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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: h.j.boot@amc.uva.nl)
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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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References

Antshel, KM (2010). ADHD, learning, and academic performance in phenylketonuria. Molecular Genetics and Metabolism 99 (Suppl. 1), S52–S58.Google Scholar
Bari, A, Robbins, TW (2013). Inhibition and impulsivity: behavioral and neural basis of response control. Progress in Neurobiology 108, 44–79.Google Scholar
Barnes, JJ, Dean, AJ, Nandam, LS, O’Connell, RG, Bellgrove, MA (2011). The molecular genetics of executive function: role of monoamine system genes. Biological Psychiatry 69, e127–e143.Google Scholar
Blau, N, van Spronsen, FJ, Levy, HL (2010). Phenylketonuria. Lancet 376, 1417–1427.CrossRefGoogle ScholarPubMed
Booij, J, Korn, P, Linszen, DH, van Royen, EA (1997). Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography. European Journal of Nuclear Medicine 24, 674–677.CrossRefGoogle ScholarPubMed
Boot, E, Booij, J, Zinkstok, J, Abeling, N, de Haan, L, Baas, F, Linszen, D, van Amelsvoort, T (2008). Disrupted dopaminergic neurotransmission in 22q11 deletion syndrome. Neuropsychopharmacology 33, 1252–1258.CrossRefGoogle ScholarPubMed
Boot, E, Booij, J, Zinkstok, JR, de Haan, L, Linszen, DH, Baas, F, van Amelsvoort, TA (2010). Striatal D2 receptor binding in 22q11 deletion syndrome: an [123I]IBZM SPECT study. Journal of Psychopharmacology 24, 1525–1531.CrossRefGoogle ScholarPubMed
Brücke, T, Wöber, C, Podreka, I, Wöber-Bingöl, C, Asenbaum, S, Aull, S, Wenger, S, Ilieva, D, Harasko-van der Meer, C, Wessely, P, Deecke, L (1995). D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. Journal of Cerebral Blood Flow and Metabolism 15, 513–518.Google Scholar
Christ, SE, Huijbregts, SC, de Sonneville, LM, White, DA (2010). Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Molecular Genetics and Metabolism 99 (Suppl. 1), S22–S32.CrossRefGoogle ScholarPubMed
Cools, R, D’Esposito, M (2011). Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biological Psychiatry 69, 113–125.Google Scholar
Corruble, E, Benyamina, A, Bayle, F, Falissard, B, Hardy, P (2003). Understanding impulsivity in severe depression? A psychometrical contribution. Progress in Neuropsychopharmacology and Biological Psychiatry 27, 829–833.CrossRefGoogle ScholarPubMed
Cropley, VL, Fujita, M, Innis, RB, Nathan, PJ (2006). Molecular imaging of the dopaminergic system and its association with human cognitive function. Biological Psychiatry 59, 898–907.Google Scholar
Dalley, JW, Roiser, JP (2012). Dopamine, serotonin and impulsivity. Neuroscience 215, 42–58.Google Scholar
de Sonneville, LM (2009). Amsterdam neuropsychological tasks: a computer-aided assessment program. In Computers in Psychology: Cognitive Ergonomics, Clinical Assessment and Computer-Assisted Learning (ed. den Brinker, B. P. L. M., Beek, P. J., Brand, A. N., Maarse, S. J., Mulder, L. J. M.), pp. 187–203. Swets & Zeitlinger: Leiden.Google Scholar
Doran, AR, Labarca, R, Wolkowitz, OM, Roy, A, Douillet, P, Pickar, D (1990). Circadian variation of plasma homovanillic acid levels is attenuated by fluphenazine in patients with schizophrenia. Archives of General Psychiatry 6, 558–563.CrossRefGoogle Scholar
Douglas, TD, Jinnah, HA, Bernhard, D, Singh, RH (2013). The effects of sapropterin on urinary monoamine metabolites in phenylketonuria. Molecular Genetics and Metabolism 109, 243–250.Google Scholar
Elsworth, JD, Leahy, DJ, Roth, RH, Redmond, DE (1987). Homovanillic acid concentrations in brain, CSF and plasma as indicators of central dopamine function in primates. Journal of Neural Transmission 68, 51–62.Google Scholar
