Disclaimer: This article is for informational purposes only and is not intended to diagnose any conditions. LifeDNA does not provide diagnostic services for any conditions mentioned in this or any other article.

What is Phenylketonuria (PKU)?

Phenylketonuria (PKU) affects about 1 in every 24000 newborns worldwide. It is a rare genetic condition that affects how the body processes a substance called phenylalanine (Phe), an amino acid which is found naturally in certain foods like meat, dairy, and some grains, and if it is not properly metabolized, it builds up in the blood and causes brain damage, leading to intellectual disability, behavioral problems, and other neurological complications.

What Causes Phenylketonuria?

PKU happens because of a problem with a gene called PAH. Normally, the PAH gene has the instructions for making an enzyme that turns phenylalanine, a substance found in some food into tyrosine, another substance (amino acid) that is important for the brain and body to work properly.

In PKU, the PAH gene doesn’t work properly. This means the enzyme can’t break down phenylalanine as it should. As a result, phenylalanine builds up in the blood, and this buildup may damage the brain over time if the condition is not treated. Sometimes, mutations in a co-enzymecalled tetrahydrobiopterin (BH4) may also cause problems.. If the BH4 isn’t working properly or there is not enough of it, this can make the PAH enzyme less effective, causing the same issue.

There are more than 60 different mutations that can affect the PAH gene and cause PKU. The severity of PKU depends on which mutation a person inherits. Some mutations cause a mild form of PKU (where the enzyme still works a little), while other mutations cause a severe form (where the enzyme doesn’t work at all).

What Are the Symptoms of PKU? 

The symptoms of PKU typically develop within the first few months of life and, if untreated, can lead to severe developmental and neurological consequences. Common symptoms include:

  • Intellectual Disability: Intellectual disability in people with PKU happens when high levels of phenylalanine build up in the brain. If the levels of phenylalanine stay too high for too long, it harms the brain and prevents it from developing normally. This may lead to problems with learning and thinking. Early treatment, like following a special diet to limit phenylalanine, can help prevent this problem and allow children to grow and learn like other kids.
  • Seizures: Seizures are another common issue for people with untreated PKU. The buildup of phenylalanine can make the brain’s electrical system go haywire, causing seizures. Seizures are when the brain’s signals become abnormal, causing uncontrolled shaking or loss of consciousness. If PKU is not treated, seizures can happen frequently. However, if PKU is diagnosed early and treated with a special diet, it can help lower the risk of seizures or make them less severe.
  • Behavioral Problems: Children with untreated PKU might have trouble with behavior. This could include things like being very hyper, getting upset easily, or having trouble getting along with others. High levels of phenylalanine affect how the brain works, especially areas that control mood and behavior. If PKU is not treated, kids may find it hard to control their feelings or actions. By following a special diet to lower phenylalanine levels, many of these behavioral problems can be improved or prevented.
  • Eczema: Eczema, a skin condition that makes the skin red, itchy, and inflamed, is also common in people with PKU. The reason for this is still not fully understood, but it is believed that the buildup of phenylalanine can affect the skin, making it more sensitive and prone to irritation. In babies and children with PKU, eczema can show up as dry or itchy patches on the skin. Treating PKU with a special diet can help reduce skin problems like eczema, and in some cases, treating the eczema directly with topical treatments may also help.
  • Hypopigmentation: People with PKU often have lighter skin, hair, and eyes than their family members. This is because phenylalanine is involved in the production of melanin, the pigment responsible for color in the skin and eyes. Elevated levels of phenylalanine can interfere with melanin production, leading to a lack of pigment in the skin, hair, and eyes, which is called hypopigmentation.
  • Microcephaly (Small Head Size): In some cases of PKU, untreated high phenylalanine levels can cause abnormal brain development, leading to microcephaly (a small head size). This condition, usually noticed in infancy, is linked to developmental delays.
  • Low Protein Tolerance: Because phenylalanine is found in most protein-rich foods, individuals with PKU must follow a strict diet low in phenylalanine. People with untreated PKU may have difficulty tolerating certain proteins and amino acids, which can further affect growth and overall health. A specialized diet is critical in managing the condition and preventing the buildup of phenylalanine.
  • Growth Problems: Due to the restriction of phenylalanine in the diet and the difficulty in metabolizing proteins, individuals with PKU may experience growth issues, especially if their dietary restrictions are not strictly followed. These issues can include slower growth rates and lower body weight compared to their peers.

How Can PKU Be Diagnosed?

PKU is usually diagnosed through newborn screening, a routine test done in many countries shortly after birth. The screening measures the blood phenylalanine levels, and if they are elevated, further tests are conducted to confirm the diagnosis.

Genetic testing can also be performed to identify mutations in the PAH gene, confirming the presence of the disorder and determining the specific mutations involved. This helps in predicting the severity of PKU and guiding treatment decisions.

How Is PKU Treated and Managed?

