Phenylketonuria (PKU)

Phenylketonuria (pronounced fen-l-kee-toh-NOOR-ee-uh), often called PKU, is an inherited disorder that that can cause intellectual and developmental disabilities (IDDs) if not treated. In PKU, the body can't process a portion of a protein called phenylalanine, which is in all foods containing protein. If the phenylalanine level gets too high, the brain can become damaged.

All children born in U.S. hospitals are tested routinely for PKU soon after birth, making it easier to diagnose and treat affected children early.

Children and adults who are treated early and consistently develop normally.¹

Depending on the level of phenylalanine and tolerance for phenylalanine in the diet, PKU is classified into two different types: classic, which is the severe form, and moderate. Therefore, each patient needs an individualized treatment plan. Some people may benefit from a medication called sapropterin dihydrochloride (brand name Kuvan®) that treats the disorder.²

Who is at risk for PKU?

Some genetic disorders, including PKU, develop more often among people whose ancestors come from a particular region. People originally from the same region frequently share versions of their genes that have been passed down from common ancestors. These can include genes with mutations or changes that can cause PKU.

In the United States, PKU is most common in people of European or Native American ancestry. It is much less common among people of African, Hispanic, or Asian ancestry.³

Children with untreated PKU appear normal at birth. But by age 3 to 6 months, they begin to lose interest in their surroundings. By age 1 year, children are developmentally delayed and their skin has less pigmentation than someone without the condition. If people with PKU do not restrict the phenylalanine in their diet, they develop severe intellectual and developmental disabilities.

Other symptoms include:

• Behavioral or social problems
• Seizures, shaking, or jerking movements in the arms and legs
• Stunted or slow growth
• Skin rashes, like eczema (pronounced EK-suh-muh)
• Small head size, called microcephaly (pronounced mahy-kroh-SEF-uh-lee)
• A musty odor in urine, breath, or skin that is a result of the extra phenylalanine in the body
• Fair skin and blue eyes, due to the body's failure to transform phenylalanine into melanin, the pigment responsible for a person's coloring¹

Some genetic disorders, including PKU, develop more often among people whose ancestors come from a particular region. People originally from the same region frequently share versions of their genes that have been passed down from common ancestors. These can include genes with mutations or changes that can cause PKU.

In the United States, PKU is most common in people of European or Native American ancestry. It is much less common among people of African, Hispanic, or Asian ancestry.²

PKU is caused by mutations in the gene that helps make an enzyme called phenylalanine hydroxylase (pronounced fen-l-AL-uh-neen hahy-DROK-suh-leys), or PAH. This enzyme is needed to convert the amino acid phenylalanine into other substances the body needs. When this gene, known as the PAH gene, is defective, the body cannot break down phenylalanine.

Amino acids help build protein, but phenylalanine can cause harm when it builds up in a person's body. In particular, nerve cells in the brain are sensitive to phenylalanine.

Many different PAH mutations result in problems with breaking down phenylalanine. Some mutations cause PKU, others cause non-PKU hyperphenylalaninemia (pronounced HAHY-per-fen-l-al-uh-nih-NEE-mee-uh) and others are silent mutations that do not have an effect.¹

Is PKU inherited?

PKU is inherited from a person's parents. The disorder is passed down in a recessive pattern, which means that for a child to develop PKU, both parents have to contribute a mutated version of the PAH gene. If both parents have PKU, their child will have PKU as well.

Sometimes, a parent does not have PKU but is a carrier, which means the parent carries a mutated PAH gene. If only one parent carries the mutated gene, the child will not develop PKU.

Even if both parents carry the mutated PAH gene, their child still may not develop PKU. This is because a child's parents each carry two versions of the PAH gene, only one of which they will pass on during conception.

If both of a child's parents are carriers, there is a 25% chance that each parent will pass on the normal PAH gene. In this case, the child will not have the disorder. Conversely, there also is a 25% chance that the carrier parents will both pass along the mutated gene, causing the child to have PKU. However, there is a 50% chance that a child will inherit one normal gene from one parent and one abnormal one from the other, making the child a carrier.

Nearly all cases of PKU are diagnosed through a blood test done on newborns.¹

Newborn Screening for PKU

All 50 U.S. states and territories require that newborns get screened for PKU. In addition to the United States, many other countries routinely screen infants for PKU.¹

Before screening for PKU was possible, most infants with the disorder developed severe intellectual disabilities. In the 1960s, researchers supported by the federal Children's Bureau determined that a test for PKU given to newborns was safe and effective. Later, the NICHD led research on the safety and effectiveness of a restricted diet to treat PKU. Since then, PKU has been almost completely eliminated as a cause of intellectual disabilities.²

How are newborns tested for PKU?

Health care providers conduct a PKU screening test using a few drops of blood from a newborn's heel. The blood sample, which can be used to screen for other conditions as well, is tested in a laboratory to determine if it has too much phenylalanine in it. The newborn screening test should be performed by the child's pediatrician if the mother did not give birth in a hospital or is discharged from the hospital before the test is performed.

