Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency

Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU). A deficiency of DPD is increasingly being recognized as the cause of an important pharmacogenetic syndrome. The importance of DPD deficiency in the aetiology of unexpected severe 5FU toxicity has been demonstrated by the fact that, in 39-59% of cases, decreased DPD activity could be detected in peripheral blood mononuclear (PBM) cells. It was observed that 55% of the patients with a decreased DPD activity suffered from grade IV neutropenia compared with 13% of the patients with a normal DPD activity (P = 0.01). Furthermore, toxicity developed significantly earlier in patients with low DPD activity than in patients with normal DPD activity (10.0+/-7.6 versus 19.1+/-15.3 days, P A), one nonsense mutation (E386X), four missense mutations (M166V, V335L, 1560S, D949V) and five polymorphisms (C29R, R21Q, S534N, 1543V, V7321). Considering the common use of 5FU in the treatment of cancer patients, the severe 5FU-related toxicities in patients with a low DPD activity and the high prevalence of the IVS14 +1G-->A mutation, analysis of the DPD activity in PBM cells or screening for the IVS14 + 1G-->A mutation should be routinely carried out prior to the start of treatment with 5F

Genetic basis of inosine triphosphate pyrophosphohydrolase (ITPA) deficiency

Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a common inherited condition characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes. The genetic basis and pathological consequences of ITPase deficiency are unknown. We have characterized the genomic structure of the ITPA gene, showing that it has eight exons. Five single nucleotide polymorphisms were identified, three silent (138GMA, 561GMA, 708GMA) and two associated with ITPase deficiency (94CMA, IVS2+21AMC). Homozygotes for the 94CMA missense mutation (Pro32 to Thr) had zero erythrocyte ITPase activity, whereas 94CMA heterozygotes averaged 22.5% of the control mean, a level of activity consistent with impaired subunit association of a dimeric enzyme. ITPase activity of IVS2+21AMC homozygotes averaged 60% of the control mean. In order to explore further the relationship between mutations and enzyme activity, we examined the association between genotype and ITPase activity in 100 healthy controls. Ten subjects were heterozygous for 94CMA (allele frequency: 0.06), 24 were heterozygotes for IVS2+21AMC (allele frequency: 0.13) and two were compound heterozygous for these mutations. The activities of IVS2+21AMC heterozygotes and 94CMA/IVS2+21AMC compound heterozygotes were 60% and 10%, respectively, of the normal control mean, suggesting that the intron mutation affects enzyme activity. In all cases when ITPase activity was below the normal range, one or both mutations were found. The ITPA genotype did not correspond to any identifiable red cell phenotype. A possible relationship between ITPase deficiency and increased drug toxicity of purine analogue drugs is proposed

Localization of the ICF syndrome to chromosome 20 by homozygosity mapping

Item does not contain fulltext7 p

Purine and pyrimidine metabolism and electrocortical brain activity during hypoxemia in near-term lambs.

Contains fulltext : 58013.pdf (publisher's version ) (Closed access)Insufficient cerebral O(2) supply leads to brain cell damage and loss of brain cell function. The relationship between the severity of hypoxemic brain cell damage and the loss of electrocortical brain activity (ECBA), as measure of brain cell function, is not yet fully elucidated in near-term newborns. We hypothesized that there is a strong relationship between cerebral purine and pyrimidine metabolism, as measures of brain cell damage, and brain cell function during hypoxemia. Nine near-term lambs (term, 147 d) were delivered at 131 (range, 120-141) d of gestation. After a stabilization period, prolonged hypoxemia (fraction of inspired oxygen, 0.10; duration, 2.5 h) was induced. Mean values of carotid artery blood flow, as a measure of cerebral blood flow, and ECBA were calculated over the last 3 min of hypoxemia. At the end of the hypoxemic period, cerebral arterial and venous blood gases were determined and CSF was obtained. CSF from 11 normoxemic siblings was used for baseline values. HPLC was used to determine purine and pyrimidine metabolites in CSF, as measures of brain cell damage. Concentrations of purine and pyrimidine metabolites were significantly higher in hypoxemic lambs than in their siblings, whereas ECBA was lower in hypoxemic lambs. Significant negative linear relationships were found between purine and pyrimidine metabolite concentrations and, respectively, cerebral O(2) supply, cerebral O(2) consumption, and ECBA. We conclude that brain cell function is related to concentrations of purine and pyrimidine metabolites in the CSF. Reduction of ECBA indeed reflects the measure of brain damage due to hypoxemia in near-term newborn lambs