PKU is primarily managed through dietary control. The treatment involves limiting foods that are high in phenylalanine, such as meat, fish, dairy products, eggs, nuts, and soy. Special low-phenylalanine medical foods are available for patients to help ensure they get the required nutrients while avoiding the harmful effects of phenylalanine. These are some common ways to manage PKU: 

  • Proper Diet: People with PKU must follow a strict diet that limits foods high in phenylalanine, like milk, meat, eggs, and nuts. This helps prevent phenylalanine from building up in the body, protecting the brain from damage and preventing problems like intellectual disability and seizures. 
  • Avoiding Aspartame: Artificially sweetened foods and drinks, and some medicines may contain aspartame, a sweet substance that contains phenylalanine. Individualized Diet Plan: Since everyone with PKU can tolerate different amounts of phenylalanine, doctors help create a custom diet plan for each person. Regular blood tests ensure that phenylalanine levels stay safe, supporting healthy development and preventing brain damage.
  • Frequent Blood Tests: Regular blood tests are used to check phenylalanine levels in people with PKU. This helps doctors adjust their diet and ensure phenylalanine levels stay low, which is crucial for normal brain development and preventing health issues.
  • Special PKU Formula: People with PKU can’t get enough nutrients from regular food, so they drink special formulas that provide essential nutrients without phenylalanine. This ensures they grow and develop normally while controlling phenylalanine levels.
  • Additional Supplements: To help with any nutritional gaps from the PKU diet, doctors may recommend supplements, like fish oil, to support development, especially in areas like motor skills. These supplements help improve overall health and development.
  • Medications : Kuvan is a medication that can help some people with PKU break down phenylalanine more effectively. However, it must be used alongside the PKU diet, as it does not work for everyone and cannot fully replace dietary management.
  • Research Treatments: New treatments like large neutral amino acid supplements, enzyme replacement therapy, and gene therapy are being researched. These could offer more ways to manage PKU, especially for people who struggle to control phenylalanine with diet alone.

These treatments work together to help people with PKU stay healthy, grow normally, and avoid the harmful effects of phenylalanine buildup.

Why Is PKU More Common in Irish and otherEuropean Populations?

PKU is found across the globe, but its prevalence is particularly high (up to 1 in 4,500 births) in individuals of Irish or other European descent. 

Research has revealed that some of the mutations in the PAH gene have specific geographic origins, particularly in European populations. For example, in Ireland, certain PAH gene mutations, such as R158Q and R408W, are common. These mutations likely originated in distinct founding events that occurred thousands of years ago, and have been passed down over generations. This genetic distribution helps explain why PKU is more common in these populations compared to others, such as those of sub-Saharan African descent.

Genetic Studies and Insights on Phenylketonuria

A study tracking 485,634 live births from 1965 to 2014 found that 64% of people with PKU were adults, and 35% had cognitive disabilities. Interestingly, 78% did not have a family history showing PKU can occur without close genetic ties. In Chile, the IVS10 mutation in the PAH gene has been linked to PKU. Studies show recurrence rates in Chile and Spain are similar, though specific mutations may vary by region.

Classic PKU causes high levels of phenylalanine in the blood, which can lead to brain damage, seizures, and developmental delays if not treated early. Babies with PKU often seem healthy at birth but develop serious health problems as they grow. They may also show signs like behavioral issues, a musty or mouse-like odor, lighter skin and hair, and skin problems such as eczema.

Ongoing research into PKU is important for improving care and long-term management. Better screening and early diagnosis can prevent the severe effects of untreated PKU. This research helps doctors provide better treatment and improve the lives of people with PKU. Understanding the genetic causes and long-term effects of PKU is key to developing better treatments and ensuring better outcomes.

What Are the Genetic and Ancestry Considerations for Families?

Because PKU is inherited in an autosomal recessive pattern, carriers, those with one copy of the mutated PAH gene do not show symptoms of the condition but may pass the mutation on to their children. Couples planning to have children may wish to undergo genetic counseling to understand their risk of passing on PKU.

PKU is more common in individuals of Irish, Northern European, as well as East-Asian descent, so families with these backgrounds should be particularly aware of the increased likelihood of carrying mutations in the PAH gene.

Research into the genetics of PKU and the PAH gene is ongoing, with studies examining the genetic variants that contribute to different forms of the disorder. Identifying the specific mutations can help improve treatment options and the development of more personalized therapies, including gene therapy and enzyme replacement therapy. Given its higher prevalence in populations of Irish and other European descent, it is especially important for these groups to be aware of the genetic risks and take advantage of newborn screening programs to ensure that PKU is detected and managed early.

Summary:

  • PKU is a genetic disorder that prevents the body from processing phenylalanine, possibly leading to brain damage if untreated.
  • PKU is caused by mutations in the PAH gene, which is responsible for producing the enzyme that breaks down phenylalanine.
  • In PKU, the enzyme phenylalanine hydroxylase does not function properly, causing phenylalanine to build up in the blood.
  • Tetrahydrobiopterin (BH4) enzyme deficiency can also worsen PKU by impairing the proper function of the PAH enzyme.
  • There are over 60 known mutations in the PAH gene, causing PKU varying in severity from mild to severe..
  • PKU symptoms, such as intellectual disability, seizures, and behavioral problems, usually appear in infants within the first few months.
  • High levels of phenylalanine harm the brain’s development, leading to learning and cognitive difficulties.
  • PKU can cause seizures due to abnormal brain activity caused by the buildup of phenylalanine.
  • Children with untreated PKU may experience hyperactivity, mood swings, and trouble interacting socially.
  • People with PKU may develop eczema, a skin condition that causes itching, redness, and inflammation due to phenylalanine buildup.
  • PKU can lead to lighter skin, hair, and eyes because phenylalanine affects melanin production.
  •  
  • PKU often causes growth issues, as patients must follow a restricted diet, leading to slower growth and lower body weight.
  • PKU may lead to behavioral issues, including hyperactivity and mood swings, due to the impact of phenylalanine on the brain.
  • Untreated PKU can result in microcephaly, a condition in which an infant’s head is smaller than normal due to abnormal brain development.
  • PKU is typically diagnosed through newborn screening, which checks phenylalanine levels in the blood.
  • Treatment for PKU primarily involves a diet restricting phenylalanine and may include medications or enzyme replacement therapy.
  • PKU is more common in Irish, other European, and East-Asian populations because of specific genetic mutations more prevalent in these groups.

References: