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Harvard Commentaries
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Harvard Commentaries
Reviewed by the Faculty of Harvard Medical School


Phenylketonuria


June 28, 2011

Genetic Testing Guide
32193
Phenylketonuria
Phenylketonuria
Phenylketonuria
htmGEN_Phenylketonuria
People with phenylketonuria lack the enzyme needed to break down the amino acid phenylalanine, which leads to a toxic build up of phenylalanine in their bodies.
398491
InteliHealth
2011-06-28
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InteliHealth Medical Content
2014-06-28

Reviewed by the Faculty of Harvard Medical School

Phenylketonuria Genetic Testing Basics

Phenylketonuria

What is phenylketonuria (PKU)?
Phenylalanine is an amino acid found in protein-rich foods. People with phenylketonuria lack the enzyme needed to break down this amino acid, which leads to a toxic buildup of phenylalanine in their bodies.

PKU has both a genetic and an environmental component. While the disease starts with a genetic problem — the lack of a critical enzyme — it's actually the presence of phenylalanine in someone's diet that causes symptoms. The main signs and symptoms include:

  • Severe intellectual disability (historically called mental retardation)
  • Small head size (microcephaly)
  • Seizures
  • Behavior problems

The disorder is most harmful if it goes undetected during a child's early development (from birth to 6 months). High levels of phenylalanine disrupt brain development. Before newborn screening for PKU began, PKU was a common cause of intellectual disability. Today, newborn screening is offered in all 50 states. By identifying babies with PKU right after they are born, treatment can begin before high levels of phenylalanine can cause brain damage.

Related Reading
Phenylketonuria

How common is phenylketonuria?
Phenylketonuria affects about one in 15,000 newborns in the United States.

Who is at risk of phenylketonuria?
Your highest risk of having a child with PKU comes if you have already had a child with phenylketonuria. Unfortunately, most people don't know they are carriers when they start having children. PKU affects people from a wide range of ethnic groups. Among people with European or Chinese ancestors, the incidence varies from about one in 10,000 to one in 15,000 live births. PKU is less common among people with an African-American or Latino background. Among people from some Arabic-speaking countries the incidence may be as high as 1 in 3,000. The incidence is lowest among people with Japanese ancestry; about one in 140,000 live births.

Is there a cure?
No, but the disease can be effectively managed. For newborns and infants with phenylketonuria, strict control of phenylalanine levels in their diets helps them to avoid intellectual disability and seizures associated with untreated PKU. Babies with PKU are given special formulas that contain other amino acids (the building blocks of protein), but not phenylalanine.

Children and adults with PKU need to limit the amount of protein in their diet and carefully monitor their phenylalanine levels on a regular basis. Decreasing the amount of protein-rich foods can decrease phenylalanine levels to a safe range. Because a low-protein diet is not healthy, people with PKU supplement their diet with special protein formulas that do not contain phenylalanine.

The Gene For Phenylketonuria

What goes wrong with this gene?
The gene that causes phenylketonuria is called phenylalanine hydroxylase (PAH). This gene tells the body how to make the PAH enzyme. This enzyme converts phenylalanine into another amino acid.

If you inherit two changes in the PAH gene, one from your mother and one from your father, you will not be able to make enough of the enzyme to convert phenylalanine into another amino acid. In turn, this causes increased levels — toxic levels — of phenylalanine in your body.

Should You Be Tested?

What is the risk of being a phenylketonuria carrier?
The chance that you or your child is a carrier depends on your family history. If someone in your immediate family (parent, brother, sister) has phenylketonuria or is a PKU carrier, you also could be a carrier. If one parent is a carrier, and the other is not, you have a 50% chance of being a carrier. If you have a brother or sister with PKU, then both your parents must be carriers, and you have a two-thirds chance of being a carrier.

Your future child's risk of being a carrier depends on whether you and your partner are carriers. If one of you is a carrier, each child will have a 50% chance of being a carrier. If both of you are carriers, each of your unborn children has a 25% chance of having PKU. The chance that your unaffected children will be carriers is two-thirds.

Should I consider prenatal testing?
To discover whether your unborn child has inherited phenylketonuria, you and your partner can seek prenatal testing. Prenatal testing is generally only available if you already have a child with PKU. The lab will look for changes in that child's PAH gene. If there are two identifiable changes in the gene, the lab will then look for those changes in you and your partner. Because each of you is a carrier, each of you should have one of the changes. The lab can look for the same changes in your fetus.

If your affected child has only one identifiable change in the gene, he or she must have another change that is undetectable. In this case, your family would need to have a DNA test called linkage analysis, which also can be performed for prenatal testing. Linkage analysis takes a lot of time, so you must plan this out before becoming pregnant.

Understanding Test Results and Options

How Do You Make Sense Of The Results?

What does a positive prenatal screening test mean for me and my child?
If your future child has two changes in the PAH gene, he or she will have phenylketonuria. Your doctor will need to test the newborn's phenylalanine level and begin treatment with low phenylalanine formula.

