Missense mutation in the adenine phosphoribosyltransferase gene causing 2, 8-dihydroxyadenine urolithiasis (original) (raw)
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Adenine Phosphoribosyltransferase Deficiency: A Rare Cause of Recurrent Urolithiasis
Journal of endourology case reports, 2017
Background: Recurrent urolithiasis is troublesome for both patient and clinician, and in most cases, an underlying cause is not found. An important and underdiagnosed cause is adenine phosphoribosyltransferase (APRT) deficiency that gives rise to 2,8-dihydroxyadenine (2,8-DHA) stones. If diagnosed early, patient morbidity as well as the financial cost of treating stone recurrence can be avoided with simple medical therapy. Case Presentation: A 36-year-old white, Caucasian male with recurrent urolithiasis was found to have 2,8-DHA stones. This was difficult to manage, as these stones were often large, bilateral, matrix in structure, and translucent on plain X-rays. He underwent a multitude of interventions including both retrograde and anterograde endoscopic approaches as well as extracorporeal shock wave lithotripsy. The specific stone type was eventually discovered through infrared spectroscopy and he was promptly commenced on allopurinol, which significantly improved his stone bur...
Molecular Genetics and Metabolism, 2014
2,8-Dihydroxyadenine (2,8-DHA) urolithiasis in people is caused by autosomal recessive mutations in the adenine phosphoribosyltransferase gene (APRT). 2,8-DHA urolithiasis has recently been reported in two dogs, but, to the authors' knowledge, no studies have yet investigated the genetic basis for susceptibility to the development of 2,8-DHA urolithiasis in this species. Our aim was to sequence APRT in dogs affected by 2,8-DHA urolithiasis and compare the results to clinically healthy dogs of similar ancestral lineages. Our hypothesis was that we would identify an autosomal recessive mutation in APRT that is associated with the disease. The case population consisted of six dogs with a history of 2,8-DHA urolithiasis: five Native American Indian Dogs (NAIDs) and a mixed breed. The control population consisted of adult NAIDs with no history of urolithiasis. We sequenced APRT and identified a missense mutation in a highly conserved codon of APRT (c.260G>A; p.Arg87Gln). The c.260A mutation was present in a homozygous state in all six dogs with 2,8-DHA urolithiasis, and it was strongly associated with the disease. This exact missense mutation has been previously reported to cause loss of APRT enzyme function in a human cell line, and it is likely a causative mutation in dogs. Therefore, the dog offers a naturally-occurring genetic animal model for 2,8-DHA urolithiasis.
NDT Plus, 2010
Adenine phosphoribosyltransferase (APRT) deficiency, a rare inborn error inherited as an autosomic recessive trait, presents with 2,8-dihydroxyadenine (2,8-DHA) crystal nephropathy. We describe clinical, biochemical and molecular findings in a renal transplant recipient with renal failure, 2,8-DHA stones and no measurable erythrocyte APRT activity. Homozygous C>G substitution at −3 in the splicing site of exon 2 (IVS2 −3 c>g) was found in the APRT gene. The patient's asymptomatic brother was heterozygous for such mutation, and his APRT activity was 23% of controls. A splicing alteration leading to incorrect gene transcription and virtually absent APRT activity is seemingly associated with the newly identified mutation.
Phenotype and Genotype Characterization of Adenine Phosphoribosyltransferase Deficiency
Journal of the American Society of Nephrology, 2010
Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder causing 2,8dihydroxyadenine 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 ϩ 2insT), which produces a truncated protein, accounted for 40.3% of the mutations. We detected the IVS4 ϩ 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.
Adenine Phosphoribosyltransferase Deficiency
Clinical Journal of the American Society of Nephrology, 2012
Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 Jérôme Harambat and Guillaume Bollée contributed equally to this study.
Two birds one stone-two rare cases of adenine phosphoribosyl transferase deficiency
International Journal of Research in Medical Sciences, 2023
Complete adenine phosphoribosyl transferase (APRT) deficiency is a rare inherited metabolic disorder that leads to the formation and hyperexcretion of 2,8-dihydroxyadenine (DHA) into urine. We had a 52-year-old male with Hypertension for 18 months, presented for routine evaluation and was found to have creatinine of 4.29 mg/dl. His urine analysis was done which showed no proteinuria or urinary sediments. His USG done demonstrated normal sized kidneys with mildly increased echogenicities. He underwent a renal Biopsy for etiology determination. Similarly, we had another case of a 54-year-old female with no comorbidities who was identified to have chronic kidney disease in 2018 with a baseline creatinine of 2 mg/dl came with uremic symptoms and history of NSAID intake in June 2019. Her creatinine peaked to 7.9 mg/dl. Urine analysis displayed 1+ proteinuria with no active sediments. Her USG of the kidneys showed normal kidneys with increased echogenicities. She underwent renal biopsy for etiology determination. Biopsy of case 1 showed chronic interstitial nephritis and case 2 showed acute interstitial nephritis. Both biopsies showed deposition of 2,8-dihydroxyadenine crystals. Genetic analysis of both cases showed an exon mutation in chromosome 16.
Archives of Clinical Nephrology, 2020
A 22-year-old male born of non-consanguineous marriage, End stage renal failure on dialysis presented with the history Key message APRT defi ciency is a rare but under recognized genetic disease. Recurrent urolithiasis and DHA nephropathy are the two clinical manifestations of APRT defi ciency and diagnosis can be made at any age and recurs after renal transplant. Allopurinol is the cornerstone in preventing recurrence. APRT activity assay and genetic testing are useful for confi rmation of diagnosis, for family screening and in diffi cult cases of urolithias or crystalline nephropathy.
Adenine phosphoribosyltransferase deficiency in children
Pediatric nephrology (Berlin, Germany), 2012
Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder characterized by 2,8-dihydroxyadenine (2,8-DHA) crystalluria that can cause nephrolithiasis and chronic kidney disease. The aim of our study was to assess the clinical presentation, diagnosis, and outcome of APRT deficiency in a large pediatric cohort. All pediatric cases of APRT deficiency confirmed at the same French reference laboratories between 1978 and 2010 were retrospectively reviewed. Twenty-one patients from 18 families were identified. The median age at diagnosis was 3 years. Diagnosis was made after one or more episodes of nephrolithiasis (17 patients), after urinary tract infection (1 patient), and by family screening (3 patients). The diagnosis was based on stone analysis and microscopic examination of urine and/or enzymatic determination of APRT on red blood cells. All children had null APRT enzyme activity in erythrocytes. APRT gene sequencing was performed on 18 patients, reve...