ref44","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s10545-015-9894-9","article-title":"Succinate-CoA ligase deficiency due to mutations in SUCLA2 and SUCLG phenotype and genotype correlations in 71 patients","volume":"39","author":"Carrozzo","year":"2016","journal-title":"J Inherit Metab Dis"},{"issue":"2","key":"10.3233\/JND-210786_ref45","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/0887-8994(96)00118-X","article-title":"Mitochondrial myopathy simulating spinal muscular atrophy","volume":"15","author":"Pons","year":"1996","journal-title":"Pediatr Neurol"},{"issue":"9","key":"10.3233\/JND-210786_ref46","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1016\/S1474-4422(11)70155-7","article-title":"FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study","volume":"10","author":"Suomalainen","year":"2011","journal-title":"Lancet Neurol"},{"issue":"21","key":"10.3233\/JND-210786_ref47","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1212\/01.wnl.0000436068.43384.ef","article-title":"Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease","volume":"81","author":"Davis","year":"2013","journal-title":"Neurology"},{"key":"10.3233\/JND-210786_ref48","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/1471-2164-15-91","article-title":"Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies","volume":"15","author":"Kalko","year":"2014","journal-title":"BMC Genomics"},{"issue":"2","key":"10.3233\/JND-210786_ref49","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1002\/jimd.12317","article-title":"A new diagnostic indication device of a biomarker growth differentiation factor 15 for mitochondrial diseases: From laboratory to automated inspection","volume":"44","author":"Koga","year":"2021","journal-title":"J Inherit Metab Dis"},{"issue":"5","key":"10.3233\/JND-210786_ref50","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1002\/ana.24506","article-title":"Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders","volume":"78","author":"Yatsuga","year":"2015","journal-title":"Ann Neurol"},{"issue":"5","key":"10.3233\/JND-210786_ref51","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1002\/jimd.12142","article-title":"Plasma FGF-21 and GDF-15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders","volume":"42","author":"Tsygankova","year":"2019","journal-title":"J Inherit Metab Dis"},{"issue":"2","key":"10.3233\/JND-210786_ref52","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/jimd.12307","article-title":"Diagnostic value of serum biomarkers FGF21 and GDF15 compared to muscle sample in mitochondrial disease","volume":"44","author":"Lehtonen","year":"2021","journal-title":"J Inherit Metab Dis"},{"issue":"1","key":"10.3233\/JND-210786_ref53","doi-asserted-by":"crossref","first-page":"10111","DOI":"10.1038\/s41598-020-66940-8","article-title":"Growth Differentiation Factor 15 is a potential biomarker of therapeutic response for TK2 deficient myopathy","volume":"10","author":"Dominguez-Gonzalez","year":"2020","journal-title":"Sci Rep"}],"container-title":["Journal of Neuromuscular Diseases"],"original-title":[],"link":[{"URL":"https:\/\/content.iospress.com\/download?id=10.3233\/JND-210786","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T23:49:57Z","timestamp":1777506597000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.3233\/JND-210786"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,1]]},"references-count":51,"journal-issue":{"issue":"2"},"URL":"https:\/\/doi.org\/10.3233\/jnd-210786","relation":{},"ISSN":["2214-3599","2214-3602"],"issn-type":[{"value":"2214-3599","type":"print"},{"value":"2214-3602","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,1]]}}}