Abstract
Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.