Metabolic Brain Disease

, Volume 33, Issue 5, pp 1609–1615 | Cite as

The influence of blood phenylalanine levels on neurocognitive function in adult PKU patients

  • A. Bartus
  • F. Palasti
  • E. Juhasz
  • E. Kiss
  • E. Simonova
  • Cs. Sumanszki
  • P. ReismannEmail author
Original Article


It is well known that hyperphenylalaninemia caused by phenylketonuria (PKU) negatively influences cognitive performance. Several tests have been used to study these functions. Until now, no universal, optimal tool has been developed for detecting PKU-caused brain dysfunctions. Using computerized neuropsychological tests during daily routine would be helpful for screening subclinical brain deficits in adult PKU patients. In a monocentric, cross-sectional study, adult patients with PKU (n = 46; median age = 29.5 years; female/male ratio = 21/25) were tested with the computerized Cambridge Cognition (CANTAB) test measuring neurocognitive functions. Patients were divided into two groups: The “on diet” group included patients whose blood Phe-level was under 600 μmol/l (n = 20), and the “loose diet” group included patients whose blood Phe-level was above 600 μmol/l (n = 26) at the examination time. The results of the PKU-affected individuals were compared with a healthy control group (n = 31; median age = 25 years; female/male ratio = 11/20). Compared with the control group, PKU patients had significantly worse test results in memory, problem-solving skills, and strategy. However, there were no significant differences in response speed or initial thinking time. There was no correlation between the blood Phe-level, tyrosine (Tyr)-level or Phe/Tyr ratio and the different cognitive test results. There were no significant differences in test results between the two PKU subgroups. Several cognitive functions measured by CANTAB are negatively influenced by hyperphenylalaninemia in adult PKU patients. However, response speed and initial thinking time were not impaired as seriously as other functions. Patients with lower Phe-levels failed to achieve better test results than patients whose Phe-levels were notably elevated.


Phenylketonuria CANTAB Neurocognitive functions Phenylalanine Protein-restricted diet 



Computerized Cambridge Cognition


Early-treated PKU


Intelligence quotient


Motor Screening Test


Phenylalanine hydroxylase






Premotor area




Stockings of Cambridge


Supplementary motor area


Spatial Working Memory





The authors wish to thank all the participants of the study.

Compliance with ethical standards

Ethical approval and consent to participate

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Semmelweis University) and with the Helsinki Declaration of 1975. The study was approved by the Hungarian ethical committee ETT TUKEB (Medical Research Council Scientific and Research Committee): reference number: 5075-2/2014/EKU). An informed consent was obtained from all patients prior to enrollment in the study.

Competing interest

Anna Bartus, Fanni Palasti, Eszter Juhasz, Erika Kiss, Erika Simonova, Csaba Sumanszki and Peter Reismann declare that they have no conflict of interest.


