Genetic disorder with a high phenotypic variability
ranging from asymptomatic to developmental delay and seizures. Increased
toxicity of 5-fluorouracil.
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 is finding is related only to a more
extensive screening program, is not clear; 1:10,000 live births in Japan has been suggested.
Autosomal recessive transmission. The defect
has been mapped to chromosome 1p22.
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 desoxy-uridine monophosphate [dUMP] to
desoxy-thymidine monophosphate [dTMP]) results in a complex that blocks the
formation of thymidylate from uracil, thereby interfering with DNA
synthesis. Approximately 80% of the administered 5-FU dose is metabolized
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
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 and delayed psychomotor development, usually
starting in the first years of life. Other signs are less frequent and may
include growth retardation, microcephaly, and other forms of dysmorphism.
Obtain a full history of the
seizures and anticonvulsant therapy (efficacy and toxicity).
No literature available about this
disorder in association with anesthesia is available. No specific
anesthesia-related problems should arise. However, sedative premedication
may be helpful in the management of patients with signs of developmental
To our knowledge, increased toxicity
of 5-FU is the only, but a potentially fatal, adverse drug effect specific
to this population. Avoid potentially epileptogenic drugs in patients with a
history of seizures (e.g., methohexital, ketamine, enflurane, atracurium,
cisatracurium, meperidine). Chronic antiepileptic therapy may induce hepatic
enzymes and therefore change the metabolism of drugs with predominately
Dihydropyrimidinase Deficiency: Very rare metabolic disease with
a highly variable clinical expression, including seizures, mental
retardation, and craniofacial anomalies.
Hereditary Thymine-Uraciluria: Allelic variant of DPD first
described by van Gennip et al. ...