Adenine phosphoribosyltransferase deficiency has been classified into two types. Type one is caused by mutant alleles of APRT*Q0 and is found in individuals from many different countries. Type one causes a complete deficiency in vivo or in vitro.[3] Type two adenine phosphoribosyltransferase deficiency is caused by mutant alleles of APRT*J results in a full enzyme defiency in vivo but only a partial deficiency in cell extracts. Type two is mainly seen in Japan.[4]
Adenine phosphoribosyltransferase deficiency can present at any age. Studies have shown that the age of diagnoses can vary from infancy to over the age of 70.[11] Some individuals with APRT deficiency remain completely asymptomatic and only get diagnosed because of familial screening. In 15% of adult cases present with renal failure requiring renal replacement therapy.[6] In some cases APRT deficiency is first diagnosed after a kidney transplant when complications arise.[12][13] The first kidney stone episode can occur within the first few months of birth or later in life.[14] In infants APRT deficiency may manifest as reddish brown diaper stains.[15]
Patients with APRT deficiency typically have normal levels of plasma uric acid, gout and hyperuricemia have been reported in heterozygotes with a partial APRT deficiency.[16][17]
Adenine phosphoribosyltransferase deficiency has an autosomal recessive pattern of inheritance.
Adenine phosphoribosyltransferase deficiency is an autosomal recessive condition[5] which means that two copies of the mutated gene must be present for adenine phosphoribosyltransferase deficiency to develop.[18]
Genetics
The adenine phosphoribosyltransferase (APRT) gene is found on chromosome 16q24, contains five exons, encompasses 2.8 kb of DNA, and has a coding region of 540 bp.[19] Complete APRT deficiency develops in people who carry mutations in both copies of the APRT gene.[10]
There is no evidence that genotype correlates with phenotype and environmental factors or modifiers might be responsible for this heterogeneity.[20]
Mechanism
All tissues express the APRT enzyme, which offers the sole metabolic route for recovering adenine from dietary and polyamine biosynthesis sources.[21]Adenine can only be found in small amounts in blood and urine because APRT catalyzes the conversion of adenine and 5-phosphoribosyl-1-pyrophosphate into inorganic pyrophosphate and 5′-adenosine monophosphate. Adenine is transformed into 8-hydroxyadenine in people without functional APRT, and xanthine dehydrogenase (XDH), formerly known as xanthine oxydase, then further metabolizes this compound to dihydroxyadenine.[22] Due to its high renal clearance, dihydroxyadenine may be secreted tubularly in addition to being filtered.[23] Thus, APRT deficiency causes elevated dihydroxyadenine levels in the urine.[24] Dihydroxyadenine precipitates in renal parenchyma and becomes extremely insoluble in urine, forming crystals that can accumulate, grow, and form stones.[25] This can lead to crystalline nephropathy.[6]
Diagnosis
Adenine phosphoribosyltransferase deficiency is diagnosed based on the identification of dihydroxyadenine by kidney stone analysis or examination of crystals in the urine.[10] The combination of infrared spectroscopy and morphologic examination under a stereomicroscope allows for the identification of dihydroxyadenine in all cases of kidney stones and should be analyzed whenever one becomes available.[26]Biochemical stone analysis is unreliable for diagnosing APRT deficiency and is unable to distinguish dihydroxyadenine from uric acid.[10] For the identification of dihydroxyadenine crystals, light and polarizing microscopy examination of crystalluria is a very helpful, noninvasive, and reasonably priced method. The most concentrated urine samples come from morning urine voids, which are ideal for studying crystalluria.[26] One way to quantify something is to count the number of crystals per volume unit,[26] which is higher in patients who are not receiving treatment.[6]
^ a b c d eEdvardsson, Vidar Orn; Sahota, Amrik; Palsson, Runolfur (September 26, 2019). "Adenine Phosphoribosyltransferase Deficiency". University of Washington, Seattle. PMID 22934314. Retrieved November 30, 2023.
^ a b c"Adenine phosphoribosyltransferase deficiency: MedlinePlus Genetics". MedlinePlus. October 1, 2012. Retrieved November 30, 2023.
^ a bHidaka, Y; Palella, T D; O'Toole, T E; Tarlé, S A; Kelley, W N (November 1, 1987). "Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme". Journal of Clinical Investigation. 80 (5). American Society for Clinical Investigation: 1409–1415. doi:10.1172/jci113219. ISSN 0021-9738. PMC 442397. PMID 3680503.
