Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia

Fernando Andrade,María Unceta Suarez,Ana Vinuesa,Leticia Ceberio,Raquel López-Oceja,Javier De Las Heras,Ainara Cano,Gorka De Frutos,Arantza Arza,Domingo González-Lamuño,Elena Aznal,Nuria López-Oslé

doi:10.3390/jcm10163674

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.

Highlights

We routinely use urine PAG as a biomarker for treatment adherence in urea cycle disorders (UCD) patients [20] and, as urine presence of PAG could be directly related to increased circulating Phe levels by decarboxylation [19], the aim of this study was to evaluate the reliability of PAG as a biomarker in PKU patients using a non-invasive measurement in urine
We used a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method [20] for urinary PAG quantification, and we show that patients with hyperphenylalaninemia present higher levels of urine PAG than sex- and age-matched healthy controls
As in our study we have shown a significant correlation between urine PAG and circulating Phe levels, we hypothesize that the PAH genotype may influence urine PAG levels, this point warrants further research

Summary

Introduction

The deficiency of the enzyme phenylalanine-4-hydroxylase (PAH), which catalyzes the conversion of the essential amino acid phenylalanine (Phe) to tyrosine, results in phenylketonuria (PKU, OMIM 261600) [1]. Since PKU was included in newborn screening (NBS) programs, dietary treatment consisting of a low-Phe diet is usually initiated soon after birth to prevent neurological damage and developmental delay. This diet is based on a marked reduction in natural protein, and may require supplementation with Phe-free protein substitutes and specially manufactured low-protein foods [2,3,4].

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