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

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

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:
Brain biochemistry in PKU is still best explained by blood phenylalanine. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain phenylalanine 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
Early online date	2 Oct 2021
DOIs	https://doi.org/10.1016/j.ymgme.2021.09.004
Publication status	Published - Nov 2021

Bibliographical note

Keywords

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

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10.1016/j.ymgme.2021.09.004

Correlations of blood and brain biochemistry in phenylketonuria
© 2021, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0.
Accepted author manuscript, 1.27 MBLicence: CC BY-NC-ND 3.0

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: Brain biochemistry in PKU is still best explained by blood phenylalanine. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain phenylalanine concentrations, necessitating a search for other additional parameters.",

keywords = "Brain biochemistry, Large Neutral Amino Acids (LNAA), Monoaminergic neurotransmitters, Neurocognitive outcome, Phenylketonuria, Plasma amino acids",

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 = "{\textcopyright} 2021, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0.",

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 = "Elsevier",

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: 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: Brain biochemistry in PKU is still best explained by blood phenylalanine. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain phenylalanine 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: Brain biochemistry in PKU is still best explained by blood phenylalanine. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain phenylalanine concentrations, necessitating a search for other additional parameters.

KW - Brain biochemistry

KW - Large Neutral Amino Acids (LNAA)

KW - Monoaminergic neurotransmitters

KW - Neurocognitive outcome

KW - Phenylketonuria

KW - Plasma amino acids

UR - https://linkinghub.elsevier.com/retrieve/pii/S1096719221007800

UR - http://www.scopus.com/inward/record.url?scp=85117066041&partnerID=8YFLogxK

U2 - 10.1016/j.ymgme.2021.09.004

DO - 10.1016/j.ymgme.2021.09.004

M3 - Article

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

Abstract

Bibliographical note

Keywords

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