Clinical and Biochemical Aspects of Dihydropyrimidinase Deficiency

Abstract

Dihydropyrimidinase (DHP, EC 3.5.2.2) catalyzes the second step in the degradation of uracil and thymine. The first step is catalyzed by dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2), the third step by β-ureidopropionase (UP, EC 3.5.1.6) and the fourth step is catalyzed by three transaminases (R)-(−)-β-aminoisobutyrate pyruvate aminotransferase (BAIBPAT, EC 2.6.1.40), β-alanine-pyruvate aminotransferase (BAPAT, EC 2.6.1.18) and β-alanine-α-ketoglutarate aminotransferase (BAKAT, EC 2.6.1.19). The first three steps of the catabolism of uracil and thymine are controlled by enzymes shared by both pathways and result in the production of the neurotransmitter acid β-alanine from uracil and the nonfunctional (R)-β-aminoisobutyrate from thymine. The thymine analogue 5-fluorouracil is degraded by the same pathway to fluoro-β-alanine. In contrast to DPD deficiency of which 50 cases have been reported^1,2 only six cases have been described with DHP deficiency and none with UP deficiency,^3–9 although secondary UP deficiency has been reported in patients with propionic acidemia.¹⁰ The reason for this difference may be a lesser frequency of DHP compared to DPD deficient individuals, but another possibility may be that patients with DHP deficiency are overlooked. Therefore, we will focus on the clinical presentation and biochemical detection of patients with DHP deficiency.