Summary

Phenylketonuria (PKU) is a rare genetic disorder caused by the deficiency of the PAH enzyme, leading to the accumulation of phenylalanine in the body.

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Overview

Symptoms of phenylketonuria can vary in severity and include musty odor, neurological problems, skin abnormalities, small head size, hyperactivity, intellectual disability, and behavioral issues. PKU is typically diagnosed through newborn screening, and the primary treatment involves a strict low-phenylalanine diet, phenylalanine-free nutritional supplements, regular monitoring, and, in some cases, medications or enzyme therapy. Careful management is crucial for pregnant women with PKU to prevent congenital disabilities. Early diagnosis and lifelong management are key to leading a healthy life with PKU.

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Prevalence & Risk factors

PKU is considered a rare disorder. The prevalence of PKU varies worldwide. In Europe, the mean prevalence is approximately 1:10,000 newborns, with a higher rate in some countries, such as Ireland and Turkey, and a very low rate in Finland.^[1] The risk factors for PKU are primarily genetic. To develop this autosomal recessive disorder, an individual must inherit two mutated copies of the PAH gene, one from each parent. When both parents are carriers of the mutated gene, there is a 25% chance that their child will be affected by PKU.

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Genetics

As mentioned above, PKU is a disorder that affects how the body processes an amino acid called phenylalanine. It is primarily caused by mutations in the PAH gene, which provides instructions for producing an enzyme called phenylalanine hydroxylase. This enzyme is crucial for converting phenylalanine into an amino acid called tyrosine. The mutations disrupt this conversion, causing phenylalanine to accumulate in the blood and brain, leading to neurotoxicity. More than 1000 variants of PAH have been reported worldwide, indicating that PKU is heterogeneous in nature. In a subset of individuals with PKU, there may also be a deficiency in BH4, which is a cofactor necessary for the proper functioning of phenylalanine hydroxylase.^[7]

According to research, most of the cases are compound heterozygous. The affected individual has mutations in both copies (alleles) of the PAH gene, but these mutations are different from each other.^[8,9]

Ongoing research focuses on gene therapies, enzyme replacement, and understanding environmental factors that can influence PKU severity and management.

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Pathophysiology

The pathophysiology revolves around the disruption of phenylalanine metabolism. In individuals with PKU, the PAH enzyme is either deficient or entirely absent, leading to the accumulation of phenylalanine. High levels of phenylalanine in the blood have toxic effects on the brain and nervous system. It can lead to the degeneration of nerve cells, interfere with the formation of myelin (the protective sheath around nerve fibers), and disrupt the balance of neurotransmitters like dopamine and serotonin, contributing to neurological symptoms and intellectual disabilities.^[2]

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Signs & Symptoms 

The symptoms can vary in severity and may be absent in some individuals, especially if they receive early diagnosis and treatment. The severity of symptoms largely depends on the levels of phenylalanine in the body and can range from mild to severe. Common signs and symptoms include:^[3-5]

• Musty Odor. Individuals with untreated PKU may have a musty or "mousy" odor in their breath, skin, or urine. This distinct odor is caused by the accumulation of phenylalanine in the body.
• Neurological Problems. PKU can lead to various neurological issues, including seizures, abnormal muscle movements, tight muscles, increased reflexes, involuntary movements, or tremors. These symptoms are more common in untreated individuals.
• Skin Abnormalities. Skin rashes, such as eczema, can occur in affected individuals, particularly if the condition is not managed with dietary restrictions.
• Lighter Skin, Hair, and Eye Color. Individuals with PKU may have lighter skin, hair, and eye color compared to their family members. This occurs because the excessive phenylalanine hinders the production of melanin, the pigment responsible for skin and hair color.
• Small Head Size (Microcephaly). Some individuals may have an unusually small head size, known as microcephaly, due to the impact of elevated phenylalanine levels on brain development.
• Hyperactivity. Hyperactivity and restlessness can be observed in individuals with untreated PKU, particularly children.
• Intellectual Disability. Without early intervention and treatment, PKU can lead to intellectual disability. The accumulation of phenylalanine in the brain can impair cognitive development, resulting in learning difficulties and developmental delays.
• Delayed Development. Affected children may experience delays in reaching developmental milestones, including speech and motor skills.
• Behavioral and Emotional Problems. The disease can contribute to behavioral and emotional challenges, such as mood swings, anxiety, and difficulties with social interactions.

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Diagnosis

PKU is typically diagnosed through newborn screening, a routine blood test conducted shortly after birth. Elevated phenylalanine levels in the blood sample can indicate the presence of the disease. Confirmatory tests, such as additional blood or urine tests and genetic testing, may be necessary to determine the type and severity.^[6]

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Therapy 

The primary goal of treatment is to maintain safe levels of phenylalanine (Phe) in the blood to prevent intellectual disability and other related health problems. Treatment strategies typically include:^{[4, 6]}

• Low-Phenylalanine Diet. The cornerstone of PKU management is a strict low-phenylalanine diet. Individuals must avoid foods high in protein, as they contain elevated phenylalanine levels. Avoid meat, dairy products, nuts, fish, and certain grains. Instead, consume foods low in protein, such as fruits and vegetables.
• Phenylalanine-Free Nutritional Supplements. Since a low-phenylalanine diet can be challenging to meet all nutritional needs, individuals often require phenylalanine-free dietary supplements. These supplements provide essential amino acids and nutrients, ensuring proper growth and overall health.
• Regular Monitoring. Regular monitoring of blood phenylalanine levels is essential to adjust the diet and treatment plan as needed. Infants, children, and adults with PKU undergo frequent blood tests to assess phenylalanine levels, especially during rapid growth or pregnancy.

• Medication (Sapropterin - Kuvan). The FDA-approved medication, sapropterin (brand name Kuvan), may be prescribed for some individuals with PKU. It works by aiding the PAH enzyme in processing phenylalanine. Not everyone with PKU responds to this medication, and its effectiveness varies among individuals.
• Enzyme Therapy (Pegvaliase - Palynziq). Pegvaliase is another FDA-approved treatment for adults with PKU, specifically when current therapies are inadequate. It involves injectable enzyme therapy to help break down phenylalanine. Due to potential side effects, it is administered under the supervision of certified healthcare providers.
• Maternal PKU Management. Pregnant women with PKU must diligently manage their phenylalanine levels to protect the developing fetus from potential harm. High phenylalanine levels during pregnancy can lead to birth defects and intellectual disabilities in the baby. Close monitoring and strict adherence to the low-phenylalanine diet are essential.

PKU management is a lifelong commitment. Even as individuals with PKU transition into adulthood, it is crucial to continue with dietary restrictions and monitoring to maintain cognitive function and overall health.

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Prevention 

While PKU cannot be prevented, early diagnosis through newborn screening is vital for the timely initiation of treatment and prevention of intellectual disabilities and other associated health problems. Women with PKU planning to become pregnant should maintain their PKU diet before conception to reduce the risk of complications in their offspring.

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Prognosis

With early and consistent treatment, most individuals with PKU can lead healthy lives and avoid severe intellectual disabilities. Regularly monitoring phenylalanine levels is crucial to ensure treatment effectiveness and make necessary dietary and therapeutic regimen adjustments.