Thymidine kinase 2 deficiency (TK2d) is a primary mitochondrial disease, a term that refers to a group of genetic disorders caused by dysfunctional mitochondrial function. Primary mitochondrial diseases are the most common genetic metabolic disease, having a prevalence of approximately one in 4,300 individuals.
Although they fall under the same umbrella term, each primary mitochondrial disease is unique, with great variability in their clinical and biochemical features.
Primary versus secondary mitochondrial disease
Mitochondrial diseases can be classified as either primary or secondary. Unlike primary diseases, secondary diseases are not genetic mitochondrial disorders. They can be caused by environmental or metabolic triggers, as well as genetic mutations that indirectly impact mitochondrial function.
Besides TK2d, examples of primary mitochondrial diseases include Leigh syndrome, Kearns-Sayre syndrome and mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome. Examples of secondary mitochondrial diseases include cancer, multiple sclerosis and Alzheimer’s disease.
What mutations can cause primary mitochondrial disease?
Primary mitochondrial diseases can be caused both by mutations in the nuclear DNA, where the majority of the genetic code is located, or the mitochondrial DNA, a chromosome found in mitochondria. TK2d, for example, is caused by mutations in the TK2 gene, which is found in the nuclear DNA.
Mutations in the mitochondrial DNA can only be inherited from the mother, while nuclear DNA mutations may be inherited from either parent.
Read more about TK2d causes and risk factors
Clinical features of primary mitochondrial disease
Primary mitochondrial disease can impact one or multiple organ symptoms or at any age; as such, the symptoms can vary quite significantly. However, some of the characteristic features of these diseases include:
- Muscle weakness.
- Drooping of the eyelids.
- Hearing loss.
- Seizures.
- Exercise intolerance.
- Diabetes.
- Poor coordination and balance.
In many cases, these diseases are progressive, but the rate of disease progression can vary.
Read more about TK2d signs and symptoms
Diagnosing primary mitochondrial diseases
Several diagnostic tests may be performed to confirm a diagnosis of primary mitochondrial disease. Depending on an individual’s symptoms, some tests may be more helpful than others.
Blood tests and analysis of cerebrospinal fluid may reveal elevated lactate levels. A high lactate-to-pyruvate ratio may also indicate mitochondrial disease, though it isn’t a definitive test. Increased 3-methylglutarylcarnitine levels in the blood and urine can signal errors in mitochondrial metabolism, too.
Because primary mitochondrial diseases are caused by mutations, genetic testing can confirm a diagnosis. Usually, this is done through a blood test, but specific tissues may also be tested. Genetic testing can be challenging, though, especially for patients with mutations that haven’t been previously identified.
In addition, biopsies of the muscle or other tissues can reveal changes in mitochondrial structure or enzyme activity.
Treating primary mitochondrial disease
Currently, no approved treatments exist for many primary mitochondrial diseases. However, recent decades have seen significant advances in therapeutic development for these conditions. From dietary alterations to targeted therapies, a wide variety of strategies are under exploration.
Doxecitine and doxribtimine powder, for example, received U.S. Food and Drug Administration (FDA) approval in November 2025 to treat individuals with TK2d. Although not a cure, this therapy — the first and only for TK2d — can help slow disease progression.
Sign up here to get the latest news, perspectives, and information about TK2d sent directly to your inbox. Registration is free and only takes a minute.
