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  • Adenine phosphoribosyltransferase (APRT) catalyzes the synthesis of AMP from adenine and 5-phosphoribosyl-1-pyrophosphate (PP-ribose-P). An inherited deficiency of this enzyme (MIM 1026000) results in inability to utilize adenine, which, in the absence of any other significant pathway of metabolism in humans, is oxidized by xanthine dehydrogenase (XDH) via the 8-hydroxy intermediate to 2,8-dihydroxyadenine (2,8-DHA). 2,8-DHA is extremely insoluble, and its accumulation in the kidney can lead to crystalluria and the formation of urinary stones. Adenine and 2,8-DHA are secreted by the human kidney, and 2,8-DHA is protein-bound in the circulation. Both these factors tend to minimize toxicity in tissues other than the kidney. Administration of exogenous adenine itself has produced 2,8-DHA nephrotoxicity in a variety of animal systems and also in humans with normal APRT activity given massive transfusions of adenine-containing blood.

  • Clinical symptoms, which include renal colic, hematuria, urinary tract infection, and dysuria, are due to 2,8-DHA stone formation or crystalluria and may be present from birth. Age at diagnosis has ranged from 5 months to 74 years, and approximately 60 percent of patients have been male. As many as 50 percent of APRT-deficient individuals may be asymptomatic. Acute renal failure may occur as the presenting symptom and can be reversible. Some patients have developed chronic renal failure, requiring dialysis or transplantation, and in a subset of these, 2,8-DHA crystals were first detected during biopsy analysis of the native or the transplanted kidney. Homozygotes do not show any evidence of immunodeficiency.

  • Except for the excretion of adenine and its metabolites, no biochemical abnormalities have been recorded. Purine production and excretion are normal, indicating that, unlike the companion enzyme hypoxanthine-guanine phosphoribosyltransferase, APRT is not vital for the overall control of purine metabolism in humans. Adenine metabolites in the urine account for 20–30 percent of total purine excretion, even on a low-purine diet. The main source of endogenous adenine is probably polyamine synthesis, of which adenine is a metabolic byproduct. Adenine-rich foods may be a contributing factor in precipitating urolithiasis.

  • Two types of APRT deficiency have been recognized, based on the level of residual enzyme activity in erythrocyte lysates. Patients with type I deficiency have no detectable activity in erythrocyte lysates. Approximately 140 such patients have been identified in many countries, including 45 in Japan. These patients are homozygotes or compound heterozygotes for null alleles. Patients with type II deficiency have significant enzyme activity (5–25 percent of wild-type in hemolysates) and have been found only in Japan to date (138 cases). Approximately 75 percent of the patients in Japan have the type II defect. The type II enzyme has reduced affinity for PP-ribose-P compared with the wild-type enzyme. In both types of deficiency, APRT activity is neither demonstrable in intact cells nor functional in vivo. Intact cells are resistant to the toxic effects of 2,6-diaminopurine (DAP) and other adenine analogues that depend on APRT for their metabolism.

  • APRT deficiency is inherited in an autosomal recessive manner. The frequency of heterozygosity is quite high ...

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