Dataset Information

Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.

ABSTRACT: Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for urinary PAG quantification in 35 participants with hyperphenylalaninemia (HPA) and 33 age- and sex-matched healthy controls. We have found that (a) PKU patients present higher urine PAG levels than healthy control subjects, and that (b) there is a significant correlation between urine PAG and circulating Phe levels in patients with HPA. In addition, we show a significant strong correlation between Phe levels from venous blood samples and from capillary finger-prick dried blood spot (DBS) samples collected at the same time in patients with HPA. Further research in order to assess the potential role of urine PAG as a non-invasive biomarker in PKU is warranted.

SUBMITTER: Andrade F

PROVIDER: S-EPMC8396897 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.

Andrade Fernando F Cano Ainara A Unceta Suarez María M Arza Arantza A Vinuesa Ana A Ceberio Leticia L López-Oslé Nuria N de Frutos Gorka G López-Oceja Raquel R Aznal Elena E González-Lamuño Domingo D de Las Heras Javier J

Journal of clinical medicine 20210819 16

Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for uri ...[more]

PMID: 34441968

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Project description:BackgroundHyperphenylalaninemia (HPA) is defined as blood phenylalanine (Phe) levels exceeding the normal values (>120 μmol/L or >2 mg/dL) and is caused by a deficiency in the enzyme phenylalanine hydroxylase (PAH). The widespread screening of Phe levels in newborn screening programs has led to a very high number of patients with HPA.MethodsThe samples were collected at various ages, not at the point of diagnosis. Nine pterin derivatives, including isoxanthopterin, sepiapterin, xanthopterin, primapterin, biopterin, neopterin, 7,8-dihydrobiopterin, 7,8-dihydroneopterin, and tetrahydrobiopterin (BH4), were analyzed in different HPA classes in serum, dried blood spots (DBS), and urine samples. A total of 18 patients, including six classical phenylketonuria (PKU), eight BH4-responsive PKU, and four mild HPA patients, were included in the study.ResultsAmong the nine pterin derivatives measured, a significant increase was observed in the levels of isoxanthopterin, biopterin, and 7,8-dihydrobiopterin in serum, dried blood spots (DBS), and urine samples of patients with HPA compared to the control group. However, elevations in isoxanthopterin, biopterin, and 7,8-dihydrobiopterin were observed in all HPA groups, although the extent of elevation varied among the different disease groups. There were also significant differences between HPA subgroups among these high values.ConclusionIn this study, it might be suggested that pterin profiling shows promising potential for its effective utilization in the differential diagnosis of HPA. Pterin profiling demonstrated its efficacy in accurately categorizing patients into distinct subtypes. This approach offers several notable advantages, including the ability to simultaneously screen multiple HPA subtypes through a single test, establish disease decision limits for pterins, shorten the time required for HPA differential diagnosis, reduce the risk of misdiagnosis, and increase overall diagnostic accuracy. This study is the most comprehensive study examining the association between HPA pterin in the literature. In our study, samples obtained from BH4-responsive PKU patients were on treatment. This may have affected the results. Preliminary findings on pterin profiles may need to be replicated in a prospective cohort of samples collected at the time of diagnosis to confirm the results.

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.

Dataset Information

Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.

Publications

Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.

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