adenine phosphoribosyltransferase deficiency

{{Infobox medical condition (new)

| name = Adenine phosphoribosyltransferase deficiency

| image = Dihydroxyadenine.png

| caption = Dihydroxyadenine, an insoluble purine

| synonyms = APRT deficiency or 2,8 Dihydroxyadenine urolithiasis

| symptoms = Kidney and urinary tract stones, Urinary tract infections, blood in the urine, and chronic kidney disease.{{Cite web |last=Edvardsson |first=Vidar Orn |last2=Sahota |first2=Amrik |last3=Palsson |first3=Runolfur |date=September 26, 2019 |title=Adenine Phosphoribosyltransferase Deficiency |url=https://www.ncbi.nlm.nih.gov/books/NBK100238/ |access-date=November 30, 2023 |publisher=University of Washington, Seattle |pmid=22934314}}

| complications = End-stage renal disease.{{Cite web |date=October 1, 2012 |title=Adenine phosphoribosyltransferase deficiency: MedlinePlus Genetics |url=https://medlineplus.gov/genetics/condition/adenine-phosphoribosyltransferase-deficiency/ |access-date=November 30, 2023 |website=MedlinePlus}}

| onset = Infancy to late adulthood.

| duration =

| types = Type 1 and type 2.

| causes = Mutations in the APRT gene.

| risks =

| diagnosis = Urine microscopy and kidney stone analysis.

| differential = Uric acid nephrolithiasis, Xanthinuria, and Primary hyperoxaluria.

| prevention =

| treatment =

| medication = Allopurinol.

| prognosis =

| frequency = 0.4% to 1.2%

| deaths =

}}

Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive metabolic disorder caused by mutations of the APRT gene.{{Cite journal |last=Valaperta |first=Rea |last2=Rizzo |first2=Vittoria |last3=Lombardi |first3=Fortunata |last4=Verdelli |first4=Chiara |last5=Piccoli |first5=Marco |last6=Ghiroldi |first6=Andrea |last7=Creo |first7=Pasquale |last8=Colombo |first8=Alessio |last9=Valisi |first9=Massimiliano |last10=Margiotta |first10=Elisabetta |last11=Panella |first11=Rossella |last12=Costa |first12=Elena |date=July 1, 2014 |title=Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation |journal=BMC Nephrology |publisher=Springer Science and Business Media LLC |volume=15 |issue=1 |page=102 |doi=10.1186/1471-2369-15-102 |issn=1471-2369 |pmc=4094445 |pmid=24986359 |doi-access=free}} Adenine phosphoribosyltransferase (APRT) catalyzes the creation of pyrophosphate and adenosine monophosphate from 5-phosphoribosyl-1-pyrophosphate and adenine. Adenine phosphoribosyltransferase is a purine salvage enzyme. Genetic mutations of adenine phosphoribosyltransferase make large amounts of 2,8-Dihydroxyadenine causing urolithiasis and renal failure.{{Cite journal |last=Bollée |first=Guillaume |last2=Dollinger |first2=Cécile |last3=Boutaud |first3=Lucile |last4=Guillemot |first4=Delphine |last5=Bensman |first5=Albert |last6=Harambat |first6=Jérôme |last7=Deteix |first7=Patrice |last8=Daudon |first8=Michel |last9=Knebelmann |first9=Bertrand |last10=Ceballos-Picot |first10=Irène |year=2010 |title=Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency |journal=Journal of the American Society of Nephrology |publisher=Ovid Technologies (Wolters Kluwer Health) |volume=21 |issue=4 |pages=679–688 |doi=10.1681/asn.2009080808 |issn=1046-6673 |pmc=2844298 |pmid=20150536 |doi-access=free}}

