Gout with purine overproduction due to increased phosphoribosylpyrophosphate synthetase activity

Two brothers with marked purine overproduction and clinical gout showed activity of the enzyme phosphoribosylpyrophosphate (PP-ribose-P) synthetase in erythrocyte lysates 2.5 to 3.0-fold greater than that found in normal subjects or in other patients with gout. Associated with the increased activity of this enzyme, which catalyzes the synthesis of the regulatory substrate PP-ribose-P from adenosine triphosphate (ATP) and ribose-5-phosphate, was an increased intracellular PP-ribose-P concentration and an increased ability of intact erythrocytes to generate PP-ribose-P. In fibroblasts cultured from one of the affected brothers, these findings were confirmed, and an increased rate of the de novo purine biosynthetic pathway was demonstrated both in fibroblasts and in the affected brothers in vivo. The association of altered PP-ribose-P synthetase activity with increased intracellular PP-ribose-P generation and increased purine synthesis suggested that the proximal cause of the patients' gout was the increased enzyme activity.Hemolysates from a daughter of one of the affected brothers contained increased enzyme activity suggesting dominant hereditary transmission of the abnormality.The increased enzyme activity appeared to reside in the enzyme protein, although no evidence for a structural alteration in the patients' enzyme has thus far been found. Increased PP-ribose-P synthetase activity was apparent over a wide range of inorganic phosphate concentrations distinguishing the present abnormality from one previously described.Increased PP-ribose-P synthetase activity represents another hereditary enzyme aberration resulting in purine overproduction and clinical gout and demonstrates that human disease states can result from overabundance of enzyme activity as well as from deficiency.     

Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman

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.     

Novel association of achalasia with hereditary sensory and motor neuropathy with sensorineural deafness

Achalasia is a primary esophageal motility disorder. Unlike diffuse esophageal spasm, it has not previously been described in association with hereditary sensory and motor neuropathy (HSMN). An 18‐year‐old‐male with HSMN with sensorineural deafness presented with a 2‐day history of dysphagia to solids and liquids. Achalasia was diagnosed after extensive investigations, and his symptoms resolved with endoscopic and definitive surgical management. His monozygotic twin brother had also been diagnosed with HSMN and suffered from chronic dysphagia, which was also subsequently diagnosed with achalasia. This is the first case to illustrate an association between HSMN with sensorineural deafness and achalasia.     

Evidence for X-linkage of human phosphoribosylpyrophosphate synthetase

The mode of genetic transmission of human phosphoribosylpyrophosphate synthetase (ribosephosphate pyrophosphokinase; ATP:D-ribose-5-phosphate pyrophosphotransferase; EC 2.7.6.1) was studied in fibroblasts cultured from members of a family with a structurally and electrophoretically altered phosphoribosylpyrophosphate synthetase that has increased activity per enzyme molecule. Enzyme activity in fibroblast lysates from the daughter of an affected male patient was intermediate to the activities in lysates from her father (and her affected paternal uncle) and from her mother and other normal individuals. Two bands of enzyme activity corresponding to normal and mutant phosphoribosylpyrophosphate synthetases were found in fibroblast lysates from the daughter after cellulose acetate strip electrophoresis. In contrast, only mutant enzyme was detectable in lysates derived from the male patients. Fibroblasts cloned from the daughter contained two phenotypically distinct (normal and mutant) populations of cells with respect to phosphoribosylpyrophosphate synthetase activity and electrophoretic mobility. These studies support assignment of the structural gene for human phosphoribosylpyrophosphate synthetase to the X-chromosome. No evidence for the presence of the normal enzyme was found in erythrocyte or lymphocyte lysates or in partially purified erythrocyte enzyme preparations from the heterozygous daughter, suggesting either nonrandom X-chromosome inactivation in precursors of these cells or selection against hematopoietic cells bearing the normal enzyme after random X-chromosome inactivation.     

