Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse

Allysa M Dijkstra,Ninke Van Vliet,Danique Van Vliet,Cristina Romani,Stephan C.J Huijbregts,Els Van Der Goot,Iris B Hovens,Eddy A Van Der Zee,Ido P Kema,M Rebecca Heiner-Fokkema,Francjan J Van Spronsen

doi:10.1016/j.ymgme.2021.09.004

Abstract

BackgroundIn phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. MethodsIn a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. ResultsPlasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. ConclusionThis study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. Take-home messageBlood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.

Highlights

Phenylketonuria (PKU; McKusick 261,600) is an inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH, EC 1.14.16.1), which catalyzes the conversion of⁎ Corresponding author at: Children's Beatrix Hospital, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.phenylalanine ammonia lyase (PAL) has become a third treatment option, metabolizing Phe into other non-toxic compounds
This study started with the observation that variances in neurocognitive and behavioural outcome in PKU cannot be fully explained by blood Phe concentrations
Several other studies have already extensively examined the relationship between plasma Phe and brain Phe concentrations [12,14,16]

Summary

Introduction

Phenylketonuria (PKU; McKusick 261,600) is an inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH, EC 1.14.16.1), which catalyzes the conversion of⁎ Corresponding author at: Children's Beatrix Hospital, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.phenylalanine ammonia lyase (PAL) has become a third treatment option, metabolizing Phe into other non-toxic compounds. Especially high brain Phe and low brain monoaminergic neurotransmitter levels seem to be responsible for cognitive and behavioural impairments in PKU [17,18,19] To this end, this study will investigate the relationships between blood and brain biochemistry in PKU. In phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Methods: In a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. Neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters

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