^ a bHidaka, Y; Tarlé, S A; Fujimori, S; Kamatani, N; Kelley, W N; Palella, T D (March 1, 1988). "Human adenine phosphoribosyltransferase deficiency. Demonstration of a single mutant allele common to the Japanese". Journal of Clinical Investigation. 81 (3). American Society for Clinical Investigation: 945–950. doi:10.1172/jci113408. ISSN 0021-9738. PMC 442550. PMID 3343350.
^ a bValaperta, Rea; Rizzo, Vittoria; Lombardi, Fortunata; Verdelli, Chiara; Piccoli, Marco; Ghiroldi, Andrea; Creo, Pasquale; Colombo, Alessio; Valisi, Massimiliano; Margiotta, Elisabetta; Panella, Rossella; Costa, Elena (July 1, 2014). "Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation". BMC Nephrology. 15 (1). Springer Science and Business Media LLC: 102. doi:10.1186/1471-2369-15-102. ISSN 1471-2369. PMC 4094445. PMID 24986359.
^ a b c dBollée, Guillaume; Dollinger, Cécile; Boutaud, Lucile; Guillemot, Delphine; Bensman, Albert; Harambat, Jérôme; Deteix, Patrice; Daudon, Michel; Knebelmann, Bertrand; Ceballos-Picot, Irène (2010). "Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency". Journal of the American Society of Nephrology. 21 (4). Ovid Technologies (Wolters Kluwer Health): 679–688. doi:10.1681/asn.2009080808. ISSN 1046-6673. PMC 2844298. PMID 20150536.
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^Harambat, Jérôme; Bollée, Guillaume; Daudon, Michel; Ceballos-Picot, Irène; Bensman, Albert (January 3, 2012). "Adenine phosphoribosyltransferase deficiency in children". Pediatric Nephrology. 27 (4). Springer Science and Business Media LLC: 571–579. doi:10.1007/s00467-011-2037-0. ISSN 0931-041X. PMID 22212387. Retrieved November 29, 2023.
^Cameron, J. S.; Moro, F.; Simmonds, H. A. (1993). "Gout, uric acid and purine metabolism in paediatric nephrology". Pediatric Nephrology. 7 (1). Springer Science and Business Media LLC: 105–118. doi:10.1007/bf00861588. ISSN 0931-041X. PMID 8439471. Retrieved November 29, 2023.
^ a b c d eBollée, Guillaume; Harambat, Jérôme; Bensman, Albert; Knebelmann, Bertrand; Daudon, Michel; Ceballos-Picot, Irène (2012). "Adenine Phosphoribosyltransferase Deficiency". Clinical Journal of the American Society of Nephrology. 7 (9). Ovid Technologies (Wolters Kluwer Health): 1521–1527. doi:10.2215/cjn.02320312. ISSN 1555-9041. PMID 22700886. Retrieved November 29, 2023.
^Kamatani, Naoyuki; Terai, Chihiro; Kuroshima, Shoko; Nishioka, Kusuki; Mikanagi, Kiyonobu (1987). "Genetic and clinical studies on 19 families with adenine phosphoribosyltransferase deficiencies". Human Genetics. 75 (2). Springer Science and Business Media LLC: 163–168. doi:10.1007/bf00591080. ISSN 0340-6717. PMID 3817810. Retrieved November 29, 2023.
^Zaidan, M.; Palsson, R.; Merieau, E.; Cornec-Le Gall, E.; Garstka, A.; Maggiore, U.; Deteix, P.; Battista, M.; Gagné, E.-R.; Ceballos-Picot, I.; Duong Van Huyen, J.-P.; Legendre, C.; Daudon, M.; Edvardsson, V.O.; Knebelmann, B. (2014). "Recurrent 2,8-Dihydroxyadenine Nephropathy: A Rare but Preventable Cause of Renal Allograft Failure". American Journal of Transplantation. 14 (11). Elsevier BV: 2623–2632. doi:10.1111/ajt.12926. ISSN 1600-6135. PMC 4560835. PMID 25307253.
^Nasr, S. H.; Sethi, S.; Cornell, L. D.; Milliner, D. S.; Boelkins, M.; Broviac, J.; Fidler, M. E. (January 11, 2010). "Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure". Nephrology Dialysis Transplantation. 25 (6). Oxford University Press (OUP): 1909–1915. doi:10.1093/ndt/gfp711. ISSN 0931-0509. PMID 20064951.
