Patient Perspectives on Living with an Ultra-Rare Mitochondrial Disease: Thymidine Kinase 2 Deficiency (TK2d)


Sponsored by Zogenix, Inc.

Real-world evidence and patient perspectives provide clarity and describe the impact of the disease beyond the clinical setting, especially in rare disorders that are newly characterized. An estimated 1 in 5,000 people have a mitochondrial disease;1 consequently, patient perspectives can support genotype and phenotype publications as well as demonstrate the burden of disease.

Like many mitochondrial disorders, the true epidemiology of thymidine kinase 2 deficiency (TK2d) is unknown. Additionally, given the recent (2001) discovery of TK2d gene mutations,2 information about the progression and diagnostic pathways of TK2d is emerging.

About TK2d

TK2d is a mitochondrial disease caused by mutations in the TK2d gene. Patients with TK2d, especially children, typically experience severe proximal myopathy that is associated with subsequent loss of motor milestones and respiratory insufficiency.3-7 Rapid progression may lead to premature death and loss of functional independence.

Because myopathic symptoms can mimic other genetic conditions (such as muscular dystrophy, Pompe disease, Spinal Muscular Atrophy, and mtDNA depletion syndromes),7 TK2d is likely under-recognized and/or misdiagnosed. The most efficient and effective means to a TK2d diagnosis is genetic testing.

Patient voices and caregiver perspectives provided by individuals and families with TK2d offer invaluable insights into the day-to-day challenges and related symptom experiences of this ultra-rare disease.

Patient Perspectives

In an effort to understand the real-world impact of TK2d, Zogenix funded a patient listening project focused in the U.S. and Mexico, that was recently presented at the National Organization for Rare Disorders (NORD) Breakthrough Summit 2021 and Mitochondrial Medicine 2021.

FIGURE. Qualitative Themes Used by Patients and Caregivers.

FIGURE. Qualitative Themes Used by Patients and Caregivers.

Eight affected individuals (2 children and 6 adults) and their caregivers were asked to share perspectives on living and managing TK2d in an informal dialogue. Qualitative methods and an exploratory listening approach allowed patient voices to be captured.

Subsequent qualitative analysis revealed that, irrespective of the age at TK2d symptom onset, current patient age, or degree of symptom severity, all patients (n=8) experienced common elements such as muscle weakness, fatigue, and mild or severe respiratory impairment.

In the study, the patients self-identified severe muscle weakness as the root cause of all symptoms, and noted the impact of that muscle weakness on their daily lives, especially to their head, neck and core. Caregivers provided examples of how motor milestone losses (related to muscle weakness) became evident at an early age. One caregiver explained, “He was a normal baby, then he started falling down a lot, walking funny, and struggling to stand up.”

Severe proximal myopathy is the root cause of most symptoms, including impaired respiratory function, difficulty eating, and generalized weakness, which resulted in relying on assistive devices, including wheelchairs, ventilators, and feeding tubes.3 One caregiver said, "By three and a half years, he was using a power wheelchair, and was 24/7 vent-dependent."

All patients in the study (100%) required some assistance in activities of daily living and relied on other assistive devices, most frequently the use of a wheelchair and ventilator. Most of the patients in the study needed invasive or non-invasive ventilator support. One caregiver said, "His body finally seemed to relax once we placed the breathing tube.”

Early-onset patients (under the age of 12 at the onset of symptoms) were most likely to require immediate respiratory intervention. Most adults experienced slower impacts to their ability to breathe and eat, but still required modified diets, tube feeding, use of CPAP or BiPAP, and some required 24-hour mechanical ventilation.

Long hospitalizations and ongoing home health support, including respiratory therapy, physical therapy, speech therapy, and feeding therapy, characterized the experience of early-onset patients while late-onset (teen/adult) patients were more likely to rely on their neurologist, pulmonologist, and primary care physician as their primary providers. Currently, supportive treatment is the standard of care, although a potential therapy for the treatment of TK2d is under investigation by Zogenix, Inc.

Overall, patient and caregiver perspectives demonstrated that TK2d patients live in an energy-conservation mode to survive. As one patient shared, “I cannot eat and talk and breathe at the same time. I cannot walk and breathe at the same time. So, I will only do one thing at a time so I can stay alive.” The voices amplified by the participants in this project underscored the resilience necessary to live with a rare and devastating disease like TK2d.

Importance of early genetic testing

The journey to diagnosis continues to be challenging for patients with mitochondrial disorders8 despite advances in access to and reduction in costs of genetic testing.

Patients and caregivers interviewed were most likely to undergo a long (3 weeks to 25 years) period of evaluation before their referring neurologist or primary care physician requested specific genetic testing. Due to the debilitating nature of mitochondrial disease and its myriad and complex symptom presentation, genetic testing is essential to diagnosing patients.

While whole-exome sequencing is becoming the new gold standard, a broad panel can also test for a range of diseases and may be more useful than a single-gene test that can only detect diseases affecting that specific gene. Common genetic tests used for diagnosing mitochondrial diseases include:

  • Whole-exome sequencing/Whole-genome sequencing (NGS: Next-generation sequencing)7,9,10
  • mtDNA genome sequencing (NGS)9
  • Multi-gene panel testing7,11
  • Single-gene testing9

In closing, providing mechanisms to listen to the voices of TK2d patients and caregivers can be empowering to those affected. As one caregiver put it, “I feel so thankful knowing someone out there cares about this rare disease.” By listening in an open-ended format, themes emerge that not only advance knowledge about TK2d, but further demonstrate the unmet need in this ultra-rare disease patient population.

For more information on recognizing mitochondrial disease, visit; for more information about TK2d, visit



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10. Theunissen TEJ, Nguyen M, Kamps R, et al. Whole Exome Sequencing Is the Preferred Strategy to Identify the Genetic Defect in Patients With a Probable or Possible Mitochondrial Cause. Front Genet. 2018;9:400. Published 2018 Oct 12.
11. Data on file. Zogenix.
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