The Disease Course of Untreated Patients with Thymidine Kinase 2 Deficiency (TK2d) Aged ≤12 Years at TK2d Symptom Onset: Findings from the Largest International TK2d Dataset
Michio Hirano1, Andrés Nascimento Osorio2, Yuanjun Ma3, Nada Boudiaf3, Richard Kim4, Susan VanMeter4, Marcus Brunnert5, Cristina Domínguez-González6
1Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA, 2Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Neuromuscular Unit, Sant Joan de Déu Hospital, Barcelona, Spain, 3UCB, Slough, UK, 4UCB, Morrisville, NC, USA, 5UCB, Monheim am Rhein, Germany, 6Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Neuromuscular Diseases Unit, Neurology Department, Hospital Universitario 12 de Octubre, Madrid, Spain; Research Institute Hospital Universitario 12 de Octubre (i+12), Madrid, Spain
Objective:
To characterize the disease course of untreated patients with thymidine kinase 2 deficiency (TK2d) aged ≤12 years at TK2d symptom onset. Disease course of patients aged >12 years at TK2d symptom onset is reported separately (abstract 2629).
Background:
TK2d is an ultra-rare, autosomal recessive, mitochondrial disease associated with progressive proximal myopathy. Management is limited to supportive care. Patients aged ≤12 years at TK2d symptom onset experience rapid disease progression, generalized weakness and many die prematurely.
Design/Methods:
Data from unique individuals with TK2d identified through literature reviews of published cases (June 2019; updated 2021) and a retrospective chart review study (NCT05017818) comprised the Integrated Summary of Efficacy–Untreated Patients Database (ISE-UPD). The ISE-UPD data and pretreatment data (NCT03701568; NCT03845712; NCT05017818) of patients later treated with pyrimidine nucleosides (ISE-pretreatment patients) formed the comprehensive disease course dataset. Survival analyses were performed only in the ISE-UPD to avoid introducing immortal time bias. Developmental motor milestones and ventilatory/feeding support were assessed.
Results:
Among those aged ≤12 years at TK2d symptom onset (N=199), 66/117 ISE-UPD patients (56.4%) died (median [95% confidence interval] time from symptom onset to death: 2.6 (1.3, 6.4) years; 51 patients censored). Most patients lost ≥1 motor milestone (ISE-UPD: 20/26 [76.9%], missing/not-at-risk: n=91; ISE-pretreatment: 41/49 [83.7%], missing/not-at-risk: n=33). Ventilatory support was used by 50/117 ISE-UPD patients (42.7%; missing: n=44) and 31/82 ISE-pretreatment patients (37.8%; missing: n=29). Feeding tubes were used by 8/117 ISE-UPD patients (6.8%; missing: n=91) and 20/82 ISE-pretreatment patients (24.4%; missing: n=30).
Conclusions:
Patients aged ≤12 years at TK2d symptom onset face a high risk of premature death, often occurring within 3 years after symptom onset. Functional outcomes (motor function loss and ventilatory/feeding support use) were comparable between ISE-UPD and ISE-pretreatment groups, highlighting the heavy, progressive burden in patients aged ≤12 years at TK2d symptom onset. UCB funded this study.
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