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^Edvardsson, Vidar; Palsson, Runolfur; Olafsson, Isleifur; Hjaltadottir, Gunnlaug; Laxdal, Thröstu (2001). "Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland". American Journal of Kidney Diseases. 38 (3). Elsevier BV: 473–480. doi:10.1053/ajkd.2001.26826. ISSN 0272-6386. PMID 11532677. Retrieved November 29, 2023.
^Delbarre, F.; Auscher, C.; Amor, B.; de Gery, A. (1974). "Gout with Adenine Phosphoribosyl Transferase Deficiency". Advances in Experimental Medicine and Biology. Vol. 41. Boston, MA: Springer US. pp. 333–339. doi:10.1007/978-1-4684-3294-7_40. ISBN 978-1-4684-3296-1. ISSN 0065-2598. PMID 4791206. Retrieved November 29, 2023.
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^Chen, Ju; Sahota, Amrik; Martin, Glenn F.; Hakoda, Masayuki; Kamatani, Naoyuki; Stambrook, Peter J.; Tischfield, Jay A. (1993). "Analysis of germline and in vivo somatic mutations in the human adenine phosphoribosyltransferase gene: Mutational hot spots at the intron 4 splice donor site and at codon 87". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 287 (2). Elsevier BV: 217–225. doi:10.1016/0027-5107(93)90014-7. ISSN 0027-5107. PMID 7685481. Retrieved November 29, 2023.
^Vernon, Hilary J.; Osborne, Christine; Tzortzaki, Eleni G.; Yang, Min; Chen, Jianmen; Rittling, Susan R.; Denhardt, David T.; Buyske, Steven; Bledsoe, Sharon B.; Evan, Andrew P.; Fairbanks, Lynette; Simmonds, H. Anne; Tischfield, J.A.Y.A.; Sahota, Amrik (2005). "Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity". Kidney International. 68 (3). Elsevier BV: 938–947. doi:10.1111/j.1523-1755.2005.00487.x. ISSN 0085-2538. PMID 16105024.
^Kamatani, Naoyuki; Kubota, Masaru; Willis, Erik H.; Frincke, Lee A.; Carson, Dennis A. (1984). "5′-Methylthioadenosine is the Major Source of Adenine in Human Cells". Advances in Experimental Medicine and Biology. Vol. 165 Pt B. Boston, MA: Springer US. pp. 83–88. doi:10.1007/978-1-4757-0390-0_18. ISBN 978-1-4757-0392-4. ISSN 0065-2598. PMID 6426269. Retrieved November 29, 2023.
^Huq, Aamira; Nand, Kushma; Juneja, Rajiv; Winship, Ingrid (October 23, 2018). "APRT deficiency: the need for early diagnosis". BMJ Case Reports. 2018. BMJ: bcr–2018–225742. doi:10.1136/bcr-2018-225742. ISSN 1757-790X. PMC 6202999. PMID 30355577.
^Ericson, Å.; Groth, T.; Niklasson, F.; De Verdier, C.-H. (1980). "Plasma concentration and renal excretion of adenine and 2,8-dihydroxyadenine after administration of adenine in man". Scandinavian Journal of Clinical and Laboratory Investigation. 40 (1). Informa UK Limited: 1–7. doi:10.3109/00365518009091520. ISSN 0036-5513. PMID 7367806. Retrieved November 29, 2023.
^Van Acker, Karel J.; Simmonds, H. Anne; Potter, Catherine; Cameron, J. Stewart (July 21, 1977). "Complete Deficiency of Adenine Phosphoribosyltransferase". New England Journal of Medicine. 297 (3). Massachusetts Medical Society: 127–132. doi:10.1056/nejm197707212970302. ISSN 0028-4793. PMID 865583. Retrieved November 29, 2023.
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Further reading
Runolfsdottir, Hrafnhildur Linnet; Palsson, Runolfur; Agustsdottir, Inger M.; Indridason, Olafur S.; Edvardsson, Vidar O. (2016). "Kidney Disease in Adenine Phosphoribosyltransferase Deficiency". American Journal of Kidney Diseases. 67 (3). Elsevier BV: 431–438. doi:10.1053/j.ajkd.2015.10.023. ISSN 0272-6386. PMC 4819988. PMID 26724837.