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Updated on December 16, 2025
Phenylketonuria (PKU) is a rare genetic disorder that disrupts the body’s ability to metabolize a substance called phenylalanine.
Phenylalanine is one of the essential amino acids. Essential amino acids are nutrients that the body cannot produce on its own and must be consumed in food. Phenylalanine is found in protein-containing foods and plays an important role in the production of the brain’s neurotransmitters, or chemical messengers.
When a person has PKU, the body cannot metabolize phenylalanine. As a result, high amounts of this amino acid build up in the blood. This can have a toxic effect on the body and cause damage to the brain. PKU can cause cognitive disability, developmental delays, seizures, and problems with mood and behavior, especially when untreated.
Are there different types of PKU?
There are several different forms of PKU, which vary in severity. Some forms are severe and carry a significant risk of brain damage and complications. Other forms are less severe, and the risk of brain damage and complications is lower.
Classic PKU
Another way to think about PKU is in terms of PAH deficiency. PAH is phenylalanine hydroxylase, an enzyme that the body needs to metabolize phenylalanine. This deficiency occurs when the genes that contain the instructions for producing this enzyme do not function normally. The genetic variations that cause PKU are inherited from a person’s biological parents.
Classic PKU is the most severe form of the disease. With classic PKU, the body produces very little PAH or no PAH at all. This type has the most significant risk of brain damage and complications.
Variant PKU and non-PKU hyperphenylalaninemia
With less severe types, there is more functioning PAH. Less severe types may be categorized as mild or moderate PKU or variant PKU. There is also non-PKU hyperphenylalaninemia, which is considered a mild form of the disease. However, non-PKU hyperphenylalaninemia can also cause reduced cognitive function, behavioral disorders, and developmental disorders.
Medications that help treat PKU
There are also medications that can help lower phenylalanine levels in some cases of PKU. These medications can be used alongside diet but cannot fully replace diet.
Medications for children and adults with PKU
Several medications are approved for children 1 month and older and adults. These medications work by increasing enzyme activity. More specifically, they act on a substance that activates PAH, called BH4.
For some people with PKU, increasing the amount of BH4 will increase the activity of PAH, which helps the body metabolize more phenylalanine and reduce the amount of phenylalanine in the blood.
There are two types of medications that can increase BH4 in people with PKU.
- A medication that contains a synthetic version of the enzyme BH4. This increases the amount of BH4 by adding more BH4 into the body. People with more mild forms of PKU are generally more responsive to this treatment, people with classic PKU are typically less responsive.
- A medication that contains a substance called sepiapterin. Sepiapterin is a precursor to the enzyme BH4. Increasing the amount of this precursor helps the body produce more BH4. This type of medication has been shown to be effective for all types of PKU.
To determine if these medications can be effective, a healthcare team may perform something called a loading test. During a loading test, a person will take a medication for a period of time. Bloodwork will be used to measure phenylalanine levels and check for a response.
Enzyme injections
Another medication option is another type of enzyme substitute that reduces blood phenylalanine levels by converting phenylalanine into two other substances, ammonia and trans-cinnamic acid. Ammonia can be metabolized by the liver. Trans-cinnamic acid is excreted by urine.
This therapy is administered with subcutaneous injections. It is approved for adults with uncontrolled phenylalanine levels. Due to a risk of life-threatening allergic reactions, it is only available through a restricted distribution program and people prescribed this therapy must carry an automatic epinephrine injection device.
