Clinical characteristics.

Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production and renal excretion of 2,8-dihydroxyadenine (DHA), which leads to kidney stone formation and crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected persons symptoms do not occur until adulthood. If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life.

Diagnosis/testing.

The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants in APRT. The detection of the characteristic round, brown DHA crystals by urine microscopy is highly suggestive of the disorder.

Management.

Treatment of manifestations: Treatment with the xanthine oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase) allopurinol or febuxostat can improve kidney function, even in individuals with advanced CKD. The prescribed dose of allopurinol and febuxostat should not routinely be reduced in affected individuals who have impaired kidney function. Ample fluid intake is advised. Surgical management of DHA nephrolithiasis is the same as for other types of kidney stones. ESRD is treated with dialysis and kidney transplantation. Even after kidney transplantation, treatment with an XOR is recommended.

Surveillance: Measurement of eGFR and urinary DHA excretion (or urine microscopy for assessment of DHA crystalluria) every 6-12 months; routine follow up to facilitate adherence to pharmacologic treatment at least annually; periodic renal ultrasound examination should be considered to evaluate for new asymptomatic kidney stones.

Agents/circumstances to avoid: Azathioprine and mercaptopurine should not be given to individuals taking either allopurinol or febuxostat.

Evaluation of relatives at risk: It is recommended that sibs of an affected individual undergo APRT enzyme activity measurement or molecular genetic testing (if the pathogenic variants in a family have been identified) to allow early diagnosis and treatment and improve long-term outcome.

Pregnancy management: The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Some post-transplantation immunosuppressive therapies can have adverse effects on the developing fetus. Ideally a thorough discussion of the risks and benefits of maternal medication use during pregnancy should take place with an appropriate health care provider prior to conception.

Genetic counseling.

APRT deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being normal. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) should be suspected in individuals with the following clinical, radiographic, laboratory, and pathology findings [Balasubramaniam et al 2016, Runolfsdottir et al 2016, Garigali et al 2019, Runolfsdottir et al 2019a].

Clinical manifestations

• Kidney stone disease and renal colic
• Chronic kidney disease (CKD)
• Crystal nephropathy (confirmed by kidney biopsy; see Pathology)
• Reddish-brown diaper stain in infants and young children
• Allograft dysfunction following kidney transplantation

Radiographic findings

• Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray.
• Ultrasound examination frequently demonstrates increased echogenicity of the kidneys.

Laboratory findings

• Urine microscopy. The round and brown DHA crystals can usually be detected by urine microscopy (Figure 1A). Small and medium-sized DHA crystals display a central Maltese cross pattern when viewed by polarized light microscopy (Figure 1B), while larger crystal aggregates do not as they are impermeable to light.
  Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [Bollée et al 2010, Edvardsson et al 2013]. (2) High urine pH in individuals with radiolucent stones provides an additional clue to the diagnosis of APRT deficiency because uric acid stones develop in acidic urine [Edvardsson et al 2013] (see Differential Diagnosis).
• Kidney stone analysis. Analysis of DHA crystals and kidney stone material using infrared or ultraviolet spectrophotometry (at both acidic and alkaline pH) and/or x-ray crystallography differentiates DHA from uric acid and xanthine, which also form radiolucent stones. Although stones in persons with APRT deficiency are predominantly composed of DHA, they may contain trace amounts of other minerals.
  • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see Establishing the Diagnosis).
  • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended.

Figure 1.

Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Conventional light microscopy shows the typical brown DHA crystals. (more...)

Pathology. Renal histopathologic findings in persons with APRT deficiency and CKD or acute allograft dysfunction are characterized by diffuse tubulointerstitial DHA crystal deposits accompanied by inflammation and fibrosis (see Figure 2), which may be observed even in individuals without a history of kidney stones [Nasr et al 2010, Zaidan et al 2014, Agrawal et al 2015, Lusco et al 2017].

Figure 2.

Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A. 2,8-dihydroxyadenine crystals are seen within tubular lumens (arrows). Significant tubular (more...)

Note: It is important not to confuse the histopathologic manifestations of DHA crystal nephropathy with those of other crystal nephropathies, particularly those caused by oxalate (particularly primary hyperoxaluria) and uric acid deposits [Nasr et al 2010].

Establishing the Diagnosis

The diagnosis of APRT deficiency is established in a proband with absent APRT enzyme activity in red cell lysates or biallelic pathogenic variants in APRT identified by molecular genetic testing (see Table 1). See Figure 3 for a diagnostic algorithm [Edvardsson et al 2013].

Figure 3.

Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From Edvardsson et al [2013]. Used with permission.

Note: Kidney stone analysis suggesting APRT deficiency is not reliable enough to establish the diagnosis.

Clinical Description

More than 400 individuals with adenine phosphoribosyltransferase (APRT) deficiency have been reported in the medical literature [Bollée et al 2010, Bollée et al 2012, Harambat et al 2012, Balasubramaniam et al 2014, Zaidan et al 2014, Runolfsdottir et al 2016, Huq et al 2018, Runolfsdottir et al 2019a, Runolfsdottir et al 2019b].

Age at presentation. APRT deficiency may present at any age; there is no typical age of clinical onset. However, in at least 50% of affected individuals, symptoms do not occur until adulthood.

• The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [Runolfsdottir et al 2016].
• Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years.
• In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing.

Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be otherwise asymptomatic [Huq et al 2018].

Kidney stone disease. Between 60% and 90% of affected individuals have already developed kidney stones at diagnosis. In the absence of pharmacotherapy (see Management, Table 4), the majority of those untreated symptomatic persons experience stone recurrence [Runolfsdottir et al 2019a], abdominal pain, and/or lower urinary tract symptoms (e.g., straining, hesitancy, dribbling, incomplete bladder emptying).

Chronic kidney disease (CKD) secondary to DHA crystal nephropathy is present in more than 50% of individuals at diagnosis [Runolfsdottir et al 2016]. As many as 15% of affected individuals have progressed to end-stage renal disease (ESRD) at the time of diagnosis of APRT deficiency [Harambat et al 2012, Runolfsdottir et al 2016].

• In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed.
• The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [Runolfsdottir et al 2019a].

ESRD. Approximately 20%-25% of affected individuals develop ESRD, usually in adult life, if adequate treatment is not provided.

• Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [Runolfsdottir et al 2019a] (see Management, Table 4).
• Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals.

APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [Neetens et al 1986; Author, personal observation], which merits further study.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established; clinical features are known to vary greatly among individuals with the same pathogenic variants [Bollée et al 2010, Runolfsdottir et al 2016].

Nomenclature

Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [Sahota et al 2001]. However, this distinction is of historical interest only, as APRT enzyme activity in intact cells has been shown to be less than 1% in both types [Kamatani et al 1985] (see APRT Enzyme Activity).

Prevalence

The estimated heterozygote frequency in different populations ranges from 0.4% to 1.2% [Hidaka et al 1987, Sahota et al 2001], suggesting that the prevalence of a homozygous state is at least 1:50,000 to 1:100,000.

If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9,000 in Europe, and 8,000 in the Americas, including at least 3,000 affected individuals in the US alone. Most of these individuals are currently unrecognized, and thus not benefitting from medical therapy.

Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [Zaidan et al 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with adenine phosphoribosyltransferase (APRT) deficiency, the evaluations in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Prevention of Primary Manifestations

Adequate treatment of APRT deficiency with allopurinol or febuxostat prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [Edvardsson et al 2001, Bollée et al 2010, Harambat et al 2012] (see Table 4).

Surveillance

No consensus surveillance guidelines have been established.

