allopurinol and Metabolism--Inborn-Errors

Adenine phosphoribosyltransferase (APRT) deficiency (OMIM #614723) is a rare autosomal recessive defect in the purine salvage pathway that causes excessive production of 2,8-dihydroxyadenine, leading to nephrolithiasis and chronic kidney disease (CKD). This case report describes the natural history of CKD in untreated APRT deficiency. We describe a novel APRT mutation (chr16:88877985 G / C; c.195 C>/G; p.His54Asp) presenting with CKD without nephrolithiasis. The patient initially required dialysis, but kidney function improved with allopurinol. We reviewed APRT deficiency reported in the literature to determine the loss of kidney function in individuals with untreated APRT deficiency and its relationship to nephrolithiasis. We identified 95 individuals in whom kidney function was assessed prior to treatment. There was a bimodal distribution of kidney failure. AKI occurred frequently in childhood due to obstructing nephrolithiasis or crystalline nephropathy and was usually reversible. CKD developed after age 20 in all patients irrespective of nephrolithiasis history, with 36/42 patients > 40 years of age having at least stage 3 CKD, and 24/42 having an eGFR > 10 mL/min/1.73m2 or being on dialysis. There were 13 adults without nephrolithiasis and 50 adults with nephrolithiasis. The mean age of end-stage renal diesease (ESRD) was 50.52 ± 13.9 for those without nephrolithiasis and 43.4 ± 15.8 years for those with nephrolithiasis (p = 0.24). APRT deficiency is associated with slowly progressive CKD that occurs independently of nephrolithiasis. Diagnosis should be considered in all individuals with chronic tubulointerstitial kidney disease, with or without the presence of nephrolithiasis. In our patient, allopurinol 300 mg/day resulted in improvement of kidney function.
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Topics: Adenine Phosphoribosyltransferase; Allopurinol; Antimetabolites; Glomerular Filtration Rate; Humans; Kidney Calculi; Male; Metabolism, Inborn Errors; Middle Aged; Nephritis, Interstitial; Renal Insufficiency, Chronic; Urolithiasis

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.

Topics: Adenine; Adenine Phosphoribosyltransferase; Allopurinol; Animals; Biomarkers; Disease Progression; Enzyme Inhibitors; Genetic Predisposition to Disease; Humans; Kidney Diseases; Metabolism, Inborn Errors; Phenotype; Predictive Value of Tests; Prognosis; Recurrence; Urolithiasis; Xanthine Dehydrogenase

Topics: Acidosis, Lactic; Acute Disease; Ammonia; Galactosemias; Humans; Hyperglycemia; Infant; Infant, Newborn; Metabolism, Inborn Errors; Microbodies; Xanthine Oxidase

Topics: alpha-Glucosidases; AMP Deaminase; Carnitine; Carnitine O-Palmitoyltransferase; Glucan 1,4-alpha-Glucosidase; Glycolysis; Humans; Metabolism, Inborn Errors; Mitochondria, Muscle; Muscular Diseases; Phosphofructokinase-1; Phosphorylases; Triglycerides; Xanthine Oxidase

Topics: Adenine Phosphoribosyltransferase; Cystinuria; Glycogen Storage Disease Type I; Humans; Hypoxanthine Phosphoribosyltransferase; Kidney Calculi; Metabolism, Inborn Errors; Orotic Acid; Oxalates; Ribose-Phosphate Pyrophosphokinase; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Acidosis, Renal Tubular; Bacterial Infections; Citrates; Crystallization; Cystinuria; Diphosphates; Female; Gastrointestinal Diseases; Humans; Hypercalcemia; Hyperparathyroidism; Magnesium; Male; Metabolism, Inborn Errors; Mucoproteins; Oxalates; Quaternary Ammonium Compounds; Sarcoidosis; Solubility; Uric Acid; Urinary Calculi; Vitamin D; Xanthine Oxidase

Topics: Adenosine Triphosphate; Allopurinol; Animals; Carbohydrate Metabolism, Inborn Errors; Fructose; Humans; Metabolic Diseases; Metabolism, Inborn Errors; Myocardial Infarction; Oxidation-Reduction; Purine Nucleotides; Ribonucleotides; Shock, Hemorrhagic; Uric Acid

Topics: Acidosis, Renal Tubular; Allopurinol; Anti-Bacterial Agents; Bacterial Infections; Cystinuria; Diet; Female; Humans; Hydrochlorothiazide; Hyperparathyroidism; Kidney Calculi; Magnesium Oxide; Male; Medullary Sponge Kidney; Metabolism, Inborn Errors; Methylene Blue; Penicillamine; Phosphates; Urinary Calculi; Xanthine Oxidase

Topics: Humans; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Pentosyltransferases; Purines; Rheumatic Diseases; Xanthine Oxidase

Topics: Allopurinol; Animals; Brain; Chromosome Aberrations; Chromosome Disorders; Guanine; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Male; Metabolism, Inborn Errors; Pentosyltransferases; Purines; Rabbits; Rats; Uric Acid