What does a positive newborn screening test mean for me and my child?
If your newborn child tests positive for phenylketonuria, he or she may have PKU. Screening tests are not foolproof, so your child will need follow-up testing to confirm a diagnosis. If your child does have PKU, he or she should be referred immediately to a doctor with expertise in amino acid disorders.

Could my child get a positive newborn screening result, but not have phenylketonuria (a false positive)?
Yes. False positives occur because the test is designed to be very sensitive in detecting elevated phenylalanine levels. If your child receives a positive screening test, he or she will need another test to confirm the high phenylalanine level. If the level remains high, your child may have phenylketonuria or some other form of high phenylalanine. The other forms of high phenylalanine are also caused by changes in the PAH gene, but the symptoms are much milder than PKU.

Could my child get a negative newborn screening result, but have phenylketonuria (a false negative)?
Yes, but the false negative rate is extremely low if the baby's blood sample is collected properly. The newborn screening looks at the level of phenylalanine in the baby's blood. Phenylalanine comes from protein, so the baby will not have any detectable change in the phenylalanine level until protein is consumed. Babies get protein from breast milk or infant formula. The more protein they eat, the higher the phenylalanine level. A false negative can come about if a baby is tested before eating enough protein. This means the baby has phenylketonuria, but simply has not consumed enough protein for the level of phenylalanine to be high.

Undetected cases of PKU may have extremely damaging results. If a baby with PKU does not receive special low-phenylalanine formula in the few days after birth, his or her phenylalanine levels will rise, leading to brain damage and other problems associated with untreated PKU.

If I test positive as a carrier, what does that mean for me and my family?
If your child has phenylketonuria, you and your partner are both carriers of the altered PAH gene. Carriers do not have PKU. They have one normal copy of the gene and one altered copy. You only need one normal or "working" copy of the gene to avoid the full disease. If you're a carrier, one or both of your parents must have been carriers, too. This means your brothers and sisters have at least a 50% chance of having inherited the gene from one of your parents.

Could I get a positive carrier test result, but not carry the disease gene (a false positive)?
Rarely, but it depends on the type of test used.

Carrier testing based on the parent's amino acid levels may produce false positives depending on the time of day and the type of food eaten, or a woman’s menstrual cycle. This type of carrier test is not accurate during pregnancy. If done correctly, the chance of a false positive is 1% or less.

Some labs test for carriers by using a DNA test or DNA sequencing to detect common changes in the gene. If your affected family member has one of these changes, the test will find whether you have it as well. There are essentially no false positives with this type of testing.

Even if you know you are a carrier because you have a child with phenylketonuria, a carrier test might not find the change. The disease could be due to a change in an untested part of the gene. To counter this, labs use another DNA test (called linkage analysis) to look for evidence of a genetic change. The false positive rate is less than 1% for this test.

Could I get a negative carrier test result, but actually carry the disease gene (a false negative)?
Rarely, but it depends on the type of test used.

Carrier testing based on the parent's amino acid level may produce false negatives. The time of day you received the test and what you have eaten prior to the test may affect the results. When the test is done under the right circumstances, the chance of a false negative is 1% or less.

While the PAH gene has more than 400 changes, many labs check only the most common changes in the gene. This test is best for when someone in your family is already known to have one of the common gene changes. In such a case, there would be essentially no false negatives when testing other family members.

DNA sequencing of the entire gene produces a low rate of false negatives — about 1% — when used on everybody with phenylketonuria. False negatives occur when someone has a DNA change that is close to, but not in, the gene. If someone in your family already has a known change in the gene, then the sequencing test will be able to find that change in other family members with essentially no false negatives.

Personal Questions

What does it mean if the test shows I am a phenylketonuria carrier?
Carriers of a phenylketonuria gene change do not develop symptoms or have any health problems related to being a carrier. The main issue is the risk of having children who are either PKU carriers or who actually have PKU.

If I carry the phenylketonuria gene, can I have children who don't have the gene?
Yes, but you need to "do the math" to understand the risks of passing on the mutated gene. If you're a phenylketonuria carrier and your partner is not, you have a 50% chance of passing the gene to each child. Even if your child inherits your copy of the PAH gene, the child will not have PKU, but simply be a carrier, like you.

If you and your partner are both PKU carriers, your child has a:

  • 25% chance of inheriting PKU (two copies of the PAH gene)
  • 50% chance of being a carrier (one PAH gene and one normal gene)
  • 25% chance of not being a carrier (two normal genes)

If I have phenylketonuria, how does it affect my children?
If you are a woman with phenylketonuria, your child can be affected even if your partner is not a carrier. Children of women with PKU can suffer serious problems, such as intellectual disability and heart defects, if the mother's phenylalanine levels are even slightly high during pregnancy. Your child can develop problems even if he or she did not inherit two copies of the gene for PKU.

