Non-PKU hyperphenylalaninemia, also called variant phenylketonuria, is an inherited (genetic) condition that prevents the body from processing proteins correctly. Your body breaks down the protein that you eat into parts called amino acids. Your body then uses those amino acids to make other proteins that it needs to function.

There are different forms of hyperphenylalaninemia (also called phenylketonuria). All the forms result in high levels of an amino acid called phenylalanine in the body.

In hyperphenylalaninemia, an enzyme called phenylalanine hydroxylase (PAH) is not made correctly. This enzyme helps change phenylalanine into other amino acids that your body needs.

When PAH is missing or severely damaged, phenylalanine cannot be processed. This more severe version of hyperphenylalaninemia is called classic phenylketonuria or PKU. When the enzyme PAH is made incorrectly but can still process some phenylalanine, this version is called non-PKU hyperphenylalaninemia. Non-PKU hyperphenylalaninemia has milder signs and symptoms compared to classic PKU.

The condition is caused by a change in the PAH gene. This gene gives your body instructions for making the enzyme phenylalanine hydroxylase. This enzyme helps break down the amino acid phenylalanine.

Without a working PAH gene, your baby’s phenylalanine hydroxylase enzyme doesn’t work as well. If phenylalanine is not broken down, it can build up to harmful levels. Babies with non-PKU hyperphenylalaninemia break down some phenylalanine, but not as much as babies without this condition. Usually, enough phenylalanine is broken down that it is not harmful to the baby.

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

Non-PKU hyperphenylalaninemia is a genetic condition. Babies inherit it from their biological (birth) parents.

• Non-PKU hyperphenylalaninemia is an autosomal recessive condition. Babies inherit it when each parent passes down a nonworking PAH gene to their baby. Only babies with two nonworking PAH genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the PAH gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the PAH gene, they have a 1 in 4 chance of having a child with non-PKU hyperphenylalaninemia.
  • Carriers for non-PKU hyperphenylalaninemia often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with non-PKU hyperphenylalaninemia.
  • Parents who already have a child with non-PKU hyperphenylalaninemia still have a 1 in 4 chance of having another child with non-PKU hyperphenylalaninemia. This 1 in 4 chance stays the same for future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Because non-PKU hyperphenylalaninemia is a mild form of classic phenylketonuria (PKU), babies with non-PKU hyperphenylalaninemia do not usually show signs or symptoms.

Newborn screening for non-PKU hyperphenylalaninemia is done using a small amount of blood collected from your baby’s heel. During screening, a special machine measures how much phenylalanine is in your baby’s blood. Babies with high levels of phenylalanine might have non-PKU hyperphenylalaninemia.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for non-PKU hyperphenylalaninemia is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood and/or urine tests
• Genetic testing using a blood sample

You should complete any recommended follow-up testing as soon as possible.

False-positive newborn screening results for this condition are rare. However, some situations can affect screening results:

• Babies who are receiving supplemental nutrition (also known as total parenteral nutrition (TPN) or hyperalimentation)
• Babies whose mothers have classic phenylketonuria (PKU)

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. In some cases, your baby's health care provider may decide it is best to watch (monitor) your baby to decide next steps.

Most babies with non-PKU hyperphenylalaninemia do not require any treatment.

Some individuals with more severe forms of non-PKU hyperphenylalaninemia might need treatment. The goal of treatment is to prevent the health problems caused by this condition. It is important to talk to your health care provider about which treatment(s) are best for your baby. Treatments may include the following:

• Restricted diet low in foods that contain phenylalanine
• Special phenylalanine-free formula
• Medications that contain a substance called BH₄ that helps the body process phenylalanine

Children with non-PKU hyperphenylalaninemia have healthy growth and development.