Topics: Allopurinol; Anemia, Pernicious; Animals; Azauridine; Carboxy-Lyases; Fatty Liver; Female; Humans; Infant, Newborn; Jaundice, Neonatal; Lipids; Metabolic Diseases; Metabolism, Inborn Errors; Milk; Myocardial Infarction; Ornithine Carbamoyltransferase; Orotic Acid; Pentosyltransferases; Pregnancy; Uric Acid

Topics: Allopurinol; Creatinine; Diet Therapy; Erythrocytes; Gout; Humans; Hypoxanthines; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Myeloproliferative Disorders; Pentosyltransferases; Prenatal Diagnosis; Protein Binding; Purines; Uric Acid

Topics: Allopurinol; Colchicine; Glycogen Storage Disease Type I; Gout; Humans; Lesch-Nyhan Syndrome; Metabolism, Inborn Errors; Pentosyltransferases; Purine Nucleotides; Purines; Uric Acid

Topics: Adolescent; Aged; Allopurinol; Female; Humans; Hydrogen-Ion Concentration; Kidney Calculi; Male; Metabolism, Inborn Errors; Middle Aged; Neoplasms; Purines; Uric Acid

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, hereditary cause of kidney stones and chronic kidney disease (CKD) which is characterized by 2,8-dihydroxyadenine renal parenchymal crystal deposition. The aim of this study was to examine outcomes of kidney transplantation in APRT deficiency patients.. Included were 13 patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, 2 from Westmead Hospital in Sydney, Australia, and 2 from Necker Hospital in Paris, France. The CKD-EPI and CKiD equations were used to calculate glomerular filtration rate estimates. Allograft survival was analyzed employing the Kaplan-Meier method. The Wilcoxon-Mann-Whitney test was used to compare alllograft outcomes according to xanthine oxidoreductase (XOR) inhibitor treatment status at transplantation.. Seventeen patients (9 females) received 22 kidney transplants. Age at first transplantation was 47.2 (14.9-67.0) years. Ten patients received XOR inhibitor therapy pretransplant (11 allografts), while 8 patients did not receive such treatment before transplantation (11 allografts). Two-year allograft survival was 91% and 55% in the 2 groups, respectively (P = 0.16). The median (range) estimated glomerular filtration rate at 2 years posttransplant was 61.3 (24.0-90.0) mL/min/1.73 m when XOR inhibitor therapy was initiated before transplantation, and 16.2 (10.0-39.0) mL/min/1.73 m (P = 0.009) when such treatment was not administered pretransplant.. Kidney allograft outcomes are good in APRT deficiency patients beginning XOR inhibitor therapy pretransplant. Delay in such treatment is a major cause of premature graft loss in these patients. Increased awareness among clinicians is imperative, promoting early diagnosis of APRT deficiency and pharmacotherapy initiation before kidney transplantation.

Topics: Adenine Phosphoribosyltransferase; Adolescent; Adult; Aged; Allopurinol; Enzyme Inhibitors; Europe; Febuxostat; Female; Graft Survival; Humans; India; Kidney Failure, Chronic; Kidney Transplantation; Male; Metabolism, Inborn Errors; Middle Aged; New South Wales; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome; United States; Urolithiasis; Xanthine Oxidase; Young Adult

Adenine phosphoribosyl transferase (APRT) deficiency is a rare genetic form of kidney stones and/or kidney failure characterized by intratubular precipitation of 2,8 dihydroxyadenine crystals. Early diagnosis and prompt management can completely reverse the kidney injury.. 44 year old Indian male, renal transplant recipient got admitted with acute graft dysfunction. Graft biopsy showed light brown refractile intratubular crystals with surrounding giant cell reaction, consistent with APRT deficiency. Patient improved after receiving allopurinol and hydration.. APRT forms a reversible cause of crystalline nephropathy. High index of suspicion is required for the correct diagnosis as timely diagnosis has therapeutic implications.

Topics: Adenine; Adenine Phosphoribosyltransferase; Adult; Allopurinol; Antimetabolites; Biopsy; Crystallization; Humans; Hydrotherapy; Kidney Transplantation; Male; Metabolism, Inborn Errors; Primary Graft Dysfunction; Urolithiasis

Adenine phosphoribosyltransferase (APRT) deficiency is a hereditary purine metabolism disorder that causes kidney stones and chronic kidney disease (CKD). The purpose of this study was to examine the course of APRT deficiency in patients who presented in childhood.. The disease course of 21 (35%) patients in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, who presented with manifestations of APRT deficiency and/or were diagnosed with the disorder before the age of 18 years, was studied. The effect of pharmacotherapy on renal manifestations and outcomes was thoroughly assessed.. Fourteen children were placed on allopurinol, 100 (25-200) mg/day, at the age of 2.6 (0.6-16.5) years. Six of these patients had experienced kidney stone events and three had developed acute kidney injury (AKI) prior to allopurinol treatment. During 18.9 (1.7-31.5) years of pharmacotherapy, stones occurred in two patients and AKI in three. Six adult patients started allopurinol treatment, 200 (100-300) mg/day, at age 29.8 (20.5-42.4) years. Five of these patients had experienced 28 stone episodes and AKI had occurred in two. Stone recurrence occurred in four patients and AKI in two during 11.2 (4.2-19.6) years of allopurinol therapy. Lack of adherence and insufficient dosing contributed to stone recurrence and AKI during pharmacotherapy. At latest follow-up, estimated glomerular filtration rate (eGFR) was 114 (70-163) and 62 (10-103) mL/min/1.73 m. Timely diagnosis and treatment of APRT deficiency decreases renal complications and preserves kidney function.

