Phenylalanine (Phe) and the brain
Significant and long-lasting neurological damage caused by high or unstable Phe continues to be explored in clinical studies.1,2 Recent research is investigating the long-term consequences of elevated blood Phe levels.3,4
Phenylketonuria (PKU) and Phe
PKU is an inherited metabolic disorder that can have a serious neurological impact.5,6 It is caused by mutations in the gene that codes for the phenylalanine hydroxylase (PAH) enzyme.6
These mutations inhibit PAH from converting the essential amino acid Phe into tyrosine (Tyr). This inhibition results in elevations in blood Phe, which contribute to elevations in brain Phe.5-7
If unmanaged, PKU can cause neurological damage and severe intellectual impairment.4,7 However, morphological changes to the brain have also been seen in early treated PKU patients, who can exhibit a wide range of symptoms.8-11
High or unstable blood Phe levels can have long-term negative effects.3,4,12 As the generation of patients with PKU diagnosed after the institution of newborn screening ages, the long-term effects of poor Phe control will become more apparent.3,4,6,12,13
High or unstable Phe can be neurotoxic4,6
Recent studies have characterized the multiple mechanisms by which high Phe changes brain morphology and disrupts function.3,4,6,12
- Disruption of neurotransmitter synthesis14
- Inhibition of cerebral protein synthesis5
- Oxidative stress15
- Inhibition of enzymes that contribute to brain energy metabolism16
- Emergence of amyloid bodies17
- Gliosis (an excess of glial cells in damaged areas of the brain)4,18
- Hypomyelination, demyelination, and white matter damage4,19
- Delay or arrest in the development of the cerebral cortex4
- Gray matter damage12
High or unstable Phe levels have also been shown to disrupt synthesis of serotonin and dopamine, and may contribute to higher rates of depression in patients with PKU. This is one of many relationships between high or unstable Phe levels and clinical manifestations of PKU that is becoming better understood.14,20
High Phe impacts critical neurotransmitters16
L-type amino acid transporter 1 (LAT-1) is a key transporter of amino acids across the
Serotonin and dopamine are neurotransmitters formed from the amino acids tryptophan (Trp) and Tyr, respectively.14 Like Phe, Trp and Tyr cross the blood-brain barrier via the LAT-1. High blood Phe competitively inhibits Tyr and Trp transport at the LAT-1 transporter, resulting in lower Trp and Tyr levels in the brain. Trp and Tyr are necessary precursors for the synthesis of serotonin and dopamine, respectively.6
In PKU, high Phe saturates LAT-15
High Phe levels in the bloodstream can block access to LAT-1 for other amino acids, including Trp and Tyr. This can prevent the transport of Trp and Tyr across the blood-brain barrier.5,14,16
A reduction in Trp and Tyr in the brain can result in reductions in serotonin and dopamine.5,14,16
Clinical outcomes include depression24,25
Lower levels of serotonin and dopamine have been associated with depression.26,27 By blocking the precursors of these neurotransmitters from entering the brain, high Phe may cause PKU patients to exhibit a range of neuropsychiatric and neurocognitive impairment, including depression, anxiety, inattention, and executive function difficulties.5
Reduction in blood Phe levels could result in normalized levels of Tyr and Trp in the brain, restoring serotonin and dopamine synthesis.5 Normalization of serotonin and dopamine levels is a common goal in the treatment of depression.28,29
High or unstable blood Phe affects every patient differently, resulting in unique clinical symptoms.27
Tell us what you think
As the first generation of early-treated PKU patients age, the long-term consequences of high or unstable Phe in this population will become more apparent.13
Let us know which of the following questions are the most critical to you and your practice.
What are the risks of a lifetime of high or unstable Phe?
What impact does high or unstable Phe have on brain morphology?
How do elevations in blood Phe impact the neurocognitive functioning of patients with PKU?
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Complete the form below so you can stay up to date on the latest in PKU research, receive access to clinical publications on PKU management, and for opportunities to connect with peers. Increasing our knowledge of the neurological effects of PKU—and their connection to clinical manifestations—may guide new approaches in management.13
We look forward to being a reliable source of information about the effects of high or unstable Phe in PKU, pathophysiology of PKU, and support tools.
- Anastasoaie V, Kurzius L, Forbes P, Waisbren S. Stability of blood phenylalanine levels and IQ in children with phenylketonuria. Mol Genet Metab. 2008;95(1-2):17-20. doi:10.1016/j.ymgme.2008.06.014.
