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

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

Mol Genet Metab. 2021 Nov;134(3):250-256. doi: 10.1016/j.ymgme.2021.09.004. Epub 2021 Oct 2.

Affiliations

¹ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands.
² School of Life and Health Sciences, Aston University, Birmingham, UK.
³ Department of Clinical Child and Adolescent Studies-Neurodevelopmental Disorders, Faculty of Social Sciences, Leiden University, Leiden, the Netherlands.
⁴ University of Groningen, Groningen Institute for Evolutionary Life Sciences (GELIFES), Department of Molecular Neurobiology, Groningen, the Netherlands.
⁵ University of Groningen, University Medical Center Groningen, Department of laboratory Medicine, Groningen, the Netherlands.
⁶ University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, the Netherlands. Electronic address: f.j.van.spronsen@umcg.nl.

PMID: 34656426
DOI: 10.1016/j.ymgme.2021.09.004

Abstract

Background: 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. 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.

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. 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.

Results: Plasma 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.

Conclusion: This 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 message: 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.

Keywords: Brain biochemistry; Large Neutral Amino Acids (LNAA); Monoaminergic neurotransmitters; Neurocognitive outcome; Phenylketonuria; Plasma amino acids.

MeSH terms

Amino Acids / blood
Animals
Brain / physiopathology*
Brain Chemistry*
Disease Models, Animal
Mice
Mice, Inbred C57BL
Neurotransmitter Agents / analysis
Phenylalanine / analysis
Phenylketonurias / blood*
Phenylketonurias / physiopathology*

Substances

Amino Acids
Neurotransmitter Agents
Phenylalanine