Topics: Acute Kidney Injury; Adenine; Adenine Phosphoribosyltransferase; Adolescent; Adult; Allopurinol; Child; Child, Preschool; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Infant; Kidney; Kidney Calculi; Male; Metabolism, Inborn Errors; Recurrence; Registries; Renal Insufficiency, Chronic; Urolithiasis; Xanthine Dehydrogenase; Young Adult

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, but significant, cause of kidney stones and progressive chronic kidney disease. The optimal treatment has not been established. The purpose of this pilot study was to compare the effect of the xanthine oxidoreductase inhibitors allopurinol and febuxostat on urinary 2,8-dihydroxyadenine (DHA) excretion in APRT deficiency patients.. Patients listed in the APRT Deficiency Registry of the Rare Kidney Stone Consortium, currently receiving allopurinol therapy, were invited to participate. The trial endpoint was the 24-h urinary DHA excretion following treatment with allopurinol (400mg/day) and febuxostat (80mg/day). Urinary DHA was measured using a novel ultra-performance liquid chromatography - electrospray tandem mass spectrometry assay.. Eight of the 10 patients invited completed the study. The median (range) 24-h urinary DHA excretion was 116 (75-289) mg at baseline, and 45 (13-112) mg after 14days of allopurinol therapy (P=0.036). At the end of the febuxostat treatment period, 4 patients had urinary DHA below detectable limits (<20ng/mL) compared with none of the participants following allopurinol treatment (P=0.036). The other 4 participants had a median 24-h urinary DHA excretion of 13.2 (10.0-13.4) mg at the completion of febuxostat therapy (P=0.036).. Urinary DHA excretion in APRT deficiency patients decreased with conventional doses of both allopurinol and febuxostat. Febuxostat was, however, significantly more efficacious than allopurinol in reducing DHA excretion in the prescribed doses. This finding, which may translate into improved outcomes of patients with APRT deficiency, should be confirmed in a larger sample.

Topics: Adenine; Adenine Phosphoribosyltransferase; Adult; Aged; Allopurinol; Cross-Over Studies; Enzyme Inhibitors; Febuxostat; Female; Humans; Iceland; Kidney Calculi; Male; Metabolism, Inborn Errors; Middle Aged; Pilot Projects; Registries; Treatment Outcome; Urolithiasis

Hereditary xanthinuria (type I) is caused by an inherited deficiency of the xanthine oxidorectase (XDH/XO), and is characterized by very low concentration of uric acid in blood and urine and high concentration of urinary xanthine, leading to urolithiasis. Type II results from a combined deficiency of XDH/XO and aldehyde oxidase. Patients present with hematuria, renal colic, urolithiasis or even acute renal failure. Clinical symptoms are the same for both types. In a third type, clinically distinct, sulfite oxidase activity is missing as well as XDH/XO and aldehyde oxidase. The prevalence is not known, but about 150 cases have been described so far. Hypouricemia is sometimes overlooked, that´s why we have set up the diagnostic flowchart. This consists of a) evaluation of uric acid concentrations in serum and urine with exclusion of primary renal hypouricemia, b) estimation of urinary xanthine, c) allopurinol loading test, which enables to distinguish type I and II; and finally assay of xanthine oxidoreductase activity in plasma with molecular genetic analysis. Following this diagnostic procedure we were able to find first patients with hereditary xanthinuria in our Czech population. We have detected nine cases, which is one of the largest group worldwide. Four patients were asymptomatic. All had profound hypouricemia, which was the first sign and led to referral to our department. Urinary concentrations of xanthine were in the range of 170-598 mmol/mol creatinine (normal < 30 mmol/mol creatinine). Hereditary xanthinuria is still unrecognized disorder and subjects with unexplained hypouricemia need detailed purine metabolic investigation.

