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 (138G-->A, 561G-->A, 708G-->A) and two associated with ITPase deficiency (94C-->A, IVS2+21A-->C). Homozygotes for the 94C-->A missense mutation (Pro32 to Thr) had zero erythrocyte ITPase activity, whereas 94C-->A 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+21A-->C 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 94C-->A (allele frequency: 0.06), 24 were heterozygotes for IVS2+21A-->C (allele frequency: 0.13) and two were compound heterozygous for these mutations. The activities of IVS2+21A-->C heterozygotes and 94C-->A/IVS2+21A-->C 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.

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The mode of action of Leflunomide, an immunomodulatory drug used in rheumatoid arthritis, is debated. This study, using 14 C-labeled de novo purine and pyrimidine synthesis precursors, proves conclusively that the prime target in proliferating human T-lymphocytes is pyrimidine biosynthesis at the level of dihydroorotic- 14 C]Glycine studies confirmed that restriction of de novo purine synthesis occurred secondary to inhibition of proliferation since this was reversed by uridine rescue, except at 100 M Leflunomide. 100 M Leflunomide markedly depleted ATP and GTP pools also, which would have serious consequences for ATP-dependent enzymes essential to the immune response, thereby explaining non-pyrimidinerelated effects reported for Leflunomide at 100 M and above.

Hyperuricemia and young-onset gout are consistent features of the phenotype associated with HNF-1beta mutations, but the mechanism is uncertain. Families with HNF-1beta mutations may fit diagnostic criteria for FJHN. Identification of HNF-1beta patients by recognizing the features of diabetes and disorders of renal development is important in resolving the genetic heterogeneity in FJHN.

Although gout and hyperuricaemia are usually thought of as conditions of indulgent male middle age, in addition to the well-known uricosuria of the newborn, there is much of importance for the paediatric nephrologist in this field. Children and infants may present chronically with stones or acutely with renal failure from crystal nephropathy, as a result of inherited deficiencies of the purine salvage enzymes hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) or of the catabolic enzyme xanthine dehydrogenase (XDH). Genetic purine overproduction in phosphoribosylpyrophosphate synthetase superactivity, or secondary to glycogen storage disease, can also present in infancy with renal complications. Children with APRT deficiency may be difficult to distinguish from those with HPRT deficiency because the insoluble product excreted, 2,8-dihydroxyadenine (2,8-DHA), is chemically very similar to uric acid. Moreover, because of the high uric acid clearance prior to puberty, hyperuricosuria rather than hyperuricaemia may provide the only clue to purine overproduction in childhood. Hyperuricaemic renal failure may be seen also in treated childhood leukaemia and lymphoma, and iatrogenic xanthine nephropathy is a potential complication of allopurinol therapy in these conditions. The latter is also an under-recognised complication of treatment in the Lesch-Nyhan syndrome or partial HPRT deficiency. The possibility of renal complications in these three situations is enhanced by infection, the use of uricosuric antibiotics and dehydration consequent upon fever, vomiting or diarrhoea. Disorders of urate transport in the renal tubule may also present in childhood. A kindred with X-linked hereditary nephrolithiasis, renal urate wasting and renal failure has been identified, but in general, the various rare types of net tubular wasting of urate into the urine are recessive and relatively benign, being found incidentally or presenting as colic from crystalluria. However, the opposite condition of a dominantly inherited increase in net urate reabsorption is far from benign, presenting as familial renal failure, with hyperuricaemia either preceding renal dysfunction or disproportionate to it. Paediatricians need to be aware of the lower plasma urate concentrations in children compared with adults when assessing plasma urate concentrations in childhood and infancy, so that early hyperuricosuria is not missed. This is of importance because most of the conditions mentioned above can be treated successfully using carefully controlled doses of allopurinol or means to render urate more soluble in the urine. Xanthine and 2,8-DHA are extremely insoluble at any pH. Whilst 2,8-DHA formation can also be controlled by allopurinol, alkali is contraindicated. A high fluid, low purine intake is the only possible therapy for XDH deficiency.