Phenylketonuria (PKU) is a type of amino acid metabolism disorder. It is inherited. If you have it, your body can't process phenylalanine (Phe). Phe is an amino acid, a building block of proteins. It is in almost all foods. If your Phe level gets too high, it can damage your brain and cause severe intellectual disability. All babies born in U.S. hospitals must now have a screening test for PKU. This makes it easier to diagnose and treat the problem early.

The best treatment for PKU is a diet of low-protein foods. There are special formulas for newborns. For older children and adults, the diet includes many fruits and vegetables. It also includes some low-protein breads, pastas, and cereals. Nutritional formulas provide the vitamins and minerals you can't get from their food.

Babies who get on this special diet soon after they are born develop normally. Many have no symptoms of PKU. It is important to stay on the diet for the rest of your life.

Phenylketonuria is an inherited disorder of metabolism that causes an increase in the blood of a chemical known as phenylalanine.

What is phenylketonuria (PKU)?

Phenylketonuria (PKU) is an inherited disorder of metabolism that causes an increase in the blood of a chemical known as phenylalanine. Phenylalanine comes from a person's diet and is used by the body to make proteins. Phenylalanine is found in all food proteins and in some artificial sweeteners. Without dietary treatment, phenylalanine can build up to harmful levels in the body, causing mental disability and other serious problems.

Women who have high levels of phenylalanine during pregnancy are at high risk for having babies born with mental disability, heart problems, small head size (microcephaly) and developmental delay. This is because the babies are exposed to their mother's very high levels of phenylalanine before they are born.

In the United States, PKU occurs in 1 in 10,000 to 1 in 15,000 newborn babies. Newborn screening has been used to detect PKU since the 1960's. As a result, the severe signs and symptoms of PKU are rarely seen.

What are the symptoms of PKU?

Symptoms of PKU range from mild to severe. Severe PKU is called classic PKU. Infants born with classic PKU appear normal for the first few months after birth. However, without treatment with a low-phenylalanine diet, these infants will develop mental retardation and behavioral problems. Other common symptoms of untreated classic PKU include seizures, developmental delay, and autism. Boys and girls who have classic PKU may also have eczema of the skin and lighter skin and hair than their family members who do not have PKU.

Babies born with less severe forms of PKU (moderate or mild PKU) may have a milder degree of mental retardation unless treated with the special diet. If the baby has only a very slight degree of PKU, often called mild hyperphenylalaninemia, there may be no problems and the special dietary treatment may not be needed.

How is PKU diagnosed?

PKU is usually diagnosed through newborn screening testing that is done shortly after birth on a blood sample (heel stick). However, PKU should be considered at any age in a person who has developmental delays or mental retardation. This is because, rarely, infants are missed by newborn screening programs.

What is the treatment for PKU?

PKU is treated by limiting the amount of protein (that contains phenylalanine) in the diet. Treatment also includes using special medical foods as well as special low-protein foods and taking vitamins and minerals. People who have PKU need to follow this diet for their lifetime. It is especially important for women who have PKU to follow the diet throughout their childbearing years.

Is PKU inherited?

PKU is inherited in families in an autosomal recessive pattern. Autosomal recessive inheritance means that a person has two copies of the gene that is altered. Usually, each parent of an individual who has PKU carries one copy of the altered gene. Since each parent also has a normal gene, they do not show signs or symptoms of PKU.

Gene alterations (mutations) in the PAH gene cause PKU. Mutations in the PAH gene cause low levels of an enzyme called phenylalanine hydroxylase. These low levels mean that phenylalanine from a person's diet cannot be metabolized (changed), so it builds up to toxic levels in the bloodstream and body. Having too much phenylalanine can cause brain damage unless diet treatment is started.

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.

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.

Is genetic testing for PKU available?

A blood sample can be used to test for the mutations that cause PKU.

Testing an Infant

A blood test that measures the phenylalanine in an infant's blood is enough to help make a PKU diagnosis. Therefore, DNA testing is not necessary. However, if a child tests positive for PKU, health care providers may recommend genetic testing because identifying the type of mutation involved can help guide selection of the most appropriate treatment plan.

A DNA test also should be performed on a child if both parents are PKU carriers and the standard newborn blood test does not show the condition. The test will definitively indicate or rule out PKU, if the disease-causing mutations in the family have been identified.

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.1 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. The disease causing mutations must have been identified before prenatal testing can be performed.

Testing Possible PKU Carriers

If a child is diagnosed with PKU, other family members may be more likely to conceive children who also will have PKU. The parents' siblings and other close blood relatives should be told that the child has PKU so that they can decide whether or not they should have DNA testing as well.

What is maternal PKU?

Maternal PKU is the term used when a woman who has PKU becomes pregnant. Most children born to PKU mothers do not have the disorder. But if a pregnant woman who has PKU does not strictly follow a low-phenylalanine diet, her child can develop serious problems. These include:

• Intellectual disabilities
• Having a head that is too small (microcephaly)
• Heart defects
• Low birth weight
• Behavioral problems

The newborn’s problems from untreated maternal PKU are caused by the high phenylalanine levels present in the mother’s blood during pregnancy—not by PKU itself. The infant does not have PKU and does not need a PKU diet. The PKU diet will not help these health problems.

Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.

If I have PKU, what steps should I take during pregnancy to protect my infant?

If you have PKU, it is very important to follow a strict low-phenylalanine diet before becoming pregnant and throughout your pregnancy.

In addition to staying on a PKU diet, also make sure to:

• Visit a PKU clinic on a regular basis
• Have your blood checked often for phenylalanine
• Ask your health care provider how much PKU formula to drink

Keep in mind that untreated maternal PKU can cause serious problems for a developing fetus.

A newborn’s problems from untreated maternal PKU are caused by the high phenylalanine levels present in the mother’s blood during pregnancy—not PKU itself. The infant does not have PKU and does not need a PKU diet. The PKU diet will not help these health problems.

Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.

What determines the severity of PKU?

A number of factors influence whether a person with PKU has mild symptoms or more severe problems.

Genetic Factors

Many different mutations of the PAH gene can cause PKU. The type of mutation greatly affects the severity of the person's symptoms.

Some mutations cause classic PKU, the most severe form of the disorder. In these cases, the enzyme that breaks down phenylalanine barely works or does not work at all. If it is not treated, classic PKU can cause severe brain damage and other serious medical problems. Some mutations allow the enzyme to work a little better than it does in classic PKU. This is sometimes called non-PKU hyperphenylalaninemia, and is also known as non-PKU HPA. Such cases come with a smaller risk of brain damage. People with very mild cases may not require treatment with a low-phenylalanine diet.

Non-genetic Factors

Genes are not the only factor that influences the severity of PKU symptoms. For example, strictly following a PKU diet greatly reduces the chances that a person will have intellectual disabilities and other problems caused by PKU. Other factors include the person's age at diagnosis and how quickly the person's blood levels of phenylalanine are brought under control.

Does a child with PKU need repeated testing?

Infants and children with PKU need frequent blood tests to measure the phenylalanine in their blood. The health care provider may suggest changes to the diet or formula the child receives if there is evidence of too much or too little phenylalanine.

Infants with PKU will be tested about once a week for the first year of their lives. After the first year, children may be tested once or twice a month. Adults also need to be checked regularly throughout their lives. Often, blood samples can be taken at home and mailed to a laboratory.

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 coloring

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.

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.

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.

Normal Function

The PAH gene provides instructions for making an enzyme called phenylalanine hydroxylase. This enzyme helps process phenylalanine, which is a building block of proteins (amino acid). Phenylalanine is obtained through the diet; it is found in certain foods (such as meat, eggs, nuts, and milk) and in some artificial sweeteners.

Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine. The enzyme works with a molecule called tetrahydrobiopterin (BH4) to carry out this chemical reaction. Tyrosine is used to make several types of hormones and a pigment called melanin, which gives hair and skin their color. It is also used to make neurotransmitters, which are chemicals that transmit signals in the brain. Tyrosine can also be broken down into smaller molecules that are used to produce energy.

Health Conditions Related to Genetic Changes

Phenylketonuria

Hundreds of variants (also called mutations) in the PAH gene have been identified in people with phenylketonuria (PKU). This condition increase the levels of phenylalanine in the blood. If PKU is not treated, phenylalanine can build up to harmful levels, causing intellectual disability and other serious health problems.

Most of the variants that cause PKU change single amino acids in phenylalanine hydroxylase. For example, the most common variant in many populations replaces the amino acid arginine with the amino acid tryptophan at position 408 (written as Arg408Trp or R408W) in phenylalanine hydroxylase. Other PAH gene variants delete small amounts of DNA from the gene or disrupt the way the gene's instructions are used to make phenylalanine hydroxylase.

PAH gene variants reduce the activity of phenylalanine hydroxylase, preventing it from processing phenylalanine 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 in people who have very low levels of phenylalanine hydroxylase activity or who have no phenylalanine hydroxylase activity at all. People with untreated classic PKU have levels of phenylalanine high enough to cause severe brain damage and other serious medical problems. Variants 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.

Other Names for This Gene

• L-Phenylalanine,tetrahydrobiopterin:oxygen oxidoreductase (4-hydroxylating)
• PH4H_HUMAN
• Phenylalaninase
• Phenylalanine 4-Hydroxylase
• Phenylalanine 4-Monooxygenase
• PKU1

Genomic Location

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

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.

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.

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.

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.

Screening for PKU Later in Life

In the United States, newborn screening identifies nearly all people born with PKU. 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.

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. 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. A person with PKU should receive treatment at a medical center that specializes in the disorder.

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.

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.

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.

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. 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.

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.

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.

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.
• Adults with PKU who do not follow a special diet may develop unstable moods and take longer to process information. 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.
• 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. Read more about maternal PKU. Women with PKU and uncontrolled phenylalanine levels also have an increased risk of pregnancy loss.