Topics: Adult; Aldehyde Oxidase; Allopurinol; Child; Child, Preschool; Czech Republic; Diagnosis, Differential; Humans; Metabolism, Inborn Errors; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Renal Tubular Transport, Inborn Errors; Uric Acid; Urinary Calculi; Xanthine; Xanthine Dehydrogenase

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder which leads to accumulation of poorly soluble 2,8-dihydroxyadenine in kidneys resulting in nephrolithiasis as well as chronic kidney disease from crystal nephropathy. This report describes a 55-year-old previously fit man who presented with shortness of breath and the investigative pathway that eventually led to a diagnosis of APRT deficiency. Early diagnosis has aided in timely institution of allopurinol, thereby improving his renal function and possibility of weaning off renal replacement therapy. Genetic testing has enabled early identification of other family members at risk and prevention of renal failure by commencing xanthine oxidoreductase (XOR) inhibitors. The issues surrounding kidney donation by a member of this family are also discussed. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition, complications of which can be easily prevented by early institution of XOR inhibitor therapy.

Topics: Adenine Phosphoribosyltransferase; Allopurinol; Early Diagnosis; Enzyme Inhibitors; Humans; Male; Metabolism, Inborn Errors; Middle Aged; Pedigree; Urolithiasis

Topics: Adenine Phosphoribosyltransferase; Allopurinol; Child, Preschool; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Metabolism, Inborn Errors; Urolithiasis

Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive disorder of uric acid metabolism that leads to formation and excretion of 2,8-dihydroxyadenine into urine. The low solubility of 2,8-dihydroxyadenine results in precipitation and formation of urinary crystals and renal stones. Patients with this disorder usually have recurrent nephrolithiasis and can develop nephropathy secondary to crystal precipitation in the renal parenchyma. The disease is most often underdiagnosed and can recur in renal transplant, causing graft failure. Lack of specific clinical manifestations, chemical and radiologic features identical to those shown with uric acid stones, and lack of awareness among clinicians are among the causes for the underdiagnoses of this treatable disease. Allopurinol, a xanthine dehydrogenase inhibitor, is the mainstay of treatment, supported by high fluid intake and dietary modifications. The possibility of adenine phosphoribosyl transferase deficiency should be considered in all cases of urolithiasis in children, patients with recurrent urolithiasis, and patients with urolithiasis associated with renal failure of unknown cause, including patients with end-stage renal disease and renal transplant recipients. Here, we report a case of a 41-year-old female patient who had a late diagnosis of 2,8-dihydroxyadenine nephropathy-induced end-stage renal disease, made on the native nephrectomy that accompanied the renal transplant, and who had a timely intervention that prevented recurrence in the graft.

Topics: Adenine; Adenine Phosphoribosyltransferase; Adult; Allopurinol; Biomarkers; Biopsy; Enzyme Inhibitors; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Metabolism, Inborn Errors; Treatment Outcome; Urolithiasis; Xanthine Dehydrogenase

Hereditary xanthinuria (HX) is a rare inherited disorder caused by a deficiency of xanthine dehydrogenase/oxidase (XDH/XO). Missing XDH/XO activity leads to undetectable levels of uric acid excessively replaced by xanthine in serum/urine. The allopurinol loading test has been traditionally used to differentiate between HX types I and II. Final confirmation of HX has been based on the biopsy finding of the absent XDH/XO activity in the small intestine or liver. We present the clinical, biochemical, ultrasound and molecular genetics findings in three new patients with HX and suggest a simple three-step approach to be used for diagnosis, typing and confirmation of HX. In the first step, the diagnosis of HX is determined by extremely low serum/urinary uric acid excessively replaced by xanthine. Second, HX is typed using urinary metabolomics. Finally, the results are confirmed by molecular genetics. We advocate for this safe and non-invasive diagnostic algorithm instead of the traditional allopurinol loading test and intestinal or liver biopsy used in the past.

Topics: Allopurinol; Child; Child, Preschool; Female; Humans; Male; Metabolism, Inborn Errors; Metabolomics; Uric Acid; Xanthine Dehydrogenase

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, revealing six homozygous and 12 compound heterozygous mutations. At diagnosis, half of the patients had decreased kidney function, and two children presented with acute renal failure. Allopurinol treatment was given to all patients at a median dose of 9 mg/kg/day. After a median follow-up of 5 years, all patients showed stabilization or improvement of kidney function, normal growth and development, and six patients had recurrence of nephrolithiasis. Based on these results, we conclude that an excellent outcome can be achieved in children with APRT deficiency who receive the proper treatment.

Topics: Adenine Phosphoribosyltransferase; Adolescent; Allopurinol; Antimetabolites; Child; Child, Preschool; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Retrospective Studies; Urolithiasis; Young Adult

This report describes the clinical, biochemical and molecular data of a 78-year-old patient with xanthine dehydrogenase deficiency presenting as rheumatoid arthritis.. Xanthinuria type I is a rare disorder of purine metabolism caused by xanthine dehydrogenase (XDH) deficiency; fewer than 150 cases have been described in the literature so far.. We describe the clinical history and urine and serum findings of a 78-year-old patient with isolated XDH deficiency presenting as rheumatoid arthritis. The diagnosis was confirmed by mutation analysis.. The patient suffered from arthral symptoms and nephrocalcinosis. Very low concentrations of uric acid were observed in her serum and urine. The allopurinol loading test indicated her xanthinuria to be type I. Analysis of genomic DNA revealed novel heterozygous deletion in exon 8 (g.27073delC, p.214QfsX4) and previously published heterozygous nucleotide missense transition in exon 25 (g.64772-C>T, p.T910M).. Hereditary xanthinuria is a rare disorder, but it also needs to be considered in patients not originating from Mediterranean countries or the Near or Middle East. Urate concentration in serum and urine may provide an initial indication of XDH deficiency before high-performance liquid chromatography (HPLC) analysis is performed. The key to identifying the disorder is a greater awareness of XDH deficiency amongst primary care physicians, nephrologists, and urologists, but also rheumatologists. The diagnosis and therapeutic management requires a multidisciplinary approach.

