Dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase (DPD) deficiency is a rare inherited metabolic disorder caused by mutations in the DPYD gene, which encodes the enzyme dihydropyrimidine dehydrogenase. This enzyme is responsible for the first and rate-limiting step in the breakdown (catabolism) of the pyrimidine bases uracil and thymine. When DPD activity is absent or significantly reduced, these pyrimidines and their metabolites accumulate in the body. The condition is also known as hereditary thymine-uraciluria, familial pyrimidinemia, or DPD deficiency. The clinical presentation of DPD deficiency is highly variable. In its complete form, which typically presents in infancy or early childhood, affected individuals may exhibit neurological abnormalities including intellectual disability, seizures (epilepsy), motor delays, microcephaly, and autistic features. Hypotonia (reduced muscle tone) and growth retardation may also be observed. However, some individuals with complete DPD deficiency may remain asymptomatic. Partial DPD deficiency is much more common in the general population and often goes undetected until the individual is exposed to fluoropyrimidine chemotherapy drugs, particularly 5-fluorouracil (5-FU) or its oral prodrug capecitabine. In these patients, even standard doses of these medications can cause severe, potentially life-threatening toxicity including mucositis, neutropenia, neurotoxicity, and diarrhea, because 5-FU is also metabolized by the DPD enzyme. There is no specific curative treatment for the underlying metabolic defect. Management of the complete deficiency form is supportive and symptomatic, focusing on seizure control with antiepileptic medications, physical therapy, and developmental support. For individuals with partial deficiency, the most critical clinical intervention is pharmacogenomic screening for DPYD variants before initiating fluoropyrimidine-based chemotherapy, allowing dose reduction or selection of alternative agents to prevent severe drug toxicity. Pre-treatment DPD testing is increasingly recommended or mandated in clinical oncology guidelines.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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