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Highlights & Basics
- Phenylketonuria (PKU) is a rare inborn error of metabolism associated with elevated blood phenylalanine. Clinical features in untreated patients include intellectual disability, seizures, and eczema.
- Early-treated patients typically have normal intellectual development with an IQ within the normal range, although subtle neurocognitive deficits are observed and there is an increased incidence of attention deficit disorder, executive functioning deficits, and mental health concerns.
- Caused by a deficiency of hepatic phenylalanine hydroxylase activity. Gene mutations are biallelic, most often compound heterozygous, and therefore residual enzyme activity and blood phenylalanine levels are variable and correlate with the severity of the disorder.
- Diagnosed by newborn screening and managed by a multidisciplinary team of specialists.
- Treatment for most patients involves restriction of dietary protein and phenylalanine, and supplementation with phenylalanine-free amino acid mixtures. Tetrahydrobiopterin (BH4)-responsive patients may also be treated with sapropterin, which may allow for a less restrictive diet in some people. Pegvaliase an enzyme substitution therapy, is a treatment option for adolescents and adults with PKU that can allow for a regular diet.
Quick Reference
History & Exam
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Definition
Epidemiology
Etiology
Pathophysiology
Citations
National Institutes of Health Consensus Development Panel. National Institutes of Health consensus development conference statement: phenylketonuria - screening and management. 2000 [internet publication].[Full Text]
Smith WE, Berry SA, Bloom K, et al. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025 Jan;27(1):101289.[Abstract][Full Text]
van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12;12(1):162.[Abstract][Full Text]
1. National Institutes of Health Consensus Development Panel. National Institutes of Health consensus development conference statement: phenylketonuria - screening and management. 2000 [internet publication].[Full Text]
2. Guldberg P, Rey F, Zschocke J, et al. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet. 1998;63:71-79. [Erratum in: Am J Hum Genet. 1998;63:1252-53.][Abstract][Full Text]
3. Elhawary NA, AlJahdali IA, Abumansour IS, et al. Genetic etiology and clinical challenges of phenylketonuria. Hum Genomics. 2022 Jul 19;16(1):22.[Abstract][Full Text]
4. Hillert A, Anikster Y, Belanger-Quintana A, et al. The Genetic Landscape and Epidemiology of Phenylketonuria. Am J Hum Genet. 2020 Aug 6;107(2):234-50.[Abstract][Full Text]
5. Kaye CI, Accurso F; Committee on Genetics, et al. Newborn screening fact sheets. Pediatrics. 2006 Sep;118(3):e934-63.[Abstract][Full Text]
6. Berry SA, Brown C, Grant M, et al. Newborn screening 50 years later: access issues faced by adults with PKU. Genet Med. 2013 Aug;15(8):591-9.[Abstract][Full Text]
7. Arnold G, Vockley J. Phenylalanine Hydroxylase Deficiency. 2000 Jan 10 [updated 2025 Mar 13]. In: Adam MP, Feldman J, Mirzaa GM, et al, eds. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. [Full Text]
8. Burton BK, Adams DJ, Grange DK, et al. Tetrahydrobiopterin therapy for phenylketonuria in infants and young children. J Pediatr. 2011 Mar;158(3):410-5.[Abstract]
9. Smith WE, Berry SA, Bloom K, et al. Phenylalanine hydroxylase deficiency diagnosis and management: a 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2025 Jan;27(1):101289.[Abstract][Full Text]
10. Burton BK, Hermida Á, Bélanger-Quintana A, et al. Management of early treated adolescents and young adults with phenylketonuria: development of international consensus recommendations using a modified Delphi approach. Mol Genet Metab. 2022 Sep-Oct;137(1-2):114-26.[Abstract][Full Text]
11. American College of Medical Genetics and Genomics. Five things physicians and patients should question. Choosing Wisely, an initiative of the ABIM Foundation. 2021 [internet publication]. [Full Text]
12. Burton BK, Grange DK, Milanowski A, et al. The response of patients with phenylketonuria and elevated serum phenylalanine to treatment with oral sapropterin dihydrochloride (6R-tetrahydrobiopterin): a phase II, multicentre, open-label screening study. J Inherit Metab Dis. 2007 Oct;30(5):700-7.[Abstract]
13. Mitchell JJ, Trakadis YJ, Scriver CR. Phenylalanine hydroxylase deficiency. Genet Med. 2011 Aug;13(8):697-707.[Abstract][Full Text]
14. Fiege B, Blau N. Assessment of tetrahydrobiopterin (BH4) responsiveness in phenylketonuria. J Pediatr. 2007 Jun;150(6):627-30.[Abstract]
15. Enns GM, Koch R, Brumm V, et al. Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol Genet Metab. 2010 Oct-Nov;101(2-3):99-109.[Abstract]
16. Levy H, Burton B, Cederbaum S, et al. Recommendations for evaluation of responsiveness to tetrahydrobiopterin (BH4) in phenylketonuria and its use in treatment. Mol Genet Metab. 2007 Dec;92(4):287-91.[Abstract]
17. Blau N, Thony B, Cotton RG, et al. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly SW, et al, eds; Childs B, Kinzler KW, Vogelstein B, assoc eds. The metabolic and molecular bases of inherited disease. 8th ed. New York, NY: McGraw-Hill; 2001:1725-76.