Topics: Aged; Allopurinol; Arthritis, Rheumatoid; Biomarkers; Chromatography, High Pressure Liquid; DNA Mutational Analysis; Exons; Female; Genetic Predisposition to Disease; Genetic Testing; Heterozygote; Humans; Metabolism, Inborn Errors; Mutation, Missense; Nephrocalcinosis; Phenotype; Predictive Value of Tests; Sequence Deletion; Uric Acid; Xanthine Dehydrogenase

Adenine phosphoribosyltransferase (APRT) deficiency is a rarely diagnosed cause of renal allograft dysfunction. We report the case of a 42-year-old man who presented in 1996 with idiopathic renal failure. Native kidney biopsy showed extensive microcrystalline interstitial nephritis. The patient subsequently underwent a living-related kidney transplant with excellent early graft function. During the next year, however, he had worsening allograft function, and allograft biopsy showed recurrent interstitial nephritis. Further chemical and spectroscopic analysis showed this lesion to be an annular microcrystalline nephritis consistent with APRT deficiency. This diagnosis was confirmed on erythrocyte assay. Treatment with allopurinol and a low-purine diet led to improvement and stabilization of renal function. APRT is a rare cause of renal allograft dysfunction requiring a high index of suspicion for early diagnosis and treatment. Increased physician awareness in the United States may hasten diagnosis and limit the morbidity associated with this disease.

Topics: Adenine Phosphoribosyltransferase; Adult; Allopurinol; Antimetabolites; Humans; Kidney; Kidney Transplantation; Male; Metabolism, Inborn Errors; Nephritis, Interstitial; Recurrence

Hypouricemia can be observed in uncommon situations as in our two patients with hereditary xanthinuria.. In the first case, hereditary xanthinuria was discovered in a 36-year-old man when routine tests revealed hypouricemia. In the second case, a 76-year-old woman, hypouricemia was also a fortuitous discovery. She had major xanthinuria and a radiotranslucid lithiasis in the right kidney.. Hereditary xanthinuria is characterized by hypouricemia, low urinary urate excretion and increased concentration of xanthine and to a lesser extent hypoxanthine. The disease results from a defect in xanthine oxidase and is considered to be transmitted by autosomal recessive heredity. This rare metabolic disorder is more often asymptomatic and detected by routine chemistry. Development of xanthine lithiasis is directly related to the low solubility of xanthine and is the main complication of the disease, occurring in 30-40% of patients. There is no effective treatment and the only useful measure is to prevent xanthine urolithiasis by maintaining urinary output above 2 l/day.

Topics: Adult; Aged; Chromosome Aberrations; Chromosome Disorders; Female; Genes, Recessive; Humans; Kidney Calculi; Male; Metabolism, Inborn Errors; Uric Acid; Xanthine; Xanthine Oxidase

Topics: Coenzymes; Female; Fibroblasts; Humans; Hypoxanthine; Infant; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Nervous System Diseases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Uric Acid; Xanthine; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Coenzymes; Female; Humans; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Pteridines; Purine-Pyrimidine Metabolism, Inborn Errors; Xanthine; Xanthine Dehydrogenase; Xanthines

Hereditary xanthinuria is a rare disorder characterized by the replacement of uric acid by xanthine and hypoxanthine in urine. Two cases of classic hereditary xanthinuria in Taiwan are herein reported. Case 1: a 30-year-old woman was by chance found to have hypouricemia. Urine and plasma purines were checked through the use of high performance liquid chromatography. Urine excretion of uric acid was 0.029 mumol (0.005 mg)/mg creatinine (30 mumol/24 hr); xanthine 1.9 mumol/mg creatinine (1935 mumol/24 hr); and hypoxanthine 0.58 mumol/mg creatinine (587 mumol/24 hr). Plasma xanthine was 9.3 mumol/L; hypoxanthine 5.8 mumol/L; and uric acid 0.5 mumol/L (0.001 mg/dL). Case 2: a brother of case 1 had a previous history of urolithiasis. Urine excretion of uric acid was 0.15 mumol (0.025 mg)/mg creatinine (189 mumol/24 hr); xanthine 1.3 mumol/mg creatinine (1620 mumol/24 hr); and hypoxanthine 0.22 mumol/mg creatinine (276 mumol/24 hr).

