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

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 (≤12 years and >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 ≤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 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.