{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T20:05:39Z","timestamp":1786824339842,"version":"build-2736575974"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T00:00:00Z","timestamp":1780444800000},"content-version":"vor","delay-in-days":153,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007775","name":"UCB","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007775","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Thymidine kinase 2 deficiency (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial disease, resulting in progressive myopathy, respiratory insufficiency and increased risk of early death. Doxecitine and doxribtimine represents the first approved treatment for thymidine kinase 2 deficiency in the USA and the EU; previously, management was restricted to supportive care. The overall understanding of the natural history of thymidine kinase 2 deficiency is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with thymidine kinase 2 deficiency as part of one of the largest international datasets to date. Data from individuals with thymidine kinase 2 deficiency identified through the review of published literature and a retrospective chart review study (NCT05017818) were pooled with pretreatment data from patients later treated with pyrimidine nucleos(t)ides (NCT03701568; NCT03845712; NCT05017818; company-supported Expanded Access Programs). Subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (\u226412 years and &amp;gt;12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, regain and use of ventilatory and feeding support. In total, 257 patients were included in the study. Most patients [n = 199 (77.4%)] had an age of symptom onset \u226412 years, while 49 (19.1%) had an age of symptom onset &amp;gt;12 years; age of onset was missing for 9 (3.5%). Kaplan\u2013Meier survival analyses estimated that the median time (95% confidence interval) from symptom onset to death was 2.6 (1.3, 6.4) years with age of symptom onset \u226412 years and 24.0 (16.0, not applicable) years with age of symptom onset &amp;gt;12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset \u226412 years [61\/75 patients (81.3%) lost \u22651 motor milestone]. Spontaneous regain of lost motor milestones was rare [3\/71 patients (4.2%), all with age of symptom onset \u226412 years]. Use of ventilatory support was observed for both subgroups [81\/199 patients (40.7%) with age of symptom onset \u226412 years (missing data, n = 73); 23\/49 patients (46.9%) with age of symptom onset &amp;gt;12 years (missing data, n = 11)]. Use of feeding tube support was also reported [28\/199 patients (14.1%) with age of symptom onset \u226412 years (missing data, n = 121); 4\/49 patients (8.2%) with age of symptom onset &amp;gt;12 years (missing data, n = 21)]. This study confirms the severe disease burden and high mortality associated with thymidine kinase 2 deficiency, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag200","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:34:02Z","timestamp":1780400042000},"source":"Crossref","is-referenced-by-count":2,"title":["Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5151-988X","authenticated-orcid":false,"given":"Cristina","family":"Dom\u00ednguez-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Neuromuscular Unit, Neurology Department, Hospital 12 de Octubre , Madrid 28041 ,","place":["Spain"]},{"name":"imas12 Research Institute Mitochondrial and Neuromuscular Research Group '12 de Octubre', , Madrid 28041 ,","place":["Spain"]},{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III , Madrid 28029 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4928-1037","authenticated-orcid":false,"given":"Caterina","family":"Garone","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna , Bologna 40138 ,","place":["Italy"]},{"name":"IRCCS Istituto delle Scienze Neurologiche, UOC Neuropsichiatria dell'et\u00e0 Pediatrica di Bologna , Bologna 40139 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4952-5732","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Nascimento","sequence":"additional","affiliation":[{"name":"Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III , Madrid 28029 ,","place":["Spain"]},{"name":"Neuromuscular Unit, Sant Joan de D\u00e9u Hospital , Barcelona 08950 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0677-015X","authenticated-orcid":false,"given":"Yuanjun","family":"Ma","sequence":"additional","affiliation":[{"name":"Real World Evidence, UCB , Slough SL1 3WE ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-3225-9240","authenticated-orcid":false,"given":"Nada","family":"Boudiaf","sequence":"additional","affiliation":[{"name":"Real World Evidence, UCB , Slough SL1 3WE ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Kim","sequence":"additional","affiliation":[{"name":"UCB Global Clinical Development, , Morrisville, NC 27560 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5994-803X","authenticated-orcid":false,"given":"Susan","family":"VanMeter","sequence":"additional","affiliation":[{"name":"UCB Global Clinical Development, , Morrisville, NC 27560 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcus","family":"Brunnert","sequence":"additional","affiliation":[{"name":"UCB Biometrics and Data Science, , Monheim am Rhein 40789 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7070-7402","authenticated-orcid":false,"given":"Michio","family":"Hirano","sequence":"additional","affiliation":[{"name":"H. Houston Merritt Center for Neuromuscular Disorders, Columbia University Irving Medical Center Department of Neurology, , New York, NY 10032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,3]]},"reference":[{"issue":"8","key":"2026061706165943800_fcag200-B1","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":"2026061706165943800_fcag200-B2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.3233\/JND-210786","article-title":"Advances in thymidine kinase 2 deficiency: Clinical aspects, translational progress, and emerging therapies","volume":"9","author":"Berardo","year":"2022","journal-title":"J Neuromuscul 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