What is phenylketonuria (PKU)?

Phenylketonuria (or PKU) is a rare, inherited disorder that prevents children from breaking down certain amino acids in their bodies. This leads to toxic levels of phenylalanine and a dangerously low level of tyrosine. In healthy children, these two amino acids work together to keep the body functioning properly. In children with PKU, the imbalance of amino acids can damage the brain and affect the body’s ability to function.

Toxic levels of phenylalanine can cause brain damage. Dangerously low levels of tyrosine can affect multiple body systems including:

• Neurotransmitters that affect mood, memory and focus
• Hormones that support adrenal and pituitary gland function, and regulate stress
• Melanin that provides pigment for skin and hair
• Proteins that serve as building blocks for body development and other life-sustaining processes

PKU is on a spectrum meaning that it can range from mild PKU (called “hyperphenylalaninemia”) to severe (called “classic PKU”). Treatment for children with PKU primarily focuses on a protein-restricted diet, but supportive treatments may also be recommended. Without treatment, children born with PKU can develop intellectual disability.

PKU is estimated to affect one in every 10,000 to 15,000 babies born in the United States.

Causes of phenylketonuria (PKU)

PKU is a genetic condition caused by changes in the PAH gene. The PAH gene provides the body with instructions to produce an enzyme called phenylalanine hydroxylase. This enzyme converts phenylalanine – an essential amino acid found in meat, eggs, milk and nuts – into tyrosine in the body. If the body does not make the phenylalanine hydroxylase enzyme, phenylalanine builds up in the body, tyrosine decreases, and symptoms occur.

PKU is inherited autosomal recessively. That means your child would have to inherit a defective PAH gene from both parents to have PKU.

If a child inherits only one defective PAH gene, they will not have any PKU symptoms. Instead, they could become carriers of the disorder and may pass the defective gene onto their children.

For children with PKU, neither copy of the PAH gene provides the proper instructions to produce the enzyme. 

Signs and symptoms of phenylketonuria (PKU)

Children with PKU often do not have any signs or symptoms at birth. However, by 6 months to one year of age, most children with the disorder will begin to show some developmental delays. 

As the disease progresses, PKU can lead to:

• Severe intellectual disability
• Delayed mental and social skills
• Behavior problems like hyperactivity
• Seizures, tremors and/or jerking movements
• A small head size (microcephaly)

Other symptoms of the disorder can include:

• Skin conditions, such as eczema 
• Lighter skin, hair and eye color due to decreased pigmentation 
• Changes in brain development due to how white matter develops

Testing and diagnosis for phenylketonuria (PKU)

In most cases, phenylketonuria is discovered during routine newborn screening tests, which are required of all babies born in hospitals in all 50 U.S. states. A simple heel prick is used to get a sample of your baby’s blood and is then sent for testing. This screening is typically completed within a day of the baby’s birth and results are available within weeks. 

Diagnosis of PKU is typically established in those who have: 

• Persistently elevated phenylalanine levels 
• Two pathogenic genetic variants identified through PAH gene sequencing 

Treatment for phenylketonuria (PKU)

There is no cure for PKU, but it can be treated by managing your child’s diet. Your child will need to avoid proteins like meat, eggs, nuts and milk as well as the artificial sweetener aspartame. This protein-restricted diet can limit the disorder’s symptoms. Dietary treatment for PKU is life-long.

In some cases, co-factor therapy and enzyme substitution therapy may be used clinically to treat PKU. Co-factor therapy uses a molecule that helps the phenylalanine hydroxylase enzyme work more efficiently, while enzyme substitution therapy provides your child with a different enzyme to break down phenylalanine in the body. 

Children with PKU should be seen regularly by physicians to monitor how effective treatment is and adjust care as needed. 

Follow-up care for PKU

Children treated for PKU at CHOP check in annually with the Metabolic Disease Program so we can track their progress and make any necessary adjustments to their treatment plan. Children and families can also access subspecialists they may need, including the Neuropsychology and Assessment Service.

CHOP is currently conducting clinical trials and researching new therapies for PKU. You can see our research studies here. An area that shows great promise is cell and gene therapy. 

Cell and gene therapy is an innovative and cutting-edge approach to treating certain genetic disorders like PKU. Researchers at CHOP have pioneered some of the first FDA-approved cell and gene therapies for use in children. And we continue to investigate new ways of treating – and potentially curing – genetic disorders in children. 

Learn how CHOP is making cell and gene therapy breakthroughs, and which FDA-approved therapies are available at CHOP.

Long term outcomes

If treated, children with PKU may develop normally, although some may still have difficulty with language skills, memory, learning and executive function. Adults who discontinue treatment may see a higher incidence of psychiatric and cognitive changes, including anxiety, depression, reduced attention span and slower reaction times.