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Background: Patients with deficient hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity present hyperuricemia and/or hyperuricosuria, with a variable degree of neurological manifestations. Hyperuricemia in HPRT deficiency is due to uric acid overproduction and is frequently treated with allopurinol. Renal uric acid excretion is sharply increased in these patients. In recent years, several renal tubular urate transporter single nucleotide polymorphisms (SNPs), including those of the GLUT9, ABCG2 and URAT1 genes, have been described that influence the renal handling of uric acid and modulate serum urate levels. In the present study, we analyzed whether GLUT9, ABCG2 and URAT1 gene SNPs are able to influence uric acid levels and allopurinol response in patients with HPRT deficiency., Methods: Three SNPs, URAT1 rs11231825, GLUT9 rs16890979 and ABCG2 rs2231142, previously associated in our population with hyperuricemia and gout, were analyzed in 27 patients with HPRT deficiency treated with allopurinol for at least 5 years., Results: Patients with HPRT deficiency having allele A of rs16890979 in the GLUT9 gene present with a lower serum urate concentration at diagnosis, before allopurinol treatment is instituted, and need lower allopurinol doses to maintain serum urate levels between 268 and 446 μmol/L (4.5 and 7.5 mg/dL). No relationship between rs2231142 in the ABCG2 gene or rs11231825 in the URAT1 gene and serum urate levels or allopurinol response was found in our patients with HPRT deficiency., Conclusions: GLUT9 SNPs influence the renal handling of uric acid and modulate serum urate levels and the response to treatment in patients with uric acid overproduction due to HPRT deficiency., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Primary gout has been associated with single-nucleotide polymorphisms (SNP) in several tubular urate transporter genes. No study has assessed the association of reabsorption and secretion urate transporter gene SNP with gout in a single cohort of documented primary patients with gout carefully subclassified as normoexcretors or underexcretors., Methods: Three reabsorption SNP (SLC22A12/URAT1, SLC2A9/GLUT9, and SLC22A11/OAT4) and 2 secretion transporter SNP (SLC17A1/NPT1 and ABCG2/BRCP) were studied in 104 patients with primary gout and in 300 control subjects. The patients were subclassified into normoexcretors and underexcretors according to their serum and 24-h urinary uric acid levels under strict conditions of dietary control., Results: Compared with control subjects, patients with gout showed different allele distributions of the 5 SNP analyzed. However, the diagnosis of underexcretor was only positively associated with the presence of the T allele of URAT1 rs11231825, the G allele of GLUT9 rs16890979, and the A allele of ABCG2 rs2231142. The association of the A allele of ABCG2 rs2231142 in normoexcretors was 10 times higher than in underexcretors. The C allele of NPT1 rs1165196 was only significantly associated with gout in patients with normal uric acid excretion., Conclusion: Gout with uric acid underexcretion is associated with transporter gene SNP related mainly to tubular reabsorption, whereas uric acid normoexcretion is associated only with tubular secretion SNP. This finding supports the concept of distinctive mechanisms to account for hyperuricemia in patients with gout with reduced or normal uric acid excretion.

Background and Objectives: Pharmacologic urate lowering therapy (ULT), at full maintenance doses, has been associated with acute gout arthritis (in up to 80% of patients). The American College of Rheumatology has recently advocated gradually titrating the maintenance dose upward to chosen serum urate target. Few studies have examined the efficacy and safety of a ULT in primary gout., Patients and Methods: The ULT regimen examined included allopurinol (50 mg/day, with increases of 50 mg/month up to 300 mg/day) and colchicine, as prophylaxis to prevent acute gouty attacks. The efficacy and safety of this regimen was examined in 42 patients in whom allopurinol was withheld for ≥3 months and restarted after this assessment and followed up for 12 months. The efficacy and safety of the ULT regimen was related to the serum urate decrease and to the incidence of acute gout flares, respectively., Results: Fifty-nine patients (mean age 59 years, 56 men) with primary gout received the gradually titrated ULT regimen. Baseline serum urate was (mean±SD) 8.4±0.8 mg/dL. At 3, 6, 9, and 12 months serum urate fell by a mean of 1.8, 2.5, 2.7, and 2.5 mg/dL, respectively (p<0.001). A serum urate level<6.0 mg/dL was achieved by 38/59 (64%) patients. During the 12 months following the start of the ULT we documented 10 acute arthritis episodes (17% of patients)., Conclusions: A gradually titrated hypouricemic regimen for 6 months in patients with primary gout appears to be effective and safe.

