The Benefit of Large Neutral Amino Acid Supplementation to a Liberalized Phenylalanine-Restricted Diet in Adult Phenylketonuria Patients: Evidence from Adult Pah-Enu2 Mice.

Danique Van Vliet,Aurora Martinez,Ido P Kema,Pim De Blaauw,M Rebecca Heiner-Fokkema,Els Van Der Goot,Eddy A Van Der Zee,Wiggert G Van Ginkel,Martijn H J R Van Faassen,Francjan J Van Spronsen

doi:10.3390/nu11092252

Abstract

Many phenylketonuria (PKU) patients cannot adhere to the severe dietary restrictions as advised by the European PKU guidelines, which can be accompanied by aggravated neuropsychological impairments that, at least in part, have been attributed to brain monoaminergic neurotransmitter deficiencies. Supplementation of large neutral amino acids (LNAA) to an unrestricted diet has previously been shown to effectively improve brain monoamines in PKU mice of various ages. To determine the additive value of LNAA supplementation to a liberalized phenylalanine-restricted diet, brain and plasma monoamine and amino acid concentrations in 10 to 16-month-old adult C57Bl/6 PKU mice on a less severe phenylalanine-restricted diet with LNAA supplementation were compared to those on a non-supplemented severe or less severe phenylalanine-restricted diet. LNAA supplementation to a less severe phenylalanine-restricted diet was found to improve both brain monoamine and phenylalanine concentrations. Compared to a severe phenylalanine-restricted diet, it was equally effective to restore brain norepinephrine and serotonin even though being less effective to reduce brain phenylalanine concentrations. These results in adult PKU mice support the idea that LNAA supplementation may enhance the effect of a less severe phenylalanine-restricted diet and suggest that cerebral outcome of PKU patients treated with a less severe phenylalanine-restricted diet may be helped by additional LNAA treatment.

Highlights

In phenylketonuria (PKU; McKusick 261600), mutations in the gene encoding for the hepatic enzyme phenylalanine hydroxylase, that normally converts phenylalanine (Phe) into tyrosine, result in toxic accumulation of Phe in blood and brain
At the end of the experiment, body weight was significantly lower in PKU mice on a less severe Phe-restricted diet with or without large neutral amino acids (LNAA) supplementation compared with a severe Phe-restricted diet (p < 0.05), but not FOR PEER REVIEW
The present study showed that substituting the synthetic Phe-free amino acid mixture for LNAA supplementation in PKU mice on a less severe Phe-restricted diet significantly increased brain norepinephrine and serotonin, and reduced brain Phe concentrations

Summary

Introduction

In phenylketonuria (PKU; McKusick 261600), mutations in the gene encoding for the hepatic enzyme phenylalanine hydroxylase, that normally converts phenylalanine (Phe) into tyrosine, result in toxic accumulation of Phe in blood and brain Following this pathophysiological concept, a Nutrients 2019, 11, 2252; doi:10.3390/nu11092252 www.mdpi.com/journal/nutrients. The principle of the severe Phe-restricted diet (limiting natural protein intake and supplementing an amino acid mixture devoid of the one(s) prior to the metabolic block) has served as an example for dietary treatment in many other inborn errors of amino acid metabolism [1] Notwithstanding these successes, even in early- and continuously treated PKU patients neuropsychological outcome remains suboptimal [2,3,4,5,6], with children and adults showing some different problems [6].

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