So, if you're a woman with PKU and are planning a pregnancy, talk to a doctor experienced with PKU before you become pregnant. You will need to monitor your phenylalanine levels closely during the entire pregnancy to ensure the health of your baby.

If I DON'T have the phenylketonuria gene, can I have children who DO have the gene?
If you are not a carrier, your children cannot inherit the gene from you. Because there is no national screening program for phenylketonuria, most people don't know they are carriers unless they have a relative with PKU. Your children could still get the gene from your partner if he or she is a carrier, but the child would not get phenylketonuria because he or she would only inherit one altered gene.

Is there any harm in finding out if I carry the gene?
Just being a carrier of the gene doesn't put you at any health risk. However, you may feel upset or guilty knowing that you carry a gene that could potentially cause a disease in your future children.

Test Details

How do the tests work?

Prenatal Diagnostic Test
Prenatal genetic testing is possible if someone in the family already has PKU, and has had a genetic test to identify the specific genetic changes. Early in the pregnancy, a doctor can use either chorionic villus sampling or amniocentesis to get a sample of tissue from the fetus. A lab then tests the tissue to determine if the fetus has inherited the changes in the phenylketonuria gene. A baby who inherits only one change in the PKU gene will be a carrier. A baby who inherits two changes will have phenylketonuria.

Talk with your obstetrician or a genetic counselor about your options.

Newborn Screening Test
A standard screening test for newborns measures the level of phenylalanine in their blood. Before your baby goes home from the hospital, a nurse will prick the child's heel to obtain a few drops of blood for testing.

Carrier Testing by Amino Acids
The same labs that test the phenylalanine level for children with phenylketonuria also test parents to determine whether they have high phenylalanine levels. The lab also tests the levels of a related amino acid called tyrosine. The levels of these amino acids can vary depending on time of day and diet, so the test is always done before noon after eating a normal breakfast. This test is not accurate during pregnancy.

Carrier Testing by DNA
Some labs examine up to 15 common changes in the gene, but there are more than 400 changes known for this gene. If your child has phenylketonuria, but you don't have one of these changes, you must have a change somewhere else in the gene.

This is the best test when other DNA testing doesn't find a change. The test reads the parts of the gene that provide direct information about how to make the PAH enzyme.

Linkage Analysis
When other tests do not detect a change in the gene, linkage analysis is the only option. This test is not done "up front" because it is more costly and time-consuming.

Linkage testing is done on a blood sample. It looks at DNA markers that are located right near the PAH gene. For example, say you knew a family that had several people affected by phenylketonuria, but the affected people do not have a detectable change in the PAH gene. All the affected people in the family inherited the same DNA marker (marker 1) while all the unaffected people in the family inherited a different DNA marker (marker 2). The disease and marker 1 are linked. When testing other people in the same family, the lab will assume a person has the disease gene if they inherit marker 1.

These markers may be different for each family, so this type of testing can only be done after someone in the family has been diagnosed with PKU.

What do the tests cost?
Each state pays for the costs of its newborn screening program.

Testing outside the newborn screening program varies by type of test. Biochemical testing for phenylalanine level costs about $50. The DNA mutation panel costs about $200 to $300. DNA sequencing costs about $800. The linkage test costs about $300 per person, but the child and both parents need to be tested, so the total cost per family would be about $900. The price for linkage testing does not include the initial cost of finding the change in the person with phenylketonuria. Costs vary slightly from one lab to another.

Does insurance pay for these tests?
Most health insurance companies pay 80% or more of the cost. Some companies pay all the cost; others won't pay any portion. If you are considering any of the carrier tests, call your insurance company and ask about its coverage.

Each state pays for the costs of its newborn screening program, but the state does not pay for screening of the relatives or any other carrier testing.

How long does it take to get results?
Amino acid test results are usually available in a few days. DNA test results typically take two to three weeks, but may be available faster for prenatal testing. The lab sends results to the medical center that ordered the test. You need to return to the center to learn your results.

Can a health insurance company raise my rates or drop me from coverage if I test positive?
In 2008, the U.S. government passed a law called GINA (Genetic Information Nondiscrimination Act). This law prohibits discrimination by health insurers and employers on the basis of genetic information. Learn more here.

Also, the Federal Health Insurance Portability and Accountability Act (HIPAA) of 1996 prohibits health insurance discrimination based on any "health status-related factor" (including genetic information) by group health plans. Unfortunately, this act does not apply to the self-employed.

Some states have enacted legislation to cover the gaps. Thirty-four states prohibit health insurance companies from using genetic information to deny coverage. Other states require specific justification for the use of genetic information in denying a claim. Texas bans the use of genetic information by any group health plans, and Alabama prohibits discrimination based upon predisposition to cancer.

Life insurance, long-term care and disability insurance are generally not covered by these laws. People with life and disability coverage provided by their employers are unlikely to have this insurance affected by a genetic test result.

Learn more about life insurance, disability insurance, and long-term care insurance laws.

Learn more about health insurance laws.

 

 

 

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