Gjedde, A, Kumakura, Y, Cumming, P, Linnet, J, Møller, A (2010). Inverted-U-shaped correlation between dopamine receptor availability in striatum and sensation seeking. Proceedings of the National Academy of Sciences 107, 3870–3875.CrossRefGoogle ScholarPubMed
Harrison, PJ, Tunbridge, EM (2008). Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology 33, 3037–3045.Google Scholar
Hartleb, J, Eue, S, Kemper, A (1993). Simultaneous analysis of homovanillic acid, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylethylene glycol and vanilmandelic acid in plasma from alcoholics by high-performance liquid chromatography with electrochemical detection. Critical comparison of solid-phase and liquid-liquid extraction methods. Journal of Chromatography 622, 161–171.Google Scholar
Hegge, KA, Horning, KK, Peitz, GJ, Hegge, K (2009). Sapropterin: a new therapeutic agent for phenylketonuria. Annals of Pharmacotherapy 43, 1466–1473.Google Scholar
Hendrikx, MM, van der Schot, LW, Slijper, FM, Huisman, J, Kalverboer, AF (1994). Phenylketonuria and some aspects of emotional development. European Journal of Pediatrics 153, 832–835.CrossRefGoogle ScholarPubMed
Huijbregts, SC, de Sonneville, LM, Licht, R, van Spronsen, FJ, Sergeant, JA (2002 a). Short-term dietary interventions in children and adolescents with treated phenylketonuria: effects on neuropsychological outcome of a well-controlled population. Journal of Inherited Metabolic Disease 25, 419–430.Google Scholar
Huijbregts, SC, de Sonneville, LM, van Spronsen, FJ, Licht, R, Sergeant, JA (2002 b). The neuropsychological profile of early and continuously treated phenylketonuria: orienting, vigilance, and maintenance v. manipulation-functions of working memory. Neuroscience & Biobehavioral Reviews 26, 697–712.Google Scholar
Huijbregts, SC, Gassio, R, Campistol, J (2013). Executive functioning in context: relevance for treatment and monitoring of phenylketonuria. Molecular Genetics and Metabolism 110 (Suppl), S25–S30.Google Scholar
Jahja, R, Huijbregts, SC, de Sonneville, LM, van der Meere, JJ, van Spronsen, FJ (2014). Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. Journal of Pediatrics 164, 895–899.Google Scholar
Joseph, B, Dyer, CA (2003). Relationship between myelin production and dopamine synthesis in the PKU mouse brain. Journal of Neurochemistry 86, 615–626.Google Scholar
Juhász, E, Kiss, E, Simonova, E, Patocs, A, Reismann, P (2016). Serum prolactin as a biomarker for the study of intracerebral dopamine effect in adult patients with phenylketonuria: a cross-sectional monocentric study. European Journal of Medical Research 21, 22.CrossRefGoogle Scholar
Kegeles, LS, Zea-Ponce, Y, Abi-Dargham, A, Rodenhiser, J, Wang, T, Weiss, R, van Heertum, RL (1999). Stability of [123I]IBZM SPECT Measurement of amphetamine-induced striatal dopamine release in humans. Synapse 31, 302–308.Google Scholar
Kendler, KS, Heninger, GR, Roth, RH (1982). Influence of dopamine agonists on plasma and brain levels of homovanillic acid. Life Sciences 30, 2063–2069.Google Scholar
Koch, R, Moats, R, Guttler, F, Guldberg, P, Nelson, M Jr. (2000). Blood-brain phenylalanine relationships in persons with phenylketonuria. Pediatrics 106, 1093–1096.Google Scholar
Kreis, R, Zwygart, K, Boesch, C, Nuoffer, JM (2009). Reproducibility of cerebral phenylalanine levels in patients with phenylketonuria determined by 1H-MR spectroscopy. Magnetic Resonance in Medicine 62, 11–16.Google Scholar
Lam, YW (2012) Clinical pharmacology of dopamine agonists. Pharmacotherapy 20, 17S–25S.Google Scholar
Landvogt, C, Mengel, E, Bartenstein, P, Buchholz, HG, Schreckenberger, M, Siessmeier, T, Scheurich, A, Feldmann, R, Weglage, J, Cumming, P, Zepp, F, Ullrich, K (2008). Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria. Journal of Cerebral Blood Flow and Metabolism 28, 824–831.Google Scholar
