PHENYLKETONURIA (PKU): EARLY DETECTION, TREATMENT OPTIONS AND LATEST ADVANCEMENTS

Medically Reviewed by Dr. Sony Sherpa (MBBS)

Phenylketonuria (PKU) is a sporadically occurring congenital disorder as a result of a deficiency in phenylalanine hydroxylase, which converts phenylalanine into other essential compounds. Without this enzyme, phenylalanine can build up in the body and cause serious health problems. 

This article will explore the causes, symptoms, treatment options, and latest advancements in PKU research.

What is Phenylketonuria?

Phenylketonuria, also known as Følling's disease^[1], is a genetic ailment that was first described by Ivar Asbjørn Følling in 1934, who observed a connection between intellectual disability and high phenylalanine levels. The condition impacts the breakdown of the amino acid phenylalanine in the body. This amino acid is found in many foods, especially those high in protein, and is the main bodily supply of the amino acid tyrosine. In those with PKU, the body is unable to convert phenylalanine into tyrosine.

When PKU is untreated, phenylalanine can build up to harmful levels in the body, leading to a variety of neurological symptoms and developmental delays.

Tyrosine supports many essential functions in the body, including^[2]:

• Production of important neurotransmitters: dopamine, norepinephrine, and epinephrine

• Production of melanin for skin and hair color

• Hormone regulation in organs like adrenal, thyroid, and pituitary glands

• Being a key component of nearly all body proteins

• Regulating the stress response, mood, and behavior

Those with PKU are often deficient in tyrosine, which magnifies their symptoms. While tyrosine is found naturally in the diet and can cross the blood-brain barrier after ingestion, most tyrosine-containing foods are high in phenylalanine, which needs to be avoided.

PKU is a relatively rare genetic disorder. However, it is one of the most common inherited metabolic diseases. The prevalence of PKU varies depending on population and ethnicity. It affects approximately 1 in 10,000 to 15,000 newborns in the United States^[3].

Types of PKU

There are two main types, i.e, classic PKU and variant PKU. Maternal PKU refers to PKU in pregnant women.

• Classic PKU: This is the most common and severe form of PKU. Individuals with classic PKU have very little or no activity of the enzyme called phenylalanine hydroxylase (PAH). This enzyme is essential for the breakdown of phenylalanine. As a result, phenylalanine levels rise dangerously high, over 1200 μmol/L, leading to the severe complications associated with untreated PKU. Strict, lifelong dietary management is essential to prevent intellectual disability and other health issues.

• Variant PKU: This encompasses a broader range of PKU with varying degrees of severity. People with variant PKU have some residual PAH enzyme activity, meaning they can process a limited amount of phenylalanine. Within this category are various subtypes, the main being mild PKU.

  • Mild PKU: Phenylalanine levels are elevated, ranging between 60–1200 μmol/L, yet are not as high as in classic PKU. Individuals may need a less strict dietary modification and long-term monitoring of phenylalanine levels.^[4]

• Maternal PKU Syndrome: This refers to a condition that can affect pregnant women with classic PKU. Even if the mother's PKU was well-managed in childhood, uncontrolled phenylalanine levels during pregnancy can be extremely harmful to the developing fetus. This type can give rise to fetal birth defects, such as microcephaly, congenital heart disease, intellectual disability, and intrauterine growth restriction, which limits fetal development and elevates the risk of miscarriage. Strict phenylalanine control before and during pregnancy is crucial for women with PKU.^[5]

Causes and Inheritance of PKU

PKU results from a shortage of the phenylalanine hydroxylase enzyme, which converts phenylalanine into tyrosine. This enzyme is produced by a gene called PAH, located on chromosome 12. When this gene is mutated or missing, the body cannot produce enough of the enzyme, leading to a buildup of phenylalanine.

