{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:39:05Z","timestamp":1790631545352,"version":"4.1.0"},"reference-count":23,"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 (TK2d) (MIM 609560) is an ultra-rare, autosomal recessive mitochondrial myopathy caused by TK2 variants, leading to mitochondrial DNA depletion and\/or multiple deletions. People with thymidine kinase 2 deficiency experience progressive myopathy, bulbar weakness and respiratory insufficiency, often losing the ability to walk, eat and breathe independently. Doxecitine and doxribtimine represents the first approved treatment for patients with thymidine kinase 2 deficiency with age of symptom onset \u226412 years by the US Food and Drug Administration and the European Medicines Agency; previously, disease management was limited to supportive care. We investigated the efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Patients treated with pyrimidine nucleos(t)ides were pooled from retrospective (NCT03701568, NCT05017818) and prospective (NCT03845712) studies and company-supported Expanded Access Programs. Untreated patients were pooled from literature reviews and a retrospective chart review study (NCT05017818). Patient subgroups were stratified by age of thymidine kinase 2 deficiency symptom onset (\u226412 years and &amp;gt;12 years). The primary outcome was survival in 50th-percentile matched pairs of treated and untreated patients. Other outcomes included status of developmental motor milestones, ventilatory and feeding tube support, and safety. In total, 218 patients were included (treated: 104; untreated: 114). Baseline demographics and characteristics were comparable between subgroups. Most patients had an age of symptom onset \u226412 years [treated: 82\/104 (78.8%); untreated: 93\/114 (81.6%)]. In the age-of-symptom-onset-\u226412-years subgroup, restricted mean survival time (95% confidence interval) was 29.2 (28.2, 30.3) years over the 30 years after symptom onset for treated patients and 14.4 (11.1, 17.6) years for untreated patients. Loss of \u22651 acquired motor milestone was more frequent before treatment start than after. Substantially more patients regained \u22651 lost motor milestone after treatment start than before. Ventilatory and feeding support were used across all age-of-symptom-onset subgroups, but some patients reduced or discontinued support after starting treatment and fewer patients initiated support after treatment start than before. Most treatment-emergent adverse events (TEAEs) did not lead to discontinuation. The most frequent TEAE was diarrhoea [43\/50 patients (86.0%)], which was generally mild or moderate and resolved with dose reduction. Serious TEAEs occurred in 28\/50 patients (56.0%); few were considered to be drug related [4\/50 (8.0%)]. In total, 3\/67 patients (4.5%) experienced a fatal serious TEAE, which were not considered to be drug related. These findings indicate that pyrimidine nucleos(t)ide therapy improves survival and functional outcomes in people with thymidine kinase 2 deficiency, especially those with age of symptom onset \u226412 years, and has an acceptable safety profile.<\/jats:p>","DOI":"10.1093\/braincomms\/fcag201","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T11:34:05Z","timestamp":1780400045000},"source":"Crossref","is-referenced-by-count":4,"title":["Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7070-7402","authenticated-orcid":false,"given":"Michio","family":"Hirano","sequence":"first","affiliation":[{"name":"Department of Neurology, H. Houston Merritt Center for Neuromuscular Disorders, Columbia University Irving Medical Center , New York, NY 10032 ,","place":["USA"]}],"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"}]},{"given":"Richard","family":"Haas","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of California San Diego and Rady Children\u2019s Hospital , San Diego, CA 92093 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Center of Medical Genetics, Prince of Wales Hospital , Shatin, Hong Kong SAR 999077 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0635-2485","authenticated-orcid":false,"given":"Irene","family":"Rebollo Mesa","sequence":"additional","affiliation":[{"name":"UCB Biometrics and Data Science, , Madrid 28020 ,","place":["Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7605-8486","authenticated-orcid":false,"given":"Carl","family":"Chiang","sequence":"additional","affiliation":[{"name":"UCB Global Clinical Development, , Morrisville, NC 27560 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6444-1501","authenticated-orcid":false,"given":"Anny-Odile","family":"Colson","sequence":"additional","affiliation":[{"name":"UCB Safety Risk Management, , Colombes, Paris 92700 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