Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.
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ABSTRACT:
SUBMITTER: Andrade F
PROVIDER: S-EPMC8396897 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:UnlabelledWe have analyzed pharmacokinetic data for glycerol phenylbutyrate (also GT4P or HPN-100) and sodium phenylbutyrate with respect to possible dosing biomarkers in patients with urea cycle disorders (UCD).Study designThese analyses are based on over 3000 urine and plasma data points from 54 adult and 11 pediatric UCD patients (ages 6-17) who participated in three clinical studies comparing ammonia control and pharmacokinetics during steady state treatment with glycerol phenylbutyrate or sodium phenylbutyrate. All patients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate or sodium phenylbutyrate in a cross over fashion and underwent 24-hour blood samples and urine sampling for phenylbutyric acid, phenylacetic acid and phenylacetylglutamine.ResultsPatients received phenylbutyric acid equivalent doses of glycerol phenylbutyrate ranging from 1.5 to 31.8 g/day and of sodium phenylbutyrate ranging from 1.3 to 31.7 g/day. Plasma metabolite levels varied widely, with average fluctuation indices ranging from 1979% to 5690% for phenylbutyric acid, 843% to 3931% for phenylacetic acid, and 881% to 1434% for phenylacetylglutamine. Mean percent recovery of phenylbutyric acid as urinary phenylacetylglutamine was 66.4 and 69.0 for pediatric patients and 68.7 and 71.4 for adult patients on glycerol phenylbutyrate and sodium phenylbutyrate, respectively. The correlation with dose was strongest for urinary phenylacetylglutamine excretion, either as morning spot urine (r = 0.730, p < 0.001) or as total 24-hour excretion (r = 0.791 p<0.001), followed by plasma phenylacetylglutamine AUC(24-hour), plasma phenylacetic acid AUC(24-hour) and phenylbutyric acid AUC(24-hour). Plasma phenylacetic acid levels in adult and pediatric patients did not show a consistent relationship with either urinary phenylacetylglutamine or ammonia control.ConclusionThe findings are collectively consistent with substantial yet variable pre-systemic (1st pass) conversion of phenylbutyric acid to phenylacetic acid and/or phenylacetylglutamine. The variability of blood metabolite levels during the day, their weaker correlation with dose, the need for multiple blood samples to capture trough and peak, and the inconsistency between phenylacetic acid and urinary phenylacetylglutamine as a marker of waste nitrogen scavenging limit the utility of plasma levels for therapeutic monitoring. By contrast, 24-hour urinary phenylacetylglutamine and morning spot urine phenylacetylglutamine correlate strongly with dose and appear to be clinically useful non-invasive biomarkers for compliance and therapeutic monitoring.
| S-EPMC3608516 | biostudies-literature
Project description:The data presented here are the biochemical parameters of 156 patients with hyperphenylalaninemia. PKU patients, who, in order to maintain optimal serum Phe concentrations, receive dietary treatment consisting of a diet low in natural protein supplemented with special low protein foods and a Phe-free amino acid mixture, vitamins and minerals. The obtained data reflects a high percentage of patients with prealbumin and selenium deficiencies, as well as an increased level of folic acid. This data article is related to the research article entitled, "Vitamin and mineral status in patients with hyperphenylalaninemia", by Crujeiras et al. [1].
