TK2-Related Mitochondrial DNA Depletion Syndrome, Myopathic Form

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a genetically heterogeneous group of disorders characterized by a significant reduction of mtDNA copy number in various tissues. The clinical manifestations are protean, yet they can be divided into myopathic, hepatocerebral, encephalomyopathic, and multisystemic forms. The molecular defects of nuclear genes responsible for biogenesis and maintenance of deoxynucleotide pools are the cause of MDS. The disorders are transmitted in an autosomal recessive fashion. Currently, there are many nuclear genes in which mutations have been associated with MDS. The majority of myopathic cases of MDS are caused by mutations in TK2. TK2 encodes thymidine kinase 2, which is an enzyme catalyzing the first and rate-limiting step of phosphorylation of pyrimidine nucleosides. Affected individuals typically present with progressive proximal muscle weakness and hypotonia at a young age. The diagnosis is supported by the elevation of creatine phosphokinase (CPK). The elevation is usually 5–10 times the upper limit of normal. Electron transport chain activity in skeletal muscle shows decreased activity in multiple complexes. The mtDNA copy number in muscle tissue is severely reduced compared to age- and tissue-matched controls. The diagnosis is confirmed by molecular genetic testing of the TK2 gene. Currently, treatment of TK2-related MDS is largely supportive. Despite supportive measures, most cases will eventually develop respiratory failure and death within a few years after diagnosis.