Topics: Adult; Female; Humans; Male; Metabolism, Inborn Errors; Xanthine; Xanthine Oxidase; Xanthines

The allopurinol challenge test was performed on 44 healthy subjects (28 children and 16 adolescents) in order to establish normal values of urinary orotic acid excretion following allopurinol ingestion in the paediatric population. The subjects were divided into three groups according to their age: 6 months to 6 years; 6 years to 10 years; and 10 years to 17 years. They were given 100 mg, 200 mg, or 300 mg of allopurinol, respectively (based on age) in a single oral dose. Maximum peak urinary orotic acid levels following ingestion of allopurinol were 13.0 (n = 14), 9.3 (n = 14), and 10.2 (n = 16) mumol/mmol creatinine in the three groups, respectively. In all children tested the peak orotic acid level was 3.1 +/- 2.7 mumol/mmol creatinine (mean +/- SD, n = 44). This allopurinol challenge test was also performed in six children with urea-cycle disorders, including five females with ornithine transcarbamylase (OTC) deficiency, all of whom demonstrated abnormally elevated levels of urinary orotic acid (peak levels of 26-134 mumol/mmol creatinine) following allopurinol ingestion.

Topics: Adolescent; Aging; Allopurinol; Child; Child, Preschool; Citrulline; Female; Humans; Infant; Male; Metabolism, Inborn Errors; Ornithine Carbamoyltransferase Deficiency Disease; Orotic Acid; Urea; Uridine

Topics: Aged; Aged, 80 and over; Allopurinol; Drug Hypersensitivity; Humans; Male; Metabolism, Inborn Errors; Oxypurinol; Pyrimidines; Uric Acid

Increased urinary excretion of xanthine, hypoxanthine, sulphite, thiosulphate and decreased serum uric acid were observed in an infant with profound failure to thrive. Other clinical findings included refractory seizures, spastic quadriplegia and profound psychomotor retardation. The patient died at 20 months of age. There were no detectable activities for xanthine oxidase and sulphite oxidase in the postmortem liver. Urothione, which is the metabolic excretory product of the molybdenum cofactor for molybdoenzymes was not present in the urine. A deficiency of the molybdenum cofactor which is common to both xanthine and sulphite oxidase is presumed to be the metabolic defect responsible for the absent activities of both enzymes.

Topics: Coenzymes; Humans; Infant, Newborn; Liver; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Xanthine; Xanthine Oxidase; Xanthines

Topics: Coenzymes; Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Metalloproteins; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Uric Acid; Xanthine Oxidase

Topics: Coenzymes; Female; Humans; Infant; Metabolism, Inborn Errors; Metalloproteins; Methods; Molybdenum; Molybdenum Cofactors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Pteridines; Sulfites; Uric Acid; Xanthine Oxidase

Topics: Humans; Infant, Newborn; Male; Metabolism, Inborn Errors; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Prenatal Diagnosis; Xanthine Oxidase

Urolithiasis resulting from inherited metabolic derangement is rare. Only 13 cases of 2,8-dihydroxyadenine stones resulting from a deficiency of the enzyme adenine phosphoribosyl transferase have been reported since 1974. Of these cases 9 have been in children with the homozygous trait. To date, 3 homozygous and 1 heterozygous adults with urolithiasis have been reported. This disease has not been associated with any other clinical or biochemical abnormalities. Treatment includes low purine diet and allopurinol. We herein report a case of complete adenine phosphoribosyl transferase deficiency associated with 2,8-dihydroxyadenine urolithiasis in the United States, bringing the total to 14 in the literature.

Topics: Adenine; Adenine Phosphoribosyltransferase; Allopurinol; Child; Heterozygote; Homozygote; Humans; Male; Metabolism, Inborn Errors; Pentosyltransferases; Purines; United States; Urinary Calculi

Topics: Amino Acid Metabolism, Inborn Errors; Female; Humans; Infant, Newborn; Infant, Newborn, Diseases; Lens Subluxation; Metabolism, Inborn Errors; Molybdenum; Oxidoreductases; Oxidoreductases Acting on Sulfur Group Donors; Xanthine Oxidase; Xanthines

Topics: Adult; Allopurinol; Anemia; Arthritis; Benzofurans; Gout; Humans; Hyperlipidemias; Hypothyroidism; Hypoxanthines; Kidney Calculi; Male; Metabolism, Inborn Errors; Pedigree; Pentosyltransferases; Uric Acid; Uricosuric Agents

Topics: Adolescent; Carbon Isotopes; Child, Preschool; Chromatography, DEAE-Cellulose; Chromatography, Gel; Electrophoresis, Polyacrylamide Gel; Female; Glyoxylates; Humans; In Vitro Techniques; L-Lactate Dehydrogenase; Liver; Male; Metabolism, Inborn Errors; Myocardium; NAD; Oxalates; Oxidation-Reduction; Spectrophotometry; Xanthine Oxidase

