Evolving care in TK2d management

How does phenotypic variability in TK2d contribute to misdiagnosis and diagnostic delay?

Phenotypic variability in TK2d ranges from rapidly progressive infantile-onset disease to more slowly progressive childhood and adult-onset forms.^1,8 This heterogeneity, combined with nonspecific symptoms, often leads to misclassification as other neuromuscular disorders and contributes to diagnostic delay.^1,8,9 Early manifestations may mimic broader myopathic or respiratory conditions, further complicating timely identification.^1,8,9

Which diagnostic strategies can help differentiate TK2d from other neuromuscular disorders?

Diagnostic challenges in TK2d stem from inconsistent use of testing strategies.^1,2,8 Applying standardized approaches may improve disease recognition. This includes:

• Early consideration of TK2d in people with unexplained progressive myopathy^5,8
• Genetic testing for definitive confirmation^2,9
• The use of appropriate molecular or mitochondrial analyses^2,9
• The use of MRI patterns in late-onset disease⁴

Incorporating these evaluations into routine practice can reduce delays associated with nonspecific or overlapping features.

What is the mechanism of action of oral pyrimidine nucleoside treatment in TK2d?

The mechanism of action of oral pyrimidine nucleoside treatment in TK2d involves the administration of deoxycytidine (dC) and deoxythymidine (dT), which:¹⁰

• Bypass defective TK2
• Support mitochondrial DNA (mtDNA) replication
• Improve cellular energy production

What clinical evidence supports the efficacy and safety of deoxycytidine and deoxythymidine treatment in TK2d?

Evidence supporting the efficacy and safety of dC/dT treatment in TK2d comes from a phase 2 trial (NCT03845712), retrospective chart reviews, and an expanded access program.¹¹ Pooled analyses have demonstrated reduced mortality risk among pediatric-onset patients treated with dC/dT.¹¹

Treatment is generally well tolerated, with reported adverse events including elevated liver enzymes and gastrointestinal symptoms, highlighting the need for baseline and ongoing monitoring.¹¹

How does having a disease-modifying treatment change how we identify patients with TK2d?

Having a disease-modifying treatment available may change how clinicians approach identifying patients with TK2d, because earlier diagnosis can allow treatment to start sooner and may improve outcomes. As a result, clinical focus shifts toward:^1,8,9

• Prompt diagnosis
• Systematic assessment of suspected cases
• Treatment pathways that accommodate age-related considerations and multidisciplinary monitoring

Key takeaways

• TK2d presents with wide phenotypic variability, contributing to misdiagnosis and diagnostic delays^1,2,8
• Inconsistent diagnostic approaches further complicate timely differentiation of TK2d from other neuromuscular disorders^3,4
• The application of standardized testing strategies can reduce delays associated with nonspecific or overlapping features^1,2,8
• Oral pyrimidine nucleoside treatment aims to bypass defective TK2 by providing dC and dT to support mtDNA maintenance¹⁰
• The availability of disease-modifying treatment increases the importance of early recognition and systematic evaluation¹⁰

References

1. Domínguez-González, 2021. Collaborative model for diagnosis and treatment of very rare diseases: Experience in Spain with thymidine kinase 2 deficiency. https://www.doi.org/10.1186/s13023-021-02030-w
2. Procaccio V, 2021. Assessment of the thymidine kinase 2 deficiency (TK2d) diagnostic and care pathways—rationale for a modified-Delphi survey consensus panel. https://doi.org/10.1002/jimd.12458
3. Berardo, 2022. Advances in thymidine kinase 2 deficiency: Clinical aspects, translational progress, and emerging therapies. https://www.doi.org/10.3233/jnd-210786
4. Domínguez-González, 2022. Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis. https://www.doi.org/10.1007/s00415-021-10957-0
5. Garone, 2018. Retrospective natural history of thymidine kinase 2 deficiency. https://www.doi.org/10.1136/jmedgenet-2017-105012 
6. Domínguez-González, 2019. Late-onset thymidine kinase 2 deficiency: A review of 18 cases. https://www.doi.org/10.1186/s13023-019-1071-z
7. Amtmann, 2023. The impact of TK2 deficiency syndrome and its treatment by nucleoside therapy on quality of life. https://www.doi.org/10.1016/j.mito.2022.10.003
8. Mancuso, 2025. National diagnostic gaps for TK2 deficiency in Italy: Insights from the AIM Multicenter Survey. https://www.doi.org/10.36185/2532-1900-1424
9. Hinojosa, 2023. Diagnostic testing in suspected primary mitochondrial myopathy. https://www.mdpi.com/2813-0413/2/1/7
10. Domínguez-González, 2025. Pyrimidine nucleos(t)ide therapy in patients with thymidine kinase 2 deficiency: A multicenter retrospective chart review study. https://www.doi.org/10.1212/wnl.0000000000213908
11. 2025. FDA approves doxecitine and doxribtimine combination therapy as first treatment for thymidine kinase 2 deficiency. https://www.neurologylive.com/view/fda-approves-doxecitine-doxribtimine-combination-therapy-first-treatment-thymidine-kinase-2-deficiency

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