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Genetic disorder with a high phenotypic variability ranging from asymptomatic to developmental delay and seizures. Increased toxicity of 5-fluorouracil.

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DPD Deficiency

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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.

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Autosomal recessive transmission. The defect has been mapped to chromosome 1p22.

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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 by DPD.

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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.

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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.

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Obtain a full history of the seizures and anticonvulsant therapy (efficacy and toxicity).

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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 delay.

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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 hepatic elimination.

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Dihydropyrimidinase Deficiency: Very rare metabolic disease with a highly variable clinical expression, including seizures, mental retardation, and craniofacial anomalies.

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Hereditary Thymine-Uraciluria: Allelic variant of DPD first described by van Gennip et al. ...

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