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Phenylketonuria (PKU)

Other Names

Hyperphenylalaninemia

Phenylalanine hydroxylase deficiency

Diagnosis Coding

E70.0, classical phenylketonuria

Disorder Category

An amino acidemia

Screening

Finding

Elevated phenylalanine, elevated phenylalanine/tyrosine ratio

Tested By

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

Overview

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.

Incidence

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]

Inheritance

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

  • Contact the family and evaluate the infant for any concerning symptoms.
  • Provide urgent treatment/referral for any significant symptoms or seizures. See the ACT Sheet for PKU (ACMG) (PDF Document 351 KB) for additional information.
  • Confirm the diagnosis, work with the following service(s): see all Newborn Screening Programs services providers (2) in our database;
  • Evaluate and continue ongoing collaborative management, consult the following service(s): we currently have no Pediatric Genetics service providers listed, please search our Services database for related services.

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 - 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.

Resources

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.

PKU (GeneReviews)
Excellent review by John J. Mitchell, MD and Charles R. Scriver, MD including clinical description, differential, management, genetic counseling, molecular genetics, and a bibliography.

Utah Newborn Screening Program - PKU (UDOH)
Information for parents and professionals about PKU; Utah Department of Health.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. It includes health supervision guidelines and other useful resources; represents a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

For Parents and Patients

Support

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

General

PKU Information - 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.

PKU (Genetics Home Reference)
Excellent, detailed review of condition for patients and families; sponsored by the U.S. National Library of Medicine.

National Urea Cycle Disorders Foundation
This non-profit organization provides support services and information for families; medical lectures on urea cycle disorders; nutrition and medication resources; and information about events and conferences.

Patient Education

What is Phenylketonuria? (GSLC)
A brief educational overview of single gene disorders that includes the genetics of Phenylketonuria (PKU); Genetic Science Learning Center at the University of Utah.

Tools

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

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

Newborn Screening Programs

See all Newborn Screening Programs services providers (2) in our database.

Pediatric Genetics

We currently have no Pediatric Genetics service providers listed; search our Services database for related services.

For other services related to this condition, browse our Services categories or search our database.

Helpful Articles

PubMed search for PKU and newborn screening, last 2 years.

Authors

Author: Nicola Longo, MD, Ph.D. - 12/2015
Content Last Updated: 12/2015

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

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