Author: Jennifer M. Kwon, MD, MPH
University of Wisconsin School of Medicine and Public Health
American Family Children’s Hospital—Madison, WI

Reviewed: June 2022

SUMMARY

Phenylketonuria (PKU) occurs when the body cannot break down a specific amino acid. Amino acids are the building blocks of protein in the body. The particular amino acid involved with PKU is called phenylalanine (Phe).

When Phe accumulates, it can affect brain development and function. Babies with PKU can have:

• Poor brain growth
• Small head size (microcephaly)
• Difficulty learning and speaking

PKU is an inherited condition. It is diagnosed when blood tests show abnormally high levels of Phe. PKU was the first disorder screened in newborns. Newborn screening and early treatment have prevented permanent brain injury and disability in children with PKU.

Disorder Overview

DESCRIPTION

PKU can cause early brain injury and abnormal neurologic development. Children with PKU cannot break down Phe. It then accumulates and affects the brain.

PKU does not seem to affect other organs. Children with untreated PKU can live many years, even into adulthood. However, their brain injury may mean they cannot care for themselves.

With newborn screening, PKU can be identified in infancy. When promptly treated, severe brain injury can be avoided. PKU treatment requires lifelong monitoring of Phe.

Women with PKU need to be especially careful. High Phe levels can cause loss of pregnancies and congenital disabilities.

SIGNS AND SYMPTOMS

Infants with untreated PKU have:

• Delayed development in infancy
• Small heads
• Seizures
• A musty odor

The severity of PKU can vary. It depends on the functioning of the enzyme that breaks down Phe. It may not be working at all or may have some function.

Even milder cases of PKU with some enzyme function are closely monitored. A careful diet ensures patients receive sufficient protein for average growth and development, but not too much Phe.

CAUSES

PKU is an inherited disorder. It is caused by changes in both copies of the gene that makes phenylalanine hydroxylase (PAH). PAH is an enzyme that breaks down Phe. Parents of an infant with PKU are called carriers. Carriers have a 25% chance of having a child with PKU. They are not affected by PKU and can eat a regular diet.

LABORATORY INVESTIGATIONS

In the US and most countries, newborn screening detects cases of PKU. Diagnosis is made by finding elevated Phe levels in the blood. Children can be treated before they develop any symptoms.

A blood test is ordered if a child is suspected of having PKU. It measures amino acids and helps diagnose this condition.

TREATMENT AND THERAPIES

PKU treatment involves providing adequate protein for normal growth and development. At the same time, it must avoid high Phe levels. PKU treatment requires a specialized team approach and may utilize:

• Special formulas
• Low-protein medical foods
• Daily medications

Patients with PKU are given a diet low in Phe. They are also given Phe-free protein supplements. (These are usually in the form of formulas or drinks.)

Dieticians with particular training plan the diets. They are often called “metabolic dieticians.” The most severe form of PKU, also called classic PKU, requires a strict diet. Those with milder PKU may have less strict diets.

The low-Phe diet can be difficult for patients and their families to follow. Patients may have to avoid common foods the rest of the family can eat (such as whole wheat bread and potatoes). Substitutions may not taste as good and can be more expensive.

Some patients with PKU can further lower their Phe levels by taking sapropterin. Sapropterin is a drug taken by mouth daily to enhance PAH function. Unfortunately, only certain patients with PKU can benefit from this medication.

Pegylated phenylalanine ammonia lyase is a medication that provides another way to reduce Phe levels. However, it requires daily subcutaneous injections. There have been some side effects, including abnormal immune responses.

Other treatments, including gene therapy, are actively being considered.

OUTLOOK

Children with PKU can lead normal and healthy lives. Early and consistent treatment is key. Brain injury that has already occurred cannot be reversed. Newborns with PKU can be diagnosed and treated before brain injury occurs.

Child Neurology Foundation (CNF) solicits resources from the community to be included on this webpage through an application process. CNF reserves the right to remove entities at any time if information is deemed inappropriate or inconsistent with the mission, vision, and values of CNF. 

Research 

ClinicalTrials.gov for Phenylketonuria (birth to 17 years).

These are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently.   

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.    

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits. 

The information in the CNF Child Neurology Disorder Directory is not intended to provide diagnosis, treatment, or medical advice and should not be considered a substitute for advice from a healthcare professional. Content provided is for informational purposes only.  CNF is not responsible for actions taken based on the information included on this webpage. Please consult with a physician or other healthcare professional regarding any medical or health related diagnosis or treatment options. 

Van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM. Phenylketonuria. Nat Rev Dis Primers. 2021 May 20;7(1):36. https://doi.org/10.1038/s41572-021-00267-0. PMID: 34017006; PMCID: PMC8591558.

MacDonald A, van Wegberg AMJ, Ahring K, Beblo S, Bélanger-Quintana A, Burlina A, Campistol J, Coşkun T, Feillet F, Giżewska M, Huijbregts SC, Leuzzi V, Maillot F, Muntau AC, Rocha JC, Romani C, Trefz F, van Spronsen FJ. PKU dietary handbook to accompany PKU guidelines. Orphanet J Rare Dis. 2020 Jun 30;15(1):171. https://doi.org/10.1186/s13023-020-01391-y. Erratum in: Orphanet J Rare Dis. 2020 Sep 1;15(1):230. PMID: 32605583; PMCID: PMC7329487.