- Hood A, Grange DK, Christ SE, Steiner R, White DA. Variability in phenylalanine control predicts IQ and executive abilities in children with phenylketonuria. Mol Genet Metab. 2014;111(4):445-451. doi:10.1016/j.ymgme.2014.01.012.
- Waisbren SE, Noel K, Fahrbach K, et al. Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta-analysis. Mol Genet Metab. 2007;92(1-2):63-70. doi:10.1016/j.ymgme.2007.05.006.
- Mastrangelo M, Chiarotti F, Berillo L, et al. The outcome of white matter abnormalities in early treated phenylketonuric patients: a retrospective longitudinal long-term study. Mol Genet Metab. 2015;116(3):171-177. doi:10.1016/j.ymgme.2015.08.005.
- de Groot MJ, Hoeksma M, Blau N, Reijngoud DJ, van Spronsen FJ. Pathogenesis of cognitive dysfunction in phenylketonuria: review of hypotheses. Mol Genet Metab. 2010;99(suppl 1):S86-S89. doi:10.1016/j.ymgme.2009.10.016.
- Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417-1427. doi:10.1016/S0140-6736(10)60961-0.
- Cleary MA. Phenylketonuria. Paediatr Child Health. 2014;25(3):108-112. doi:10.1016/j.paed.2014.10.006.
- Huijbregts SCJ, de Sonneville LMJ, Licht R, van Spronsen FJ, Verkerk PH, Sergeant JA. Sustained attention and inhibition of cognitive interference in treated phenylketonuria: associations with concurrent and lifetime phenylalanine concentrations. Neuropsychologia. 2002;40(1):7-15. doi:10.1016/S0028-3932(01)00078-1.
- Nardecchia F, Manti F, Chiarotti F, Carducci C, Carducci C, Leuzzi V. Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: a longitudinal study. Mol Genet Metab. 2015;115(2-3):84-90. doi:10.1016/j.ymgme.2015.04.003.
- Bilder DA, Noel JK, Baker ER, et al. Systematic review and meta-analysis of neuropsychiatric symptoms and executive functioning in adults with phenylketonuria [published online November 2, 2016]. Dev Neuropsychol. doi:10.1080/87565641.2016.1243109.
- Bilder DA, Burton BK, Coon H, et al. Psychiatric symptoms in adults with phenylketonuria. Mol Genet Metab. 2013;108(3):155-160. doi:10.1016/j.ymgme.2012.12.006.
- Christ SE, Price MH, Bodner KE, Saville C, Moffitt AJ, Peck D. Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria. Mol Genet Metab. 2016;118(1):3-8. doi:10.1016/j.ymgme.2016.02.004.
- Vockley J, Andersson HC, Antshel KM, et al; for American College of Medical Genetics and Genomics Therapeutic Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-190. doi:10.1038/gim.2013.157.
- Brumm VL, Bilder D, Waisbren SE. Psychiatric symptoms and disorders in phenylketonuria. Mol Genet Metab. 2010;99(suppl 1):S59- S63. doi:10.1016/j.ymgme.2009.10.182.
- Sanayama Y, Nagasaka H, Takayanagi M, et al. Experimental evidence that phenylalanine is strongly associated to oxidative stress in adolescents and adults with phenylketonuria. Mol Genet Metab. 2011;103(3):220-225. doi:10.1016/j.ymgme.2011.03.019.
- Schuck PF, Malgarin F, Cararo JH, Cardoso F, Streck EL, Ferreira GC. Phenylketonuria pathophysiology: on the role of metabolic alterations. Aging Dis. 2016;6(5):390-399. doi:10.14336/AD.2015.0827.
- Adler-Abramovich L, Vaks L, Carny O, et al. Phenylalanine assembly into toxic fibrils suggests amyloid etiology in phenylketonuria. Nat Chem Biol. 2012;8(8):701-706. doi:10.1038/nchembio.1002.
- Dorland's Illustrated Medical Dictionary. 32nd ed. Philadelphia, PA: Elsevier Saunders; 2012.
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- ten Hoedt AE, de Sonneville LMJ, Francois B, et al. High phenylalanine levels directly affect mood and sustained attention in adults with phenylketonuria: a randomised, double-blind, placebo-controlled, crossover trial. J Inherit Metab Dis. 2011;34(1):165-171. doi:10.1007/s10545-010-9253-9.
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