Thymidine kinase 2 defects can cause multi-tissue mtDNA depletion syndrome.

Mitochondrial DNA depletion syndrome (MDS) is a severe recessively inherited disease of childhood. It manifests most often in infancy, is rapidly progressive and leads to early death. MDS is caused by an increasing number of nuclear genes leading to multisystemic or tissue-specific decrease in mitochondrial DNA (mtDNA) copy number. Thymidine kinase 2 (TK2) has been reported to cause a myopathic form of MDS. We report here the clinical, autopsy and molecular genetic findings of rapidly progressive fatal infantile mitochondrial syndrome. All of our seven patients had rapidly progressive myopathy/encephalomyopathy, leading to respiratory failure within the first 3 years of life, with high creatine kinase values and dystrophic changes in the muscle with cytochrome c oxidase-negative fibres. In addition, two patients also had terminal-phase seizures, one had epilepsia partialis continua and one had cortical laminar necrosis. We identified two different homozygous or compound heterozygous mutations in the TK2 gene in all the patients: c.739 C s -> T and c.898 C -> T, leading to p.R172W and p.R225W changes at conserved protein sites. R172W mutation led to myopathy or encephalomyopathy with the onset during the first months of life, and was associated with severe mtDNA depletion in the muscle, brain and liver. Homozygosity for R225W mutation manifested during the second year of life as a myopathy, and showed muscle-specific mtDNA depletion. Both mutations originated from single ancient founders, with Finnish origin and enrichment for the new R172W mutation, and possibly Scandinavian ancestral origin for the R225W. We conclude that TK2 mutations may manifest as infantile-onset fatal myopathy with dystrophic features, but should be considered also in infantile progressive encephalomyopathy with wide-spread mtDNA depletion.