Phenylketonuria

Last reviewed: June 2019

Last updated: September 2018

Summary

A rare inborn error of metabolism associated with elevated blood phenylalanine. Clinical features in the untreated patient include intellectual disability, defects in executive functioning, seizures, and eczema.

Caused by a deficiency of hepatic phenylalanine hydroxylase activity. Gene mutations are heterogeneous, 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.

Treated patients have an IQ within the normal range, although subtle neurocognitive deficits are observed and there is an increased incidence of attention deficit disorder and failure to do well at school.

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.

Definition

Phenylketonuria (PKU) is an autosomal-recessive inborn error of amino acid metabolism characterized by elevated (typically >10 mg/dL) blood phenylalanine (phe), which, if untreated, results in intellectual disability, seizures, and eczema. Patients with elevated blood phe below the threshold requiring treatment are referred to as having hyperphenylalaninemia (hyperphe). Both disorders are the result of mutations in the gene for phenylalanine hydroxylase (PAH), and represent a spectrum of severity.

History and exam

Key diagnostic factors

family history of PKU
positive newborn screen for PKU

Full details

Other diagnostic factors

intellectual disability
microcephaly
eczema
light pigmentation of eyes and hair
seizures
mousy odor of urine

Full details

Risk factors

family history of PKU
white ancestry

Full details

Diagnostic investigations

1st investigations to order

newborn screening for metabolic disorders

Full details

Investigations to consider

quantitative plasma amino acid analysis
blood dihydropteridine reductase (DHPR) assay
urine neopterin to biopterin ratio
mutation analysis of phenylalanine hydroxylase gene
tetrahydrobiopterin (BH4)-responsiveness test

Full details

Treatment algorithm

ACUTE

all patients

Contributors

Authors VIEW ALL 

Barbara K. Burton, MD

Professor of Pediatrics

Northwestern University Feinberg School of Medicine

Director

PKU Clinic

Ann and Robert H. Lurie Children’s Hospital of Chicago

Chicago

Disclosures

BKB has received consulting fees and funding for the conduct of clinical trials from BioMarin Pharmaceutical, the manufacturer of sapropterin and pegvaliase (pegylated phenylalanine ammonia-lyase).

Peer reviewers VIEW ALL 

Harvey L. Levy, MD

Senior Physician in Medicine/Genetics

Children's Hospital Boston

Professor of Pediatrics

Harvard Medical School

Boston

Disclosures

HLL has served on the PKU Scientific Advisory Board for BioMarin Pharmaceuticals Inc. and has received consultation fees from the company for attending meetings, giving lectures, and participating in symposia. BioMarin markets treatment for phenylketonuria.

Berthold Koletzko, MD

Professor of Pediatrics

University of Munich

Head of Division of Metabolic Diseases and Nutritional Medicine

Dr von Hauner Children's Hospital

Ludwig-Maximilians-University of Munich

Lindwurmstr

Germany

Disclosures

BK has received research support from Danone Medical Nutrition and is the recipient of a Freedom to Discover Award of the Bristol Myers Squibb Foundation.

Use of this content is subject to our disclaimer

Phenylketonuria

Summary

Definition

History and exam

Key diagnostic factors

Other diagnostic factors

Risk factors

Diagnostic investigations

1st investigations to order

Investigations to consider

Treatment algorithm

all patients

Contributors

Authors VIEW ALL 

Barbara K. Burton, MD

Disclosures

Peer reviewers VIEW ALL 

Harvey L. Levy, MD

Disclosures

Berthold Koletzko, MD

Disclosures

Differentials

Guidelines

Patient leaflets

View PDF