Thymidine Kinase 2 Deficiency in the Era of Approved Therapy: From Diagnosis to Evidence Across the Disease Spectrum

ABSTRACT

Thymidine kinase 2 deficiency (TK2d) is an ultra‐rare autosomal recessive mitochondrial DNA (mtDNA) maintenance disorder caused by pathogenic variants in the nuclear TK2 gene. Loss of TK2 activity disrupts intramitochondrial deoxynucleotide pools, impairing mtDNA replication and resulting in a spectrum of quantitative (mtDNA depletion) and qualitative (multiple deletions) alterations whose severity is a key determinant of prognosis. Clinically, TK2d presents as a continuous phenotypic spectrum, from rapidly progressive infantile disease to adult‐onset forms, predominantly manifesting as progressive myopathy with early bulbar and respiratory involvement, the principal drivers of morbidity and mortality, with overall severity inversely correlated with age at onset. Central nervous system involvement may occur in severe early‐onset cases, whilst extramuscular manifestations are otherwise limited, with sensorineural hearing loss and subclinical axonal sensory neuropathy described across the spectrum. Circulating biomarkers, particularly GDF‐15, support diagnosis, correlate with disease severity and show dynamic changes with treatment; serum creatinine, muscle MRI fat fraction and forced vital capacity further contribute to prognostic stratification. Oral supplementation with doxecitine and doxribtimine, recently approved by the FDA (2025) and EMA (2026) for patients with symptom onset ≤ 12 years, represents the first disease‐modifying therapy for TK2d, demonstrating marked survival benefit, stabilisation of disease progression and partial recovery of motor function. Evidence in adult patients remains limited and largely retrospective, underscoring the need for dedicated prospective studies with outcome measures sensitive to slowly progressive phenotypes.