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.{{Cite journal |last=Hidaka |first=Y |last2=Palella |first2=T D |last3=O'Toole |first3=T E |last4=Tarlé |first4=S A |last5=Kelley |first5=W N |date=November 1, 1987 |title=Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme. |journal=Journal of Clinical Investigation |publisher=American Society for Clinical Investigation |volume=80 |issue=5 |pages=1409–1415 |doi=10.1172/jci113219 |issn=0021-9738 |pmc=442397 |pmid=3680503 |doi-access=free}} 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.{{Cite journal |last=Hidaka |first=Y |last2=Tarlé |first2=S A |last3=Fujimori |first3=S |last4=Kamatani |first4=N |last5=Kelley |first5=W N |last6=Palella |first6=T D |date=March 1, 1988 |title=Human adenine phosphoribosyltransferase deficiency. Demonstration of a single mutant allele common to the Japanese. |journal=Journal of Clinical Investigation |publisher=American Society for Clinical Investigation |volume=81 |issue=3 |pages=945–950 |doi=10.1172/jci113408 |issn=0021-9738 |pmc=442550 |pmid=3343350 |doi-access=free}}

APRT deficiency is often identified by the presence of dihydroxyadenine in urine and kidney stones. Other diagnostic tests for APRT deficiency include urine microscopy, kidney stone analysis, renal biopsy, APRT activity, and genetic testing.{{Cite journal |last=Bollée |first=Guillaume |year=2014 |title=Adenine phosphoribosyltransferase deficiency: Leave no stone unturned |journal=World Journal of Clinical Urology |publisher=Baishideng Publishing Group Inc. |volume=3 |issue=3 |page=218 |doi=10.5410/wjcu.v3.i3.218 |issn=2219-2816 |doi-access=free}} Treatment of adenine phosphoribosyltransferase deficiency includes allopurinol and can prevent kidney stones and chronic kidney disease in most patients.{{Cite journal |last=Harambat |first=Jérôme |last2=Bollée |first2=Guillaume |last3=Daudon |first3=Michel |last4=Ceballos-Picot |first4=Irène |last5=Bensman |first5=Albert |date=January 3, 2012 |title=Adenine phosphoribosyltransferase deficiency in children |url=https://pubmed.ncbi.nlm.nih.gov/22212387/ |journal=Pediatric Nephrology |publisher=Springer Science and Business Media LLC |volume=27 |issue=4 |pages=571–579 |doi=10.1007/s00467-011-2037-0 |issn=0931-041X |pmid=22212387 |access-date=November 29, 2023}}

Signs and symptoms

Adenine phosphoribosyltransferase deficiency commonly manifests as symptoms of the kidneys and urinary tract such as nephrolithiasis, urolithiasis, crystalline nephropathy, hematuria, acute kidney injury, chronic kidney disease, and Urinary tract infections.{{Cite journal |last=Cameron |first=J. S. |last2=Moro |first2=F. |last3=Simmonds |first3=H. A. |author-link3=Anne Simmonds |year=1993 |title=Gout, uric acid and purine metabolism in paediatric nephrology |url=https://pubmed.ncbi.nlm.nih.gov/8439471/ |journal=Pediatric Nephrology |publisher=Springer Science and Business Media LLC |volume=7 |issue=1 |pages=105–118 |doi=10.1007/bf00861588 |issn=0931-041X |pmid=8439471 |access-date=November 29, 2023}} No extrarenal symptoms have been documented.{{Cite journal |last=Bollée |first=Guillaume |last2=Harambat |first2=Jérôme |last3=Bensman |first3=Albert |last4=Knebelmann |first4=Bertrand |last5=Daudon |first5=Michel |last6=Ceballos-Picot |first6=Irène |year=2012 |title=Adenine Phosphoribosyltransferase Deficiency |url=https://journals.lww.com/CJASN/Fulltext/2012/09000/Adenine_Phosphoribosyltransferase_Deficiency.20.aspx |journal=Clinical Journal of the American Society of Nephrology |publisher=Ovid Technologies (Wolters Kluwer Health) |volume=7 |issue=9 |pages=1521–1527 |doi=10.2215/cjn.02320312 |issn=1555-9041 |pmid=22700886 |access-date=November 29, 2023 |doi-access=free|url-access=subscription }}