The reference range for urinary uric acid excretion has not been precisely defined. Different urinary variables have been proposed to determine the renal contribution to increased or decreased serum urate concentrations. We examined which urinary variable best indicates uric acid excretion over a wide range of serum urate concentrations. Purine metabolism was studied in 10 healthy male subjects (aged 26-58 years) both at their endogenous normal serum urate levels (normouricemic state) and after the oral administration of allopurinol (300 mg/24 h for 5 days) and ribonucleic acid (4 g/8 h for 4 days) to decrease (hypouricemic state) and increase (hyperuricemic state) serum urate concentrations, respectively. The results from patients with several conditions known to affect uric acid synthesis and/or the renal excretion of uric acid were used to validate a constructed nomogram. Over a wide range of mean serum urate levels (from 2.7 to 9.5 mg/dL) and mean 24-hour urinary uric acid excretion (171 to 1368 mg/[24 h 1.73 m(2)]), the highest correlation coefficient between serum urate and uric acid excretion was obtained for the 24-hour uric acid determination (r = 0.928; P < .001). The constructed nomogram allowed the definition of the mechanism underlying hyperuricemia and hypouricemia in patients with a myriad of diseases known to affect purine metabolism. The urinary variable that best correlates with a wide range of serum urate concentrations is 24-hour urinary uric acid excretion. The constructed nomogram allows the identification of the kidney contribution to a given purine metabolic abnormality., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Post-hoc analyses of the GREACE and the LIFE trials have renewed the interest in elevated serum uric acid (SUA) as a factor contributing to atherosclerotic cardiovascular disease (CVD) and in the possible benefit derived from its pharmacological reduction. The results of these trials are consistent with reports indicating favourable effects of SUA lowering treatment with allopurinol on the rate of cardiovascular complications in patients with coronary heart disease, congestive heart failure and dilated cardiomyopathy. Two recent overviews have concluded that, while in population samples at relatively low risk of CVD, SUA is at best a very weak predictor of CVD, by contrast it is a significant independent predictor among subjects at high or very high risk. This raises the question of a different meaning of excess SUA levels under different circumstances. Whereas in uncomplicated obese, insulin-resistant and hypertensive patients SUA levels increase mainly as a consequence of impaired renal excretion, in conditions of local ischemia an increased production of uric acid occurs in parallel with that of reactive oxygen species (ROS). Thus, although clinical and experimental evidence suggest that uric acid has actually antioxidant properties, it is conceivable that under these conditions its antioxidant activity is overcome by the pro-oxidant and pro-inflammatory effects of ROS accumulation. At present, there is no solid evidence to recommend treatment of the mild asymptomatic hyperuricemia associated with obesity, diabetes and/or hypertension (up to 10mg/dL). By contrast, similar SUA elevations in patients at higher cardiovascular risk should be taken more seriously. A controlled trial to investigate the effects of SUA reduction in these patients, while monitoring concomitant changes in parameters of oxidative stress and inflammation, is warranted.

Overactivity of phosphoribosylpyrophosphate synthetase (PRS) is an X chromosome-linked disorder of purine metabolism that is characterized by gout with uric acid overproduction and, in some families, neurodevelopmental impairment. We present the case of a 24-year-old Spanish woman with renal colic and hyperuricemia, which first manifested at age 11 years. Results of enzymatic and genetic studies supported the view that accelerated purine nucleotide and uric acid production in this woman resulted from defective allosteric regulation of PRS activity, which is, in turn, a consequence of a mutation in one of the patient's PRPS1 genes: an A-to-T substitution at nucleotide 578, encoding leucine for histidine at amino acid residue 192 of the mature PRS1 isoform. A previous example of disordered regulation of PRS1 activity in a family with a different substitution at the same amino acid residue strengthens this proposed mechanism. This is the first reported instance of PRS overactivity in which the propositus and sole affected family member is a woman.

