Phenylketonuria (PKU)

Other Names


Phenylalanine hydroxylase deficiency

Diagnosis Coding

E70.0, classical phenylketonuria

Disorder Category

An amino acidemia



Elevated phenylalanine, elevated phenylalanine/tyrosine ratio

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.95% [Schulze: 2003]


Deficiency of phenylalanine hydroxylase (PAH), the enzyme responsible for converting phenylalanine to tyrosine, results in accumulation of phenylalanine (Phe) with toxic effects on brain development.


The incidence of PKU in the U.S. is approximately 1:23,000 births, although in the African-American population, incidence is about 1:50,000. [Therrell: 2014]


Autosomal recessive

Maternal & Family History

Benign forms of PKU can present with minimal elevations of phenylalanine levels (maximal plasma phenylalanine <360 micromolar), cause no symptoms, and require no therapy. Mild forms of phenylketonuria can present with slightly increased phenylalanine levels (maximal plasma phenylalanine 360-1000 micromolar), are usually easy to control with diet, and respond to therapy with sapropterin. Yet, children born to women with PKU are at risk for "maternal PKU" because high levels of phenylalanine are teratogenic.

Elevated phenylalanine levels can be caused by defects in the synthesis or recycling of tetrahydrobiopterin, an essential co-factor of phenylalanine hydroxylase. Since tetrahydrobiopterin is also a cofactor of other enzymes involved in neurotransmitter synthesis, at-risk patients need to be identified as soon as possible to start appropriate therapy.

Prenatal Testing

DNA testing by amniocentesis or CVS

Clinical Characteristics

With treatment by early introduction and maintenance of special diet, normal IQ and development can be expected. Without treatment, patients with classic PKU have no symptoms at birth, but usually develop them by 6 months of age.

Initial symptoms may include:
  • A musty or "mousy" odor of the body and urine
  • Developmental delays in sitting, crawling, and standing
  • Microcephaly
If patients remain untreated they may develop:
  • Decreased skin and hair pigmentation (due to lack of tyrosine)
  • Eczema
  • Seizures
  • Profound mental retardation
A diet low in protein and phenylalanine needs to be continued for life. [Camp: 2014] The diet needs to be supplemented with tyrosine, which becomes an essential amino acid in this condition. With relaxation of diet, patients have increased deficits in executive function, attention deficit disorder and problems in school. Some patients respond to therapy with tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase that stimulates residual enzyme activity in responsive mutant enzymes.

Follow-up Testing after Positive Screen

Quantitative plasma amino acid analysis, red blood cell DHPR assay; urine neopterin profile (the latter two tests to exclude defects in tetrahydrobiopterin synthesis or recycling); DNA testing for PAH gene mutations

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill (see PKU - Information for Parents (STAR-G)).
  • Support initiation and maintenance of phenylalanine-restricted diet and supplementation of tyrosine and essential amino acids.
  • Avoid the sugar substitute aspartame ("NutraSweet," "Equal," "Sweet Mate," and Canderel") in diet drinks and medications.
  • Perform regular blood and urine tests to monitor Phe levels and diet as indicated.
  • Assist in management of irreversible consequences as necessary, particularly with developmental and educational interventions.
  • See the Portal’s diagnosis and management module for PKU and Pterin Defects.

Specialty Care Collaboration

A dietician may work with the family to devise an optimal approach to dietary management.


Information & Support

For Professionals

Confirmatory Algorithm for PKU (ACMG) (PDF Document 73 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Phenylalanine Hydroxylase Deficiency (GeneReviews)
Detailed information addressing clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

For Parents and Patients


PKU Listserv
Share ideas and concerns with other PKU parents; login required.


PKU - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received an initial diagnosis of a newborn disorder; Screening, Technology and Research in Genetics.

Phenylketonuria (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

National Urea Cycle Disorders Foundation
Support and information that includes medical lectures on urea cycle disorders, nutrition and medication resources, and information about events and conferences.


ACT Sheet for PKU (ACMG) (PDF Document 351 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Confirmatory Algorithm for PKU (ACMG) (PDF Document 73 KB)
Resource for clinicians to help confirm diagnosis; American College of Medical Genetics.

Services for Patients & Families in Rhode Island (RI)

Genetics clinic services throughout the US can be found through the Genetics Clinic Services Search Engine (ACMG).

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.

Authors & Reviewers

Initial publication: March 2007; last update/revision: December 2015
Current Authors and Reviewers:
Author: Nicola Longo, MD, Ph.D.

Page Bibliography

Camp KM, Parisi MA, Acosta PB, Berry GT, Bilder DA, Blau N, Bodamer OA, Brosco JP, et al.
Phenylketonuria Scientific Review Conference: state of the science and future research needs.
Mol Genet Metab. 2014;112(2):87-122. PubMed abstract
Though its title suggests a focus on research, this also represents a consensus on best approaches to care.

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text