Agents/Circumstances to Avoid

Azathioprine and mercaptopurine should be avoided by individuals taking XOR inhibitors (allopurinol or febuxostat). Inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or mercaptopurine, leading to toxicity.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Approximately 15% of individuals with APRT deficiency may be asymptomatic [Bollée et al 2010, Runolfsdottir et al 2016]; these individuals are usually identified during family screening.

Evaluations can include the following:

• Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants.
• APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied.

Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rabbits or rats; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation.

Animal studies using high doses of febuxostat in rats and rabbits have not supported a teratogenic effect. However, very high doses in pregnant rats have been associated with neonatal loss and low pup birthweight.

Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus.

A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception.

See MotherToBaby for further information on medication use during pregnancy.

Therapies and Assays Under Investigation

Urinary DHA measurements. The authors' group has recently developed a urinary DHA assay using ultra-high-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) [Thorsteinsdottir et al 2016], which is expected to facilitate both the clinical diagnosis and monitoring of pharmacotherapy of individuals with APRT deficiency [Edvardsson et al 2018]. Further clinical studies to examine the sensitivity and specificity of the assay are currently under way.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Adenine phosphoribosyltransferase (APRT) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one APRT pathogenic variant).
• Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of inheriting two APRT pathogenic variants, a 50% chance of inheriting one pathogenic variant and being an asymptomatic carrier, and a 25% chance of inheriting two benign alleles.
• As many as 15%-20% of individuals who have inherited two APRT pathogenic variants may be asymptomatic despite their abnormal urinary DHA excretion [Edvardsson et al 2001, Bollée et al 2010]. Such individuals are usually identified during family screening.
• Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder.

Offspring of a proband. Unless an individual with APRT deficiency has children with an affected individual or a carrier, his/her offspring will be obligate heterozygotes (carriers) for a pathogenic variant in APRT.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an APRT pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the APRT pathogenic variants in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Testing of at-risk asymptomatic sibs of individuals with APRT deficiency is possible after molecular genetic testing has identified the specific pathogenic variants in the family. Because an effective treatment is available, this testing is appropriate to consider for at-risk sibs regardless of age. However, such testing should be performed in the context of formal genetic counseling, and is not useful in predicting age at symptom onset, type and severity of symptoms, or rate of progression in asymptomatic individuals.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling – including discussion of potential risks to offspring, the availability of effective, preventive drug treatment (see Table 4 and Prevention of Primary Manifestations), and reproductive options – to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the APRT pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for APRT deficiency are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

APRT is a five-exon gene with a coding region of 540 bp. APRT encodes APRT, a cytoplasmic enzyme that catalyzes the Mg⁺⁺-dependent synthesis of 5'-adenosine monophosphate from adenine and 5-phosphoribosyl-1-pyrophosphate (PRPP) [Sahota et al 2001]. The enzyme is a homodimer [Sahota et al 2001].

The crystal structure of recombinant human APRT in complex with adenosine monophosphate (AMP) has been determined [Silva et al 2004]. The protein, which comprises nine β-strands and six α-helices, forms three domains:

• A core that includes the PRPP-binding motif
• A flexible loop besides the core region which may be involved in the catalytic function
• A variable region primarily involved in base recognition

Mechanism of disease causation. APRT deficiency occurs through a loss-of-function mechanism. APRT activity in red cell lysates from individuals with APRT deficiency is typically less than 1% of control values [Sahota et al 2001]. The two reported exceptions are noted in Table 7 [Deng et al 2001].

More than 50 pathogenic variants have been identified in the coding region of APRT in over 300 affected individuals from more than 25 countries, including at least 200 individuals from Japan.

Rarely, large deletions of both APRT and GALNS, pathogenic variants in which cause mucopolysaccharidosis type IVA, have been reported [Fukuda et al 1996, Wang et al 1999]. Of note, a complex deletion of 254 base pairs with insertion of eight base pairs has also been reported (see Table 7).

Consensus Statements / Published Guidelines

• Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2013 Suppl 3:1–150. online Available. Accessed 2-28-22.

