Helping families and clinicians connect the signs that may point to TK2d

By Cristy Balcells, Global Patient Engagement Lead, Rare Diseases at UCB, and Fabian Somers, Vice President Asset Head Rare and Ultra-Rare Diseases, UCB

TK2 deficiency, or Thymidine Kinase 2 deficiency (TK2d), is an ultra-rare genetic mitochondrial disease characterised by progressive muscle weakness that can affect walking, eating and breathing.¹ It is caused by changes in the TK2 gene, which prevents the body from producing enough of an enzyme needed to keep mitochondria, the cells' energy producers, working properly. Without this enzyme, mitochondria cannot maintain their DNA effectively, leading to reduced energy production and the symptoms associated with the condition.² Because symptoms often overlap with other neuromuscular and mitochondrial disorders, diagnosis can be delayed.³

This article explores why earlier recognition, genetic testing and collaboration between families, clinicians and rare disease communities are key for improving the diagnostic journey.

A diagnosis often begins with subtle signs that something is not quite right. For families with thymidine kinase 2 deficiency (TK2d), finding an explanation for those first concerns can take time.

TK2d is ultra-rare and can present differently from person to person, with symptoms that can overlap with other neuromuscular or mitochondrial diseases. Progressive muscle weakness may affect walking, eating and breathing, making it difficult to differentiate TK2d versus other conditions in clinical practice.^1-7

As we mark TK2d Awareness Day and World Mitochondrial Disease Week, we have been thinking about what it really takes to help families find answers sooner, though we come to that question from different places. Whether the perspective is personal as a caregiver and advocate, or clinical as a leader in rare disease therapeutic development, we believe earlier recognition starts with listening to patients and caregivers as much as it does with science.

The first signs of TK2d may not form a clear clinical pattern. What we hear from the community is how hard it can be to explain small changes, like pausing more often when walking, finding the stairs more difficult to climb or noticing that everyday activities take more effort than they used to, which create a growing sense that something is wrong and often lead to appointments where each answer raises another question.⁸ These experiences are frequent and can provide important clues alongside the clinical signs that healthcare professionals (HCPs) see in front of them.⁸

We also see this uncertainty from a clinical perspective, where earlier recognition can help turn a muddled path into a clearer direction and can help healthcare professionals ask the next important question.⁵

Genetic testing can be an important turning point to achieving a diagnosis, helping put a name to what families have been living through by identifying disease-causing variants in the TK2 gene.^{5, 9-11}

Together with all the observed signs and changes, they point to the same need to bring TK2d into the conversation earlier when symptoms suggest a mitochondrial or neuromuscular disorder. This is especially important in an ultra-rare disease like TK2d, where diagnosis is inherently challenging.¹ Clinician education is important, coupling clinical features and triggers that prompt further evaluation and genetic testing alongside the real-world experience and voices of those living with the disease.

People living with TK2d, caregivers, advocacy groups, clinicians, researchers and industry partners all have a role in shortening the path to diagnosis and ensuring TK2d is considered when the clinical pattern fits. A consultation can only capture a snapshot of what someone is experiencing. Families, however, see how symptoms show up and change in everyday life, whether it’s changes in mobility or energy or the impact on activities that may once have felt routine.

Through our conversations with rare disease communities, we have seen how important it is to acknowledge these experiences as valuable context to enhance the clinical picture.

Beyond the progressive physical impact, TK2d has a significant impact on people’s mood, social and working lives, leaving them to feel disconnected.⁸ Furthermore, the emotional weight caused by waiting for an answer adds to the complexity and challenge of the journey. Putting a name to the condition they’ve been managing can help families make sense of symptoms and have more meaningful conversations with healthcare teams.

These discussions can also help HCPs as, when they understand the medical features and lived experience behind them, they are better placed to recognise when testing may be appropriate and how to provide support. While unrealistic to assume that all healthcare providers have in-depth awareness of all ultra-rare and rare conditions, clinical awareness of the signs and symptoms associated with rare neuromuscular disorders helps to raise suspicion and accelerates the path to a confirmed genetic diagnosis.

Bringing TK2d into the diagnostic conversation is more than identifying a rare condition. It is about seeing the people behind the symptoms and helping HCPs recognise when it may be time to go deeper. When lived experience and clinical knowledge come together, awareness becomes more useful for everyone involved. It can help families feel heard, and clinicians consider the right next steps sooner, moving people closer to the answers they need.

1.The Lilly Foundation. Thymidine Kinase 2 Deficiency (TK2d). Available at: https://www.thelilyfoundation.org.uk/affected-by-mito/all-about-mito/thymidine-kinase-2-deficiency-tk2d/ Last accessed: September 2026 

2.National Institute of Health. TK2-related mitochondrial DNA depletion syndrome, myopathic form. https://medlineplus.gov/genetics/condition/tk2-related-mitochondrial-dna-depletion-syndrome-myopathic-form/ Last accessed: September 2026 

3.Cleveland Clinic. Mitochondrial Diseases. https://my.clevelandclinic.org/health/diseases/15612-mitochondrial-diseases Last accessed: September 2026 

4.Garone C, et al. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018;55(8):515-21. 

5.Wang J, et al. TK2-Related Mitochondrial DNA Maintenance Defect, Myopathic Form. 2018. In: Adam MP, et al., Seattle: University of Washington, Seattle; 1993-2022. https://www.ncbi.nlm.nih.gov/books/NBK114628/. Accessed August 2026. 

6.Berardo A, et al. Advances in Thymidine Kinase 2 Deficiency: Clinical Aspects, Translational Progress, and Emerging Therapies. J Neuromuscul Dis. 2022;9(2):225-235. 

7.Domínguez-González C, et al. Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis. 2019;14(1):100. 

8.Karaa A, et al. Patients’ lived experience of thymidine kinase 2 deficiency: the online survey-based assessment of TK2d patient perspectives study. Ther. Adv. Rare Dis. 2026;7. 

9.Parikh S, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689–701. 

10.de Barcelos IP, Emmanuele V, Hirano M. Advances in primary mitochondrial myopathies (PMM). Curr Opin Neurol. 2019;32(5):715-721. 

11.Dominguez-Gonzalez C et al. Muscle MRI characteristic pattern for late-onset TK2 deficiency diagnosis. J Neurol. 2022;269:3550–3562.

Last updated: September 2026

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