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Brain dysfunction in phenylketonuria: is phenylalanine toxicity the only possible cause?
F J van Spronsen1, Marieke Hoeksma, Dirk-Jan Reijngoud
1Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. f.j.van.spronsen@bkk.umcg.nl
Journal of Inherited Metabolic Disease
|February 5, 2009
Summary
Phenylketonuria (PKU) treatment aims to prevent intellectual disability. However, some cognitive issues persist, possibly due to deficiencies in other large neutral amino acids, not just high phenylalanine levels.
Area of Science:
- Biochemistry
- Neuroscience
- Metabolic Disorders
Background:
- Phenylketonuria (PKU) is managed with a low-protein diet and amino acid supplements.
- Despite treatment, some patients experience residual neuropsychological deficits.
- The exact pathology of cognitive dysfunction in PKU remains unclear.
Purpose of the Study:
- To explore alternative hypotheses regarding the pathogenesis of cognitive dysfunction in PKU.
- To re-evaluate treatment strategies for PKU, considering broader amino acid balance.
- To investigate the role of large neutral amino acid (LNAA) deficiencies in brain function.
Main Methods:
- Review of existing literature on PKU pathophysiology and treatment.
- Analysis of the impact of high plasma phenylalanine on blood-brain barrier transport of LNAAs.
- Consideration of findings from animal models of PKU, including protein synthesis disturbances.
Main Results:
- High plasma phenylalanine affects LNAA transport, increasing brain phenylalanine and decreasing other LNAAs.
- While phenylalanine neurotoxicity is known, LNAA deficiency may also impair cognitive function.
- Studies in a PKU mouse model suggest disturbed cerebral protein synthesis linked to LNAA shortage.
Conclusions:
- Cognitive dysfunction in PKU may stem from LNAA deficiencies in the brain, not solely high phenylalanine.
- Treatment goals for PKU might need to shift towards normalizing all cerebral LNAA concentrations.
- Further research is crucial to elucidate the impact of LNAA deficiencies on brain function in PKU.
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