Thymidine kinase 2 deficiency

Thymidine kinase 2 deficiency (TK2 deficiency, TK2D) is a rare, genetic mitochondrial myopathy (MDDS - mitochondrial DNA depletion syndrome) caused by mutations in the TK2 gene. It leads to impaired mitochondrial DNA replication, which results in a loss of function of the affected tissue - especially skeletal muscle.

Causes and genetics

An autosomal recessive mutation in the TK2 gene, which codes for the mitochondrial enzyme thymidine kinase 2, is responsible. This enzyme is essential for mitochondrial DNA synthesis. A deficiency in TK2 leads to a decrease in mitochondrial DNA with consecutive loss of function of the body cells - especially in energy-intensive tissues such as skeletal muscles.

Subtypes

The disease can be clinically divided into three main forms:

• Early childhood form (infantile onset): Most severe form of TK2D with manifestation before 1 year of age; usually with rapid disease progression, respiratory failure and high mortality within the first few years of life. Some infants also develop encephalopathy.
• Infantile form (childhood onset): Occurs at preschool or school age; often with progressive weakness, loss of motor skills and respiratory complications. The course of the disease is slower than in the early childhood form, but most children are dependent on a wheelchair before the age of 10. Life expectancy varies, but many sufferers only reach adolescence due to respiratory failure.
• Adult form (late onset): Onset in early adolescence or adulthood (after the age of 12) with slowly progressive muscle weakness. Symptoms increase over time, but most sufferers do not completely lose their ability to walk. However, many are dependent on walking aids. Life expectancy is usually around 20 to 30 years after the onset of symptoms, with respiratory failure being the most common cause of death.

Prognosis

The prognosis depends largely on the age at the onset of the disease. Early childhood courses are usually severe and associated with a significantly reduced life expectancy. Late manifestations show a slower progression, often with mobility retained for decades.