Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-->A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity. We evaluated the importance of DPD deficiency, gender and the presence of the IVS14؉1G>A mutation in the etiology of 5-FU toxicity. In 61% of cases, decreased DPD activity could be detected in peripheral blood mononuclear cells. Furthermore, the number of females (65%) in the total group of patients appeared to be higher than the number of males (35%) (p ‫؍‬ 0.03). Patients with partial DPD deficiency appeared to have a 3.4-fold higher risk of developing grade IV neutropenia than patients with normal DPD activity. Analysis of the DPYD gene of patients suffering from grade IV neutropenia for the presence of the IVS14؉1G>A mutation showed that 50% of the patients investigated were heterozygous or homozygous for the IVS14؉1G>A mutation. Adopting a threshold level for DPD activity of 70% of that observed in the normal population, 14% of the population is prone to the development of severe 5-FU-associated toxicity. Below this threshold level, 90% of individuals heterozygous for a mutation in the DPYD gene can be identified. Considering the common use of 5-FU in the treatment of cancer, the severe 5-FU-related toxicities in patients with low DPD activity and the apparently high prevalence of the IVS14؉1G>A mutation, screening of patients at risk before administration of 5-FU is warranted. © 2002 Wiley-Liss, Inc.Key words: dihydropyrimidine dehydrogenase; pharmacogenetics; 5-fluorouracil; neutropenia 5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents for the systemic treatment of cancers arising from the gastrointestinal tract, breast, and head and neck. Due to the limited efficacy of 5-FU as a single drug, optimal administration schedules as well as combinations with other drugs have been investigated. 1,2 Long-term continuous i.v. infusion of 5-FU is superior to bolus injections in terms of response rate; however, only a small increase in median survival was observed. 1,2 To mimic the infusion schedules of 5-FU, prodrugs of 5-FU have been developed, which can be administered orally. In this respect, capecitabine has shown promising results in patients with advanced colorectal cancer and metastatic breast cancer. 3,4 Owing to the fact that 5-FU has a relatively narrow therapeutic index, toxicity increases as the dose is increased, resulting in escalated plasma levels of the drug. 5,6 Irrespective of the administration schedule of 5-FU or prodrugs thereof, 5-FU must first be metabolized to the nucleotide level to exert its cytotoxicity.An important determinant in predicting the toxicity as well as the efficacy of 5-FU might be the activity of dihydropyrimidine dehydrogenase (DPD). DPD is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases uracil and thymine but also of the thymine analogue 5-FU. It has been report...