Adenine phosphoribosyltransferase deficiency in the United Kingdom: two novel mutations and a cross-sectional survey

Abstract

Background: Adenine phosphoribosyltransferase deficiency is an inborn error of metabolism that can cause kidney disease from crystalline nephropathy or kidney stones.

Methods: We present three cases from a single centre with varied presentations to illustrate how increasing awareness led to better patient identification. We then undertook a cross-sectional survey of all the patients identified from the Purine Research Laboratory in the UK since 1974.

Results: Our index case presented with recurrent nephrolithiasis and was diagnosed on stone analysis, the second case presented with acute kidney injury and the third case was identified from a biopsy undertaken for acute on chronic kidney injury. Genetic studies identified two novel mutations. Twenty patients were retrospectively identified. The mean age at diagnosis was 25 years (range 2-70); eight were <20 years, seven were 20-40 years and five were >40 years. Five of the 20 patients were deceased, 3 after end-stage renal disease (ESRD). Twelve have normal renal function, one had CKD stage 3, one had severe kidney disease and one was on dialysis.

Conclusions: Adenine phosphoribosyltransferase deficiency presents in a wide spectrum in all age groups. Patients can be completely asymptomatic and kidney disease may be incorrectly attributed to other conditions. Outcome is poor in late diagnosis and there is a high prevalence of ESRD. Patients with unexplained renal stone disease or deterioration in kidney function should be considered for screening. Identification and surveillance of patients in the UK can improve. There is now a rare disease registry with meetings organized that include patients, families and health care providers to improve awareness.

Keywords: adenine phosphoribosyltransferase deficiency; chronic kidney disease; kidney stones; outcomes.

Fig. 1.

Diagram showing the adenine salvage pathway. Lack of salvage by APRT causes accumulation of adenine and production of 2,8-dihydroxyadenine by the action of xanthine dehydrogenase. PRPP, phosphoribosyl pyrophosphate; APRT, adenine phosphoribosyltransferase.

Fig. 2.

CT scan of index case shows large calculus in the left kidney with marked atrophy.

Fig. 3.

Native kidney biopsies. (A) Native renal biopsy from case 2 showing tubular crystalline deposits of 2,8-dihydroxyadenine with inflammatory changes suggestive of tubular interstitial nephritis (×400 magnification). (B) Biopsy shown under polarizing light demonstrating birefringence (×400 magnification). (C) Native kidney biopsy from case 3 showing marked scarring with mild diabetic changes (×100 magnification). (D) Chronic inflammatory changes around crystalline deposits are also present (×250 magnification).

Fig. 4.

Family tree of case 1 (index case arrowed) and case 2. A third brother was diagnosed in the community. The three known affected siblings did not attend regular outpatient appointments; our index case became more adherent when he was symptomatic with renal failure and was approaching dialysis. The remaining two siblings have not come forward for screening with urine testing. Consanguinity is shown and awareness of the carrier status of offspring and the wider family will allow early treatment for future generations.

Fig. 5.

Trends in serum creatinine. (A) Graph showing the trend in creatinine from our index case with some stabilization of kidney function after initiating allopurinol (arrowed) before eventually reaching ESRD. (B) Graph showing resolution of AKI in case 2 from both presentations treated with intravenous fluids. (C) Graph showing the trend in serum creatinine in case 3 with improvement of renal function following initiation of allopurinol (arrow).