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Complete hypoxanthine–guanine phosphoribosyl-transferase (HPRT) deficiency in humans results in theLesch–Nyhan syndrome which is characterized,among other features, by compulsive self-injuriousbehavior. HPRT-deficient mice generated using mouseembryonic stem cells exhibit none of the behavioralsymptoms associated with the Lesch–Nyhan syn-drome. Administration of drugs that inhibit adeninephosphoribosyltransferase (APRT) in HPRT-deficientmice has produced the suggestion that deficiency ofAPRT in combination with HPRT-deficiency in micemay lead to self-mutilation behavior [C. L. Wu and D. W.Melton (1993) Nature Genet. 3, 235–240]. To test thisproposition, we bred HPRT–APRT-deficient mice. Al-though the doubly-deficient mice excrete adenine andits highly insoluble derivative, 2,8-dihydroxyadenine,which are also associated with human APRT defi-ciency, additional abnormalities or any self-injuriousbehavior were not detected. Thus, APRT–HPRT-defi-cient mice, which are devoid of any purine salvagepathways, show no novel phenotype and are not amodel for the behavioral abnormalities associated withthe Lesch–Nyhan syndrome as previously suggested.INTRODUCTIONThe Lesch–Nyhan syndrome is an X-linked disorder characterizedby hyperuricemia, choreoathetosis, spasticity, mental retardationand, most strikingly, compulsive self-injurious behavior (1). Itresults from a complete lack of hypoxanthine–guanine phosphoribo-syltransferase (HPRT, EC 2.4.2.8), the enzyme that convertshypoxanthine or guanine to inosine monophosphate or guanosinemonophosphate, respectively. The role of HPRT deficiency ingenerating the behavioral abnormalities seen in Lesch–Nyhansyndrome is not understood.Several attempts to generate animal models for Lesch–Nyhansyndrome using pharmacological or surgical interventions havedone little to link purine metabolism to behavioral abnormalities. Inaddition, HPRT-deficient mouse embryonic stem (ES) cells havebeen used to produce HPRT-deficient mice (2,3). Although thesemice were mutant for the same gene that is mutant in humans withLesch–Nyhan syndrome, they were essentially normal and healthywith only subtle changes in brain dopamine levels (4,5).Since differences in purine metabolism between rodents andman could be responsible for the different consequences of HPRTdeficiency, Wu and Melton investigated the effect of reducedadenine phosphoribosyltransferase (APRT, EC 2.4.2.7) activityon HPRT-deficient mice (6). APRT, a purine salvage enzymesimilar to HPRT, converts adenine to adenosine monophosphate(7). Wu and Melton treated five 9–12 month-old HPRT-deficientmice with the APRT enzyme inhibitor 9-ethyladenine. All five ofthe treated mice, but none of the control mice, were reported todevelop self-inflicted injuries caused by overgrooming, within48–130 days after treatment began. Self-injurious behavior wasdefined to include all grooming with fore and hind legs, nibblingand biting. A second set of younger (6–8 week-old) HPRT-defi-cient mice injected with 9-ethyladenine or caffeine were alsoreported to show an increase in self-injurious behavior during thetreatment period. They concluded from their drug studies thatAPRT does play a more important role in purine metabolism inmouse as compared with man and that partial inhibition of APRTactivity produces a model for human Lesch–Nyhan syndrome. Atthe time that this study was performed, APRT-deficient mice werenot available to confirm the role of this enzyme in preventing thebehavioral symptoms associated with total HPRT deficiency.Recently, we have generated APRT-deficient mice using homolo-gous recombination in ES cells and an appropriate breeding strategy(8). APRT-deficient mice excrete adenine and its insoluble oxidationproduct, 2,8-dihydroxyadenine (DHA) which is characteristic of thehuman deficiency. In addition, these mice develop the DHA kidneystones and renal failure seen in untreated APRT-deficient humans.APRT-deficient mice are, therefore, an excellent model for theclinical symptoms of the deficiency.To test the hypothesis that APRT deficiency, in conjunction withHPRT deficiency in mice, can produce the behavioral symptoms ofLesch–Nyhan syndrome, we bred the nonfunctional APRT alleleinto an HPRT-deficient mouse background. Mice deficient in both

Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.

1. A compound identified as orotidine has been found in the erythrocytes of all subjects on allopurinol. 2. The erythrocyte orotidine concentrations were much higher in patients with renal failure or with the Lesch-Nyhan syndrome. 3. In addition, increased amounts of oxypurinol-7-riboside were excreted in the urine by both of these groups compared with control subjects or with patients with normal renal function on allopurinol. 4. A good correlation was found between urinary oxypurinol-7-riboside excretion and erythrocyte orotidine concentrations. 5. Increased erythrocyte levels of the pyrimidine-sugar UDP-glucose were also found in patients with the highest orotidine levels. 6. The combined results suggest a derangement of pyrimidine nucleotide metabolism during allopurinol therapy. We propose that erythrocyte orotidine formation results primarily from inhibition of orotidine-5′-mono-phosphate decarboxylase by oxypurinol-7-ribotide.

This paper illustrates several important points relating to the use of allopurinol in renal failure, or situations of purine overproduction: It is very easy to give too much allopurinol. Most of the side effects (bone marrow depression, exfoliative dermatitis, etc) are the result of overdosage due to the retention of oxipurinol, an effect exaggerated by thiazide diuretics. Monitoring of plasma oxipurinol levels (ideally less than 100 mumol/l) by high-pressure liquid chromatography is helpful for adjusting dosage in renal failure. Some estimate of the anticipated purine excess is equally vital in deciding dosage during tumour lysis if the risk of urate nephropathy is not to be substituted for the certainty of xanthine nephropathy. In this situation the use of allopurinol may even be questioned. Patients with HGPRT deficiency are exquisitely sensitive to allopurinol, and careful monitoring of the effect on urinary purine levels is essential if xanthine colic is to be avoided.