Literature Cited

• Agrawal V, Gibson PC, Sahota A, Nasr SH. Crystalline nephropathy in an identical twin. Am J Kidney Dis. 2015;65:A17–9. [PMC free article: PMC5926183] [PubMed: 25919501]
• Balasubramaniam GS, Arenas-Hernandez M, Escuredo E, Fairbanks L, Marinaki T, Mapplebeck S, Sheaff M, Almond MK. Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey. Clin Kidney J. 2016;9:800–6. [PMC free article: PMC5162415] [PubMed: 27994857]
• Balasubramaniam S, Duley JA, Christodoulou J. Inborn errors of purine metabolism: clinical update and therapies. J Inherit Metab Dis. 2014;37:669–86. [PubMed: 24972650]
• Bollée G, Dollinger C, Boutaud L, Guillemot D, Bensman A, Harambat J, Deteix P, Daudon M, Knebelmann B, Ceballos-Picot I. Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency. J Am Soc Nephrol. 2010;21:679–88. [PMC free article: PMC2844298] [PubMed: 20150536]
• Bollée G, Harambat J, Bensman A, Knebelmann B, Daudon M, Ceballos-Picot I. Adenine phosphoribosyltransferase deficiency. Clin J Am Soc Nephrol. 2012;7:1521–7. [PubMed: 22700886]
• Deng L, Yang M, Fründ S, Wessel T, De Abreu RA, Tischfield JA, Sahota A. 2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT. Mol Genet Metab. 2001;72:260–4. [PubMed: 11243733]
• Di Pietro V, Perruzza I, Amorini AM, Balducci A, Ceccarelli L, Lazzarino G, Barsotti P, Giardina B, Tavazzi B. Clinical, biochemical and molecular diagnosis of a compound homozygote for the 254 bp deletion-8 bp insertion of the APRT gene suffering from severe renal failure. Clin Biochem. 2007;40:73–80. [PubMed: 17126311]
• Edvardsson V, Palsson R, Olafsson I, Hjaltadottir G, Laxdal T. Clinical features and genotype of adenine phosphoribosyltransferase deficiency in Iceland. Am J Kidney Dis. 2001;38:473–80. [PubMed: 11532677]
• Edvardsson VO, Goldfarb DS, Lieske JC, Beara-Lasic L, Anglani F, Milliner DS, Palsson R. Hereditary causes of kidney stones and chronic kidney disease. Pediatr Nephrol. 2013;28:1923–42. [PMC free article: PMC4138059] [PubMed: 23334384]
• Edvardsson VO, Runolfsdottir HL, Thorsteinsdottir UA, Sch, Agustsdottir IM, Oddsdottir GS, Eiriksson F, Goldfarb DS, Thorsteinsdottir M, Palsson R. Comparison of the effect of allopurinol and febuxostat on urinary 2,8-dihydroxyadenine excretion in patients with adenine phosphoribosyltransferase deficiency (APRTd): a clinical trial. Eur J Intern Med. 2018;48:75–9. [PMC free article: PMC5817015] [PubMed: 29241594]
• Fukuda S, Tomatsu S, Masuno M, Ogawa T, Yamagishi A, Rezvi GM, Sukegawa K, Shimozawa N, Suzuki Y, Kondo N, Imaizumi K, Kuroki Y, Okabe T, Orii T. Mucopolysaccharidosis IVA: submicroscopic deletion of 16q24.3 and a novel R386C mutation of N-acetylgalactosamine-6-sulfate sulfatase gene in a classical Morquio disease. Hum Mutat. 1996;7:123–34. [PubMed: 8829629]
• Garigali G, Marra G, Rizzo V, de Liso F, Berrettini A, Daudon M, Fogazzi GB. A virtuous diagnostic and therapeutic roadmap triggered by a motivated and skilful urinary sediment examination. Clin Chim Acta. 2019;492:23–5. [PubMed: 30707895]
• Harambat J, Bollée G, Daudon M, Ceballos-Picot I, Bensman A, et al. Adenine phosphoribosyltransferase deficiency in children. Pediatr Nephrol. 2012;27:571–9. [PubMed: 22212387]
• Hidaka Y, Palella TD, O'Toole TE, Tarle SA, Kelley WN. Human adenine phosphoribosyltransferase. Identification of allelic mutations at the nucleotide level as a cause of complete deficiency of the enzyme. J Clin Invest. 1987;80:1409–15. [PMC free article: PMC442397] [PubMed: 3680503]
• Huq A, Nand K, Juneja R, Winship I. APRT deficiency: the need for early diagnosis. BMJ Case Rep. 2018:bcr-2018-225742. pii. [PMC free article: PMC6202999] [PubMed: 30355577]