| S-EPMC4543207 | biostudies-literature
Project description:The role of the gut microbiome in human health, and non-invasive measurement of gut dysbiosis are of increasing clinical interest. New high-throughput methods are required for the rapid measurement of gut microbial metabolites and to establish reference ranges in human populations. We used ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) -- positive and negative electrospray ionization modes, multiple reaction monitoring transitions -- to simultaneously measure three urinary metabolites (phenylacetylglutamine, 4-cresyl sulphate and hippurate) that are potential biomarkers of gut function, among multi-ethnic US men and women aged 40-59 from the INTERMAP epidemiologic study (n = 2000, two timed 24-hr urine collections/person). Metabolite concentrations were quantified via stable isotope labeled internal standards. The assay was linear in the ranges 1ng/mL (lower limit of quantification) to 1000ng/mL (phenylacetylglutamine and 4-cresyl sulfate) and 3ng/mL to 3000ng/mL (hippurate). These quantitative data provide new urinary reference ranges for population-based human samples: mean (standard deviation) 24-hr urinary excretion for phenylacetylglutamine was: 1283.0 (751.7) ?mol/24-hr (men), 1145.9 (635.5) ?mol/24-hr (women); for 4-cresyl sulphate, 1002.5 (737.1) ?mol/24-hr (men), 1031.8 (687.9) ?mol/24-hr (women); for hippurate, 6284.6 (4008.1) ?mol/24-hr (men), 4793.0 (3293.3) ?mol/24-hr (women). Metabolic profiling by UPLC-MS/MS in a large sample of free-living individuals has provided new data on urinary reference ranges for three urinary microbial co-metabolites, and demonstrates the applicability of this approach to epidemiological investigations.
| S-EPMC3740387 | biostudies-literature
Project description:BACKGROUND:There is evidence in support of low bone density in young patients with disorders of phenylalanine metabolism; however, little is known about muscle and fat mass in these patients, especially in those with mild hyperphenylalaninemia (mHPA). OBJECTIVES:We aimed to evaluate body composition of children and adolescents with early-diagnosed disorders of phenylalanine metabolism. PATIENTS AND METHODS:The study was conducted in the Institute of Child Health, which is the national center that performs newborn screening. Bone, muscle, and fat mass of 48 patients with phenylketonuria (PKU) and 32 patients with mild mHPA, aged five to 18 years, were compared to 57 age- and sex-matched controls. Dual energy X-ray absorptiometry was used for this purpose. RESULTS:Compared to controls, bone mineral density (BMD) was lower in patients with PKU (mean total body BMD z score, 0.11; P = 0.03) and in those with mild mHPA (mean lumbar BMD z score, -0.34; P = 0.01). Lean body mass and fat mass were not significantly affected in the study group. Comparison between the two patients groups did not reveal any difference in body composition profiles; however, pubertal status appeared important for within-group comparisons. Fat mass was significantly increased in teenagers with PKU, which was more evident in those with poor dietary compliance irrespective of gender (fat mass z score, 0.66; P = 0.018). Finally, positive correlations were found not only between bone, muscle, and fat mass in both groups, but also between fat mass and Phenylalanine levels in patients with PKU (r, 0.46; P = 0.001). CONCLUSIONS:Bone mineral density appears suboptimal in young patients with disorders of phenylalanine metabolism. Adolescents seemed more prone to obesity, especially when their dietary adherence was poor, whereas muscle mass was not considerably affected. To ensure healthier bones and less fat content, close follow-up as well as proper lifestyle advice is needed.
| S-EPMC4166007 | biostudies-literature
Project description:BackgroundHyperphenylalaninemia is the most common genetic metabolic disease. Early treatment prevents brain injury effectively. The present study aimed to detect the exact amino acid status of patients with hyperphenylalaninemia before treatment.MethodsData of 116 newborn patients from our Newborn Screening Center and 161 older patients from our clinic before treatment were collected. The content of 17 amino acids in their blood was determined by tandem mass spectrometry and compared with normal controls. Relationship between phenylalanine and other amino acids in patients was analyzed using the smoothing curve fitting and threshold effect analysis.ResultsMost amino acids in the blood of patients were within the normal range; however, they were different significantly from those of the normal children. Newborn patients showed higher phenylalanine (346.30 vs 45.90 µmol/L), valine (121.50 vs 110.30 µmol/L), citrulline, ornithine and lower tyrosine (52.97 vs 66.12 µmol/L), threonine (68.68 vs 78.21 µmol/L), glutamine levels than observed in normal newborns. Older patients showed significantly higher phenylalanine (844.00 vs 51.82 µmol/L), valine (117.60 vs 110.90 µmol/L), histidine, serine and lower tyrosine (55.97 vs 67.31 µmol/L), threonine (35.94 vs 51.89 µmol/L), alanine, asparagine, glutamic acid, methionine, arginine, glycine, ornithine, glutamine content than found in matched normal children. Tyrosine, valine, ornithine, and threonine in newborn patients and tyrosine, glycine, glutamine, and threonine in older patients had a nonlinear correlation with phenylalanine levels with obvious threshold effect and clear inflection points.ConclusionSignificant difference was observed in the amino acid status between pretherapeutic hyperphenylalaninemia patients and normal children. Some amino acids showed notable threshold effect with phenylalanine level in a nonlinear pattern.
