Abstract
Phenylketonuria (PKU) is caused by a deficiency or inactivity of the enzyme phenylalanine hydroxylase that converts phenylalanine (Phe) to tyrosine (Tyr). It has been proposed that a reduction of brain Tyr levels, as well as reduced activity of the key regulatory enzyme of dopamine (DA) synthesis tyrosine hydroxylase, leads to a depletion in DA activity in patients with PKU. We report a case of a 56-year-old woman with an intellectual disability due to late diagnosis of PKU and parkinsonism, with a modest clinical response to levodopa therapy.
We hypothesize that the signs of parkinsonism might be caused by the depletion of DA activity in the brain. Clinicians should be alert on parkinsonian symptoms in patients with PKU, particularly in those treated with agents that negatively influence DA transmission.
Competing interests: None declared
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Blau N, van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376:1417–1427
Brenton DP, Pietz J (2000) Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities. Eur J Pediatr 159(Suppl 2):S114–S120
Brücke T, Wöber C, Podreka I et al (1995) D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study. J Cereb Blood Flow Metab 15:513–518
Burlina AB, Bonafé L, Ferrari V, Suppiej A, Zacchello F, Burlina AP (2000) Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment. J Inherit Metab Dis 23:313–316
Cleary MA, Walter JH, Wraith JE et al (1994) Magnetic resonance imaging of the brain in phenylketonuria. Lancet 344:87–90
Cummings JL, Fine MJ, Grachev ID et al (2014) Effective and efficient diagnosis of parkinsonism: the role of dopamine transporter SPECT imaging with ioflupane I-123 injection (DaTscan™). Am J Manag Care 20:S97–S109
De Groot MJ, Hoeksma M, Reijngoud DJ et al (2013) Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis. Orphanet J Rare Dis 8:133
Evans AH, Costa DC, Gacinovic S et al (2004) L-DOPA-Responsive Parkinson’s syndrome in association with phenylketonuria: in vivo dopamine transporter and D2 receptor findings. Mov Disord 19:1232–1236
Hanley WB, Lee AW, Hanley AJ et al (2000) “Hypotyrosinemia” in phenylketonuria. Mol Genet Metab 69:286–294
Landvogt C, Mengel E, Bartenstein P et al (2008) Reduced cerebral fluoro-L-dopamine uptake in adult patients suffering from phenylketonuria. J Cereb Blood Flow Metab 28:824–831
McDonnell GV, Esmonde TF, Hadden DR, Morrow JI (1998) A neurological evaluation of adult phenylketonuria in Northern Ireland. Eur Neurol 39:38–43
McKean CM (1972) The effects of high phenylalanine concentrations on serotonin and catecholamine metabolism in the human brain. Brain Res 47:469–476
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. Eur J Pediatr 155:S78–S81
Paine RS (1957) The variability in manifestations of untreated patients with phenylketonuria (phenylpyruvic aciduria). Pediatrics 20:290–302
Pascucci T, Giacovazzo G, Andolina D et al (2012) (2012) In vivo catecholaminergic metabolism in the medial prefrontal cortex of ENU2 mice: an investigation of the cortical dopamine deficit in phenylketonuria. J Inherit Metab Dis 35:1001–1009
Pietz J, Kreis R, Schmidt H, Meyding-Lamade UK, Rupp A, Boesch C (1996) Phenylketonuria: findings at MR imaging and localized in vivo H-1 MR spectroscopy of the brain in patients with early treatment. Radiology 201:413–420
Pietz J, Dunckelmann R, Rupp A et al (1998) Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr 157:824–830
Ramaker C, Marinus J, Stiggelbout AM, van Hilten BJ (2002) Systematic evaluation of rating scales for impairment and disability in Parkinson’s disease. Mov Disord 17:867–876
Thompson AJ, Smith I, Brenton D et al (1990) Neurological deterioration in young adults with phenylketonuria. Lancet 336:602–605
Weglage J, Pietsch M, Funders B, Koch HG, Ullrich K (1995) Neurological findings in early treated phenylketonuria. Acta Paediatr 84:411–415
Williams RA, Mamotte CD, Burnett JR (2008) Phenylketonuria: an inborn error of phenylalanine metabolism. Clin Biochem Rev 29:31–41
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Additional information
Communicated by: Carla E. Hollak
Appendices
Synopsis
Our case illustrates a slight decrease of symptoms of parkinsonism after introduction of levodopa in a patient suffering from PKU. Signs of parkinsonism might be caused by DA depletion in the brain. Symptoms might be aggravated or provoked by agents that negatively influence DA transmission.
Compliance with Ethics Guidelines
Conflict of Interest
Marieke Velema, Erik Boot, Marc Engelen, and Carla Hollak declare that they have no conflict of interest.
Informed Consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the legal representative of the patient for being included in the study.
Contribution of the Authors
Marieke Velema: involved in the conception and design and drafting the article
Erik Boot: involved in the conception and design and revising the article critically
Marc Engelen: involved in the conception and design and revising the article critically
Carla Hollak: involved in the conception and design and revising the article critically. Guarantor
Rights and permissions
Copyright information
© 2014 SSIEM and Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Velema, M., Boot, E., Engelen, M., Hollak, C. (2014). Parkinsonism in Phenylketonuria: A Consequence of Dopamine Depletion?. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 20. JIMD Reports, vol 20. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_386
Download citation
DOI: https://doi.org/10.1007/8904_2014_386
Received:
Revised:
Accepted:
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-662-46699-5
Online ISBN: 978-3-662-46700-8
eBook Packages: MedicineMedicine (R0)