tk2

TK2, or thymidine kinase 2, is a mitochondrial enzyme encoded by the TK2 gene on chromosome 16q22.1. It phosphorylates certain deoxyribonucleosides, notably thymidine and deoxycytidine, within the mitochondria. This activity supplies deoxyribonucleotide triphosphates needed for mitochondrial DNA replication and repair, supporting mitochondrial DNA maintenance especially in postmitotic tissues such as skeletal muscle.

The TK2 gene is expressed in a variety of tissues, with notable activity in muscle, heart, and brain. Pathogenic variants in TK2 reduce or abolish enzyme activity, leading to mitochondrial DNA depletion syndrome (MDDS). The resulting mtDNA instability causes deficiencies in mitochondrial function that primarily affect muscle and other high-energy-demand tissues.

Clinically, TK2-related MDDS presents on a spectrum. Infantile-onset myopathy is common, characterized by hypotonia, proximal muscle weakness, respiratory failure, feeding difficulties, and elevated lactate. Other individuals may present later in childhood or adulthood with progressive myopathy, ptosis, or scapular winging. The disorder is typically caused by biallelic TK2 variants, and tissue testing often shows reduced mtDNA copy number.

Diagnosis combines clinical assessment with genetic testing confirming bi-allelic TK2 mutations. Muscle biopsy can reveal mtDNA depletion and characteristic histology such as ragged-red fibers; biochemical testing may show impaired oxidative phosphorylation.

There is no approved disease-modifying therapy for TK2-related MDDS. Management is supportive, including physical and respiratory therapy. Experimental approaches, such as oral deoxynucleoside therapy (deoxycytidine and deoxythymidine), have been reported in individual cases to raise mtDNA content and stabilize or improve function, but data are limited. Research continues into therapies such as gene-based strategies. Prognosis varies with age of onset and severity.