Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency

Bakkeren, J. A. J. M.; Abreu, Ronney A. De; Sengers, R. C. A.; Gabreëls, F.J.M.; Maas, J.; Renier, W.O.

doi:10.1016/0009-8981(84)90206-7

Cited by 97 publications

(40 citation statements)

References 9 publications

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“…This variability, which is partially attributed to genetic defects of the DPD gene (DPYD), leads to differential responses of cancer patients, resistance to or increased toxicity of 5-FU (van Kuilenburg 2004). Complete DPD deficiency is also associated with the inherited metabolic disorder, thymine-uraciluria, which is characterized by neurological problems in pediatric patients (Bakkeren et al 1984).…”

Section: Introductionmentioning

confidence: 99%

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

et al. 2007

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Dihydropyrimidine dehydrogenase (DPD) is an inactivating and rate-limiting enzyme for 5-fluorouracil (5-FU), and its deficiency is associated with a risk for developing a severe or fatal toxicity to 5-FU. In this study, to search for genetic variations of DPYD encoding DPD in Japanese, the putative promoter region, all exons, and flanking introns of DPYD were sequenced from 341 subjects including cancer patients treated with 5-FU. Fifty-five genetic variations, including 38 novel ones, were found and consisted of 4 in the 5 0 -flanking region, 21 (5 synonymous and 16 nonsynonymous) in the coding exons, and 30 in the introns.

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Section: Introductionmentioning

confidence: 99%

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

et al. 2007

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“…Since 70-80% of the administered 5-FU is degraded in vivo by DPD to fluorinated ␤ -alanine (3), the level of DPD activity is a major determinant in the toxicity of 5-FU. DPD deficiency was first described in pediatric patients exhibiting thymine-uraciluria, which is associated with a variety of symptoms including convulsive disorders (epilepsy), microcephaly, and mental retardation (4)(5)(6)(7). Since the first report of an adult cancer patient that under 5-FU chemotherapy developed severe toxicity and had low DPD activity (8), additional cases of DPD deficiency have been reported (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.

Wei¹,

McLeod²,

McMURROUGH³

et al. 1996

J. Clin. Invest.

325

168

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Dihydropyrimidine dehydrogenase (DPD) deficiency constitutes an inborn error in pyrimidine metabolism associated with thymine-uraciluria in pediatric patients and an increased risk of toxicity in cancer patients receiving 5-fluorouracil (5-FU) treatment. The molecular basis for DPD deficiency in a British family having a cancer patient that exhibited grade IV toxicity 10 d after 5-FU treatment was analyzed. A 165-bp deletion spanning a complete exon of the DPYD gene was found in some members of the pedigree having low DPD catalytic activity. Direct sequencing of lymphocyte DNA from these subjects revealed the presence of a G to A point mutation at the 5 Ј -splicing site consensus sequence (GT to AT) that leads to skipping of the entire exon preceding the mutation during pre-RNA transcription and processing. A PCR-based diagnostic method was developed to determine that the mutation is found in Caucasian and Asian populations. This mutation was also detected in a Dutch patient with thymine-uraciluria and completely lacking DPD activity. A genotyping test for the G to A splicing point mutation could be useful in predicting cancer patients prone to toxicity upon administration of potentially toxic 5-FU and for genetic screening of heterozygous carriers and homozygous deficient subjects. ( J. Clin. Invest. 1996. 98:610-615.)

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“…Epileptic or convulsive attacks were reported in more than half of the cases with a near complete deficiency of DPD (Van Gennip et al 1981a, 1987aBakkeren et al 1984;Berger et al 1984;Wilcken et al 1985;Braakhekke et al 1987;Brockstedt et al 1990); in three out of the four patients with DHP deficiency (Duran et al 1990;Henderson et al 1993;Ohba et al 1994;Van Gennip et al 1997); in the one patient with presumed BAKAT deficiency (Scriver et al 1966); and in the patient with a proven partial deficiency (±30% of normal activity) of BAKAT in fibroblasts (Higgins et al 1994). Both of these last two patients also had a striking lethargy.…”

Section: Clinical Aspects Of Pyrimidine Degradation Defects Symptomatmentioning

confidence: 99%

“…Two other defects of pyrimidine catabolism have been discovered more recently: inherited DPD deficiency was first proposed in 1981 in a patient with thymine-uraciluria (Van Gennip et al 1981a) and was demonstrated in 1984 (Bakkeren et al 1984); the first patient with presumed DHP deficiency as detected in 1990 (Duran et al 1990) and the enzyme defect was demonstrated in liver in 1996 . Deficiencies of BAPAT and UP have not yet been discovered in man; UP deficiency has been shown in C57B1/6 mice (Dagg et al 1964).…”

mentioning

confidence: 99%

Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

Gennip

Abeling

Vreken

et al. 1997

J of Inher Metab Disea

103

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The pyrimidines, uracil and thymine, are degraded in four steps. The first three steps of pyrimidine catabolism, controlled by enzymes shared by both pathways, result in the production of the neurotransmitter amino acid β‐alanine from uracil and the nonfunctional (R)‐(‐)‐β‐aminoisobutyrate from thymine. The fourth step is controlled by several aminotransferases, which have different affinities for β‐alanine, β‐aminoisobutyrate and GABA. Defects concerning the first three steps all lead to a reduced production of β‐alanine; defects of the transaminases involving the metabolism of β‐alanine and GABA lead to accumulation of these neurotransmitter substances. In addition, other metabolites will accumulate or be reduced depending on the specific enzyme defect. Analysis of the abnormal concentrations of these metabolites in the body fluids is essential for the detection of patients with pyrimidine degradation defects. Clinically these disorders are often overlooked because symptomatology is highly aspecific. The growth in our knowledge concerning inborn errors of pyrimidine degradation has emphasized the importance of the clinical awareness of these defects as a possible cause of neurological disease and a contraindication for treatment of cancer patients with certain pyrimidine analogues. The various defects are discussed and attention is paid to clinical, genetic and diagnostic aspects.

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Elevated urine, blood and cerebrospinal fluid levels of uracil and thymine in a child with dihydrothymine dehydrogenase deficiency

Cited by 97 publications

References 9 publications

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

Genetic variations and haplotype structures of the DPYD gene encoding dihydropyrimidine dehydrogenase in Japanese and their ethnic differences

Molecular basis of the human dihydropyrimidine dehydrogenase deficiency and 5-fluorouracil toxicity.

Inborn errors of pyrimidine degradation: Clinical, biochemical and molecular aspects

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