• Ikeda H, Watanabe T, Toyama D, Isoyama K. Use of LightCycler mutation analysis to detect type II adenine phosphoribosyltransferase deficiency in two patients with 2,8-dihydroxyadeninuria. CEN Case Rep. 2016;5:34–9. [PMC free article: PMC5411657] [PubMed: 28509161]
• Kamatani N, Takeuchi F, Nishida Y, Yamanaka H, Nishioka K, Tatara K, Fujimori S, Kaneko K, Akaoka I, Tofuku Y. Severe impairment in adenine metabolism with a partial deficiency of adenine phosphoribosyltransferase. Metabolism. 1985;34:164–8. [PubMed: 3871499]
• Lusco MA, Fogo AB, Najafian B, Alpers CE. AJKD Atlas of Renal Pathology: 2,8-dihydroxyadeninuria. Am J Kidney Dis. 2017;69:e15–e16. [PubMed: 28236886]
• Menardi C, Schneider R, Neuschmid-Kaspar F, Klocker H, Hirsch-Kauffmann M, Auer B, Schweiger M. Human APRT deficiency: indication for multiple origins of the most common Caucasian mutation and detection of a novel type of mutation involving intrastrand-templated repair. Hum Mutat. 1997;10:251–5. [PubMed: 9298830]
• Nasr SH, Sethi S, Cornell LD, Milliner DS, Boelkins M, Broviac J, Fidler ME. Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure. Nephrol Dial Transplant. 2010;25:1909–15. [PubMed: 20064951]
• Neetens A, Van Acker KJ, Marien N. Corneal dystrophy and total adenine phosphoribosyltransferase (APRT) deficiency. Bull Soc Belge Ophtalmol. 1986;213:93–7. [PubMed: 3487363]
• Runolfsdottir HL, Palsson R, Agustsdottir IM, Indridason OS, Edvardsson VO. Kidney disease in adenine phosphoribosyltransferase deficiency. Am J Kidney Dis. 2016;67:431–8. [PMC free article: PMC4819988] [PubMed: 26724837]
• Runolfsdottir HL, Palsson R, Agustsdottir IM, Indridason OS, Edvardsson VO. Renal outcome of APRT deficiency presenting in childhood. Pediatr Nephrol. 2019a;34:435–42. [PMC free article: PMC6349544] [PubMed: 30443743]
• Runolfsdottir HL, Palsson R, Thorsteinsdottir UA, Indridason OS, Agustsdottir IMS, Oddsdottir GS, Thorsteinsdottir M, Edvardsson VO. Urinary 2,8-dihydroxyadenine excretion in patients with adenine phosphoribosyltransferase deficiency, carriers and healthy control subjects. Mol Genet Metab. 2019b;128:144–50. [PMC free article: PMC6864267] [PubMed: 31378568]
• Sahota AS, Tischfield JA, Kamatani N, Simmonds HA. Adenine phosphoribosyltransferase deficiency and 2,8-dihydroxyadenine lithiasis. In: Scriver CR, Sly WS, Valle D, Vogelstein B, Childs B, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001:2571-84.
• Silva M, Silva CH, Iulek J, Thiemann OH. Three-dimensional structure of human adenine phosphoribosyltransferase and its relation to DHA-urolithiasis. Biochemistry. 2004;43:7663–71. [PubMed: 15196008]
• Thorsteinsdottir M, Thorsteinsdottir UA, Eiriksson FF, Runolfsdottir HL, Agustsdottir IM, Oddsdottir S, Sigurdsson BB, Hardarson HK, Kamble NR, Sigurdsson ST, Edvardsson VO, Palsson R. Quantitative UPLC-MS/MS assay of urinary 2,8-dihydroxyadenine for diagnosis and management of adenine phosphoribosyltransferase deficiency. J Chromatogr B Analyt Technol Biomed Life Sci. 2016;1036-1037:170–7. [PMC free article: PMC5445224] [PubMed: 27770717]
• Wang L, Ou X, Sebesta I, Vondrak K, Krijt J, Elleder M, Poupetova H, Ledvinova J, Zeman J, Simmonds HA, Tischfield JA, Sahota A. Combined adenine phosphoribosyltransferase and N-acetylgalactosamine-6-sulfate sulfatase deficiency. Mol Genet Metab. 1999;68:78–85. [PubMed: 10479485]
• Zaidan M, Palsson R, Merieau E, Cornec-Le Gall E, Garstka A, Maggiore U, Deteix P, Battista M, Gagné ER, Ceballos-Picot I, Duong Van Huyen JP, Legendre C, Daudon M, Edvardsson VO, Knebelmann B. Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure. Am J Transplant. 2014;14:2623–32. [PMC free article: PMC4560835] [PubMed: 25307253]

