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Cerebral dopamine deficiency, plasma monoamine alterations and neurocognitive deficits in adults with phenylketonuria

Published online by Cambridge University Press:  29 May 2017

E. Boot ,
C. E. M. Hollak ,
S. C. J. Huijbregts ,
R. Jahja ,
D. van Vliet ,
A. J. Nederveen ,
D. H. Nieman ,
A. M. Bosch ,
L. J. Bour  and
A. J. Bakermans
...Show all authors
E. Boot*
Affiliation:
Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, and Center for Mental Health, University Health Network, Toronto, Ontario, Canada Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada Clinical Genetics Research Program, Center for Addiction and Mental Health, Toronto, Ontario, Canada
C. E. M. Hollak
Affiliation:
Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
S. C. J. Huijbregts
Affiliation:
Department of Clinical Child and Adolescent Studies & Leiden, Institute for Brain and Cognition, Leiden University, Leiden, The Netherlands
R. Jahja
Affiliation:
Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
D. van Vliet
Affiliation:
Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
A. J. Nederveen
Affiliation:
Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
D. H. Nieman
Affiliation:
Department of Psychiatry, Academic Medical Center, Amsterdam, The Netherlands
A. M. Bosch
Affiliation:
Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands
L. J. Bour
Affiliation:
Department of Neurology and Clinical Neurophysiology, Academic Medical Center, Amsterdam, The Netherlands
A. J. Bakermans
Affiliation:
Department of Radiology, Academic Medical Center, Amsterdam, The Netherlands
N. G. G. M. Abeling
Affiliation:
Laboratory for Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands
A. S. Bassett
Affiliation:
The Dalglish Family 22q Clinic for Adults with 22q11.2 Deletion Syndrome, and Center for Mental Health, University Health Network, Toronto, Ontario, Canada Clinical Genetics Research Program, Center for Addiction and Mental Health, Toronto, Ontario, Canada Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
T. A. M. J. van Amelsvoort
Affiliation:
Department of Psychiatry and Psychology, Maastricht University, Maastricht, The Netherlands
F. J. van Spronsen
Affiliation:
Division of Metabolic Diseases, University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands
J. Booij
Affiliation:
Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
*
*Address for correspondence: E. Boot, Department of Nuclear Medicine, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. (Email: [email protected])
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Abstract

Background

Phenylketonuria (PKU), a genetic metabolic disorder that is characterized by the inability to convert phenylalanine to tyrosine, leads to severe intellectual disability and other cerebral complications if left untreated. Dietary treatment, initiated soon after birth, prevents most brain-related complications. A leading hypothesis postulates that a shortage of brain monoamines may be associated with neurocognitive deficits that are observable even in early-treated PKU. However, there is a paucity of evidence as yet for this hypothesis.

Methods

We therefore assessed in vivo striatal dopamine D2/3 receptor (D2/3R) availability and plasma monoamine metabolite levels together with measures of impulsivity and executive functioning in 18 adults with PKU and average intellect (31.2 ± 7.4 years, nine females), most of whom were early and continuously treated. Comparison data from 12 healthy controls that did not differ in gender and age were available.

Results

Mean D2/3R availability was significantly higher (13%; p = 0.032) in the PKU group (n = 15) than in the controls, which may reflect reduced synaptic brain dopamine levels in PKU. The PKU group had lower plasma levels of homovanillic acid (p < 0.001) and 3-methoxy-4-hydroxy-phenylglycol (p < 0.0001), the predominant metabolites of dopamine and norepinephrine, respectively. Self-reported impulsivity levels were significantly higher in the PKU group compared with healthy controls (p = 0.033). Within the PKU group, D2/3R availability showed a positive correlation with both impulsivity (r = 0.72, p = 0.003) and the error rate during a cognitive flexibility task (r = 0.59, p = 0.020).

Conclusions

These findings provide further support for the hypothesis that executive functioning deficits in treated adult PKU may be associated with cerebral dopamine deficiency.

Keywords

Dopamineexecutive functionimpulsivitymonoaminesphenylketonuria
Type
Original Articles
Information
Psychological Medicine , Volume 47 , Issue 16 , December 2017 , pp. 2854 - 2865
Copyright
Copyright © Cambridge University Press 2017 

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