| S-EPMC7083473 | biostudies-literature
Project description:Colonic microbial metabolism substantially contributes to uremic solute production. p-Cresyl sulfate and indoxyl sulfate are the main representatives of solutes of microbial origin and also, protein-bound solutes, exhibiting high protein-binding affinity and dependence on tubular secretion. Phenylacetylglutamine is another microbial metabolite with high dependence on tubular secretion but low protein-binding affinity. The relevance of such solutes is unknown. Therefore, we prospectively followed 488 patients with CKD stages 1-5 and a measurement of serum phenylacetylglutamine by liquid chromatography-mass spectrometry. In a subgroup, we determined 24-hour urinary excretion as a surrogate of intestinal uptake as well as renal clearance of phenylacetylglutamine. We performed outcome analysis for mortality (51 events) and cardiovascular disease (75 events). Serum phenylacetylglutamine level correlated with 24-hour urinary excretion (rho=0.55; P<0.001) and clearance of phenylacetylglutamine (rho=-0.76; P<0.001). Phenylacetylglutamine clearance also correlated with eGFR (rho=0.84; P<0.001). Furthermore, serum phenylacetylglutamine level associated with mortality (hazard ratio per 1-SD increase, 1.77; 95% confidence interval, 1.22 to 2.57; P=0.003) and cardiovascular disease (hazard ratio, 1.79; 95% confidence interval, 1.32 to 2.41; P<0.001) after adjustment for age, sex, presence of diabetes mellitus, prior cardiovascular disease, and eGFR. Thus, serum phenylacetylglutamine level is elevated in patients with more advanced CKD and determined by intestinal uptake and renal clearance, and it is not fully accounted for by differences in eGFR. High serum phenylacetylglutamine level is a strong and independent risk factor for mortality and cardiovascular disease, suggesting the relevance of microbial metabolism and/or tubular dysfunction in CKD, irrespective of protein binding.
| S-EPMC5084895 | biostudies-literature
Project description:Creatine (Cr) levels are strongly dependent on diets, including animal-derived proteins. Cr is an important metabolite as it represents a source of stored energy to support physical performance and potentially sustain positive effects such as improving memory or intelligence. This study was planned to assess Cr levels in PKU children adhering to a diet low in phenylalanine (Phe) content and compared with those of children with mild hyperphenylalaninemia (MHP) on a free diet. This retrospective pilot study analyzed Cr levels from Guthrie cards in 25 PKU and 35 MHP subjects. Anthropomorphic and nutritional data of the study populations were assessed, compared and correlated. Cr levels of PKU subjects were significantly lower than those of MHP subjects and correlated to the low intake of animal proteins. Although no deficiencies in PKU subjects were identified, PKU subjects were found to have a 26-fold higher risk of displaying Cr levels <25° percentile than MHP counterparts. This pilot study suggests that Cr levels might be concerningly low in PKU children adhering to a low-Phe diet. Confirmatory studies are needed in PKU patients of different age groups to assess Cr levels and the potential benefits on physical and intellectual performance of Cr supplementation.