Author Notes

Vidar Orn Edvardsson, MD
Children's Medical Center, Office 21-D
Landspítali –The National University Hospital of Iceland
Hringbraut, 101 Reykjavik, Iceland
Tel: +354-543-1000; Fax: + 354-543-3021
Email: vidare@landspitali.is and rarekidneystones@landspitali.is

Amrik Sahota, PhD, Consultant
APRT Deficiency Research Program
Department of Genetics
Life Sciences Building
Rutgers University
145 Bevier Road
Piscataway, NJ 08854, USA
Tel: 732-445-7185; Fax: 732-445-1147
Email: sahota@biology.rutgers.edu

Runolfur Palsson, MD
Division of Nephrology, Office 14-F
Landspítali – The National University Hospital of Iceland
Hringbraut, 101 Reykjavik, Iceland
Tel: +354-543-1000; Fax: + 354-543-6467
Email: runolfur@landspitali.is and rarekidneystones@landspitali.is

The official website of the Rare Kidney Stone Consortium: rarekidneystones.org

The APRT Deficiency Research Program at Landspítali – The National University Hospital of Iceland, headed by Drs Vidar Orn Edvardsson and Runolfur Palsson, is part of the international Rare Kidney Stone Consortium (RKSC) (rarekidneystones.org) founded in 2009 with support from the National Institute of Diabetes and Digestive and Kidney Diseases and the Office of Rare Diseases Research at the US National Institutes of Health.

Acknowledgments

Authors V Edvardsson and R Palsson gratefully acknowledge the support of the Rare Kidney Stone Consortium (U54DK083908), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research. The Rare Kidney Stone Consortium is funded through a collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases. We thank Hrafnhildur Linnet Runolfsdottir, MD, Faculty of Medicine, School of Health Sciences, University of Iceland, and Landspítali – The National University Hospital of Iceland, Reykjavik, Iceland, for generating the images of the urinary DHA crystals, and Sverrir Hardarson, MD, Department of Pathology, Landspítali – The National University Hospital of Iceland, for providing the photomicrographs of the kidney biopsy specimens.

Revision History

• 26 September 2019 (ma) Comprehensive update posted live
• 18 June 2015 (me) Comprehensive update posted live
• 30 August 2012 (me) Review posted live
• 2 May 2012 (ve) Original submission