Background: Hyperuricemia can be the consequence of an increased urate production, a decreased renal excretion, or both. An increased prevalence of hyperuricemia has been described in essential hypertensive patients partly due to a decreased renal urinary urate excretion (UUE). Hyperuricemia has been shown to be associated with an increased risk of cardiovascular disease in hypertensive patients in some but not in all epidemiological studies in which this relationship has been investigated., Objective: To assess the influence of low UUE in the association between serum urate, renal function and hypertension severity., Patients and Methods: This cross-sectional study was carried out in a sample of 677 male hypertensive patients, aged 35-60 years, with essential arterial hypertension consecutively attended in a hospital hypertension unit. The presence of hypertension-related organ damage at diagnosis was classified according to classical WHO criteria as grade 1, 2 or 3. Urate underexcretion was defined as 24-h urinary urate below the product serum urate x 100., Results: Mean serum urate levels were 6.4 +/- 1.6 mg/dl in the total sample. Hyperuricemia (serum urate >7 mg/dl) was present in 28.5% of patients and only 17.0% had underexcretory hyperuricemia. This subgroup of patients exhibited the higher rate of hypertension-related target organ damage (TOD). A multivariate analysis, showed that underexcretory hyperuricemia but not hyperuricemia remained an independent predictor of TOD (odds ratio 2.5. 95% CI 1.6-3.89). Serum urate correlated positively with serum creatinine in hyperuricemic patients (r = 0.50, p < 0.001), but not in patients with underexcretory hyperuricemia (r = 0.21, p = 0.18)., Conclusions: Underexcretory hyperuricemia is strongly related to hypertensive organ damage and this relationship does not seem to be mediated by a decreased renal function. This aspect could underline the predictive value of hyperuricemia independently of serum creatinine. UUE could improve the clinical predictive value of hyperuricemia as a cardiovascular risk factor.

Background: Serum urate is commonly elevated in essential hypertension (26-33%). Some studies have claimed that losartan increases urinary uric acid excretion and diminishes serum urate levels. However, a detailed, controlled study on the influence of losartan on uric acid metabolism in hypertensive patients has not been performed and the existent results are conflicting. Two small studies claimed that losartan reduced serum urate levels but only one showed a simultaneous increased uric acid excretion rate. The development of several AT1 receptor blockers raises the question whether these antihypertensive drugs influence uric acid metabolism., Study: In a randomized, prospective (4 weeks), double blind, parallel study we have compared the influence of losartan (50 mg/day) versus eprosartan (600 mg/day) on uric acid metabolism in 58 patients with mild to moderate essential hypertension. The mean uric acid to creatinine ratio change from baseline at 4 weeks was +0.11 for losartan and -0.04 for eprosartan (P < 0.01). The mean increase in 24-h urinary uric acid excretion with losartan was +0.7 mmol/24 h (25% increase from baseline). The change in serum urate levels versus baseline was similar after 4 weeks with losartan (-23.4 mumol/l) and eprosartan (-19.5 mumol/l). Patients with hyperuricemia in both treatment groups showed similar modifications of uric acid metabolism compared with non-hyperuricemic subjects. Blood pressure control was achieved in 22 patients (73%) with eprosartan and in 16 (53%) with losartan., Conclusions: Losartan increased uric acid excretion in hypertensive patients but eprosartan did not. Neither AT1 receptor antagonist substantially modified serum urate concentrations.

Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency. [ABSTRACT FROM PUBLISHER]

Abstract: Hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency is a genetic disease of purine metabolism resulting in uric acid overproduction. Allopurinol, which inhibits the enzyme xanthine oxidase and reduces uric acid synthesis, is widely used for the treatment of gout and uric acid overproduction. The aim of the study was to analyze the long-term efficacy and safety of allopurinol in patients with HPRT deficiency. Nineteen patients (13 with Lesch-Nyhan syndrome and 6 with partial HPRT deficiency) were treated with allopurinol (mean dose, 6.4 mg/kg body weight per day; range, 3.7-9.7 mg/kg body weight per day) and followed up for at least 12 months (mean follow-up, 7.6 years). The efficacy of allopurinol was evaluated by serial measurement of purine metabolic parameters and renal function as well as by clinical manifestations. Safety was assessed by recording adverse events. Treatment with allopurinol normalized serum urate level in all patients and resulted in a mean reduction in serum urate of 47%. Allopurinol treatment was associated with a mean 74% reduction in urinary uric acid-to-creatinine ratio. In contrast, allopurinol treatment increased mean hypoxanthine and xanthine urinary excretion rates 5.4- and 9.5-fold, respectively, compared with baseline levels. The decrease in uric acid excretion in complete and partial HPRT-deficient patients was not accompanied by a stoichiometric substitution of hypoxanthine and xanthine excretion rates. Allopurinol-related biochemical changes were similar in patients with either complete or partial HPRT deficiency. Renal function remained stable or improved with treatment. Three patients had urolithiasis during allopurinol treatment. In 2 patients, xanthine stones were documented and they required allopurinol dose adjustments aimed at reducing excessive oxypurine excretion rates. No allopurinol hypersensitivity reactions occurred. Neurologic manifestations were not influenced by allopurinol therapy. In conclusion, allopurinol is efficacious and generally safe for the treatment of uric acid overproduction in patients with HPRT deficiencies. Xanthine lithiasis, developing as a consequence of allopurinol therapy, should be preventable by adjustment of allopurinol dose. [Copyright &y& Elsevier]