18. van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. 2017 Oct 12;12(1):162.[Abstract][Full Text]
19. American College of Obstetricians and Gynocologists. Practice bulletin no. 802: management of women with phenylalanine hydroxylase deficiency (phenylketonuria). Apr 2020 [internet publication].
20. Sarkissian CN, Gamez A, Wang L, et al. Preclinical evaluation of multiple species of PEGylated recombinant phenylalanine ammonia lyase for the treatment of phenylketonuria. Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20894-9.[Abstract][Full Text]
21. Hydery T, Coppenrath VA. A comprehensive review of pegvaliase, an enzyme substitution therapy for the treatment of phenylketonuria. Drug Target Insights. 2019;13:1177392819857089.[Abstract][Full Text]
22. Pietz J, Kreis R, Rupp A, et al. Large neutral amino acids block phenylalanine transport into brain tissue in patients with phenylketonuria. J Clin Invest. 1999 Apr;103(8):1169-78.[Abstract][Full Text]
23. Matalon R, Michals-Matalon K, Bhatia G, et al. Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine. J Inherit Metab Dis. 2007 Apr;30(2):153-8.[Abstract]
24. Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2015;(3):CD008005.[Abstract][Full Text]
25. Martinez M, Harding CO, Schwank G, et al. State-of-the-art 2023 on gene therapy for phenylketonuria. J Inherit Metab Dis. 2024 Jan;47(1):80-92.[Abstract][Full Text]
26. Pey AL, Ying M, Cremades N, et al. Identification of pharmacological chaperones as potential therapeutic agents to treat phenylketonuria. J Clin Invest. 2008 Aug;118(8):2858-67.[Abstract][Full Text]
27. Muntau AC, Longo N, Ezgu F, et al. Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2024 Oct 5;404(10460):1333-45.[Abstract]
28. Genetic Metabolic Dietitians International. Nutrition management guideline for phenylketonuria (PKU) [internet publication].
29. Christ SE, Huijbregts SC, de Sonneville LM, et al. Executive function in early-treated phenylketounuria: profile and underlying mechanisms. Mol Genet Metab. 2010;99(suppl 1):S22-32.[Abstract]
30. Arnold G, Vladutiu CJ, Orlowski CC, et al. Prevalence of stimulant use for attentional dysfunction in children with phenylketonuria. J Inherit Metab Dis. 2004;27(2):137-43.[Abstract]
31. Smith I, Knowles J. Behaviour in early treated phenylketonuria: a systematic review. Eur J Pediatr. 2000 Oct;159(suppl 2):S89-93.[Abstract]
32. Zeman J, Bayer M, Stepan J. Bone mineral density in patients with phenylketonuria. Acta Paediatr. 1999 Dec;88(12):1348-51.[Abstract]
33. Lenke RR, Levy HL. Maternal phenylketonuria and hyperphenylalaninemia. An international survey of the outcome of treated and untreated pregnancies. N Engl J Med. 1980 Nov 20;303(21):1202-8.[Abstract]
34. Prick BW, Hop WC, Duvekot JJ. Maternal phenylketonuria and hyperphenylalaninemia in pregnancy: pregnancy complications and neonatal sequelae in untreated and treated pregnancies. Am J Clin Nutr. 2012 Feb;95(2):374-82.[Abstract]
35. Adams AD, Fiesco-Roa MÓ, Wong L, et al. Phenylalanine hydroxylase deficiency treatment and management: a systematic evidence review of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2023 Sep;25(9):100358.[Abstract][Full Text]
