Thymidine Kinase 2 deficiency (TK2d)

Thymidine Kinase 2 deficiency (TK2d) is a rare, life-threatening, genetic mitochondrial disease characterized by progressive and severe muscle weakness (myopathy), which can impact the ability to walk, eat, and breathe independently.1,2,3,4,5

Mitochondrial diseases are a group of rare, often life-threatening, genetic conditions that affect the parts of our body that need the most energy – the muscles, heart, and brain.2,3,6 
 

There are three main subtypes of TK2d 

  1. Early-onset TK2d begins before the age of 1-4 years. This subtype of TK2d rapidly progresses to death often in 1-2 years.7
  2. Childhood-onset TK2d begins between the ages of 1 and 12. Most individuals with this subtype of TK2d survive more than 13 years after the first emergence of disease symptoms.7
  3. Late-onset TK2d begins after 12 years of age. In general, individuals with this subtype of TK2d may be expected to live 23 years after disease onset.7

Impact of TK2d on people’s lives

It is challenging to accurately estimate the prevalence of TK2d as it is a relatively newly characterized disease and not widely known; however, estimates suggest a worldwide prevalence of less than one case per 1,000,000 people.1,8

The impact of TK2d is far reaching, affecting multiple health, physical, quality-of-life, and psychosocial domains.7

TK2d affects nearly all aspects of life as children do not achieve normal developmental motor milestones, or lose those already gained, and adults lose their functional independence as they develop problems with breathing, eating, and walking.9  

 

The lived experiences of Connie, Yamgur, Fanny, Jared and Doreen

Listen to the day-to-day experiences and challenges faced by Connie, Yamgur, Fanny, Jared and Doreen, all living with TK2d, and learn why there is such an urgent need to increase awareness of rare diseases like TK2d.
 

Signs and symptoms of TK2d

TK2d can present in different ways and affect different parts of the body.2,3,4

For people living with TK2d, symptoms can vary based on their disease subtype.1,3 Common signs of TK2d are weakness of limbs, difficulty swallowing and respiratory muscle weakness.2

Symptoms can differ from person to person and can present at any age from infancy up until late adulthood.2


Less frequent symptoms associated with early-onset TK2d include:1,3

Heart problems

Kidney problems

Epilepsy

Multiple bone fractures


For those living with childhood or late-onset forms of TK2d, less frequent symptoms include:1,3

Difficulty or inability to move the eye

Drooping eyelids

Respiratory difficulties

Hearing loss

Treatment and unmet need

There are currently no health-authority-approved therapies for TK2d, and treatment primarily consists of supportive care that requires the involvement of a multidisciplinary healthcare team.3,9,10  This typically consisting of a pulmonologist, neurologist, geneticist, and primary care physician along with several allied health professionals.10

As a result, there is an urgent need to bring more targeted, well-tolerated treatment options to physicians and patients.

The challenging treatment pathway

TK2d has overlapping phenotypes with many other neuromuscular and mitochondrial myopathies, which may result in people with TK2d being undiagnosed or misdiagnosed. TK2d can be misdiagnosed as other diseases including Pompe, spinal muscular atrophy (SMA) type 1 or 2, and facioscapulohumeral dystrophy.1,2,3

 



Whilst muscle biopsy and skeletal muscle MRI are diagnostic tools for TK2d, genetic testing is the gold standard to confirm a diagnosis.3,11,12,13  Not all types of genetic tests will identify a TK2 mutation though, so current literature recommends applying a broad-panel approach to arrive at the fastest diagnosis of a person who is suspected of having a mitochondrial myopathy.3,11

Using technology as part of a holistic approach to disease management

To help manage TK2d symptoms and address muscle weakness, a healthcare team may recommend medical equipment and devices, such as:3,14

 

 

UCB is committed to bringing long-term value to the lives of people living with TK2d beyond its treatment portfolio. By doing so, we hope to better serve patients and potentially improve their care.

Additional resources

The United Mitochondrial Disease Foundation (UMDF) is a network of the top clinicians, hospitals, and researchers dedicated to fighting mitochondrial disease. They’re committed to funding the best science across the world and provide critical programs to patient families. 

 

 

International Mito Patients is a network of national patient organisations involved in Mito. The national patient organisations support and advocate for patients, fund research, increase awareness and improve education in their country. 

MitoAction is a nonprofit organization founded by patients, parents, and Boston healthcare leaders who had a vision of improving quality-of-life for children and adults with mitochondrial disease. Its mission is to make a measurable impact in the lives of those who are affected by mitochondrial disease.

References
  1. 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.
  2. Garone C, et al. Retrospective natural history of thymidine kinase 2 deficiency. J Med Genet. 2018;55(8):515-21.
  3. 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 September 2024.
  4. Domínguez-González C, et al. Late-onset thymidine kinase 2 deficiency: a review of 18 cases. Orphanet J Rare Dis. 2019;14(1):100.
  5. 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/#genes. Accessed September 2024.
  6. Cleveland Clinic. Mitochondrial Diseases. https://my.clevelandclinic.org/health/diseases/15612-mitochondrial-diseases. Accessed September 2024.
  7. Amtmann D, et al. The impact of TK2 deficiency syndrome and its treatment by nucleoside therapy on quality of life. Mitochondrion. 2023;68:1-9.
  8. Orphanet. Mitochondrial DNA depletion syndrome, myopathic form. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=254875. Accessed September 2024.
  9. US FDA TK2d Patient Listening Session. Available at: https://www.umdf.org/tk2d-patient-listening-session-january-2022. Accessed September 2024.
  10. Balcells CF. 2021. NORD Breakthrough Summit 2021. 
  11. 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.
  12. de Barcelos IP, Emmanuele V, Hirano M. Advances in primary mitochondrial myopathies (PMM). Curr Opin Neurol. 2019;32(5):715-721.
  13. Dominguez-Gonzalez C et al. Muscle MRI characteristic pattern for late‑onset TK2 deficiency diagnosis. J Neurol. 2022;269:3550–3562.
  14. El-Hattab AW, Scaglia F. Mitochondrial DNA depletion syndromes: review and updates of genetic basis, manifestations, and therapeutic options. Neurotherapeutics. 2013;10(2):186-98.