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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	250-256
Number of pages	7
Journal	Molecular Genetics and Metabolism
Volume	134
Issue number	3
DOIs	https://doi.org/10.1016/j.ymgme.2021.09.004
Publication status	Published - Nov-2021

Keywords

Phenylketonuria
Brain biochemistry
Plasma amino acids
Large Neutral Amino Acids (LNAA)
Monoaminergic neurotransmitters
Neurocognitive outcome
AMINO-ACID-TRANSPORT
PHENYLALANINE LEVELS
TREATED PHENYLKETONURIA
CLINICAL-SIGNIFICANCE
ADULTS
TYROSINE
FLUCTUATIONS
SPECTROSCOPY
DYSFUNCTION
DOPAMINE

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AL: Adaptive Life
Etienne, R. (Coordinator), Kas, M. (Coordinator), Olff, H. (Coordinator), Weissing, F. (Coordinator) & Groothuis, T. (Coordinator)
01/01/2016 → 01/01/2026
Project: Research
AL-II: The role of the microbiome in disease–associated mental and behavioral problems: The case of phenylketonuria (PKU)
van der Zee, E. (PI), Falcao Salles, J. (PI), van Spronsen, F. (PI) & van der Goot, E. (PhD student)
01/07/2017 → 01/08/2023
Project: Research

Cite this

Dijkstra, A. M., van Vliet, N., van Vliet, D., Romani, C., Huijbregts, S. C. J., van der Goot, E., Hovens, I. B., van der Zee, E. A., Kema, I. P., Heiner-Fokkema, M. R., & van Spronsen, F. J. (2021). Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse. Molecular Genetics and Metabolism, 134(3), 250-256. https://doi.org/10.1016/j.ymgme.2021.09.004

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

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 = "Phenylketonuria, Brain biochemistry, Plasma amino acids, Large Neutral Amino Acids (LNAA), Monoaminergic neurotransmitters, Neurocognitive outcome, AMINO-ACID-TRANSPORT, PHENYLALANINE LEVELS, TREATED PHENYLKETONURIA, CLINICAL-SIGNIFICANCE, ADULTS, TYROSINE, FLUCTUATIONS, SPECTROSCOPY, DYSFUNCTION, DOPAMINE",

author = "Dijkstra, \{Allysa M\} and \{van Vliet\}, Ninke and \{van Vliet\}, Danique and Cristina Romani and Huijbregts, \{Stephan C J\} and \{van der Goot\}, Els and Hovens, \{Iris B\} and \{van der Zee\}, \{Eddy A\} and Kema, \{Ido P\} and Heiner-Fokkema, \{M Rebecca\} and \{van Spronsen\}, \{Francjan J\}",

note = "Copyright {\textcopyright} 2021. Published by Elsevier Inc.",

year = "2021",

month = nov,

doi = "10.1016/j.ymgme.2021.09.004",

language = "English",

volume = "134",

pages = "250--256",

journal = "Molecular Genetics and Metabolism",

issn = "1096-7192",

publisher = "ACADEMIC PRESS INC ELSEVIER SCIENCE",

number = "3",

}

Dijkstra, AM, van Vliet, N, van Vliet, D, Romani, C, Huijbregts, SCJ , van der Goot, E, Hovens, IB, van der Zee, EA , Kema, IP , Heiner-Fokkema, MR & van Spronsen, FJ 2021, 'Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse', Molecular Genetics and Metabolism, vol. 134, no. 3, pp. 250-256. https://doi.org/10.1016/j.ymgme.2021.09.004

TY - JOUR

T1 - Correlations of blood and brain biochemistry in phenylketonuria

T2 - Results from the Pah-enu2 PKU mouse

AU - Dijkstra, Allysa M

AU - van Vliet, Ninke

AU - van Vliet, Danique

AU - Romani, Cristina

AU - Huijbregts, Stephan C J

AU - van der Goot, Els

AU - Hovens, Iris B

AU - van der Zee, Eddy A

AU - Kema, Ido P

AU - Heiner-Fokkema, M Rebecca

AU - van Spronsen, Francjan J

PY - 2021/11

Y1 - 2021/11

N2 - 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.

AB - 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.

KW - Phenylketonuria

KW - Brain biochemistry

KW - Plasma amino acids

KW - Large Neutral Amino Acids (LNAA)

KW - Monoaminergic neurotransmitters

KW - Neurocognitive outcome

KW - AMINO-ACID-TRANSPORT

KW - PHENYLALANINE LEVELS

KW - TREATED PHENYLKETONURIA

KW - CLINICAL-SIGNIFICANCE

KW - ADULTS

KW - TYROSINE

KW - FLUCTUATIONS

KW - SPECTROSCOPY

KW - DYSFUNCTION

KW - DOPAMINE

U2 - 10.1016/j.ymgme.2021.09.004

DO - 10.1016/j.ymgme.2021.09.004

M3 - Article

C2 - 34656426

SN - 1096-7192

VL - 134

SP - 250

EP - 256

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 3

ER -

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

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Keywords

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AL: Adaptive Life

AL-II: The role of the microbiome in disease–associated mental and behavioral problems: The case of phenylketonuria (PKU)

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