Topics: Adult; Allopurinol; Child; Child, Preschool; Diphosphates; Erythrocytes; Female; Gout; Humans; Infant; Kidney Calculi; Male; Metabolism, Inborn Errors; Phosphotransferases; Purines; Uric Acid

Topics: Adult; Child, Preschool; Female; Humans; Liver; Male; Metabolism, Inborn Errors; Middle Aged; Uric Acid; Urinary Calculi; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Child; Diet; Humans; Male; Metabolism, Inborn Errors; Purinones; Urinary Calculi; Xanthines

Topics: Allopurinol; Child; Female; Glycolates; Glyoxylates; Humans; Isocarboxazid; Ketoglutaric Acids; Kidney Calculi; Metabolism, Inborn Errors; Muscles; Oxalates; Pyridoxine; Uric Acid

Topics: Alcohols; Allopurinol; Azaserine; Carbon Isotopes; Cell Line; Fibroblasts; Formates; Glycine; Guanine Nucleotides; Humans; Hypoxanthines; Metabolism; Metabolism, Inborn Errors; Molecular Biology; Mutation; Nucleic Acids; Orotic Acid; Pentosephosphates; Phosphoric Acids; Purines; Pyrimidines; Ribonucleotides; Ribose; Skin; Transferases

Topics: Allopurinol; Androsterone; Colchicine; Gout; Gymnastics; Humans; Indomethacin; Kinins; Long-Term Care; Metabolism, Inborn Errors; Physical Education and Training; Purine-Pyrimidine Metabolism, Inborn Errors; Time Factors; Uric Acid; Uricosuric Agents

Topics: Adolescent; Adult; Alcohol Oxidoreductases; Child; Glycolates; Glyoxylates; Humans; Kidney; Ligases; Liver; Metabolism, Inborn Errors; Nephrocalcinosis; Oxalates; Oxidoreductases; Urinary Calculi; Vitamin B 6 Deficiency; Xanthine Oxidase

Topics: Adult; Allopurinol; Gout; Guanine; Humans; Hypoxanthines; Joint Diseases; Kidney Calculi; Metabolism, Inborn Errors; Molecular Biology; Phosphotransferases; Purines; Uric Acid

Certain gouty subjects with excessive de novo purine synthesis are deficient in hypoxanthineguanine phosphoribosyltransferase (HG-PRTase [EC 2.4.2.8]). The mechanism of accelerated uric acid formation in these patients was explored by measuring the incorporation of glycine-(14)C into various urinary purine bases of normal and enzyme-deficient subjects during treatment with the xanthine oxidase inhibitor, allopurinol. In the presence of normal HG-PRTase activity, allopurinol reduced purine biosynthesis as demonstrated by diminished excretion of total urinary purine or by reduction of glycine-(14)C incorporation into hypoxanthine, xanthine, and uric acid to less than one-half of control values. A boy with the Lesch-Nyhan syndrome was resistant to this effect of allopurinol while a patient with 12.5% of normal enzyme activity had an equivocal response. Three patients with normal HG-PRTase activity had a mean molar ratio of hypoxanthine to xanthine in the urine of 0.28, whereas two subjects who were deficient in HG-PRTase had reversal of this ratio (1.01 and 1.04). The patterns of (14)C-labeling observed in HG-PRTase deficiency reflected the role of hypoxanthine as precursor of xanthine. The data indicate that excessive uric acid in HG-PRTase deficiency is derived from hypoxanthine which is insufficiently reutilized and, as a consequence thereof, catabolized inordinately to uric acid. The data provide evidence for cyclic interconversion of adenine and hypoxanthine derivatives. Cleavage of inosinic acid to hypoxanthine via inosine does not contribute significantly to the formation of uric acid in either normal man or in patients with HG-PRTase deficiency.HG-PRTase was not completely absent in red blood cells from a boy with the Lesch-Nyhan syndrome; with hypoxanthine as substrate, the activity in erythrocyte hemolysates was 0.64% of normal values.

Topics: Adult; Allopurinol; Athetosis; Carbon Isotopes; Child; Chorea; Compulsive Behavior; Deficiency Diseases; Glycine; Gout; Guanine; Humans; Hypoxanthines; Inositol; Intellectual Disability; Metabolism, Inborn Errors; Nucleosides; Purines; Self Mutilation; Transferases; Uric Acid

Topics: Adenine; Allopurinol; Athetosis; Bone Marrow; Carbon Isotopes; Child; Child, Preschool; Chorea; Compulsive Behavior; Diet Therapy; Erythrocytes; Folic Acid; Glycine; Humans; Intellectual Disability; Male; Metabolism, Inborn Errors; Movement Disorders; Purines; Self Mutilation; Transferases; Uric Acid; Vitamin B 12

Topics: Allopurinol; Amino Acids; Athetosis; Carbon Isotopes; Child, Preschool; Chorea; Compulsive Behavior; Diet Therapy; Glutamates; Glycine; Humans; Infant; Intellectual Disability; Male; Metabolism, Inborn Errors; Movement Disorders; Purines; Self Mutilation; Uric Acid

