Phenylketonuria

Phenylketonuria is a rare inherited disorder that, without treatment, can cause serious brain damage. With early diagnosis through newborn screening and lifelong management, people with PKU can live healthy, full lives.

Table of contents

• What is Phenylketonuria?
• What causes PKU?
• Signs and symptoms
• How PKU is diagnosed
• Treatment and management
• PKU and pregnancy
• Living with PKU
• Outlook

What is Phenylketonuria?

Phenylketonuria, commonly known as PKU, is a rare inherited disorder that affects how the body processes protein. People with PKU cannot properly break down a building block of protein called phenylalanine, which is an amino acid found in most protein-containing foods and some artificial sweeteners^[1].

When phenylalanine builds up to high levels in the blood and brain, it can cause serious damage, particularly to the developing brain. This can lead to intellectual disability and other serious health problems if left untreated^[2].

PKU occurs in approximately 1 in 25,000 newborns in the United States, though this varies among different ethnic groups and geographic regions^[3]. Fortunately, all babies born in U.S. hospitals are screened for PKU shortly after birth, allowing treatment to begin right away and preventing severe complications^[1].

What causes PKU?

PKU is caused by changes in the PAH gene. This gene provides instructions for making an enzyme called phenylalanine hydroxylase, which is responsible for breaking down phenylalanine in the body. When this gene has changes (also called mutations or pathogenic variants), the enzyme may be missing or not work properly^[3].

There are over 1,000 different mutations that can cause PKU, with the most common one replacing an amino acid called arginine with tryptophan at position 408. Most mutations result in the enzyme misfolding or becoming unstable^[5].

PKU is inherited in an autosomal recessive pattern. This means a baby needs to receive one changed copy of the gene from each biological parent to develop the condition. If both parents carry one changed gene, they have a 25% chance with each pregnancy of having a child with PKU^[2].

The severity of PKU varies depending on how much enzyme activity remains. Classic PKU, the most severe form, occurs when there is very low or no enzyme activity, resulting in blood phenylalanine levels greater than 1,200 micromolar. Less severe forms include mild PKU (600 to 1,200 micromolar) and mild hyperphenylalaninemia (less than 600 micromolar)^[5].

Signs and symptoms

Newborns with PKU appear completely normal at birth. Without treatment, signs typically begin to appear within the first few months of life. The first noticeable sign is often developmental delays^[2].

By the time an untreated baby is around one year old, other symptoms may include:

• A musty or mouse-like odor to their breath, skin, and urine caused by too much phenylalanine^[1]
• Lighter skin, hair, and eye color compared to other family members^[1]
• Skin rashes, such as eczema^[2]
• Growth delays^[2]
• Small head size^[2]
• Nausea and vomiting^[2]
• Tremors^[2]

If PKU remains untreated, severe complications develop, including permanent intellectual disability, seizures, behavioral problems like hyperactivity and self-harm, learning disabilities, and psychiatric disorders^[3].

Even adults with untreated or poorly managed PKU may experience symptoms. These can include mental “fogginess,” decreased mental clarity, attention problems, mood-related issues including anxiety and depression, poor self-control, irritability, and reduced ability to plan and prioritize tasks. However, these symptoms can often be at least partly reversed by returning to treatment^[4].

How PKU is diagnosed

PKU is usually identified through newborn screening, a blood test performed on all babies in the United States and many other countries. All 50 U.S. states require newborns to be screened for PKU. PKU was actually the first condition tested for when newborn screening began in the 1960s^[4].

The test is performed a day or two after birth. A nurse or laboratory technician collects a few drops of blood from the baby’s heel. For accurate results, the test should be done after the baby is 24 hours old and has had some protein in their diet^[7].

If the screening test suggests PKU, the baby will need additional tests to confirm the diagnosis. These may include more blood tests, urine tests, and genetic testing to identify the specific gene changes causing the condition^[7].

If you have PKU or a family history of it, your healthcare provider may recommend screening tests before pregnancy or birth to identify carriers of the condition^[7].

Treatment and management

PKU requires lifelong care that should begin within the first week or two after birth. The cornerstone of treatment is a specially designed diet that has very low levels of phenylalanine. Because phenylalanine is found in nearly all proteins, people with PKU must strictly limit or avoid high-protein foods^[4].

Dietary management

The PKU diet involves limiting protein from regular food while consuming a special medical formula that provides all necessary amino acids except phenylalanine. This formula is essential for meeting protein and nutritional needs while avoiding harmful phenylalanine buildup^[7].

