The rare mitochondrial disease thymidine kinase 2 deficiency (TK2d) was only identified quite recently. While research continues, understanding and treatment of the disease has improved significantly in the past 25 years.
1980s: The discovery of mitochondrial pathologies
In 1988, mitochondrial pathologies were diagnosed for the first time, when one group of researchers found mitochondrial DNA (mtDNA) deletions in muscle biopsies from patients with unexplained muscle weakness, and another group identified an mtDNA gene point mutation in a family with Leber’s hereditary optic neuropathy.
2000s: The first TK2d cases identified
TK2d was first described in 2001 in an article in Nature Genetics. The article describes the cases of four children with severe myopathy who had very low levels of thymidine kinase 2 (TK2) enzymatic activity, elevated creatine kinase, multiple mitochondrial respiratory chain defects and low mtDNA copy numbers in skeletal muscle. The mutation of the TK2 gene was identified as the cause. However, very little was understood about the origins of the disease.
Over the following years, case reports and case series identified more patients with the condition, and began building an understanding that TK2d can mean varying symptoms between different patients.
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2010s: Expanding disease knowledge
In the 2010s, new research papers began to mention cases in adults as well as children. In 2018, a group of researchers reviewed 92 patient case reports and classified symptoms of varying severity, different ages of disease onset and life expectancy. Based on this review of 92 patients, three different subtypes of TK2d were determined:
- Infantile-onset.
- Childhood-onset.
- Late-onset.
Molecular genetic testing or next-generation sequencing began to be used in the diagnosis of TK2d.
New clinical studies were started and further research provided more information on disease progression. Awareness around the disease began to grow and treatment options were explored.
Advances in treatment
Initially, treatment of TK2d focused on supportive treatment to help manage symptoms, with no options to slow disease progression or reduce symptom severity.
In 2014 the first study on deoxynucleoside therapy as a possible therapy for TK2d was published; this research examined the therapy’s effect on a TK2d mouse model the study’s authors had developed, and paved the way for testing of the therapy in humans.
In 2019, the first research on the clinical benefits of deoxynucleoside therapy in patients with TK2d was reported.
Clinical studies continued, and in 2025, the first medical treatment of TK2d in adults and children was approved by the FDA. Doxecitine and doxribtimine have been shown to improve survival and stabilize or restore motor function, breathing and feeding ability.
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