Journal of Inherited Metabolic Disease

, 32:46

Brain dysfunction in phenylketonuria: Is phenylalanine toxicity the only possible cause?

  • F. J. van Spronsen
  • Marieke Hoeksma
  • Dirk-Jan Reijngoud
BH4 and PKU

DOI: 10.1007/s10545-008-0946-2

Cite this article as:
van Spronsen, F.J., Hoeksma, M. & Reijngoud, DJ. J Inherit Metab Dis (2009) 32: 46. doi:10.1007/s10545-008-0946-2


In phenylketonuria, mental retardation is prevented by a diet that severely restricts natural protein and is supplemented with a phenylalanine-free amino acid mixture. The result is an almost normal outcome, although some neuropsychological disturbances remain. The pathology underlying cognitive dysfunction in phenylketonuria is unknown, although it is clear that the high plasma concentrations of phenylalanine influence the blood–brain barrier transport of large neutral amino acids. The high plasma phenylalanine concentrations increase phenylalanine entry into brain and restrict the entry of other large neutral amino acids. In the literature, emphasis has been on high brain phenylalanine as the pathological substrate that causes mental retardation. Phenylalanine was found to interfere with different cerebral enzyme systems. However, apart from the neurotoxicity of phenylalanine, a deficiency of the other large neutral amino acids in brain may also be an important factor affecting cognitive function in phenylketonuria. Cerebral protein synthesis was found to be disturbed in a mouse model of phenylketonuria and could be caused by shortage of large neutral amino acids instead of high levels of phenylalanine. Therefore, in this review we emphasize the possibility of a different idea about the pathogenesis of mental dysfunction in phenylketonuria patients and the aim of treatment strategies. The aim of treatment in phenylketonuria might be to normalize cerebral concentrations of all large neutral amino acids rather than prevent high cerebral phenylalanine concentrations alone. In-depth studies are necessary to investigate the role of large neutral amino acid deficiencies in brain.



blood–brain barrier


large neutral amino acids


magnetic resonance spectroscopy


phenylalanine hydroxylase



Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • F. J. van Spronsen
    • 1
    • 2
  • Marieke Hoeksma
    • 1
    • 2
  • Dirk-Jan Reijngoud
    • 2
    • 3
  1. 1.Beatrix Children’s HospitalUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  2. 2.Center for Liver, Digestive and Metabolic Diseases, GUIDE Graduate School for Drug ExplorationUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
  3. 3.Laboratory of Metabolic DiseasesUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands