C. F. Potter

Complete deficiency of adenine phosphoribosyltransferase. Report of a family.

We studied the clinical and biochemical manifestations of complete adenine phosphoribosyltransferase deficiency in the kindred of a male homozygous child excreting stones of 2,8-dihydroxyade-nine. Abnormal amounts of adenine, 8-hydroxyade-nine and 2,8-dihydroxyadenine (25 per cent of total purine metabolites) appeared in the urine of the propositus and his clinically normal brother, but not in heterozygotes or a control. Adenine phosphoribosyl-transferase activity in erythrocytes was less than 1 per cent of normal in both homozygotes and varied from 20 to 57 per cent of normal in six heterozygotes. Heterozygotes exhibited neither hyperuricemia nor gout. Treatment of the propositus with allopurinol and a low purine diet stopped stone formation. In addition, excretion of 2,8-dihydroxyadenine decreased. An autosomal recessive mode of inheritance with variable expression in the phenotype is indicated. Homozygotes may be detected by their raised urinary adenine levels or absence of detectable erythrocyte adenine phosphoribosyltransferase activity (or both).

2, 8-Dihydroxyadeninuria: Or When is a Uric Acid Stone not a Uric Acid Stone?

Purine nucleotides important for normal cellular metabolism are derived endogenously from de novo synthesis and also from recycling of pre-formed purines via the so-called salvage pathway (Figure 1). The latter pathway contains a number of enzymes, the absence of which can lead to disturbances of purine metabolism and also severe clinical symptoms1. An example is the deficiency of the salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) which can lead either to the Lesch-Nyhan syndrome or X-linked gout1.

Purine and pyrimidine metabolism in hereditary orotic aciduria: some unexpected effects of allopurinol

Abstract. Purine and pyrimidine metabolism have been investigated in the longest surviving case of hereditary orotic aciduria after 15 years of chronic uridine therapy. Several unusual features were recorded:

Renal Failure in Young Subjects with Familial Gout

The classical patient with gout is usually an older male, and gout is rare in premenopausal females1. Until recently, renal failure was common in gout2, but is now rare3. Renal involvement however, as judged by low urine pH and proteinuria, remains common1,3,4, although concentrating ability and GFR are not usually different from age-matched controls3. Conversely, gout is rarely diagnosed in renal failure from other causes, despite mild hyperuricaemia as part of the general retention of nitrogenous waste4,5. If all patients entering terminal renal failure and offered dialysis or transplantation are examined, less than 1% have gout recorded as the cause (Table 1).

A Controlled Study of the Effect of Long Term Allopurinol Treatment on Renal Function in Gout

An association between gout and kidney dysfunction has been long recognised. It is a reasonable presumption that gout might be the cause of the renal disease.1 Hypertension, urolithiasis and urinary infection may contribute to this association but it is far from certain whether hyperuricaemia itself may exert a deleterious effect. The available data have been variously interpreted as showing that hyperuricaemia is detrimental2 or of no consequence.3

Tienilic Acid in the Treatment of Gout and Hypertension

Hypertension is not infrequently associated with gout.1 In this context, diuretics are often precluded because they invariably accentuate hyperuricaemia. The advent of tienilic acid, a diuretic with hypotensive and uricosuric properties may simplify the treatment of hypertension associated with hyperuricaemia,2 and may also obviate the need for a concurrent hypouricaemic drug. The present study assessed the effects of tienilic acid on gouty patients.

Influence of Purine Content of Diet and Allopurinol on Uric Acid and Oxalate Excretion Levels

A defect of the purine salvage enzyme adenine phosphoribosyl-transferase (APRT) results in lithiasis in some but not all homozygotes for the defect. The stones are frequently mistaken for uric acid1, but are really composed of an insoluble analogue, 2,8- dihydroxyadenine (2,8-DHA), excreted in consequence of the defect (see Simmonds et al. this symposium). The present studies were an attempt to establish whether any variation in oxalate or urate excretion with diet could explain the asymptomatic status of one of two male siblings homozygous for the defect. A preliminary study of diet and allopurinol on purine excretion has been reported elsewhere2. The rationale for the investigations was based on the association frequently reported between dietary purine intake and increased uric acid levels in oxalate stone formers3, and the beneficial effect of allopurinol in reducing (a) the absorption of dietary purine in an animal model4; (b) the incidence of lithiasis in some oxalate stone formers5; (c) any further stone formation on a low purine diet in one of two siblings under investigation2.

Inheritance of Adenine Phosphoribosyltransferase (APRT) Deficiency

Recognition of the importance of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the control of purine metabolism lead to systematic investigations of the companion purine salvage enzyme, adenine phosphoribosyltransferase (APRT). This was followed by the discovery of individuals (considered to be heterozygous for the defect) with reduced APRT activity in erythrocyte lysates. Within a relatively short time, five such individuals and their families — a total of 82 individuals — 39 of whom had reduced erythrocyte APRT activity, were investigated (1–5). Disturbances of urate metabolism, accompanied in some instances by gout and/or urolithiasis, were found in 4 heterozygotes from three kindreds. HGPRT activity was normal in all. The possibility of an X linked inheritance could not be excluded from the first pedigrees (1). Subsequently the presence of identical disturbances in family members with normal erythrocyte APRT made any direct correlation between abnormal urate metabolism and APRT deficiency unlikely (Table); an autosomal recessive mode of inheritance was also proposed from detailed family investigations. The segregation of the defect varied widely.

Purine and Pyrimidine Metabolism in Hereditary Oroticaciduria During a 15 Year Follow-Up Study

Pyrimidines and purines are vital to the body; each has many important independent functions, as well as being essential components of DNA and RNA.

Evidence of A New Syndrome Involving Hereditary Uric Acid Overproduction, Neurological Complications and Deafness

Hypoxanthiye-guanine phosphoribosyltransferase (HGPRT: EC 2.4.2.8) deficiency is an X-linked recessive disorder which may present in early infancy as the Lesch-Nyhan syndrome associated with gross purine overproduction, neurological abnormalities and bizarre self-mutilating behaviour. Less severe forms have been reported in adults with gouty arthritis and/or renal complications but a complete absence of neurological abnormalities1.