Phenylketonuria

Phenylketonuria (PKU): Condition Information

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 phenylketonuria, 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 phenylketonuria 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, phenylketonuria 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 phenylketonuria?

Some genetic disorders, including phenylketonuria, 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 phenylketonuria.

In the United States, phenylketonuria 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)

What are common symptoms of phenylketonuria?

Children with untreated phenylketonuria 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 phenylketonuria 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 coloring.(4)

Who is at risk for phenylketonuria?

Some genetic disorders, including phenylketonuria, 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 phenylketonuria.

In the United States, phenylketonuria 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)

What causes phenylketonuria?

Phenylketonuria 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 phenylketonuria, others cause non-phenylketonuria 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 phenylketonuriainherited?

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

Sometimes, a parent does not have phenylketonuria 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 phenylketonuria.

Even if both parents carry the mutated PAH gene, their child still may not develop phenylketonuria. 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 phenylketonuria. 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.

How do health care providers diagnose phenylketonuria?

Nearly all cases of phenylketonuria are diagnosed through a blood test done on newborns.(5)

Newborn Screening for phenylketonuria

All 50 U.S. states and territories require that newborns get screened for phenylketonuria. In addition to the United States, many other countries routinely screen infants for phenylketonuria.(5)

Before screening for phenylketonuria 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 phenylketonuria given to newborns was safe and effective. Later, the NICHD led research on the safety and effectiveness of a restricted diet to treat phenylketonuria. Since then, phenylketonuria has been almost completely eliminated as a cause of intellectual disabilities.(6)

How are newborns tested for phenylketonuria?

Health care providers conduct a phenylketonuria 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 phenylketonuria?

If your newborn's screening test comes back positive for phenylketonuria, 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 phenylketonuria. If your child does have phenylketonuria, getting treatment quickly will help protect your child's health.(7)

Your health care providers may also suggest genetic testing to look at the mutations in genes that cause phenylketonuria. This testing is not required to figure out whether your child has phenylketonuria, 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.(8)

Screening for phenylketonuria later in life

In the United States, newborn screening identifies nearly all people born with phenylketonuria.(1) However, there are concerns that cases of phenylketonuria 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 phenylketonuria testing if a person of any age has developmental delays or an intellectual disability.(9)

Testing during pregnancy

A pregnant woman can request a prenatal DNA test to learn whether or not her child will be born with phenylketonuria. 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.(10) This discussion may be particularly useful for parents who already have one child with phenylketonuria, because they have a higher-than-average chance of conceiving another child with the disorder.

What are common treatments for phenylketonuria?

There is no cure for phenylketonuria, but treatment can prevent intellectual disabilities and other health problems.(1) A person with phenylketonuria 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 phenylketonuria diet

People with phenylketonuria 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 phenylketonuria stay on the diet throughout their lives for better physical and mental health.(11,12)

It is especially important for a pregnant woman with phenylketonuria to strictly follow the low-phenylalanine diet throughout her pregnancy to ensure the healthy development of her infant.(9)

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

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

People with phenylketonuria 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.(11)

Often, people with phenylketonuria also have to limit their intake of lower-protein foods, such as certain fruits and vegetables. However, a phenylketonuria 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 phenylketonuria 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.(12,13) Following the diet is especially important during pregnancy.

However, the phenylketonuria 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 phenylketonuria formula

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

A newborn who is diagnosed with phenylketonuria 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.(11)

Medication for phenylketonuria

The U.S. Food and Drug Administration (FDA) has approved the drug sapropterin dihydrochloride (Kuvan®) for the treatment of phenylketonuria. 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 phenylketonuria diet.(2)

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 phenylketonuria

NICHD-supported researchers and other scientists are exploring additional treatments for phenylketonuria. 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.(14)

If phenylketonuria is not treated, what problems occur?

