Clinical Manifestations

The clinical manifestations of high blood Phe

Connecting high blood Phe levels to clinical manifestations may guide new approaches in management.1

High or unstable Phe levels can impact patient outcomes2-4

In clinical studies, patients with phenylketonuria (PKU) exhibit a range of suboptimal outcomes, which can correlate with perturbations in blood Phe levels2-4

Some of these outcomes are:

NEUROCOGNITIVE There is as much as a


decline in IQ for every 100 µm increase in lifetime blood Phe level5



more likely to have psychiatric disorders compared with patients without PKU3

NEUROLOGICAL Early-treated patients with PKU may show a likelihood of


as many seizures compared with patients without PKU4,6

The increased prevalence of depression may be directly related to the effects of Phe on serotonin and dopamine in the brain.7-9

Lifetime exposure to high or unstable Phe levels has been shown to have a significant correlation with anxiety and stress.10 Additionally, greater Phe-to-tyrosine ratios in the blood have been associated with increased depression and anxiety.10,11

Even patients well-managed by diet alone may not be able to control the clinical impacts of high or unstable Phe and may experience suboptimal outcomes associated with poor metabolic control.1,12,13

In the management of PKU, the American College of Medical Genetics and Genomics (ACMG) guidelines recommend6:

  • Initiation of treatment for PKU should be undertaken as early as possible—preferably within the first week of life
  • Treatment goals should be to maintain Phe levels of 120–360 μmol/L for all patients of all ages
  • All patients, including those with late or untreated PAH deficiency, may benefit from institution of therapy
  • Treatment for PAH deficiency should be lifelong

Tools for the clinic

There are many different neurological, neurocognitive, and neuropsychiatric symptoms that PKU patients can experience.3-5 In particular, there are tools available to help measure issues with cognitive and social functioning commonly seen in patients with PKU.

A sample of tools used in PKU studies includes:14

1 1

Clinics should evaluate their patients along 3 primary domains: adaptive behavior, executive functioning, and social or emotional functioning. The relevant tools for evaluation should reflect the age of the patient, as the same tools used for children may not be best-suited for adults.

In a randomized trial, high or unstable Phe levels were directly correlated with a negative effect on mood and neuropsychological performance in adults with PKU as measured by the POMSr questionnaire.9

Monitoring mood disorders may help track a patient’s progress over time.11

You can change the future of PKU

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.1

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.


  1. 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.
  2. 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.
  3. Pietz J, Fätkenheuer B, Burgard P, Armbruster M, Esser G, Schmidt H. Psychiatric disorders in adult patients with early-treated phenylketonuria. Pediatrics. 1997;99(3):345-350. doi:10.1542/peds.99.3.345.
  4. 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.
  5. 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.
  6. Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS. Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia. 2005;46(7):1133-1139. doi:10.1111/j.1528-1167.2005.01605.x.
  7. 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.
  8. 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.
  9. 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.
  10. Clacy A, Sharman R, McGill J. Depression, anxiety, and stress in young adults with phenylketonuria: associations with biochemistry. J Dev Behav Pediatr. 2014;35(6):388-391. doi:10.1097/DBP.0000000000000072.
  11. Sharman R, Sullivan K, Young RM, McGill J. Depressive symptoms in adolescents with early and continuously treated phenylketonuria: associations with phenylalanine and tyrosine levels. Gene. 2012;504(2):288-291. doi:10.1016/j.gene.2012.05.007.
  12. 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.
  13. Cleary MA. Phenylketonuria. Paediatr Child Health. 2014;25(3):108-112. doi:10.1016/j.paed.2014.10.006.
  14. Waisbren S, White DA. Screening for cognitive and social-emotional problems in individuals with PKU: tools for use in the metabolic clinic. Mol Genet Metab. 2010;99(suppl 1):S96-S99. doi: 10.1016/j.ymgme.2009.10.006.