For unknown reasons, phenylalanine becomes toxic when allowed to build in the system. Research shows that it damages the myelin sheath that insulates the nerves, which is directly proportional to the neurological damage seen in children with untreated PKU. The combination of demyelination, toxicity-related inflammation, and neurotransmitter suppression results in mental retardation and neurodevelopmental problems.

More than 1000 gene mutations can result in various types of PKU. PAH gene variants often involve single amino acid changes. Arg408Trp is the most common gene variant that replaces arginine with tryptophan in the enzyme phenylalanine hydroxylase. Some variants delete DNA or disrupt the gene's instructions for making this critical enzyme.^[6]

In rare cases, PKU can also be caused by a deficiency of the enzyme tetrahydrobiopterin (BH4), which is responsible for activating phenylalanine hydroxylase. This type of PKU is known as variant PKU and results from mutations in the gene responsible for producing BH4.

Risk Factors for PKU

The prevalence of PKU is higher for those of Caucasian, Turkish, and Native American ancestry.

PKU is an autosomal recessive disorder, meaning parents must carry a mutated copy of the PAH gene for their child to inherit it. If both parents are carriers, there is a one in four chance that their child will have PKU.

Symptoms of PKU

The symptoms of PKU can vary in accordance with the severity of the disorder. In classic PKU, symptoms usually appear within the first few months of life and can include^[7]:

• Intellectual disability

• Delayed development

• Seizures

• Tight muscles

• Tremors

• Behavioral problems, such as hyperactivity

• Skin rashes

• Pale skin, eye, and hair color

• A musty odor in the breath, skin, and urine due to phenylacetic acid

In mild or variant PKU, symptoms may be less severe and may not appear until later in childhood or adulthood.

Some studies suggest that tyrosine is important for managing the stress response and that higher levels of tyrosine promote a higher level of resilience in animals responding to an acute stressor^[8]. Those with PKU may not tolerate stress as well due to possessing lower levels of available tyrosine and higher levels of inactive phenylalanine.

Complications of PKU

If left untreated, PKU can cause serious health complications, including:

• Heart problems

• Stunted growth

• Microcephaly (tiny head size)

• Vision problems

The condition is potentially fatal if left untreated.

How Long Do Babies with PKU Live?

With proper management and treatment, babies with PKU can go on to live long and healthy lives. However, if left untreated, PKU can lead to severe complications and potential mortality.

Diagnosis of PKU

PKU is usually diagnosed through newborn screening^[9], which is a routine test performed on all newborns in many countries around the globe. This involves testing the metabolites in a small blood sample from the baby's heel for various genetic disorders, including PKU. Early detection is vital, allowing immediate dietary intervention to prevent irreversible damage.

If a newborn screening test returns positive for PKU, further testing can confirm the diagnosis. This may include:

• Blood Tests: These accurately measure the level of phenylalanine in the blood. High levels strongly indicate PKU. Repeated blood tests help monitor the effectiveness of treatment.

• Genetic Testing: This can identify specific mutations in the PAH gene responsible for PKU. Genetic testing helps confirm the diagnosis, determine the type of PKU, and assess the risk of passing it on to future children.

Treatment Options and Long-Term Management

The primary treatment for PKU is a strict low-phenylalanine diet that avoids foods high in protein, such as meat, dairy, and certain grains. Instead, individuals with PKU must follow a special low-protein diet that a registered dietitian carefully monitors. Dietary modifications combined with therapy are not curative for the most advanced forms, yet they help slow down the disease’s progress.

As a complement to dietary restrictions, individuals with PKU may also benefit from taking supplements of tyrosine, which is the amino acid that is lacking in their bodies. This can help to prevent deficiencies of essential neurotransmitters and hormones.

Selenium, copper, magnesium, and zinc deficiencies may occur due to dietary therapy for PKU. Mineral supplementation may benefit those with the condition with the guidance of a nutritionist.

In recent years, a new treatment option has become available for individuals with PKU^[10]:

• Sapropterin (Kuvan) is a targeted medication that can lower the levels of phenylalanine in the blood by activating the enzyme phenylalanine hydroxylase. This medication is only effective for individuals with mild or variant PKU and must be taken daily.

