Adenine HGPRT deficiency

Recently a new cause of supposed uric acid stones in children was identified independently by two groups (2, 3), a defect of the companion salvage enzyme adenine phos-phoribosyltransferase (APRT). This results in an inability to salvage the purine base adenine, which is then picked up by xanthine oxidase and converted to the extremely insoluble analogue of uric acid, 2,8-dihydroxyadenine (2,8-DHA) (Fig. 1). In contrast to HGPRT deficiency, other than the urolithiasis, these children are normal and heterozygotes have no clinical abnormality. 

Treatment in both children involved the use of allopurinol - but at a lesser dosage (5 mg/kg/2hh) because of the retention of the principal metabolite oxipurinol in severe renal failure Careftil monitoring of plasma oxipurinol levels is desirable For the HGPRT deficient child alkali was also given to enhance uric acid solubility It was not prescribed in the APRT deficient child since 2 8-dihyroxy adenine solubility is unaffected by alkali and its use may even be contraindicated ... 

The extremely low red cell NAD levels also indicate involvement of pyridine nucleotide metabolism in the clinical expression of this disorder. PP-ribose-P is require for the formation of the pyridine nucleotides NAD and NADP both are vi al to the erythrocyte. However, high, rather than low NAD levels would be anticipated and have been found by us in both HGPRT and PNP deficient red cells it is possible that the raised NAD in the latter reflect the raised PP-ribose-P levels found in PNP and HGPRT deficiency. PP-ribose-P levels were not raised in NB s red cells and the NAD values were extremely low. The latter finding may also be associated with the observed inability of the intact red cells to stimulate the re-cycling of hypoxanthine or adenine at high phosphate and suggest that NAD may be necessary for the stabilisation of erythrocyte PP-ribose-P. This would in turn... 

Increased intracellular levels of PP-ribose-P have been implicated in the cause of certain hyperuricemic states associated with uric acid overproduction. Fibroblasts from two patients with the Lesch-Nyhan syndrome were found previously to have an elevated intracellular concentration of PP-ribose-P with a normal rate of PP-ribose-P production (Rosenbloom, et al., 1968). Green and Seegmiller (1969) subsequently reported a mean PP-ribose-P value of 47.1 in erythrocytes from seven patients with HGPRT deficiency. We have confirmed these elevated PP-ribose-P levels in three additional patients with the Lesch-Nyhan syndrome with values of 20.5, 39.4 and 49.5 juM (Table 1). The mothers of these patients are obligate heterozygotes and have normal PP-ribose-P levels. Two diseases associated with a deficiency of other PRT enzymes are not associated with altered erythrocyte PP-ribose-P levels (Table 1). PP-ribose-P levels were in the normal range in one patient with a partial deficiency of adenine phosphoribosyltransferase (APRT) and in one patient with orotic aciduria, which is due to a deficiency... 

Cultured human skin fibroblasts are commonly utilized in the detection of hemizygosity and heterozygosity for hypoxanthine-guanine phosphoribosyltrans-ferase (HGPRT) deficiency. Two obstacles are encountered in the determination of HGPRT and adenine phosphoribosyl-transferase (APRT) in extracts of cultured skin fibroblasts the sensitivity of these enzymes in dilute cell suspension to freezing and thawing (l), and the presence of nucleotidase activity (2). 

The Lesch-Nyhan Syndrome (LNS) is a rare x-linked neurological disease of children characterized by choreoathetosis, spasticity, mental retardation and compulsive self mutilation accompanied by excessive purine production and hyperuricemia (l). The virtually complete deficiency of activity of a purine salvage enzyme, hypoxanthine-guanine phosphoribosyl-transferase (HGPRT) (EC 2.4.2.8.) (2), due to structural gene mutation (3 4) has been shown to be the basic abnormality in this disease. In erythrocytes of LNS patients, HGPRT deficiency has been found to be associated with increased activity and relative thermal stability of adenine phosphoribosyltransferase (APRT) (EC 2.4.2.7 ) (5 6) an autosomally determined enzyme (7) ... 

Adenine phosphoribosyltransferase activity assayed by an analogous method using 0.6 mM adenine-8-l C (specific activity 4 mCI/mmole) was not significantly altered in any of the HGPRT-deficient clones (Table II). Starch gel electrophoresis using a method only slightly modified from that of Watson et. al. (19) showed no difference in electrophoretic mobility of mutants partially deficient in HGPRT (Fig. 3) but could not be used to examine the clones with severely deficient enzyme activity. 

Adenine (APRT) and hypoxanthine-guanine (HGPRT) phosphorg bgsyl-transferase deficiency were originally identified in children ... 

At the present time, we just report some experimental results of a study on the mechanism of action of allopurinol (U-hydroxy-pyrazolo (3, -d ) pyrimidine) and thiopurinol k thiopyrazolo (3, d) pyrimidine) on de novo biosynthesis of uric acid. In this present work, we have compared effect of alio and thiopurinol on oxypurine (xanthine and hypoxanthine) urinary excretion with their rate of synthesis of ribonucleotides in vitro by erythrocyte hemolysate in some particular enzymatic deficiencies (hypoxanthine-guanine phosphoribosyltransferase HGPRT, adenine phosphoribosyl-transferase APRT and xanthinuria). 

Partial deficiency of HGPRT, a salvage enzyme of purine metabolism, has been demonstrated to be the primary abnormality causing purine overproduction in a small proportion of patients with gout (l-4). The quantitative deviation in the activity of this enzyme has been shown by Kelley et al. to be associated with decreased stability to thermal inactivation (2). These authors suggest that in the affected subjects HGPRT is structurally altered. Furthermore, in some of these patients erythrocyte adenine phosphoribosyltransferase (APRT) activity was found to be increased and relatively thermostable (2). 

Recent advances in the understanding of human purine metabolism have been stimulated by the discovery of specific inborn errors of this pathway in man. In particular, the demonstration of the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in the Lesch-Nyhan syndrome and in some patients with gout has contributed essential information on the regulation of purine biosynthesis novo and on the critical role of this reutilization pathway in central nervous system function in man. The search for other disorders led to the description of a partial deficiency of adenine phosphoribosyltransferase (APRT) in four members in three generations of one family. Each of the subjects partially deficient in APRT exhibited a normal serum urate concentration and the propositus had a normal excretion of uric acid (Kelley, et al., 1968). We have investigated a second family partially deficient in APRT (Fox and Kelley, in press). 

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