COMBINED DEFICIENCIES OF NADPH-DEPENDENT AND NADH-DEPENDENT DIHYDROPYRIMIDINE DEHYDROGENASES, A NEW FINDING IN A FAMILY WITH THYMINE-URACILURIA

Dihydropyrimidine dehydrogenase (DHPD, EC 1.3.1.2) catalyses the first step of pyrimidine degradation. Patients suffering from a deficiency of this enzyme present with thymine-uraciluria, which is used for their detection (Van Gennip et al 1993). Clinical symptomatology is not very characteristic. The most frequently occurring symptoms appear to be convulsions and mental retardation, and accordingly most patients were detected by analysis of urinary pyrimidines within a framework of metabolite screening because of a suspected inborn error (Van Gennip et al 1994). The other patients were diagnosed after presenting with neurotoxic symptoms during treatment of their malignancies with 5-fluorouracil (5-FU), which is catabolized via the same pathway as uracil (Diasio et al 1988). The mode of inheritance of DHPD deficiency is autosomal recessive. The gene frequency is not known but, based on the Dutch experience (13 patients within a decade), must be rather high. This observation together with the frequent use of 5-FU in chemotherapeutic drug regimens contribute significantly to the clinical relevance of the defect. DHPD activity can be measured in many cells and tissues, such as lymphocytes, monocytes, fibroblasts and liver. The DHPD enzyme in human tissues is known to be dependent on NADH as a co-substrate. However, we discovered recently that NADH-dependent activity can also be measured in human liver, fibroblasts and leukocytes (Van Kuilenburg et al, unpublished). It is not known whether the deficiency of the enzyme is equally expressed in the tissues mentioned and whether both the NADPH-dependent and NADH-dependent activities of DHPD are involved. Carrier detection of DHPD deficiency by analysis of enzyme activity in leukocytes and fibroblasts seems not to be reliable. However, the enzyme activity shows a circadian rhythm and this may have contributed to the overlapping results of measurements in carriers and non-carriers. We investigated the activity of DHPD in leukocytes and fibroblasts of a patient with thymine-uraciluria and of his family members. We speculated whether the expression of DHPD was comparable in both tissues using NADPH or NADH as co-substrate and whether the reliability of carrier detection could be improved by taking circadian variation into consideration.