DPYS encodes dihydropyrimidinase (DHP), a zinc-containing hydrolase that catalyzes the second step of pyrimidine catabolism by reversibly opening the pyrimidine ring 1. DHP converts dihydrouracil to N-carbamyl-alanine and dihydrothymine to N-carbamyl-amino isobutyrate, acting downstream of dihydropyrimidine dehydrogenase in fluoropyrimidine drug metabolism 2. Functionally, DHP operates as an oligomeric complex, with variants affecting enzymatic activity through reduced expression, proteasomal degradation, or impaired oligomerization 1. DPYS variants significantly influence fluoropyrimidine chemotherapy toxicity; rare loss-of-function mutations confer approximately fourfold increased risk of severe cumulative toxicity, and the rare variant burden in DPYS is emerging as a pharmacogenetic marker for precision dosing 3. However, common DPYS polymorphisms show population-dependent predictive value, with limited association observed in Canadian cohorts 4. Clinical disease associations include dihydropyrimidinase deficiency, an inborn error of pyrimidine metabolism presenting with variable phenotypes from asymptomatic to neurological manifestations 5. Recently, DPYS mutations have been identified as a novel cause of juvenile levodopa-responsive parkinsonism, expanding the recognized neurological complications of dihydropyrimidinase deficiency 6.