Foods that must be avoided or strictly limited include:

• Meat, poultry, fish, and eggs^[3]
• Dairy products including milk and cheese^[3]
• Nuts, seeds, and legumes^[4]
• Soy products and tofu^[4]
• Many grains including wheat, oats, rye, barley, and quinoa^[4]
• The artificial sweetener aspartame, found in diet sodas and many low-calorie foods^[7]

Many fruits and vegetables naturally contain very little phenylalanine and can be eaten freely. These include apples, bananas, berries, mango, peaches, pineapple, cabbage, carrots, cucumber, lettuce, onions, and tomatoes. Some fruits and vegetables contain slightly more phenylalanine and may be eaten in measured amounts^[15].

Special low-protein foods have been developed specifically for people with PKU. These include low-protein breads, pasta, flour mixes, and egg replacers that can expand menu options^[15].

Every person with PKU has different tolerance levels for phenylalanine. Some can eat more protein than others. Phenylalanine levels are monitored through regular blood tests—weekly or biweekly in young infants, and perhaps once per month in older children and adults. Most U.S. facilities recommend maintaining phenylalanine levels between 2 and 6 mg/dL (120-360 micromolar)^[13].

Medications and new treatments

Several medications can reduce or even eliminate the need for dietary restrictions in some people with PKU:

Sapropterin (brand name Kuvan) is a vitamin cofactor approved in 2008 that helps the body break down phenylalanine. It works by increasing the activity of any remaining enzyme in people who have some residual function^[4].

Pegvaliase (brand name Palynziq) is a substitute enzyme called phenylalanine ammonia lyase that breaks down phenylalanine. Approved by the FDA in 2018 for adults with PKU, it is injected daily under the skin. This treatment can get blood phenylalanine levels down to normal, allowing many patients to eat a regular diet for the first time in their lives^[10].

More palatable medical formulas have also been developed. One type is made with glycomacropeptide, a byproduct of cheesemaking that contains very limited amounts of phenylalanine. This can be incorporated into protein drinks and is more pleasant to consume than traditional formulas^[12].

PKU and pregnancy

Women with PKU face special challenges when planning for pregnancy. High phenylalanine levels during pregnancy can cause serious harm to the developing baby, a condition known as maternal PKU syndrome^[3].

If a pregnant woman with PKU does not maintain strict control of her phenylalanine levels, her baby may be born with:

• Intellectual disability and brain damage^[3]
• Low birth weight^[2]
• Small head size (microcephaly)^[2]
• Heart defects^[2]
• Facial differences^[2]
• Behavioral problems^[2]

Women with untreated PKU also have a higher risk of miscarriage^[2].

The good news is that with careful planning and strict metabolic control, women with PKU can have healthy babies. It is essential to achieve target phenylalanine levels before becoming pregnant and maintain them throughout the pregnancy^[3].

Living with PKU

Living with PKU requires ongoing commitment, but with proper management, people with this condition can lead full, active, and successful lives^[4].

Children who begin treatment as newborns and maintain it throughout childhood typically experience normal growth and development. Those who stop treatment later in childhood or as adults may develop cognitive and mental health symptoms, but these can often be at least partly reversed by resuming treatment^[4].

Managing PKU is a lifelong endeavor that requires support from family and the healthcare team. Most patients with PKU are followed in specialized metabolic disease clinics throughout their lives by a team that includes a metabolic physician and a metabolic dietitian. This team helps with growth monitoring, development tracking, and addressing any mental health or psychosocial concerns^[13].

Many adults with PKU who have been away from treatment for years don’t realize that new treatment options exist. Several hospitals now have programs specifically designed to bring these adults back into care. Even when people are past the age when they would sustain cognitive deficits, returning to treatment can improve symptoms like brain fog, anxiety, depression, irritability, and decreased mental clarity^[10].

Social support and maintaining a positive attitude toward treatment are important factors in successfully managing the condition throughout life. Building connections with others who have PKU through support groups and online communities can be helpful^[17].

Outlook

The outlook for people with PKU has improved dramatically since newborn screening and dietary treatment became available. Children who are diagnosed early and receive proper treatment can expect typical psychomotor development and normal health^[5].

Because all babies born in U.S. hospitals are screened for PKU and treatment can start promptly, the severe signs and symptoms of classic PKU are now rarely seen^[3].

While PKU is a rare genetic disease that currently has no cure, recognizing it early and starting treatment right away can help prevent intellectual disability and major health problems^[1]. With every available treatment option and lifelong management, people with PKU can keep their brains healthy and focused, enjoying healthy, productive lives^[4].