What if my newborn tests positive for PKU?

If your newborn's screening test comes back positive for PKU, your child will need additional tests to confirm that he or she definitely has the disorder. It is very important to follow your health care providers' instructions for further tests. These tests may be blood or urine tests that may show whether or not the child has PKU. If your child does have PKU, getting treatment quickly will help protect your child's health.³

Your health care providers may also suggest genetic testing to look at the mutations in genes that cause PKU. This testing is not required to figure out whether your child has PKU, but it will help identify the specific type of genetic mutation causing the disorder. This information may be useful for determining the best treatment plan going forward.⁴

Screening for PKU Later in Life

In the United States, newborn screening identifies nearly all people born with PKU.¹ However, there are concerns that cases of PKU could be missed due to errors at any step of the screening process—specimen collection, laboratory procedures, treatment initiation, or clinical follow-up. Missed cases are considered to be extremely rare. Because of these rare cases, health professionals recommend PKU testing if a person of any age has developmental delays or an intellectual disability.⁵

Testing during Pregnancy

A pregnant woman can request a prenatal DNA test to learn whether or not her child will be born with PKU. To perform this test, a health care provider takes some cells, either through a needle inserted into the abdomen or a small tube inserted into the vagina. A genetic counselor who understands the risks and benefits of genetic testing can help explain the choices available for testing.⁶ This discussion may be particularly useful for parents who already have one child with PKU, because they have a higher-than-average chance of conceiving another child with the disorder.

There is no cure for PKU, but treatment can prevent intellectual disabilities and other health problems.¹ A person with PKU should receive treatment at a medical center that specializes in the disorder. (Visit the Resources and Publications section for ways to locate a center.)

The PKU Diet

People with PKU need to follow a diet that limits foods with phenylalanine. The diet should be followed carefully and be started as soon after birth as possible. In the past, experts believed that it was safe for people to stop following the diet as they got older. However, they now recommend that people with PKU stay on the diet throughout their lives for better physical and mental health.^1,2

It is especially important for a pregnant woman with PKU to strictly follow the low-phenylalanine diet throughout her pregnancy to ensure the healthy development of her infant.³

People with PKU need to avoid various high-protein foods, including:

• Milk and cheese
• Eggs
• Nuts
• Soybeans
• Beans
• Chicken, beef, or pork
• Fish
• Peas
• Beer

People with PKU also need to avoid the sweetener aspartame, which is in some foods, drinks, medications, and vitamins. Aspartame releases phenylalanine when it is digested, so it raises the level of phenylalanine in a person's blood.¹

Often, people with PKU also have to limit their intake of lower-protein foods, such as certain fruits and vegetables. However, a PKU diet can include low-protein noodles and other special products.

The amount of phenylalanine that is safe to consume differs for each person. Therefore, a person with PKU needs to work with a health care professional to develop an individualized diet. The goal is to eat only the amount of phenylalanine necessary for healthy growth and body processes but not any extra. Frequent blood tests and doctor visits are necessary to help determine how well the diet is working. Some relaxation of the diet may be possible as a child gets older, but the recommendation today is lifelong adherence to the diet.^2,4 Following the diet is especially important during pregnancy.

However, the PKU diet can be very challenging. Getting support from friends and family or a support group can help. Sticking with the diet ensures better functioning and improved overall health.

A PKU Formula

People who follow the PKU diet will not get enough essential nutrients from food. Therefore, they must drink a special formula.

A newborn who is diagnosed with PKU should receive special infant formula. The formula may be mixed with a small amount of breast milk or regular infant formula to make sure the child gets enough phenylalanine for normal development but not enough to cause harm.

Older children and adults receive a different formula to meet their nutritional needs. This formula should be consumed every day throughout a person's life.

In addition to the formula, health care professionals may recommend other supplements. For example, fish oil may be recommended to help with fine motor coordination and other aspects of development.¹

Medication for PKU

The U.S. Food and Drug Administration (FDA) has approved the drug sapropterin dihydrochloride (Kuvan®) for the treatment of PKU. Kuvan® is a form of BH4, which is a substance in the body that helps break down phenylalanine. However, having too little BH4 is only one reason a person may not break down phenylalanine. Therefore, Kuvan® only helps some people reduce the phenylalanine in their blood. Even if the medication helps, it will not decrease the phenylalanine to the desired amount and must be used together with the PKU diet.⁵

When the FDA approved Kuvan®, the agency suggested that research on the medication continue to determine its long-term safety and effectiveness.

Other Treatments for PKU

NICHD-supported researchers and other scientists are exploring additional treatments for PKU. These treatments include large neutral amino acid supplementation, which may help prevent phenylalanine from entering the brain, and enzyme replacement therapy, which uses a substance similar to the enzyme that usually breaks down phenylalanine. Researchers are also investigating the possibility of using gene therapy, which involves injecting new genes to break down phenylalanine. That would result in the breakdown of phenylalanine and decreased blood phenylalanine levels.⁶

Children and adults who do not receive treatment for PKU may develop a variety of symptoms.