  1. Albrecht J, Garbade SF, Burgard P (2009) Neuropsychological speed tests and blood phenylalanine levels in patients with phenylketonuria. A meta-analysis. Neurosci Behav Rev 33:414–421CrossRefGoogle Scholar
  2. Anderson PJ, Wood SJ, Francis DE, Coleman L, Anderson V, Boneh A (2007) Are neuropsychological impairments in children with early-treated phenylketonuria (PKU) related to white matter abnormalities or elevated phenylalanine levels? Dev Neuropsychol 32:645–668CrossRefPubMedGoogle Scholar
  3. Bik-Multanowski M, Pietrzyk JJ (2011) Use of computerized neuropsychological tests and of nuclear magnetic resonance spectroscopy in clinical assessment of adult patients with phenylketonuria. Przegl Lek 68:127–131PubMedGoogle Scholar
  4. Bik-Multanowski M, Pietrzyk JJ, Mozrzymas R (2011) Routine use of CANTAB system for detection of neuropsychological deficits in patients with PKU. Mol Genet Metab 102:210–213CrossRefPubMedGoogle Scholar
  5. Blau N, Erlandsen H (2004) The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Mol Genet Metab 82:101–111CrossRefPubMedGoogle Scholar
  6. Burgard P, Ullrich K, Ballhausen D, Hennermann JB, Hollak CEM, Langeveld M, Karall D, Konstantopoulou V, Maier EM, Lang F, Lachmann R, Murphy E, Garbade S, Hoffmann GF, Kölker S, Lindner M, Zschocke J (2017) Issues with European guidelines for phenylketonuria. Lancet Diabetes Endocrionol 5:681–683CrossRefGoogle Scholar
  7. Camp KM, Parisi M, Acosta P, Berry G, Bilder D, Blau N, Bodamer O et al (2014) Phenylketonuria scientific review conference: state of the science and future research needs. Mol Genet Metab 112:87–122CrossRefPubMedGoogle Scholar
  8. Channon S, Mockler C, Lee P (2005) Executive functioning and speed of processing in phenylketonuria. Neuropsychology 19:679–686CrossRefPubMedGoogle Scholar
  9. Christ SE, Huijbregts SC, de Sonneville LM, White DA (2010) Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab 99(Suppl 1):S22–S32CrossRefPubMedGoogle Scholar
  10. Di Ciommo V, Forcella E, Cotugno G (2012) Living with phenylketonuria from the point of view of children, adolescents, and young adults: a qualitative study. J Dev Behav Pediatr 33:229–235CrossRefPubMedGoogle Scholar
  11. Feldmann R, Denecke M, Grenzebach M, Weglage J (2005) Frontal lobe dependent functions in treated phenylketonuria: blood phenylalanine concentrations and long-term deficits in adolescents and young adults. J Inherit Metab Dis 28:445–455CrossRefPubMedGoogle Scholar
  12. Griffiths P, Smith C, Harvie A (1997) Transitory hyperphenylalaninaemia in children with continuously treated phenylketonuria. Am J Ment Retard 102:27–36CrossRefPubMedGoogle Scholar
  13. Jahja R, Huijbregts S, De Sonneville L, Van der Meere J, Bosch A, Hollak C, Rubio-Gozalbo E et al (2013) Mental health and social functioning in early-treated phenylketonuria: the PKU-COBESO study. Mol Genet Metab 110:S57–S61CrossRefPubMedGoogle Scholar
  14. 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. J Pediatr 164:895–899CrossRefPubMedGoogle Scholar
  15. Jahja R, Huijbregts SCJ, de Sonneville LMJ, van der Meere JJ, Legemaat AM, Bosch AM, Hollak CEM et al (2017a) Cognitive profile an mental health in adult phenylketonuria: a PKU-COVESO study. Nuropsychology 31:437–447CrossRefGoogle Scholar
  16. Jahja R, van Spronsen FJ, de Sonneville LMJ, van der Meere JJ, Bosch AM, Hollak CEM et al (2017b) Long-term follow-up of cognition and mental health in adult phenylketonuria: a PKU-COBESO study. Behav Genet 47:486–497CrossRefPubMedPubMedCentralGoogle Scholar
  17. Janos AL, Grange DK, Steiner RD, White DA (2012) Processing speed and executive abilities in children with phenylketonuria. Neuropsychology 26:735–743CrossRefPubMedPubMedCentralGoogle Scholar
  18. Koch R, Burton B, Hoganson G, Peterson R, Rhead W, Rouse B, Scott R et al (2002) Phenylketonuria in adulthood: a collaborative study. J Inherit Metab Dis 25:333–346CrossRefPubMedGoogle Scholar
  19. Moyle JJ, Fox AM, Bynevelt M, Arthur M, Burnett JR (2007a) A neuropsychological profile of off-diet adults with phenylketonuria. J Clin Exp Neuropsychol 29:436–441CrossRefPubMedGoogle Scholar
  20. Moyle JJ, Fox AM, Arthur M, Bynevelt M, Burnett JR (2007b) Meta-analysis of neuropsychological symptoms of adolesents and adults with PKU. Neuropsychol Rev 17:91–101CrossRefPubMedGoogle Scholar
  21. Nardecchia F, Manti F, Chiarotti F, Carducci C, Carducci C, Leuzzi V (2015) Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: a longitudinal study. Mol Genet Metab 115:84–90CrossRefPubMedGoogle Scholar
  22. Perri RL, Berchicci M, Spinelli D, Di Russo F (2014) Individual differences in response speed and accuracy are associated to specific brain activities of two interacting systems. Front Behav Neurosci 8:251PubMedPubMedCentralGoogle Scholar
  23. Scriver CR, Beaudet AL, Sly WS, Valle D (1996) The metabolic and molecular bases of inherited disease, 7th edn. McGraw–Hill, New York, pp 1015–1075Google Scholar
  24. Sharman R, Sullivan K, Young R, McGill J (2015) Executive function in adolescents with PKU and their siblings: associations with biochemistry. Mol Genet Metab Rep 4:87–88CrossRefPubMedPubMedCentralGoogle Scholar
  25. van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Gizewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, Trefs FK, van Rijn M, Walter JH, MacDonald A (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol 5:743–756CrossRefPubMedGoogle Scholar
  26. Vockley J, Andersson HC, Antshel KM, Braverman NE, Burton BK, Frazier DM, Mitchell J, Smith WE, Thompson BH, Berry SA, American College of Medical Genetics and Genomics Therapeutics Committee (2014) Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med 16:188–200CrossRefPubMedGoogle Scholar
  27. Waisbren SE, Schnell RR, Levy HL (1980) Diet termination in children with phenylketonuria: a review of psychological assessments used to determine outcome. J Inherit Metab Dis 3:149–153CrossRefPubMedGoogle Scholar
  28. Weglage J, Pietsch M, Feldmann R, Koch HG, Zschocke J, Hoffmann G, Muntau-Heger A, Denecke J, Guldberg P, Güttler F, Möller H, Wendel U, Ullrich K, Harms E (2001) Normal clinical outcoma in untreated subjects with mild hyperphenylalaninemia. Pediatr Res 49:532–536CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.2nd Department of Internal MedicineSemmelweis UniversityBudapestHungary
  2. 2.1st Department of PediatricsSemmelweis UniversityBudapestHungary

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