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.{{Cite journal |last=Kamatani |first=Naoyuki |last2=Terai |first2=Chihiro |last3=Kuroshima |first3=Shoko |last4=Nishioka |first4=Kusuki |last5=Mikanagi |first5=Kiyonobu |year=1987 |title=Genetic and clinical studies on 19 families with adenine phosphoribosyltransferase deficiencies |url=https://pubmed.ncbi.nlm.nih.gov/3817810/ |journal=Human Genetics |publisher=Springer Science and Business Media LLC |volume=75 |issue=2 |pages=163–168 |doi=10.1007/bf00591080 |issn=0340-6717 |pmid=3817810 |access-date=November 29, 2023}} 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. In some cases APRT deficiency is first diagnosed after a kidney transplant when complications arise.{{Cite journal |last=Zaidan |first=M. |last2=Palsson |first2=R. |last3=Merieau |first3=E. |last4=Cornec-Le Gall |first4=E. |last5=Garstka |first5=A. |last6=Maggiore |first6=U. |last7=Deteix |first7=P. |last8=Battista |first8=M. |last9=Gagné |first9=E.-R. |last10=Ceballos-Picot |first10=I. |last11=Duong Van Huyen |first11=J.-P. |last12=Legendre |first12=C. |last13=Daudon |first13=M. |last14=Edvardsson |first14=V.O. |last15=Knebelmann |first15=B. |year=2014 |title=Recurrent 2,8-Dihydroxyadenine Nephropathy: A Rare but Preventable Cause of Renal Allograft Failure |journal=American Journal of Transplantation |publisher=Elsevier BV |volume=14 |issue=11 |pages=2623–2632 |doi=10.1111/ajt.12926 |issn=1600-6135 |pmc=4560835 |pmid=25307253 |doi-access=free}}{{Cite journal |last=Nasr |first=S. H. |last2=Sethi |first2=S. |last3=Cornell |first3=L. D. |last4=Milliner |first4=D. S. |last5=Boelkins |first5=M. |last6=Broviac |first6=J. |last7=Fidler |first7=M. E. |date=January 11, 2010 |title=Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure |journal=Nephrology Dialysis Transplantation |publisher=Oxford University Press (OUP) |volume=25 |issue=6 |pages=1909–1915 |doi=10.1093/ndt/gfp711 |issn=0931-0509 |pmid=20064951 |doi-access=free}} The first kidney stone episode can occur within the first few months of birth or later in life.{{Cite journal |last=Fujimori |first=S. |last2=Akaoka |first2=I. |last3=Sakamoto |first3=K. |last4=Yamanaka |first4=H. |last5=Nishioka |first5=K. |last6=Kamatani |first6=N. |year=1985 |title=Common characteristics of mutant adenine phosphoribosyltransferases from four separate Japanese families with 2,8-dihydroxyadenine urolithiasis associated with partial enzyme deficiencies |url=https://pubmed.ncbi.nlm.nih.gov/3876264/ |journal=Human Genetics |publisher=Springer Science and Business Media LLC |volume=71 |issue=2 |pages=171–176 |doi=10.1007/bf00283377 |issn=0340-6717 |pmid=3876264 |access-date=November 29, 2023}} In infants APRT deficiency may manifest as reddish brown diaper stains.{{Cite journal |last=Edvardsson |first=Vidar |last2=Palsson |first2=Runolfur |last3=Olafsson |first3=Isleifur |last4=Hjaltadottir |first4=Gunnlaug |last5=Laxdal |first5=Thröstu |year=2001 |title=Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland |url=https://pubmed.ncbi.nlm.nih.gov/11532677/ |journal=American Journal of Kidney Diseases |publisher=Elsevier BV |volume=38 |issue=3 |pages=473–480 |doi=10.1053/ajkd.2001.26826 |issn=0272-6386 |pmid=11532677 |access-date=November 29, 2023}}

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.{{Cite book |last=Delbarre |first=F. |url=https://pubmed.ncbi.nlm.nih.gov/4791206/ |title=Advances in Experimental Medicine and Biology |last2=Auscher |first2=C. |last3=Amor |first3=B. |last4=de Gery |first4=A. |publisher=Springer US |year=1974 |isbn=978-1-4684-3296-1 |volume=41 |publication-place=Boston, MA |pages=333–339 |chapter=Gout with Adenine Phosphoribosyl Transferase Deficiency |doi=10.1007/978-1-4684-3294-7_40 |issn=0065-2598 |pmid=4791206 |access-date=November 29, 2023}}{{Cite journal |last=CHEN |first=CHUNG-JEN |last2=SCHUMACHER |first2=H. RALPH |year=2009 |title=Adenine Phosphoribosyltransferase Deficiency in a Chinese Man with Early-onset Gout |journal=The Journal of Rheumatology |volume=36 |issue=5 |pages=1090–1091 |doi=10.3899/jrheum.081051 |issn=0315-162X |pmid=19435978 |doi-access=free}}

= Complications =

Dihydroxyadenine crystals precipitate inside the interstitium and renal tubules as well as cause severe kidney damage. Dihydroxyadenine nephropathy can initially present acutely and lead to renal failure within days to weeks. More commonly dihydroxyadenine nephropathy may develop insidiously, causing a progressive decline in kidney function over the span of several years. Dehydration can trigger acute renal failure which causes urine supersaturation, oliguria, and precipitation of dihydroxyadenine.