• Children with PKU who are not treated may develop symptoms including behavioral problems, seizures, and severe intellectual and developmental disabilities.¹
• Adults with PKU who do not follow a special diet may develop unstable moods² and take longer to process information.³ Adults with high phenylalanine levels who go back on a PKU diet may be able to improve their mental functioning and slow down any damage to their central nervous systems.⁴
• Pregnant Women with PKU who do not strictly follow a low-phenylalanine diet may give birth to a child with serious problems, including intellectual and developmental disabilities, a head that is too small (microcephaly), heart defects, and low birth weight.⁵ Read more about maternal PKU. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.⁶

The NICHD supports and conducts research on a wide range of topics related to PKU and other metabolic disorders. Research areas include newborn screening, healthy fetal development in pregnant women with PKU, and the pathophysiology of PKU-related intellectual disabilities. Key NICHD research issues include the following:

• Newborn screening: Efforts focus on making improvements to screening technology, supporting longitudinal research on the health of children identified through screening, and expanding access to data from screening for translational research.
• Therapeutic interventions: Researchers are currently investigating the use of gene therapy interventions. Other interventions, such as lifelong dietary treatment, have been studied in the past and continue to be of interest.
• Psychosocial issues: Researchers have developed multiple studies in this area. Recently, they explored issues such as family adaptation to a PKU diagnosis.
• Pathophysiology: Scientists are exploring processes and metabolism as they relate to brain functioning in PKU and other disorders.

The NICHD's PKU-related portfolio is maintained largely through the Intellectual and Developmental Disabilities Branch (IDDB). The Institute supports diverse projects, including research on pregnancy and PKU, gene therapy, improved screening, and pathophysiology of the disorder.

• Institute Activities and Advances
• Other Activities and Advances

Institute Activities and Advances

Since its establishment, the NICHD has played a major role in PKU-related research. In the 1960s, federal Children's Bureau-supported researchers demonstrated the effectiveness of a PKU screening test that could easily and inexpensively screen for the disorder on a mass basis. Soon after, the NICHD led research on the safety and effectiveness of a restricted diet to treat PKU among newborns who had been identified using the screening test. As a result of the test and the Institute's follow-up research, PKU has been nearly eliminated as a cause of intellectual disabilities in the United States.

The NICHD continues to address newborn screening for PKU and other disorders through the Hunter Kelly Newborn Screening Research Program. The program is authorized to conduct, coordinate, and expand research in a number of screening-related areas. The topics of study include:

• Identifying new screening methods and technologies
• Educating the workforce of health care providers about screening
• Developing and implementing information systems for parents and providers


• Establishing a network of state programs for screening newborns

Other NICHD projects look at the psychosocial aspects of screening, such as how family members respond to, share, and use information gained when a newborn is diagnosed.

NICHD-supported researchers also have explored other issues central to understanding PKU and improving the lives of people who live with the disorder. One particularly significant focus has been maternal PKU. A collaborative study of women with PKU, which was initiated by the NICHD, found that women who followed a low-phenylalanine diet before and during pregnancy prevented intellectual disabilities in their offspring. The largest and most definitive clinical study of maternal PKU to date, the project also demonstrated the efficacy of dietary treatment in reducing the incidence of microcephaly, intrauterine growth retardation, and congenital heart disease among offspring.

Other Institute research focuses on aspects of PKU dietary treatments. For example, NICHD-supported researchers found that adults and adolescents on a PKU diet often had low blood levels of important fatty acids. As a result, they recommended adding supplements that provided key fatty acids as appropriate for patients.

NICHD-supported research also explores emerging treatments for PKU, such as gene therapy. For example, some researchers are studying mice to better understand the expression of the phenylalanine metabolizing system in muscles.

Other Activities and Advances

• The NICHD has been playing a key role in developing and updating guidelines for detecting and managing PKU. The Institute was heavily involved in the 2000 NIH Consensus Development Conference on Phenylketonuria, which first developed the guidelines; now NICHD researchers and other experts are updating them to include recent scientific advances. Visit http://www.nichd.nih.gov/news/resources/spotlight/Pages/020912-PKU.aspx for more information about this updating effort. Information about the 2012 update meetings is available at http://www.sciencedirect.com/science/article/pii/S1096719214000857 .
• The NICHD supports the Newborn Screening Translational Research Network . The Network is developing a system for clinics and other screening providers to collect long-term follow-up and outcome data for use in research on PKU and other disorders.
• The NICHD-funded Cochrane Neonatal Research Group conducts systematic reviews of randomized controlled trials in neonatal medicine. One review published in 2010 assessed research on dietary interventions for PKU .