Autosomal recessive mutations in the thymidine kinase 2 gene (TK2) cause mitochondrial DNA depletion and/or multiple deletions due to loss of TK2 enzyme activity and unbalanced deoxynucleotide triphosphate (dNTP) pools. To bypass Tk2 deficiency, Dr. Michio Hirano’s group administered deoxycytidine and deoxythymidine monophosphates (dCMP+dTMP) to the Tk2?/? knock-in mouse model from postnatal day 4, when mutant mice are phenotypically normal, but biochemically affected. Treated mice showed raised dTTP concentrations, increased levels of mtDNA, amelioration of mitochondrial respiratory chain enzyme activities, and significantly prolong their lifespan (34 days with treatment versus 13 days untreated). A second trial of dCMP+dTMP each at 400 mg/kg/day showed even greater phenotypic and biochemical improvements. In conclusion, dCMP/dTMP supplementation is the first effective pharmacologic treatment for Tk2 deficiency.
Posted by Nicola Brunetti-Pierri, MD