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
Cristina Domínguez-González1, Andrés Nascimento Osorio2, Yuanjun Ma3, Nada Boudiaf3, Richard Kim4, Susan VanMeter4, Marcus Brunnert5, Michio Hirano6
1Biomedical 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, 2Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Neuromuscular Unit, Sant Juan de Déu Hospital, Barcelona, Spain, 3UCB Slough, UK, 4UCB, Morrisville, NC, USA, 5UCB, Monheim am Rhein, Germany, 6Department of Neurology, Columbia University Irving Medical Center, New York, NY, USA
Objective:
To describe the disease course of untreated patients with thymidine kinase 2 deficiency (TK2d) aged >12 years at TK2d symptom onset. Disease course in patients aged ≤12 years at TK2d symptom onset is reported separately (abstract 3690).
Background:
TK2d is an autosomal recessive, mitochondrial disease associated with progressive proximal myopathy. Patients typically lose the ability to walk, eat and breathe independently. Management is limited to supportive care. TK2d is ultra-rare, so disease course data in patients aged >12 years at TK2d symptom onset are limited.
Design/Methods:
Unique individuals with TK2d were identified through literature reviews of published cases (June 2019; updated 2021) and a retrospective chart review study (NCT05017818) (Integrated Summary of Efficacy [ISE]–Untreated Patients Database [UPD]). ISE-UPD data and pretreatment data (NCT03701568; NCT03845712; NCT05017818) for patients later treated with pyrimidine nucleosides (ISE-pretreatment patients) formed the comprehensive disease course dataset. Ventilatory/feeding support and developmental motor milestones were assessed. Survival analyses were performed only in the ISE-UPD to avoid introducing an immortal time bias.
Results:
Among those aged >12 years at TK2d symptom onset (N=49), 6/27 ISE-UPD patients (22.2%) died (median [95% confidence interval] time from symptom onset to death: 24.0 [16.0, not applicable] years; 22 patients censored). Ventilatory support was used by 14/27 ISE-UPD patients (51.9%; missing: n=6) and 9/22 ISE-pretreatment patients (40.9%; missing: n=5). Feeding tubes were used by 0/27 ISE-UPD patients (missing: n=15) and 4/22 ISE-pretreatment patients (18.2%; missing: n=6). One patient (ISE-UPD) discontinued ventilatory support; none discontinued feeding support. Running was the most commonly lost motor milestone (ISE-UPD: 2/11 [18.2%]; ISE-pretreatment: 7/15 [46.7%]).
Conclusions:
Outcomes were broadly comparable between ISE-UPD and ISE-pretreatment groups, indicating substantial disease burden, often leading to ventilatory support and premature death, in patients aged >12 years at TK2d symptom onset. Further research could confirm relevant outcome measures in this patient group. UCB funded this study.
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