Causes

Image:Autorecessive.svg.]]

Adenine phosphoribosyltransferase deficiency is an autosomal recessive condition which means that two copies of the mutated gene must be present for adenine phosphoribosyltransferase deficiency to develop.{{Cite web |title=Autosomal recessive: MedlinePlus Medical Encyclopedia |url=https://medlineplus.gov/ency/article/002052.htm |access-date=November 30, 2023 |website=MedlinePlus}}

= 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.{{Cite journal |last=Chen |first=Ju |last2=Sahota |first2=Amrik |last3=Martin |first3=Glenn F. |last4=Hakoda |first4=Masayuki |last5=Kamatani |first5=Naoyuki |last6=Stambrook |first6=Peter J. |last7=Tischfield |first7=Jay A. |year=1993 |title=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 |url=https://pubmed.ncbi.nlm.nih.gov/7685481/ |journal=Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis |publisher=Elsevier BV |volume=287 |issue=2 |pages=217–225 |doi=10.1016/0027-5107(93)90014-7 |issn=0027-5107 |pmid=7685481 |access-date=November 29, 2023}} Complete APRT deficiency develops in people who carry mutations in both copies of the APRT gene.

There is no evidence that genotype correlates with phenotype and environmental factors or modifiers might be responsible for this heterogeneity.{{Cite journal |last=Vernon |first=Hilary J. |last2=Osborne |first2=Christine |last3=Tzortzaki |first3=Eleni G. |last4=Yang |first4=Min |last5=Chen |first5=Jianmen |last6=Rittling |first6=Susan R. |last7=Denhardt |first7=David T. |last8=Buyske |first8=Steven |last9=Bledsoe |first9=Sharon B. |last10=Evan |first10=Andrew P. |last11=Fairbanks |first11=Lynette |last12=Simmonds |first12=H. Anne |last13=Tischfield |first13=J.A.Y.A. |last14=Sahota |first14=Amrik |year=2005 |title=Aprt/Opn double knockout mice: Osteopontin is a modifier of kidney stone disease severity |journal=Kidney International |publisher=Elsevier BV |volume=68 |issue=3 |pages=938–947 |doi=10.1111/j.1523-1755.2005.00487.x |issn=0085-2538 |pmid=16105024 |doi-access=free}}