Laruelle, M, Abi-Dargham, A, van Dyck, CH, Rosenblatt, W, Zea-Ponce, Y, Zoghbi, SS, Baldwin, RM, Charney, DS, Hoffer, PB, Kung, HF, Innis, RB (1995). SPECT imaging of striatal dopamine release after amphetamine challenge. Journal of Nuclear Medicine 36, 1182–1190.Google Scholar
Leuzzi, V, Tosetti, M, Montanaro, D, Carducci, C, Artiola, C, Carducci, C, Antonozzi, I, Burroni, M, Carnevale, F, Chiarotti, F, Popolizio, T, Giannatempo, GM, D’Alesio, V, Scarabino, T (2007). The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study. Journal of Inherited Metabolic Disease 30, 209–216.CrossRefGoogle ScholarPubMed
McKean, CM (1972). The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Research 47, 469–476.Google Scholar
Mehta, MA, Gumaste, D, Montgomery, AJ, McTavish, SFB, Grasby, PM (2005). The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels. Psychopharmacology (2005) 180, 654–663.Google Scholar
Moats, RA, Moseley, KD, Koch, R, Nelson, M Jr. (2003). Brain phenylalanine concentrations in phenylketonuria: research and treatment of adults. Pediatrics 112, 1575–1579.CrossRefGoogle ScholarPubMed
Moore, S, Spackman, DH, Stein, WH (1958). Chromatography of amino acids on sulfonated polystyrene resins: an improved system. Analytical Chemistry 30, 1185–1190.Google Scholar
Nadler, HL, Hsia, DY (1961). Epinephrine metabolism in phenylketonuria. Proceedings of the Society for Experimental Biology and Medicine 107, 721–723.Google Scholar
Paans, AM, Pruim, J, Smit, GP, Visser, G, Willemsen, AT, Ullrich, K (1996). Neurotransmitter positron emission tomographic-studies in adults with phenylketonuria, a pilot study. European Journal of Pediatrics 155 (Suppl. 1), S78–S81.Google Scholar
Pascucci, T, Ventura, R, Puglisi-Allegra, S, Cabib, S (2002). Deficits in brain serotonin synthesis in a genetic mouse model of phenylketonuria. Neuroreport 13, 2561–2564.Google Scholar
Patton, JH, Stanford, MS, Barratt, ES (1995). Factor structure of the Barratt impulsiveness scale. Journal of Clinical Psychology 51, 768–774.Google Scholar
Pickar, D, Breier, A, Kelsoe, J (1988). Plasma homovanillic acid as an index of central dopaminergic activity: studies in schizophrenic patients. Annals of the New York Academy of Sciences 537, 339–346.Google Scholar
Pietz, J, Kreis, R, Boesch, C, Penzien, J, Rating, D, Herschkowitz, N (1995). The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy. Pediatric Research 38, 657–663.Google Scholar
Puglisi-Allegra, S, Cabib, S, Pascucci, T, Ventura, R, Cali, F, Romano, V (2000). Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria. Neuroreport 11, 1361–1364.CrossRefGoogle Scholar
Rashed, MS, Ozand, PT, Bucknall, MP, Little, D (1995). Diagnosis of inborn errors of metabolism from blood spots by acylcarnitines and amino acids profiling using automated electrospray tandem mass spectrometry. Pediatric Research 38, 324–331.Google Scholar
Reise, SP, Moore, TM, Sabb, FW, Brown, AK, London, ED (2013). The Barratt Impulsiveness Scale-11: reassessment of its structure in a community sample. Psychological Assessment 25, 631–642.Google Scholar
Schmaal, L, Veltman, DJ, Nederveen, A, van den Brink, W, Goudriaan, AE (2012). N-acetylcysteine normalizes glutamate levels in cocaine-dependent patients: a randomized crossover magnetic resonance spectroscopy study. Neuropsychopharmacology 37, 2143–2152.Google Scholar
Sijens, PE, Oudkerk, M, Reijngoud, DJ, Leenders, KL, de Valk, HW, van Spronsen, FJ (2004). 1H MR chemical shift imaging detection of phenylalanine in patients suffering from phenylketonuria (PKU). European Radiology 14, 1895–1900.Google Scholar
