Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset

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2026
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Abstract
Abstract Thymidine kinase 2 deficiency (TK2d) (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 TK2d in the USA and the EU; previously, management was restricted to supportive care. Understanding of the TK2d natural history is limited. Our study describes the baseline characteristics, survival and disease progression of untreated patients with TK2d as part of one of the largest international datasets to date. Data from individuals with TK2d 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 TK2d symptom onset (≤12 years and >12 years). Key outcomes measured included survival, developmental motor milestone attainment, loss, and 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 ≤12 years, while 49 (19.1%) had an age of symptom onset >12 years; age of onset was missing for 9 (3.5%). Kaplan–Meier 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 ≤12 years and 24.0 (16.0, not applicable) years with age of symptom onset >12 years. Loss of previously acquired motor milestones was observed across both subgroups, though most frequently in those with age of symptom onset ≤12 years (61/75 patients [81.3%] lost ≥1 motor milestone). Spontaneous regain of lost motor milestones was rare (3/71 patients [4.2%], all with age of symptom onset ≤12 years). Use of ventilatory support was observed for both subgroups (81/199 patients [40.7%] with age of symptom onset ≤12 years [missing data, n = 73]; 23/49 patients [46.9%] with age of symptom onset >12 years [missing data, n = 11]). Use of feeding tube support was also reported (28/199 patients [14.1%] with age of symptom onset ≤12 years [missing data, n = 121]; 4/49 patients [8.2%] with age of symptom onset >12 years [missing data, n = 21]). This study confirms the severe disease burden and high mortality associated with TK2d, underscoring the devastating impact on quality of life. This comprehensive dataset provides a valuable resource for informing clinical management and future therapeutic strategies.
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Authors Cristina Domínguez-González, Caterina Garone, A. Nascimento, Yuanjun Ma, Nada Boudiaf, R. Kim, Susan VanMeter, Marcus Brunnert, Michio Hirano
Journal Brain communications
Year 2026
DOI
10.1093/braincomms/fcag200
URL
https://doi.org/10.1093/braincomms/fcag200
Keywords Keywords not found

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