Genetic disorder with a high phenotypic variability ranging from asymptomatic to developmental delay and seizures. There is an increased life-threatening toxicity when the patient receives 5-fluorouracil, a chemotherapeutic agent for the treatment of cancer.
Only approximately 50 cases have been described, with the majority reported from the Netherlands. Whether the prevalence is higher in the Netherlands, or whether this finding is related only to a more extensive screening program, is not clear. The incidence is estimated at 1:10,000 live births in Japan. It is suspected that women are more at risk than men. There is some evidence that it is more common among African-Americans than it is reported for Caucasians. More recent investigations have suggested that approximately 8% of the population is affected with at least a partial dihydropyrimidine dehydrogenase (DPD) deficiency.
Autosomal recessive transmission. The defect has been mapped to chromosome 1p22. This enzyme deficiency causes alterations in the metabolism of uracil (one of the four nucleobases that forms the nucleic acid of the RNA), and thymine (one of the four nucleobases that forms the nucleic acid of the DNA). Laboratory screening for genetic polymorphisms affecting the DPYD gene usually identify less than 5% of patients bearing critical mutations, whereas functional studies suggest that up to 20% of patients could actually have various levels of DPD deficiency.
The rate-limiting step in the degradation of uracil and thymine is catalyzed by the nicotinamide adenine dinucleotide phosphate (NADPH)-dependent enzyme dihydropyrimidine dehydrogenase (DPD) and results in the formation of 5,6-dihydrouracil and 5,6-dihydrothymine, respectively (also dihydropyrimidinuria). Although this enzyme is found in many organs throughout the body, the highest concentrations are found in the liver and leukocytes (monocytes and lymphocytes). Increased toxicity (neurotoxicity more pronounced than cardiotoxicity) has been reported for 5-fluorouracil (5-FU) administered in regular doses to these patients. Covalent binding of a metabolite of 5-FU to thymidylate synthase (the enzyme catalyzing the conversion of deoxyuridine monophosphate [dUMP] to deoxythymidine monophosphate [dTMP]) results in an enzymatic complex that stops the formation of thymidylate from uracil, thereby interfering with DNA synthesis. Approximately 80% of the administered 5-FU dose is metabolized by DPD.
High urinary concentrations of uracil and thymine and low concentrations of N-carbamyl-β-alanine and N-carbamyl-β-aminoisobutyric acid (because of a lack of 5,6-dihydrouracil and 5,6-dihydrothymine, respectively) are usually the first findings in the search for an inborn error of metabolism in these patients. The diagnosis is finally confirmed by measuring DPD activity in liver cells, fibroblasts, or leukocytes.
The range of phenotypic variability is considerable. Whereas some patients are diagnosed only after they undergo 5-FU therapy, which resulted in increased toxicity, others (approximately 50%) present with seizures ...