Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8-dihydroxyadenine stones and renal failure secondary to intratubular crystalline precipitation. Little is known regarding the clinical presentation of APRT deficiency, especially in the white population. We retrospectively reviewed all 53 cases of APRT deficiency (from 43 families) identified at a single institution between 1978 and 2009. The median age at diagnosis was 36.3 years (range 0.5 to 78.0 years). In many patients, a several-year delay separated the onset of symptoms and diagnosis. Of the 40 patients from 33 families with full clinical data available, 14 (35%) had decreased renal function at diagnosis. Diagnosis occurred in six (15%) patients after reaching ESRD, with five diagnoses made at the time of disease recurrence in a renal allograft. Eight (20%) patients reached ESRD during a median follow-up of 74 months. Thirty-one families underwent APRT sequencing, which identified 54 (87%) mutant alleles on the 62 chromosomes analyzed. We identified 18 distinct mutations. A single T insertion in a splice donor site in intron 4 (IVS4 + 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 + 2insT mutation in two (0.98%) of 204 chromosomes of healthy newborns. This report, which is the largest published series of APRT deficiency to date, highlights the underdiagnosis and potential severity of this disease. Early diagnosis is crucial for initiation of effective treatment with allopurinol and for prevention of renal complications.

Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency

Adenine phosphoribosyltransferase (APRT) deficiency in humans is an autosomal recessive syndrome characterized by the urinary excretion of adenine and the highly insoluble compound 2,8-dihydroxyadenine (DHA) that can produce kidney stones or renal failure. Targeted homologous recombination in embryonic stem cells was used to produce mice that lack APRT. Mice homozygous for a null Aprt allele excrete adenine and DHA crystals in the urine. Renal histopathology showed extensive tubular dilation, inflammation, necrosis, and fibrosis that varied in severity between different mouse backgrounds. Thus, biochemical and histological changes in these mice mimic the human disease and provide a suitable model of human hereditary nephrolithiasis.

https://www.pnas.org/content/pnas/93/11/5307.full.pdf

Adenine phosphoribosyltransferase-deficient mice develop 2,8-dihydroxyadenine nephrolithiasis.

Complete adenine phosphoribosyltransferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. The low solubility of DHA results in precipitation of this compound and the formation of urinary crystals and stones. The disease can present as recurrent urolithiasis or nephropathy secondary to crystal precipitation into renal parenchyma (DHA nephropathy). The diagnostic tools available-including stone analysis, crystalluria, and APRT activity measurement-make the diagnosis easy to confirm when APRT deficiency is suspected. However, the disease can present at any age, and the variability of symptoms can present a diagnostic challenge to many physicians. The early recognition and treatment of APRT deficiency are of crucial importance for preventing irreversible loss of renal function, which still occurs in a non-negligible proportion of cases. This review summarizes the genetic and metabolic mechanisms underlying stone formation and renal disease, along with the diagnosis and management of APRT deficiency.

/pdf/adenine-phosphoribosyltransferase-deficiency-3pif4phuus.pdf

Adenine phosphoribosyltransferase deficiency.

Few studies have examined the relative risk of recurrence of different stone types The object of the present study was to evaluate the tendency for stone recurrence as a function of major mineral composition of the stones and morphological characteristics of the stones This study was carried out using 38,274 stones for which we had data available to specify if the stone was from the first or a subsequent urinary stone episode Stones were analyzed for morphology by stereomicroscope and for composition by infrared spectroscopy Overall, 427% of stones were from patients who had had a previous stone event, with these being more frequent in men (444%) than in women (389%, p < 00001) Age of first stone occurrence was lowest for dihydroxyadenine (157 ± 166 years) and highest for anhydrous uric acid (625 ± 149 years), with the average age of first stones of calcium oxalate falling in the middle (407 ± 146 years for calcium oxalate dihydrate, and 484 ± 151 years for calcium oxalate monohydrate, COM) By composition alone, COM was among the least recurrent of stones, with only 380% of COM stones coming from patients who had had a previous episode; however, when the different morphological types of COM were considered, type Ic—which displays a light color, budding surface and unorganized section—had a significantly greater rate of recurrence, at 824% (p < 00001), than did other morphologies of COM Similarly, for stones composed of apatite, morphological type IVa2—a unique form with cracks visible beneath a glossy surface—had a higher rate of recurrence than other apatite morphologies (788 vs 39–42%, p < 00001) Stone mineral type alone is insufficient for identifying the potential of recurrence of the stones Instead, the addition of stone morphology may allow the diagnosis of highly recurrent stones, even among common mineral types (eg, COM) that in general are less recurrent

/pdf/recurrence-rates-of-urinary-calculi-according-to-stone-1ec2fg9mdm.pdf

Recurrence rates of urinary calculi according to stone composition and morphology

Background 2,8-dihydroxyadeninuria (DHA) disease (also called 2,8 dihydroxyadeninuria) is a rare autosomal recessive disorder caused by complete adenine phosphoribosyltransferase deficiency and typically manifests as recurrent nephrolithiasis. Only rare cases of DHA nephrolithiasis have been reported from the USA. Herein, we report three American patients who developed DHA crystalline nephropathy leading to end-stage renal disease (ESRD) with recurrence in the allograft. Methods Three cases of DHA crystalline nephropathy were identified from the Renal Pathology Laboratory of Mayo Clinic. Detailed clinical and pathologic descriptions are provided. Results All three patients were Caucasian adults with no history of obstructive nephropathy. Two patients had no history of nephrolithiasis and one had a single episode of stones 36 years prior to presentation. All patients presented with severe renal failure with a mean serum creatinine of 7.5 mg/dl. Renal biopsies revealed numerous tubular and interstitial brown DHA crystals, tubular degenerative changes and moderate to marked tubulointerstitial scarring. Two patients were initially misdiagnosed, one as primary hyperoxaluria and the other as chronic interstitial nephritis. All three patients progressed to ESRD, within 1 month following renal biopsy in two and after 9 months in one. All three patients underwent renal transplantation with early disease recurrence in three allografts in two patients. Conclusions DHA disease is an under-recognized condition that can lead to irreversible renal failure and frequently recurs in the transplant. It should be included in the differential diagnosis of crystalline nephropathy, even in the absence of history of nephrolithiasis.

/pdf/crystalline-nephropathy-due-to-2-8-dihydroxyadeninuria-an-818jvpby1m.pdf

Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure

We report a case of homozygous adenine phosphoribosyl transferase (APRT) deficiency associated with 2,8-dihydroxyadenine stones recurrent in a patient with a renal transplant. The disease was diagnosed 23 years after the initial episode of renal colic. At that time the disease was unknown. Our patient is only the second case of this disorder reported from the United States. Correct diagnosis is important because long-term maintenance with allopurinol and a low purine diet can effectively prevent stone formation and renal failure.

2, 8-dihydroxyadenine urolithiasis: Report of a case first diagnosed after renal transplant

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2, 8-dihydroxyadenine urolithiasis: Report of a case first diagnosed after renal transplant