冠心病与血尿酸的关系

目的　确定血尿酸是否与冠心病独立相关以及是否与性别有关。方法　 35 5例行冠状动脉 (冠脉 )造影的患者分为两组 ,以性别、年龄、体重指数、空腹血糖、总胆固醇、甘油三酯、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、血尿酸、纤维蛋白原、吸烟量、高血压病病史、冠心病家族史等多重危险因素及冠脉评分进行多变量分析。结果　女性以血尿酸的四等分计算每组的冠脉评分 ,显示血尿酸越高 ,冠脉评分越高 ,而男性无此关系。多元logistic回归分析显示 :性别、纤维蛋白原、空腹血糖、吸烟等级与冠心病独立相关 (P值均 <0 0 5 ) ,年龄与冠心病有独立相关的趋势 (P =0 0 5 6 ) ,血尿酸与冠心病无独立相关 (P >0 0 5 )。逐步回归分析结果显示 :年龄、性别、纤维蛋白原、空腹血糖、总胆固醇与冠脉评分独立相关 (P值均 <0 0 5 ) ,血尿酸与冠脉评分无独立相关 (P >0 0 5 )。以女性病人专门进行多元逐步回归分析 ,血尿酸与冠心病及冠脉评分均无独立相关。结论　女性血尿酸越高 ,冠脉评分越高 ,但无论男女 ,血尿酸与冠心病及冠脉狭窄严重程度无独立相关。     

Phosphoribosylpyrophosphate synthetase superactivity: A study of five patients with catalytic defects in the enzyme

Superactive phosphoribosylpyrophosphate (PRPP) synthetases were characterized in fibroblasts and erythrocytes from 5 unrelated men with gout and/or hyperuricemia and uric acid overproduction. The kinetic basis of enzyme superactivity in all patients was increased maximal reaction velocity. Affinities of the enzymes for substrates and activators and responsiveness to inhibitors were normal, and levels of immunoreactive enzyme in patient and control fibroblast and erythrocyte extracts were comparable. Enzymes purified to homogeneity from 2 patients confirmed the presence of isolated catalytic defects. Altered physical properties of certain of the superactive enzymes suggested the presence of several distinctive structural defects among the aberrant forms. Fibroblasts from each affected patient showed increased PRPP concentration and generation, as well as accelerated rates of all PRPP-requiring purine nucleotide synthetic pathways. These findings support the concept that enzyme superactivity results in uric acid overproduction as a consequence of increased rates of PRPP and purine nucleotide synthesis. Cultured cells from female relatives of 2 patients showed evidence for the heterozygous carrier state, as measured both by enzyme activities and by rates of PRPP and purine synthesis. The clinical phenotype in 4 patients was limited to early adult-onset gout and its consequences, whereas the fifth patient expressed a familial constellation of hyperuricemia, sensorineural deafness, ataxia, and renal insufficiency. The severity of the derangements in PRPP synthetase and in PRPP and purine synthesis in cells from the 5 patients, however, was comparable. The neurologic accompaniments of enzyme superactivity found in 1 family described here, and in 2 others described previously, thus may not necessarily be consequences of primary defects in PRPP synthetase.     

Tick-borne encephalitis complicated by monoplegia and sensorineural deafness

Tick-borne encephalitis (TBE) is rarely seen in Britain. We report a case of TBE in a 44-year-old Swedish woman presenting to an accident and emergency department in London. The clinical features of the case, while in many ways typical, were nonspecific and led to difficulty in early diagnosis. The course of the illness was complicated by monoplegia and evidence of bulbar involvement with sensorineural deafness. The last is a very rare manifestation of TBE. With increasing foreign travel, TBE is likely to present more commonly in the U.K. and should be considered in any case of febrile illness with neurological complications following travel abroad. Serological tests to aid early diagnosis should be more readily available.     

