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Phenylketonuria: a rare, autosomal recessive disorder1,2

Genetics of phenylketonuria (PKU)

  • Phenylketonuria (PKU) is caused by variants in the gene PAH, which encodes the enzyme phenylalanine hydroxylase (PAH).3,4
  • PAH is expressed mainly in the liver3
  • PAH defects can range from mild folding defects in the protein to absence or deficiency of PAH expression2
  • PAH deficiency presents a spectrum of severity. Most severe are individuals with complete enzyme deficiency, or classical PKU (blood phenylalanine [Phe] levels >1200 µmol/L)2
  • As PAH catalyzes the hydroxylation of Phe to tyrosine (Tyr), PAH deficiency impairs the conversion of Phe to Tyr. This causes the amino acid Phe to build up in the blood and brain leading to a range of intellectual disabilities, as well as neurological, neuropsychiatric, and psychosocial consequences3
  • PKU is inherited as an autosomal recessive condition. Those who have only 1 PAH mutation (eg, parents of a child with phenylketonuria) are carriers and have none of the biochemical or clinical characteristics of PKU3
Chemical structure of Phe image

High and/or variable Phe levels can have neurotoxic effects on the brain6

Blood-barrier physiology image
Elevated Phe changes in brain white matter image

Elevated Phe in the brain affects normal white matter morphology and impairs neurotransmitter synthesis10

Elevated Phe changes in brain white matter image
Elevated Phe changes in brain white matter image

Learn more about PKU

Adult challenges in PKU icon

Learn about the challenges of adult PKU1,15

Above target Phe range icon

67% of adults with PKU are above guideline target Phe ranges16

Stay connected with the latest PKU information

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  1. Ashe K, Kelso W, Farrand S, et al. Psychiatric and cognitive aspects of phenylketonuria: the limitations of diet and promise of new treatments. Front Psychiatry. 2019;10:561. doi:10.3389/fpsyt.2019.00561.
  2. Vockley J, Andersson HC, Antshel KM, et al; American College of Medical Genetics and Genomics Therapeutic Committee. Phenylalanine hydroxylase deficiency: diagnosis and management guidelines. Genet Med. 2014;16(2):188-200.
  3. Blau N, van Spronsen FJ, Levy HL. Phenylketonuria. Lancet. 2010;376(9750):1417-1427.
  4. Rocha JC, MacDonald A. Treatment options and dietary supplements for patients with phenylketonuria. Expert Opin Orphan Drugs. 2018;6(11):667-681.
  5. National Library of Medicine. Compound summary: phenylalanine. Published September 16, 2004. Updated December 10, 2022. Accessed December 15, 2022.
  6. Anastoasoaie 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.
  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.
  8. 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.
  9. 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.
  10. Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010;99(suppl 1):S3-S9.
  11. 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.
  12. Adler-Abramovich, LA, Vaks L, Carny O, et al. Phenylalanine assembly into toxic fibrils suggest amyloid etiology in phenylketonuria. Nat Chem Biol. 2012;8(8):701-706.
  13. White DA, Antenor-Dorsey JV, Grange DK, et al. White matter integrity and executive abilities following treatment with tetrahydrobiopterin (BH4) in individuals with phenylketonuria. Mol Genet Metab. 2013;110(3):213–217.
  14. Cleary MA, Walter JH, Wraith JE, White F, Tyler K, Jenkins JP. Magnetic resonance imaging in phenylketonuria: Reversal of cerebral white matter change. J Pediatr. 1995;127(2):251–255.
  15. Brown CS, Lichter-Konecki U. Phenylketonuria (PKU): a problem solved? Mol Genet Metab Rep. 2016;6:8-12.
  16. Jurecki ER, Cederbaum S, Kopesky J, et al. Adherence to clinic recommendations among patients with phenylketonuria in the United States. Mol Genet Metab. 2017;120(3):190-197.
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