Bi-allelic DPYD, TK2, and TYMP variants that participate in the de novo synthesis pathway have been reported in individuals manifesting the neuro-gastrointestinal and skeletal-muscle aging disorder dihydropyramidine dehydrogenase deficiency (DYD [MIM: 274270]) and mitochondrial DNA depletion syndrome types 1 and 2 (MTDPS1 and 2 [MIM: 609560; MIM: 603041]).50, 51, 52. Here, TK2 is linked to mitochondrial DNA depletion syndrome 1.