Adenine phosphoribosyltransferase deficiency

Key-words Disease name and synonyms Definition Excluded diseases Diagnosis criteria Differential diagnosis Prevalence Molecular defect Clinical description Management including treatment Etiology Diagnostic methods Antenatal diagnosis Unresolved questions References Abstract Adenine phosphoribosyltransferase (APRT) catalyzes the synthesis of AMP (adenosine monophosphate) from adenine and 5'-phosphoribosyl-1-pyrophosphate (PP-ribose-P) in the presence of magnesium (Mg2+). In APRT deficiency, adenine is oxidized, via 8-hydroxyadenine (8-HA), to 2,8-dihydroxyadenine (2,8-DHA), by xanthine dehydrogenase. Adenine is formed, as a by-product of polyamine synthesis, from 5'-methylthioadenosine by the action of 5'methylthioadenosine phosphorylase (MTAP). This is probablyAdenine phosphoribosyltransferase (APRT) catalyzes the synthesis of AMP (adenosine monophosphate) from adenine and 5'-phosphoribosyl-1-pyrophosphate (PP-ribose-P) in the presence of magnesium (Mg2+). In APRT deficiency, adenine is oxidized, via 8-hydroxyadenine (8-HA), to 2,8-dihydroxyadenine (2,8-DHA), by xanthine dehydrogenase. Adenine is formed, as a by-product of polyamine synthesis, from 5'-methylthioadenosine by the action of 5'methylthioadenosine phosphorylase (MTAP). This is probably the principal route of adenine formation in vivo. The defect is inherited as an autosomal recessive trait. The gene is located on chromosome 16q24. Two types of homozygotes have been found, based on APRT activity in erythrocyte lysates. Type I patients, predominantly Caucasian, have undetectable activity, Type II, found only in Japan, have 10-25% of normal activity due to a kinetic abnormality evident only under non-physiological conditions. No activity is demonstrable in either I or II in intact erythrocytes under physiological conditions. Heterozygosity for both defects is high (0.4 to 1.2 per hundred) which suggests homozygosity of the order of 1 in 250,000 to 1 in 33,000. Clinical symptoms colic, hematuria, urinary tract infection and dysuria are due to 2,8-DHA crystalluria or stones. Acute renal failure may be the presenting symptom and can be reversible, but undiagnosed homozygotes have progressed to chronic renal failure, dialysis and transplantation. In older subjects 2,8-DHA crystals have been detected first at renal biopsy following transplantation. Approximately 15% of homozygotes have been completely symptomless, but crystalluria is present in all homozygotes from birth. Allopurinol has prevented 2,8-DHA formation; lithotripsy has proved beneficial. Key-words APRT: adenine phosphoribosyltransferase; 2,8-DHA: 2,8-dihydroxyadenine; 8-HA: 8-hydroxyadenine; 2HA: 2-hydroxyadenine; HPLC/RPLC: high performance/reversed phase liquid chromatography, XDH: xanthine dehydrogenase (also termed xanthine oxidase). Simmonds HA. Adenine phosphoribosyltransferase deficiency. Orphanet Encyclopedia, July 2003. http://www.orpha.net/data/patho/GB/uk-APRT.pdf 1 Disease name and synonyms Adenosine phosphoribosyltransferase deficiency 2,8 dihydroxyadenine urolithiasis. Definition Adenine phosphoribosyltransferase (APRT: EC 2.4.2.7) normally catalyses the formation of 5'AMP (adenylic acid) and pyrophosphate (PPi) from adenine and PP-ribose-P. Since AMP can also be formed by the de novo pathway APRT is generally considered a salvage enzyme and in Man and higher animals provides the only mechanism by which free adenine can be converted to the nucleotide [1]. The main source of endogenous adenine is the polyamine pathway of which adenine is a metabolic endproduct. The inability to salvage adenine in APRT deficiency results in its alternative metabolism by xanthine dehydrogenase (XDH) via the 8-hydroxy intermediate to the extremely nephrotoxic end-product, 2,8-dihydroxyadenine (2,8-DHA). Deficiency of APRT is inherited as an autosomal recessive trait [1]. The gene is located on chromosome 16q24 [2]. Excluded diseases 2,8-DHA stones were previously mistaken for uric acid stones because of their identical chemical reactivity. Likewise, 2,8-DHA stones may be confused with xanthine stones. All three stone types are radiolucent and show up as a starry picture on ultrasonography. Consequently, diseases leading to excess excretion of xanthine or uric acid must be excluded as well by more reliable methods of stone analysis, coupled with erythrocyte enzyme assay and HPLC/RPLC as described below [1]. Diagnosis criteria The chief clinical manifestation directly related to the defect is 2,8-DHA crystalluria or urolithiasis. This can lead to intratubular deposition/blockage and presentation of homozygotes in acute, or acute on chronic, renal failure, sometimes in coma, or following rejection of a transplanted kidney [1-3,4]. Varying ability to supersaturate the urine may explain the existence of affected and asymptomatic sibs in several families. The apparent lack of in vivo toxicity to tissues other than the kidney may relate to the high degree of protein binding and the fact that 2,8-DHA, like adenine, is secreted by the human kidney [1]. Differential diagnosis Both symptomatic and asymptomatic homozygotes may be identified by the characteristic round brown 2,8-DHA crystals in the urine, with a maltese cross birefringence by polarized light microscopy [1,5]. The diagnosis can be confirmed from the adenine and the 2,8DHA excreted, together with the absence of functional APRT activity in intact erythrocytes [1]. The latter will be impossible to establish if recent transfusion has formed an essential part of the therapy [3]. Correct identification of 2,8-DHA stones requires ultraviolet (UV), infrared (IR), mass spectrometry (MS), x-ray crystallography, High-Performance or Reversed-Phase Liquid Chromatography (HPLC, RPLC), capillary electrophoresis or tandem MS. Three adenine derivatives are excreted; adenine, 8hydroxyadenine (8-HA), and 2,8-DHA (approximate proportion 1.0:0.03:1.5) [1]. Total urinary purine end product (uric acid + precursor oxypurines + adenine derivatives) is normal (0.05 to 0.1 mM/kg/24h), with adenine metabolites comprising 30 percent of this total [1]. Homozygotes generally have normal levels of uric acid in plasma and urine and no other abnormal purines or pyrimidines are excreted. All other biochemical and hematological factors have been normal [1]. Prevalence The frequency of heterozygosity for APRT deficiency in Caucasians is 0.4-1.1% , and 0.5% to 1.2% for the Japanese [1,7] which suggests homozygosity of the order of 1 in 250,000 to 1 in 33,000. This is similar to some of the more common autosomal recessive disorders, but the number of observed cases is lower than expected. Twenty-one patients have been reported from France the largest number from any country in Europe. [4]. The potentially lethal nature of the defect when unrecognized, and the asymptomatic status in others, may be contributory. Death may also occur in utero [1]. Subjects with no detectable APRT lysate activity (type I defect) have been reported from 18 countries, excluding Japan [1-5]. Iceland, with 23 homozygotes from 16 families among a total population of 267,000 inhabitants, has the largest number on a per capita basis [5]. Among the 200 plus APRT deficient individuals in Japan, 45 have the type I defect [1,6,7]. The remainder have erythrocyte lysate APRT activity up to 25% of normal (type II defect) and have been found only in Japan [1,6,7]. Between 8 and 21% of individuals with either type of defect have been asymptomatic and approximately 60% of symptomatic subjects have been male in both instances [1]. Adults now comprise 60% of type I cases [1,4] while 75% of all Japanese patients