| S-EPMC8148514 | biostudies-literature
Project description:A timely detection of patients with tetrahydrobiopterin (BH4) -deficient types of hyperphenylalaninemia (HPABH4) is important for assignment of correct therapy, allowing to avoid complications. Often HPABH4 patients receive the same therapy as phenylalanine hydroxylase (PAH) -deficiency (phenylketonuria) patients-dietary treatment-and do not receive substitutive BH4 therapy until the diagnosis is confirmed by molecular genetic means. In this study, we present a cohort of 30 Russian patients with HPABH4 with detected variants in genes causing different types of HPA. Family diagnostics and biochemical urinary pterin spectrum analyses were carried out. HPABH4A is shown to be the prevalent type, 83.3% of all HPABH4 cases. The mutation spectrum for the PTS gene was defined, the most common variants in Russia were p.Thr106Met-32%, p.Asn72Lys-20%, p.Arg9His-8%, p.Ser32Gly-6%. We also detected 7 novel PTS variants and 3 novel QDPR variants. HPABH4 prevalence was estimated to be 0.5-0.9% of all HPA cases in Russia, which is significantly lower than in European countries on average, China, and Saudi Arabia. The results of this research show the necessity of introducing differential diagnostics for HPABH4 into neonatal screening practice.
| S-EPMC8023510 | biostudies-literature
Project description:Background: To discover novel metabolic biomarkers of ischemic stroke (IS), we carried out a two-stage metabolomic profiling of IS patients and healthy controls using untargeted and targeted metabolomic approaches. Methods: We applied untargeted liquid chromatography-mass spectrometry (LC-MS) to detect the plasma metabolomic profiles of 150 acute IS patients and 50 healthy controls. The candidate differential microbiota-derived metabolite phenylacetylglutamine (PAGln) was validated in 751 patients with IS and 200 healthy controls. We evaluated the associations between PAGln levels and the severity and functional outcomes of patients with IS. Clinical mild stroke was defined as the National Institutes of Health Stroke Scale (NIHSS) score 0-5, and moderate-severe stroke as NIHSS score >5. A favorable outcome at 3 months after IS was defined as the modified Rankin Scale (mRS) score 0-2, and unfavorable outcome as mRS score 3-6. Results: In untargeted metabolomic analysis, we detected 120 differential metabolites between patients with IS and healthy controls. Significantly altered metabolic pathways were purine metabolism, TCA cycle, steroid hormone biosynthesis, and pantothenate and CoA biosynthesis. Elevated plasma PAGln levels in IS patients, compared with healthy controls, were observed in untargeted LC-MS analysis and confirmed by targeted quantification (median 2.0 vs. 1.0 μmol/L; p < 0.001). Patients with moderate-severe stroke symptoms and unfavorable short-term outcomes also had higher levels of PAGln both in discovery and validation stage. After adjusting for potential confounders, high PAGln levels were independently associated with IS (OR = 3.183, 95% CI 1.671-6.066 for the middle tertile and OR = 9.362, 95% CI 3.797-23.083 for the highest tertile, compared with the lowest tertile) and the risk of unfavorable short-term outcomes (OR = 2.286, 95% CI 1.188-4.401 for the highest tertile). Conclusions: IS patients had higher plasma levels of PAGln than healthy controls. PAGln might be a potential biomarker for IS and unfavorable functional outcomes in patients with IS.
| S-EPMC8733610 | biostudies-literature
Project description:Treatment of urine or of a urine extract with periodate followed by treatment of the acidic oxidation products with sodium bismuthate gave a mixture of neutral end products consisting only or predominantly of 17-oxoandrostanes derived from the corresponding urinary pregnane-17,21-diol-20-ones. The mixture of end products was resolved by gas-liquid or paper chromatography. The latter technique was used to determine cortisol secretion rates and the results were found to be in reasonable agreement with those obtained by a double-isotope method. Gas-liquid-chromatographic characterization of steroidal 4-en-3-ones is described.
| S-EPMC1179628 | biostudies-other