Topics: Adult; Aged; Allopurinol; Calculi; Erythrocytes; Genes, Recessive; Gout; Guanine; Heterozygote; Humans; Hypoxanthines; Male; Metabolism, Inborn Errors; Methods; Middle Aged; Pedigree; Sex Chromosomes; Transferases; Uric Acid

Topics: Allantoin; Animals; Dogs; Infrared Rays; Metabolism, Inborn Errors; Purines; Spectrum Analysis; Ultraviolet Rays; Uric Acid; Urinary Calculi; X-Ray Diffraction; Xanthine Oxidase; Xanthines

1. The presence of hypoxanthine and xanthine in the skeletal muscle of two patients with congenital xanthine oxidase deficiency (xanthinuria) was demonstrated by high-resolution mass spectrometry. 2. Evidence was obtained for the presence of a trace of hypoxanthine only in normal muscle. 3. Dry pulverized tissue was introduced directly into the mass spectrometer and preliminary chemical processing of the tissue was therefore unnecessary. 4. The criteria for the mass-spectrometric identification of hypoxanthine and xanthine in the tissue and the significance of the observations are discussed.

Topics: Adult; Chemical Phenomena; Chemistry, Physical; Female; Humans; Hypoxanthines; Male; Metabolism, Inborn Errors; Muscles; Spectrum Analysis; Xanthine Oxidase; Xanthines

Topics: Adult; Allopurinol; Aminohippuric Acids; Electromyography; Humans; Hypoxanthines; Kidney Function Tests; Male; Metabolism, Inborn Errors; Muscles; Muscular Diseases; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Adenine; Allopurinol; Athetosis; Child, Preschool; Diet Therapy; Genes, Recessive; Humans; Male; Metabolism, Inborn Errors; Nucleotides; Psychomotor Disorders; Purines; Self Mutilation; Sex Chromosomes; Transferases; Uric Acid

Topics: Adenine; Adolescent; Adult; Aged; Allopurinol; Child; Creatinine; Glucosyltransferases; Gout; Guanine; Humans; Hypoxanthines; Male; Metabolism, Inborn Errors; Middle Aged; Purines; Uric Acid; Xanthines

Topics: Allopurinol; Colchicine; Female; Gout; Humans; Male; Metabolism, Inborn Errors; Purines; Sex Factors; Uric Acid; Xanthine Oxidase

A case of xanthinuria is briefly described, and the results of in vivo studies with (14)C-labeled oxypurines are discussed. The data demonstrate that the rate of the turnover of uric acid is normal, despite an extremely small uric acid pool. Xanthine and hypoxanthine pools were measured and their metabolism evaluated. The bulk of the daily pool of 276 mg of xanthine, but only 6% of the 960 mg of hypoxanthine, is excreted. Thus, xanthine appears to be a metabolic end product, whereas hypoxanthine is an active intermediate. Biochemical implications of this finding are discussed.

Topics: Arthritis; Carbon Isotopes; Creatinine; Female; Guanine; Humans; Hypoxanthines; Metabolism, Inborn Errors; Middle Aged; Psoriasis; Purines; RNA; Spectrophotometry; Urate Oxidase; Uric Acid; Xanthine Oxidase; Xanthines

Topics: Allopurinol; Humans; Infant; Infant, Newborn; Intellectual Disability; Male; Metabolism, Inborn Errors; Muscle Cramp; Self Mutilation; Uric Acid

Topics: Adolescent; Adult; Allopurinol; Child; Child, Preschool; Female; Humans; Kidney Calculi; Male; Metabolism, Inborn Errors; Nephrocalcinosis; Oxalates

Topics: Allopurinol; Guanine; Humans; Hypoxanthines; Intellectual Disability; Kidney Diseases; Metabolism, Inborn Errors; Nervous System Diseases; Sex Chromosomes; Transferases; Uremia; Uric Acid; Xanthine Oxidase

Topics: Adenosine Triphosphate; Allopurinol; Anemia; Brain Diseases; Carbon Isotopes; Child, Preschool; Erythrocytes; Fibroblasts; Humans; Infant; Intellectual Disability; Kidney Diseases; Male; Metabolism, Inborn Errors; Purines; Self Mutilation; Transferases; Uric Acid

Topics: Adolescent; Animals; Female; Humans; Male; Metabolism, Inborn Errors; Rats; Uric Acid; Urinary Calculi; Xanthine Oxidase; Xanthines

Topics: Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Enzyme Therapy; Hematuria; Humans; Male; Metabolism, Inborn Errors; Self Mutilation; Uric Acid; Urinary Calculi; Xanthine Oxidase

Topics: Adenine; Carbon Isotopes; Chromatography; Guanine; Humans; Hypoxanthines; Male; Metabolism, Inborn Errors; Nucleotides; Purine-Pyrimidine Metabolism, Inborn Errors; Purines; Spectrophotometry; Uric Acid; Urine; Xanthine Oxidase; Xanthines