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PKU: a rare, autosomal recessive disorder1,2

Genetics of PKU

  • Most cases (~98%) of phenylketonuria (PKU) are caused by variants in the gene encoding the phenylalanine hydroxylase (PAH) enzyme resulting in low enzymatic activity3,4
  • 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

Phe metabolism3

Information Graphic
Information graphic

High and/or variable Phe levels can have neurotoxic effects on the brain5

 

Blood-brain barrier physiology5,6

Adapted from van Spronsen et al. Nat Rev Dis Primers. 2021

Elevated Phe in the brain affects normal white matter morphology and impairs neurotransmitter synthesis7

Learn more about PKU

The burden of PKU impacts daily life.1

Learn how

References: 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. van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines of phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017;12(1):162. doi:10.1186/s13023-017-0685-2. 6. van Spronsen FJ, Blau N, Harding C, et al. Phenylketonuria. Nat Rev Dis Primers. 2021;7(1):36. doi:10.1038/s41572-021-00267-0. 7. Anderson PJ, Leuzzi V. White matter pathology in phenylketonuria. Mol Genet Metab. 2010;99(suppl 1):S3-S9. 8. 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. 9. 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. 10. 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. 11. Adler-Abramovich L, Vaks L, Carny O, et al. Phenylalanine assembly into toxic fibrils suggest amyloid etiology in phenylketonuria. Nat Chem Biol. 2012;8(8):701-706.