Thymidine kinase 2 (TK2) deficiency is a rare mitochondrial DNA maintenance disorder caused by biallelic pathogenic variants in TK2. Recognition of childhood, juvenile, and adult-onset presentations has broadened the clinical spectrum and highlights the need to consider TK2 deficiency beyond the classic infantile phenotype.
A major advance has been the regulatory approval of doxecitine/doxribtimine, an oral deoxypyrimidine substrate enhancement therapy intended to support mtDNA replication in TK2 deficiency. It is the first disease-specific treatment approved for genetically confirmed TK2 deficiency in patients with symptom onset at or before 12 years of age.
Recent natural history and treatment studies have strengthened the evidence base for TK2 deficiency and demonstrated clinically meaningful benefits of pyrimidine nucleos(t)ide therapy. Long-term observational data also suggest sustained benefit in later-onset phenotypes, although these observations extend beyond the current approved indication.
Despite growing awareness of the disease, diagnostic approaches remain heterogeneous across neuromuscular practice. Variability in the inclusion of TK2 in neuromuscular gene panels and in the evaluation of unresolved myopathies indicates an ongoing need for harmonized molecular testing and earlier recognition.
As targeted therapy becomes available, timely molecular diagnosis of TK2 deficiency across paediatric and adult presentations will be increasingly important for optimizing patient care.
Key Points:
- Recognition of the phenotypic spectrum of TK2 deficiency has expanded beyond severe infantile disease to include juvenile, and adult-onset presentations.
- Doxecitine/doxribtimine is the first disease-specific therapy approved for genetically confirmed TK2 deficiency in patients with symptom onset at or before 12 years of age.
- Recent natural history and treatment studies strengthen the evidence base for TK2 deficiency and reinforce the importance of timely molecular diagnosis in clinical practice.
References:
- Domínguez-González C et al. Disease burden of untreated thymidine kinase 2 deficiency: insights from a large patient dataset. Brain Commun. 2026 Jun 3;8(3):fcag200. doi: 10.1093/braincomms/fcag200.
- Hirano M et al. Efficacy and safety of pyrimidine nucleos(t)ide therapy in thymidine kinase 2 deficiency. Brain Commun. 2026 Jun 3;8(3):fcag201. doi: 10.1093/braincomms/fcag201
- Mancuso M, Lamperti C, Musumeci O. National diagnostic gaps for TK2 Deficiency in Italy: insights from the AIM Multicenter Survey. Acta Myol. 2025 Sep;44(3):93-95. doi: 10.36185/2532-1900-1424.
Publish on behalf of the Scientific Panel on Neurogenetics