Paediatric implications for some adult disorders : Scientific proceedings of the 4th Unigate Workshop, held at the Royal Academy of Physicians, St. Andrews Place, London, N.W. 1, May 1976 / edited by Donald Barltrop.

Unigate Paediatric Workshop 1976 : Royal College of Physicians)

Date:: 1977

Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

Credit: Paediatric implications for some adult disorders : Scientific proceedings of the 4th Unigate Workshop, held at the Royal Academy of Physicians, St. Andrews Place, London, N.W. 1, May 1976 / edited by Donald Barltrop. Source: Wellcome Collection.

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$16 R. W. E. Watts inhibitors ADP and GDP, whereas Becker et al. (1973) reported increased enzyme activity at all orthophosphate concentrations and normal sensi¬ tivity to ADP and GDP. The enzyme defect has been demonstrated in both sexes and is considered to be transmitted as an autosomal dominant although X- linked recessive inheritance cannot be completely excluded on the basis of enzyme determinations on eryth ocytes. Although the enzyme defect has been demon¬ strated in females to the same degree as in affected males, gout and urolithiasis have only been observed in males. In some cases these have begun around the age of puberty or shortly thereafter. Glucose-6-phosphatase deficiency {Type I glycogen storage disease) Glucose-6-phosphatase deficiency is associated with increased purine biosynthesis de novo as well as with urate retention produced by the lactic acidosis and ketoacidosis which occurs in the disorder. The mechanism whereby purine biosynthesis is acceler¬ ated has not been established but it is suggested that glucose-6-phosphatase deficiency increases carbo¬ hydrate metabolism via the phospho-gluconate shunt pathway; this causes increased generation of ribose- 5-phosphate which is converted to PRPP by PRPP synthetase. The increased availability of PRPP then favours the disaggregation of PRPP amidotrans- ferase into its active subunits. The clinical complications of hyperuricaemia do not usually occur in glycogen storage disease until adolescence or early adult life. Tophaceous gout and sodium urate nephropathy are more common than urolithiasis, presumably because the excretion of the excessive uric acid is reduced by the action of the circulating organic acids. Adults with Type I Glyco¬ gen Storage Disease are often crippled by gout at an early age. Allopurinol treatment is recommended if the hyperuricaemia consistently exceeds 9 mg per 100 ml (0-536 mmol) or if there is hyperuric aciduria [> 600 mg (3-54 mmol) per 24 hr for adults] when the oatient is taking a purine free diet after a 5-day equilibration period on the same diet. Increased glutathione reductase activity Hyperuricaemia and gout were reported to be associated with the increased glutathione reductase activity which accompanies the presence of an elec- trophoretically fast-moving variant of this enzyme (Long, 1967). This enzyme variant has a high inci¬ dence in negroes and eppears to have an autosomal recessive pattern of inheritance. Increased glutathione reductase activity would increase NADP+ genera¬ tion at the expense of NADPH ; this would promote glucose metabolism via the phosphogluconate shunt pathway with increased generation of ribose-5-phos- phate and hence PRPP. Although the original reports drew attention to an increased incidence of gout it is reasonable to anticipate an increased incidence of urinary stone also, because purine biosynthesis de novo will be accelerated and uric acid excretion in¬ creased, if the postulated mechanism is correct, and there is no restriction of renal uric acid excretion. The underlying abnormality is an inherited one and so might be expected to produce the complications of excessive uric acid synthesis in early life. Further work is needed to determine if the gluta¬ thione reductase variant is associated with increased intracellular concentrations of PRPP and to confirm its association with gout and urolithiasis in other surveys. 2,8-Dihydroxyadeninuria This syndrome arises from complete deficiency of adenine phosphoribosyltransferase (APRT) (EC 2.4. 2.7). The children present with crystalluria and radio- translucent stones, which are composed of 2,8-di- hydroxyadenine with a little admixed uric acid. The urinary excretion of adenine is increased. There are no neuropsychiatrie or other clinical manifestations, and the uric acid levels in blood and urine are normal (Cartier and Hamet, 1974; Simmondse/o/., 1976a, b). The 2,8-dihydroxyadenine is formed by the xan¬ thine oxidase (EC 1.2.3.2) catalysed oxidation of adenine, which presumably accumulates because of non-utilization via the salvage pathway. The origin of the free adenine is of interest because purine nucleoside Phosphorylase (EC 2.4.2.1) is said to have a low activity with respect to adenosine in mamma¬ lian tissues (Simmonds et al., 1976a). 2,8-Dihydroxyadenine is much less soluble in urine than uric acid, 1 ¡^g/ml and 150 (Jig/ml respec¬ tively at pH 5-0, and 3 (xg/ml and 2,000 (J-g/ml respectively at pH 7 0. The patients have been initially regarded as having uric acid stones because 2,8-dihydroxyadenine re¬ acts mole for mole as uric acid in the colorimetrie assays, and the co-precipitated uric acid was detected when the stones were examined by differential ultra¬ violet light spectrophotometry with uricase. Mass spectrometric and/or infra-red spectroscopic methods are needed. The increased adenine excretion can be demonstrated by high voltage electrophoresis. Partial APRT deficiency had been previously re¬ ported in 4 families. It appeared to be inherited as a harmless autosomal trait. These individuals were identified on the basis of their erythrocyte APRT activities and their levels of 2,8-dihydroxyadenine excretion are unknown. The co-existence of gout and partial APRT deficiency in some families is con¬ sidered to be coincidental, the hyperuricaemia and the enzyme defect segregating separately. It is not known if the cases of complete APRT$