Stemerdink, BA, Kalverboer, AF, van der Meere, JJ, van der Molen, MW, Huisman, J, de Jong, LWA, Slijper, FME, Verkerk, PH, van Spronsen, FJ (2000). Behaviour and school achievement in patients with early and continuously treated phenylketonuria. Journal of Inherited Metabolic Disease 23, 548–562.Google Scholar
Strisciuglio, P, Concolino, D (2014). New strategies for the treatment of phenylketonuria (PKU). Metabolites 4, 1007–1017.Google Scholar
Surtees, R, Blau, N (2000). The neurochemistry of phenylketonuria. European Journal of Pediatrics 159 (Suppl. 2), S109–S113.Google Scholar
Ullrich, K, Weglage, J, Oberwittler, C, Pietsch, M, Funders, B, van Eckhardstein, H, Colombo, JP (1994). Effect of L-dopa on pattern visual evoked potentials (P-100) and neuropsychological tests in untreated adult patients with phenylketonuria. Journal of Inherited Metabolic Disease 17, 349–352.Google Scholar
Ullrich, K, Weglage, J, Oberwittler, C, Pietsch, M, Funders, B, van Eckhardstein, H, Colombo, JP (1996). Effect of L-dopa on visual evoked potentials and neuropsychological tests in adult phenylketonuria patients. European Journal of Pediatrics 155 (Suppl. 1), S74–S77.CrossRefGoogle ScholarPubMed
van Spronsen, FJ, de Groot, MJ, Hoeksma, M, Reijngoud, DJ, van Rijn, M (2010). Large neutral amino acids in the treatment of PKU: from theory to practice. Journal of Inherited Metabolic Disease 33, 671–676.Google Scholar
van Spronsen, FJ, Hoeksma, M, Reijngoud, DJ (2009). Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause? Journal of Inherited Metabolic Disease 32, 46–51.Google Scholar
van Vliet, D, Anjema, K, Jahja, R, de Groot, MJ, Liemburg, GB, Heiner-Fokkema, MR, van der Zee, EA, Derks, TGJ, Kema, IP, van Spronsen, FJ (2015 a). BH4 treatment in BH4-responsive PKU patients: preliminary data on blood prolactin concentrations suggest increased cerebral dopamine concentrations. Molecular Genetics and Metabolism 114, 29–33.Google Scholar
van Vliet, D, Bruinenberg, VM, Mazzola, PN, van Faassen, MH, de Blaauw, P, Kema, IP, Heiner-Fokkema, RM, van Anholt, RD, van der Zee, EA, van Spronsen, FJ (2015 b). Large neutral amino acid supplementation exerts its effect through three synergistic mechanisms: proof of principle in phenylketonuria mice. PLoS ONE 10, e0143833.CrossRefGoogle ScholarPubMed
van Vliet, D, Bruinenberg, VM, Mazzola, PN, van Faassen, MH, de Blaauw, P, Pascucci, T, Puglisi-Allegra, S, Kema, IP, Heiner-Fokkema, MR, van der Zee, EA, van Spronsen, FJ (2016). Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model. American Journal of Clinical Nutrition 104, 1292–1300.Google Scholar
Waisbren, SE, Noel, K, Fahrbach, K, Cella, C, Frame, D, Dorenbaum, A, Levy, H (2007). Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Molecular Genetics and Metabolism 92, 63–70.Google Scholar
Weglage, J, Moller, HE, Wiedermann, D, Cipcic-Schmidt, S, Zschocke, J, Ullrich, K (1998). In vivo NMR spectroscopy in patients with phenylketonuria: clinical significance of interindividual differences in brain phenylalanine concentrations. Journal of Inherited Metabolic Disease 21, 81–82.Google Scholar
Weglage, J, Wiedermann, D, Denecke, J, Feldmann, R, Koch, HG, Ullrich, K, Harms, E, Möller, HE (2001). Individual blood-brain barrier phenylalanine transport determines clinical outcome in phenylketonuria. Annals of Neurology 50, 463–467.Google Scholar
Winn, SR, Scherer, T, Thony, B, Harding, CO (2016). High dose sapropterin dihydrochloride therapy improves monoamine neurotransmitter turnover in murine phenylketonuria (PKU). Molecular Genetics and Metabolism 117, 5–11.Google Scholar
Yang, YK, Yao, WJ, McEvoy, JP, Chu, CL, Lee, IH, Chen, PS, Yeh, TL, Chiu, NT (2006). Striatal dopamine D2/D3 receptor availability in male smokers. Psychiatry Research 146, 87–90.Google Scholar
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