Abstract: Post-hoc analyses of the GREACE and the LIFE trials have renewed the interest in elevated serum uric acid (SUA) as a factor contributing to atherosclerotic cardiovascular disease (CVD) and in the possible benefit derived from its pharmacological reduction. The results of these trials are consistent with reports indicating favourable effects of SUA lowering treatment with allopurinol on the rate of cardiovascular complications in patients with coronary heart disease, congestive heart failure and dilated cardiomyopathy. Two recent overviews have concluded that, while in population samples at relatively low risk of CVD, SUA is at best a very weak predictor of CVD, by contrast it is a significant independent predictor among subjects at high or very high risk. This raises the question of a different meaning of excess SUA levels under different circumstances. Whereas in uncomplicated obese, insulin-resistant and hypertensive patients SUA levels increase mainly as a consequence of impaired renal excretion, in conditions of local ischemia an increased production of uric acid occurs in parallel with that of reactive oxygen species (ROS). Thus, although clinical and experimental evidence suggest that uric acid has actually antioxidant properties, it is conceivable that under these conditions its antioxidant activity is overcome by the pro-oxidant and pro-inflammatory effects of ROS accumulation. At present, there is no solid evidence to recommend treatment of the mild asymptomatic hyperuricemia associated with obesity, diabetes and/or hypertension (up to 10mg/dL). By contrast, similar SUA elevations in patients at higher cardiovascular risk should be taken more seriously. A controlled trial to investigate the effects of SUA reduction in these patients, while monitoring concomitant changes in parameters of oxidative stress and inflammation, is warranted. [Copyright &y& Elsevier]

Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1/380,000 live births in Canada, and 1/235,000 live births in Spain. Uric acid overproduction is present in all HPRT-deficient patients and is associated with lithiasis and gout. Neurological manifestations include severe action dystonia, choreoathetosis, ballismus, cognitive and attention deficit, and self-injurious behaviour. The most severe forms are known as Lesch-Nyhan syndrome (patients are normal at birth and diagnosis can be accomplished when psychomotor delay becomes apparent). Partial HPRT-deficient patients present these symptoms with a different intensity, and in the least severe forms symptoms may be unapparent. Megaloblastic anaemia is also associated with the disease. Inheritance of HPRT deficiency is X-linked recessive, thus males are generally affected and heterozygous female are carriers (usually asymptomatic). Human HPRT is encoded by a single structural gene on the long arm of the X chromosome at Xq26. To date, more than 300 disease-associated mutations in the HPRT1 gene have been identified. The diagnosis is based on clinical and biochemical findings (hyperuricemia and hyperuricosuria associated with psychomotor delay), and enzymatic (HPRT activity determination in haemolysate, intact erythrocytes or fibroblasts) and molecular tests. Molecular diagnosis allows faster and more accurate carrier and prenatal diagnosis. Prenatal diagnosis can be performed with amniotic cells obtained by amniocentesis at about 15-18 weeks' gestation, or chorionic villus cells obtained at about 10-12 weeks' gestation. Uric acid overproduction can be managed by allopurinol treatment. Doses must be carefully adjusted to avoid xanthine lithiasis. The lack of precise understanding of the neurological dysfunction has precluded development of useful therapies. Spasticity, when present, and dystonia can be managed with benzodiazepines and gamma-aminobutyric acid inhibitors such as baclofen. Physical rehabilitation, including management of dysarthria and dysphagia, special devices to enable hand control, appropriate walking aids, and a programme of posture management to prevent deformities are recommended. Self-injurious behaviour must be managed by a combination of physical restraints, behavioural and pharmaceutical treatments. [ABSTRACT FROM AUTHOR]