• Pegvaliase is a medication used to treat adults with Phenylketonuria whose phenylalanine levels cannot be adequately controlled through diet alone. It falls under the category of enzyme replacement therapy and works by directly breaking down phenylalanine in the blood. While pegvaliase has shown promise, it is not yet approved for use in children with PKU. Additionally, long-term effects on dietary restrictions and cognitive function are still under investigation.

Phenylketonuria Foods to Avoid

Individuals with PKU must avoid sweeteners high in phenylalanine, such as aspartame, and foods that are high in protein, including:

• Meat (beef, pork, chicken, etc.)

• Fish

• Dairy products (milk, cheese, yogurt, etc.)

• Eggs

• Legumes (beans, lentils, peas, etc.)

• Nuts and seeds

• Certain grains (wheat, oats, rice, etc.)

Individuals with PKU need to work closely with a registered dietitian who can guide them in developing a meal plan that meets their nutritional needs while also avoiding foods that are high in phenylalanine.

Living with PKU

Living with PKU can be challenging, even with proper management and support. Those with the mildest forms of the disorder are likely to lead fulfilling lives with proper treatment, while those with severe forms may still suffer from neurological problems. It is important for individuals with PKU to follow a strict low-phenylalanine diet and to work with a qualified dietitian to ensure they are meeting their nutritional requirements.

It is also vital for individuals with PKU to opt for regular check-ups with a healthcare provider to monitor their phenylalanine levels and overall health. They may also benefit from joining support groups or connecting with others who have PKU to share experiences and tips for managing the disorder.

Latest Advancements in PKU Research

The research community continues to make impressive strides toward improved early detection, novel treatments, and dietary management of PKU:

• Enhanced screening sensitivity and comprehensiveness: Researchers are developing screening methods that use advanced technologies like mass spectrometry. This allows for the detection of a wider range of PKU variations and related metabolic disorders. Early, accurate detection is critical to ensure timely treatment and prevent long-term complications^[11].

• Non-invasive techniques: While a blood test remains the standard, researchers are exploring alternative, non-invasive screening methods. These could include analysis of saliva, urine, or even breath samples collected from newborns.

• Gene Therapy Potential: Gene therapy aims to correct the underlying genetic defect in PKU. Several approaches are being explored^[12]:

  • Gene addition: Delivering a functioning gene copy responsible for producing the PAH enzyme, which breaks down phenylalanine, restoring the body's natural ability to process Phe.

  • Gene editing: Using tools like CRISPR to directly modify the mutated gene, potentially offering a long-term solution.

  • Promising early results: Studies in animal models have been encouraging, demonstrating a reduction in Phe levels and improvements in PKU symptoms. Human clinical trials are ongoing, offering hope for a potential cure.

• Improved medical formulas: The development of medical formulas with reduced phenylalanine content while still providing essential nutrients is an active area of research. The aim is to create palatable and more convenient options to help with diet adherence.

• Phenylalanine-removing supplements: Researchers are working on enzymes or other substances that can precisely remove phenylalanine from the body. These supplements have the potential to make the standard PKU diet less restrictive.^[13]

• Large Neutral Amino Acids (LNAA): LNAAs compete with phenylalanine for transport across the blood-brain barrier. Research into the possible advantages of LNAA supplementation in PKU management is still ongoing.^[14]

Conclusion

Phenylketonuria is a rare hereditary condition that affects the bodily breakdown of the amino acid phenylalanine. The prime cause of the condition is enzyme phenylalanine hydroxylase deficiency, which can lead to serious health complications if left untreated.

Supplements and medication may be used in addition to a strict low-phenylalanine diet as part of PKU treatment. Ongoing research is being done to improve the understanding and treatment of this disorder, and with proper management, individuals with PKU can lead healthy and fulfilling lives.

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