血尿酸、颈动脉内中膜厚度与粥样硬化斑块稳定性关系的研究

目的研究冠心病患者血尿酸、颈动脉内膜厚度与粥样硬化斑块稳定性的的关系。方法选择冠状动脉造影确诊的冠心病(CHD)患者81例为实验组,其中血尿酸正常组(Uric≤416 mmol/L)50例,高尿酸血症(Uric>416 mmol L)组31例;冠状动脉造影排除冠心病的患者21例。颈动脉彩超测定颈动脉内中膜厚度,并分析其与斑块稳定性的关系。结果 (1)尿酸与颈动脉内中膜厚度、冠脉Gensin积分呈正直线相关(r=0.506,P<0.05;r=0.321,P<0.05),与高密度脂蛋白呈负相关(r=-0.210,P>0.05),但无直线相关性;(2)高血尿酸组空腹血糖、颈动脉内中膜厚度、冠脉Gensi-ni积分明显高于尿酸正常组,有统计学意义(P<0.05)。结论血尿酸水平与颈动脉内中膜厚度和冠脉Gensini积分有正相关性,与高密度脂蛋白负相关。血尿酸与颈动脉内中膜厚度可以联合预测粥样硬化斑块不稳定性的指标。     

Age and sex dependent association of uric acid and incident hypertension

Background and aimsA previous meta-analysis suggested that the relationship between hyperuricemia and hypertension may be stronger in younger individuals and women. We aimed to investigate the age and sex dependent association of uric acid (UA) and incident hypertension.Methods and resultsWe analyzed data from the Health Examinees Study, a community-based prospective cohort study conducted in Korea from 2004 to 2013. It included 29,088 non-hypertensive subjects aged 40–79 (age, 52.5 ± 7.8 years; men, 31.4%) who had serum UA measurement and participated in the follow-up survey. The risk factors of hypertension were assessed using Cox regression. Over a mean 3.8 years of follow-up, 1388 men (15.2%) and 1942 women (9.7%) were newly diagnosed with hypertension. Upon age- and sex-based stratification, the risk of hypertension was highest in hyperuricemic subjects aged 40–49 years (HR: women, 2.16; men, 1.30). Across the entire cohort, the risk of incident hypertension was higher in groups with higher serum UA levels, and highest in women aged 40–49 years (HR, 1.44; P < 0.001). On multivariable linear regression analysis, the higher the baseline serum UA level, the greater the increase in blood pressure during follow-up, and this effect was strongest in women aged 40–49 years (β = 0.87 and P < 0.01 for systolic blood pressure).ConclusionsThe relationship between uric acid and incident hypertension tended to be dependent on age and sex. Younger women are at highest risk of UA-related incident hypertension.     

Developmental window of sensorineural deafness in biotinidase-deficient mice

Biotinidase deficiency is an autosomal recessively inherited disorder that results in the inability to recycle the vitamin, biotin. If untreated, the disorder can result in a range of neurological and cutaneous symptoms, including sensorineural deficits and deafness. To understand early mechanistic abnormalities that may precede more generalized and nonspecific effects of metabolic deficits such as weight loss and acidosis, we have analyzed auditory brainstem responses (ABRs) in biotinidase-deficient knockout (Btd ^?/? ) mice in the periweaning period with or without dietary biotin supplementation. We find significant increases in the latency of wave V of the ABR elicited by pure tone stimuli at one octave intervals, which precede substantial increases in ABR thresholds. Finer interpeak latency analyses of these changes indicate they are confined to the latter ABR waves associated with the CNS and likely reflect slowed brainstem transmission time. In contrast, peripheral nervous system conduction velocity appears normal. Further, we find that biotin-supplementation after the onset of symptoms reverses the latency shifts, which has significant relevance for early treatment in patients. Finally, ABR latencies in Btd ^?/? mice fed a biotin-supplemented diet for the first month of life appear refractory to transmission time slowing during a subsequent bout of biotin deficiency. These data suggest a transient vulnerability window for biotin deficiency in the auditory brainstem. Finally, we also observe a developmental vulnerability window involving follicular melanosome production or melanocyte survival. Sensorineural deafness precedes peripheral hearing loss in developmental biotinidase deficiency and is transient if rescued by dietary biotin within a short developmental window.     

血尿酸与冠心病的相关性分析

目的分析研究冠心病和血尿酸的形成、扩散与患者治疗、恢复之间的关系。方法抽取近年来在我院给予血尿酸检测的冠心病病人180例（实验组）,并且再次抽取在这期间在我院进行常规体检的健康人群180例（对照组）当做对比分析观察。结果实验组病人的血尿酸含量：（421．23±43．52）μmol／L;对照组的血尿酸含量：（362．45±40．57）μmol／L,两组间差异具有统计学意义（P〈0．05）;然而心绞痛和陈旧性心肌梗死病人的血尿酸水平明显优于急性心肌梗死以及对照组病人,其差异具有统计学意义（P〈0．05）;急性心肌梗死病人的血尿酸水平（平均）和对照组差异不具有统计学意义（P〈0．05）。结论冠心病的形成、扩散是造成患者血尿酸的浓度升高的重要因素,对于冠心病病人应该采取定期对血尿酸进行检测,这样对及时预防这种疾病的发生具有非常大的帮助,对病人的生活质量起到至关重要的作用．具有临床推广价值应用。     

Familial idiopathic hypoparathyroidism, sensorineural deafness and renal dysplasia

We describe a 27-year-old woman with familial idiopathic hypoparathyroidism, bilateral sensorineural deafness and right renal aplasia. There was a family history of deafness in her father and two other family members with sensorineural deafness, one of whom had hypoparathyroidism. To our knowledge, there have been four previous reports of idiopathic hypoparathyroidism associated with sensorineural deafness and renal dysplasia. The clinical features were not identical to any of the four previous reports. Although no chromosome abnormalities were present in the patient using standard trypsin G-banding analysis, we speculate that some common genetic mutation caused hypoparathyroidism, sensorineural deafness and renal dysplasia.     

Ultra-processed foods: Cross-sectional and longitudinal association with uric acid and hyperuricemia in ELSA-Brasil

Background and aimsFood intake influences uric acid (UA) levels and hyperuricemia (HU), but evidence on the role of ultra-processed foods (UPFs) are scarce. The association between UPFs consumption and (1) HU prevalence and UA levels; (2) HU cumulative incidence; and (3) UA level change over a 4-year period was investigated.Methods and resultsCross-sectional and longitudinal analyses were performed using baseline (2008–2010, aged 35–74 years) and second visit (2012–2014) data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Participants with glomerular filtration rate <60 mL/min/1.73 m2, bariatric surgery, implausible caloric intake, and using urate-lowering therapy (ULT) at baseline were excluded (all analyses). Participants with HU at baseline were excluded from longitudinal analyses. UPFs consumption was assessed using a food frequency questionnaire (FFQ) and categorized by the NOVA classification system (100 g/day). HU was defined as UA≥6.8 mg/dL. Linear, logistic, and mixed-effect linear regressions investigated the associations between UPFs consumption and UA/HU, adjusted for covariates. The final samples included 13,923 (cross-sectional) and 10,517 (longitudinal) individuals. The prevalence of HU was 18.7%, and the cumulative incidence was 4.9%. Greater UPFs consumption was associated with a greater prevalence of HU (OR:1.025 95%CI: 1.006; 1.044) and higher UA levels (β:0.024 95%CI: 0.016; 0.032). Every additional consumption of 100 g/day of UPFs raised the 4-year cumulative incidence of HU by 5.6% (95%CI: 1.021; 1.092). However, UPFs were not associated with the pace of UA level changes during the study period.ConclusionThe present study shows that greater UPFs consumption is associated with another deleterious health consequence: higher UA levels and the risk of having HU.     

Sex and age interaction with genetic association of atherogenic uric acid concentrations

BackgroundHigh serum uric acid levels are associated with gout, atherosclerosis and cardiovascular disease. Three genes (SLC2A9, ABCG2, and SLC17A3) were reported to be involved in the regulation of uric acid levels.ResearchDesign and Methods: SNPs rs2231142 (ABCG2) and rs1165205 (SLC17A3) were genotyped in three cohorts (n = 4492) and combined with previously genotyped SNPs within SLC2A9 (rs6855911, rs7442295, rs6449213, rs12510549).ResultsEach copy of the minor allele decreased uric acid levels by 0.30–0.38 mg/dL for SLC2A9 (p values: 10^?20–10^?36) and increased levels by 0.34 mg/dL for ABCG2 (p = 1.1 × 10^?16). SLC17A3 influenced uric acid levels only modestly. Together the SNPs showed graded associations with uric acid levels of 0.111 mg/dL per risk allele (p = 3.8 × 10^?42). In addition, we observed a sex-specific interaction of age with the association of SLC2A9 SNPs with uric acid levels, where increasing age strengthened the association of SNPs in women and decreased the association in men.ConclusionsGenetic variants within SLC2A9, ABCG2 and SLC17A3 show highly significant associations with uric acid levels, and for SNPs within SLC2A9 this association is strongly modified by age and sex.     

Serum uric acid level and association with cognitive impairment and dementia: systematic review and meta-analysis

Serum uric acid (sUA) level may be associated with cognitive impairment/dementia. It is possible this relationship varies with dementia subtype, particularly between vascular dementias (VaD) and Alzheimer’s (AD) or Parkinson’s disease (PDD)-related dementia. We aimed to present a synthesis of all published data on sUA and relationship with dementia/cognition through systematic review and meta-analysis. We included studies that assessed the association between sUA and any measure of cognitive function or a clinical diagnosis of dementia. We pre-defined subgroup analyses for patients with AD, VaD, PDD, mild cognitive impairment (MCI), and mixed or undifferentiated. We assessed risk of bias/generalizability, and where data allowed, we performed meta-analysis to describe pooled measures of association across studies. From 4811 titles, 46 papers (n?=?16,688 participants) met our selection criteria. Compared to controls, sUA was lower in dementia (SDM ?0.33 (95%CI)). There were differences in association by dementia type with apparent association for AD (SDM ?0.33 (95%CI)) and PDD (SDM ?0.67 (95%CI)) but not in cases of mixed dementia (SDM 0.19 (95%CI)) or VaD (SDM ?0.05 (95%CI)). There was no correlation between scores on Mini-Mental State Examination and sUA level (summary r 0.08, p?=?0.27), except in patients with PDD (r 0.16, p?=?0.003). Our conclusions are limited by clinical heterogeneity and risk of bias in studies. Accepting this caveat, the relationship between sUA and dementia/cognitive impairment is not consistent across all dementia groups and in particular may differ in patients with VaD compared to other dementia subtypes.     

Gender-related association of serum uric acid and left ventricular hypertrophy in hypertension.

BACKGROUND: The aim of the present study was to determine whether sex differences contribute to the association of serum uric acid and left ventricular hypertrophy in individuals with hypertension. METHODS AND RESULTS: Seventy participants with essential hypertension (34 men, 36 women; 54.4 +/- 1.6 years old) were enrolled to undergo echocardiography to calculate the left ventricular mass index (LVMI). Twenty-four-hour ambulatory blood pressure monitoring was done to assess blood pressure level precisely. The LVMI was significantly correlated with serum uric acid (r = 0.295, p = 0.013) in all participants. After controlling for factors such as age, sex, mean 24-h systolic blood pressure, creatinine clearance, and duration of hypertension, serum uric acid was still found to be significantly and independently associated with LVMI. Because serum uric acid was significantly higher in men than in women (6.8 +/- 0.3 and 5.1 +/- 0.2 mg/dl, respectively), subsequent analysis was performed by gender. Multiple regression analysis revealed that the LVMI was significantly and independently associated with serum uric acid in women, but not in men. CONCLUSIONS: The potential effect of uric acid on LV hypertrophy is more pronounced in female than in males with essential hypertension.