Genetics

What is phenylketonuria?
Phenylketonuria (commonly known as PKU) is an inherited disorder that increases the levels of a substance called phenylalanine in the blood. Phenylalanine is a building block of proteins (an amino acid) that is obtained through the diet. It is found in all proteins and in some artificial sweeteners. If PKU is not treated, phenylalanine can build up to harmful levels in the body, causing intellectual disability and other serious health problems.

The signs and symptoms of PKU vary from mild to severe. The most severe form of this disorder is known as classic PKU. Infants with classic PKU appear normal until they are a few months old. Without treatment with a special low-phenylalanine diet, these children develop permanent intellectual disability. Seizures, delayed development, behavioral problems, and psychiatric disorders are also common. Untreated individuals may have a musty or mouse-like odor as a side effect of excess phenylalanine in the body. Children with classic PKU tend to have lighter skin and hair than unaffected family members and are also likely to have skin disorders such as eczema.

Less severe forms of this condition, sometimes called variant PKU and non-PKU hyperphenylalaninemia, have a smaller risk of brain damage. People with very mild cases may not require treatment with a low-phenylalanine diet.

Babies born to mothers with PKU and uncontrolled phenylalanine levels (women who no longer follow a low-phenylalanine diet) have a significant risk of intellectual disability because they are exposed to very high levels of phenylalanine before birth. These infants may also have a low birth weight and grow more slowly than other children. Other characteristic medical problems include heart defects or other heart problems, an abnormally small head size (microcephaly), and behavioral problems. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.

How common is phenylketonuria?
The occurrence of PKU varies among ethnic groups and geographic regions worldwide. In the United States, PKU occurs in 1 in 10,000 to 15,000 newborns. Most cases of PKU are detected shortly after birth by newborn screening, and treatment is started promptly. As a result, the severe signs and symptoms of classic PKU are rarely seen.

What genes are related to phenylketonuria?
Mutations in the PAH gene cause phenylketonuria.

The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme converts the amino acid phenylalanine to other important compounds in the body. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. As a result, this amino acid can build up to toxic levels in the blood and other tissues. Because nerve cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts of this substance can cause brain damage.

Classic PKU, the most severe form of the disorder, occurs when phenylalanine hydroxylase activity is severely reduced or absent. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious medical problems. Mutations in the PAH gene that allow the enzyme to retain some activity result in milder versions of this condition, such as variant PKU or non-PKU hyperphenylalaninemia.

Changes in other genes may influence the severity of PKU, but little is known about these additional genetic factors.

Read more about the PAH gene.

How do people inherit phenylketonuria?
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about treatment for phenylketonuria?
These resources address the management of phenylketonuria and may include treatment providers.

GeneReviews
Genetic Alliance
MedlinePlus Encyclopedia: Phenylketonuria
MedlinePlus Encyclopedia: Serum Phenylalanine Screening
You might also find information on treatment of phenylketonuria in Educational resources and Patient support.

Where can I find additional information about phenylketonuria?
You may find the following resources about phenylketonuria helpful. These materials are written for the general public.

MedlinePlus - Health information (4 links)
Additional NIH Resources - National Institutes of Health (3 links)
Educational resources - Information pages (16 links)
Patient support - For patients and families (7 links)
You may also be interested in these resources, which are designed for healthcare professionals and researchers.

Gene Reviews - Clinical summary
Gene Tests - DNA tests ordered by healthcare professionals
ACTion Sheets - Newborn screening follow up (1 link)
ClinicalTrials.gov - Linking patients to medical research
PubMed - Recent literature
Online Books - Medical and science texts
Scriver's Online Metabolic and Molecular Bases of Inherited Disease (OMMBID): Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency
OMIM - Genetic disorder catalog
What other names do people use for phenylketonuria?
Deficiency Disease, Phenylalanine Hydroxylase
Folling Disease
Folling's Disease
PAH deficiency
Phenylalanine Hydroxylase Deficiency Disease
PKU
See How are genetic conditions and genes named? in the Handbook.

What if I still have specific questions about phenylketonuria?
See How can I find a genetics professional in my area? in the Handbook.
Ask the Genetic and Rare Diseases Information Center.
Submit your question to Ask the Geneticist.
Where can I find general information about genetic conditions?
The Handbook provides basic information about genetics in clear language.

What does it mean if a disorder seems to run in my family?
What are the different ways in which a genetic condition can be inherited?
If a genetic disorder runs in my family, what are the chances that my children will have the condition?
Why are some genetic conditions more common in particular ethnic groups?
These links provide additional genetics resources that may be useful.

Genetics and health
Resources for Patients and Families
Resources for Health Professionals