Mechanism

All tissues express the APRT enzyme, which offers the sole metabolic route for recovering adenine from dietary and polyamine biosynthesis sources.{{Cite book |last=Kamatani |first=Naoyuki |url=https://pubmed.ncbi.nlm.nih.gov/6426269/ |title=Advances in Experimental Medicine and Biology |last2=Kubota |first2=Masaru |last3=Willis |first3=Erik H. |last4=Frincke |first4=Lee A. |last5=Carson |first5=Dennis A. |publisher=Springer US |year=1984 |isbn=978-1-4757-0392-4 |volume=165 Pt B |publication-place=Boston, MA |pages=83–88 |chapter=5′-Methylthioadenosine is the Major Source of Adenine in Human Cells |doi=10.1007/978-1-4757-0390-0_18 |issn=0065-2598 |pmid=6426269 |access-date=November 29, 2023}} 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.{{Cite journal |last=Huq |first=Aamira |last2=Nand |first2=Kushma |last3=Juneja |first3=Rajiv |last4=Winship |first4=Ingrid |date=October 23, 2018 |title=APRT deficiency: the need for early diagnosis |journal=BMJ Case Reports |publisher=BMJ |volume=2018 |pages=bcr–2018–225742 |doi=10.1136/bcr-2018-225742 |issn=1757-790X |pmc=6202999 |pmid=30355577 |doi-access=free}} Due to its high renal clearance, dihydroxyadenine may be secreted tubularly in addition to being filtered.{{Cite journal |last=Ericson |first=Å. |last2=Groth |first2=T. |last3=Niklasson |first3=F. |last4=De Verdier |first4=C.-H. |year=1980 |title=Plasma concentration and renal excretion of adenine and 2,8-dihydroxyadenine after administration of adenine in man |url=https://pubmed.ncbi.nlm.nih.gov/7367806/ |journal=Scandinavian Journal of Clinical and Laboratory Investigation |publisher=Informa UK Limited |volume=40 |issue=1 |pages=1–7 |doi=10.3109/00365518009091520 |issn=0036-5513 |pmid=7367806 |access-date=November 29, 2023}} Thus, APRT deficiency causes elevated dihydroxyadenine levels in the urine.{{Cite journal |last=Van Acker |first=Karel J. |last2=Simmonds |first2=H. Anne |last3=Potter |first3=Catherine |last4=Cameron |first4=J. Stewart |date=July 21, 1977 |title=Complete Deficiency of Adenine Phosphoribosyltransferase |url=https://pubmed.ncbi.nlm.nih.gov/865583/ |journal=New England Journal of Medicine |publisher=Massachusetts Medical Society |volume=297 |issue=3 |pages=127–132 |doi=10.1056/nejm197707212970302 |issn=0028-4793 |pmid=865583 |access-date=November 29, 2023}} Dihydroxyadenine precipitates in renal parenchyma and becomes extremely insoluble in urine, forming crystals that can accumulate, grow, and form stones.{{Cite journal |last=Hesse |first=A. |last2=Miersc |first2=W.-D. |last3=Classen |first3=A. |last4=Thon |first4=A. |last5=Doppler |first5=W. |year=1988 |title=2,8-Dihydroxyadeninuria: Laboratory Diagnosis and Therapy Control |url=https://pubmed.ncbi.nlm.nih.gov/3176201/ |journal=Urologia Internationalis |publisher=S. Karger AG |volume=43 |issue=3 |pages=174–178 |doi=10.1159/000281332 |issn=1423-0399 |pmid=3176201 |access-date=November 29, 2023}} This can lead to crystalline nephropathy.

Diagnosis

Adenine phosphoribosyltransferase deficiency is diagnosed based on the identification of dihydroxyadenine by kidney stone analysis or examination of crystals in the urine. 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.{{Cite journal |last=Daudon |first=Michel |last2=Jungers |first2=Paul |date=October 19, 2004 |title=Clinical Value of Crystalluria and Quantitative Morphoconstitutional Analysis of Urinary Calculi |url=http://www.ncbi.nlm.nih.gov/pubmed/15499212 |journal=Nephron Physiology |publisher=S. Karger AG |volume=98 |issue=2 |pages=31–36 |doi=10.1159/000080261 |issn=1660-2137 |pmid=15499212 |access-date=November 29, 2023}} Biochemical stone analysis is unreliable for diagnosing APRT deficiency and is unable to distinguish dihydroxyadenine from uric acid. 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. One way to quantify something is to count the number of crystals per volume unit, which is higher in patients who are not receiving treatment.

Treatment

References

External links

[https://www.rarekidneystones.org/dha/ Rare Kidney Stone Consortium]
[https://ukkidney.org/rare-renal/clinician/aprt-deficiency UK Kidney Association]

{{Medical resources

| ICD11 = {{ICD11|5C55.0Y}}

| ICD10 = {{ICD10|E79.8}}

| ICD10CM =

| ICD9 = {{ICD9|277.2}}

| ICDO =

| OMIM = 614723

| MeshID = C538228

| DiseasesDB = 32632

| SNOMED CT = 124274002

| Curlie =

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| PatientUK =

| NCI =

| GeneReviewsNBK = NBK100238

| GeneReviewsName = Adenine Phosphoribosyltransferase Deficiency

| NORD =

| GARDNum = 546

| GARDName = Adenine phosphoribosyltransferase deficiency

| RP =

| AO =

| WO =

| OrthoInfo =

| Orphanet = 976

| Scholia = Q4682223

| OB =

}}

Category:Autosomal recessive disorders

Category:Kidney diseases

Category:Inborn errors of purine-pyrimidine metabolism