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

• Children with phenylketonuria who are not treated may develop symptoms including behavioral problems, seizures, and severe intellectual and developmental disabilities.(11)
• Adults with phenylketonuria who do not follow a special diet may develop unstable moods(14) and take longer to process information.(6) Adults with high phenylalanine levels who go back on a phenylketonuria diet may be able to improve their mental functioning and slow down any damage to their central nervous systems.(15)
• Pregnant Women with phenylketonuria 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.(9) Read more about maternal phenylketonuria. Women with phenylketonuria and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.(4)

1. NICHD. (2000, updated 2006). Report of the NIH consensus development conference on phenylketonuria (PKU): Screening and management. Retrieved May 15, 2012, from https://www.nichd.nih.gov/publications/pubs/pku/index
2. U.S. Food and Drug Administration. (2007, December). FDA Approves Kuvan for Treatment of Phenylketonuria (PKU), December 13, 2007. Retrieved June 22, 2012, from https://wayback.archive-it.org/7993/20161022203137/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109039.htm
3. Kaye, C. I., Committee on Genetics, Accurso, F., La Franchi, S., Lane, P. A., Hope, N., et al. (2006). Newborn screening fact sheets. Pediatrics, 118(3), e934–963.
4. Genetics Home Reference. (2012). Phenylketonuria. Retrieved June 22, 2012, from https://medlineplus.gov/genetics/condition/phenylketonuria/.

5. Medline Plus. (2011, June). Newborn screening tests. Retrieved June 22, 2012, from https://www.nlm.nih.gov/medlineplus/ency/article/007257.htm.

6. NICHD. (2003). 40 years of human development research: Advancing science, enriching lives. Washington, DC: U.S. Department of Health and Human Services.

7. Baby's First Test. (n.d.). Classic phenylketonuria. Retrieved May 15, 2012, from https://www.babysfirsttest.org/newborn-screening/conditions/classic-phenylketonuria-pku.

8. Screening, Technology, and Research in Genetics. (2007). Amino acid disorders: Phenylketonuria [Fact sheet]. Retrieved May 15, 2012, from https://www.newbornscreening.info/Parents/aminoaciddisorders/PKU.html.

9. National Human Genome Research Institute. (2010). Learning about phenylketonuria (PKU). Retrieved May 15, 2012, from https://www.genome.gov/25020037.

10. Screening, Technology, and Research in Genetics. (2007). Amino acid disorders: Phenylketonuria [Fact sheet]. Retrieved May 15, 2012, from https://www.newbornscreening.info/Parents/aminoaciddisorders/PKU.html.

11. PubMed Health. (2011). Phenylketonuria. Retrieved May 15, 2012, from https://www.ncbi.nlm.nih.gov/p....

12. Poustie V. J., & Wildgoose, J. (2010) Dietary interventions for phenylketonuria. Cochrane Database of Systematic Reviews, 1.

13. PubMed Health. (2011). Phenylketonuria. Retrieved May 15, 2012, from https://www.ncbi.nlm.nih.gov/p....

14. Bélanger-Quintana, A., Burlina, A., Harding, C.O., & Muntau, A.C. (2011). Up-to-date knowledge on different treatment strategies for phenylketonuria. Molecular Genetics and Metabolism, 10, S19–S25.

15. Schuett, V. (2000, Winter). Study shows long-term beneficial effects of the PKU diet, even for late-diagnosed persons. National PKU News. Retrieved June 22, 2012, from https://pkunews.org/diet-intervention-guidelines-for-adults-with-untreated-pku/

For more information:

March of Dimes
1275 Mamaroneck Avenue
White Plains, NY 10605
National Office Phone:
914-997-4488
https://www.marchofdimes.org/

PKU News
https://pkunews.org/

National PKU Alliance
https://www.npkua.org/

This information was developed by the National Institutes of Health, National Institute of Child Health & Human Development.

National Institutes of Health, National Institute of Child Health & Human Development. Phenylketonuria (PKU): Condition Information. Available at: https://www.nichd.nih.gov/health/topics/pku/conditioninfo/Pages/default.aspx. Last accessed January 21, 2014.

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