What is phenylketonuria (PKU), what causes it, and how can it be treated?

Sourav PanNovember 9, 2024

Answered

Phenylketonuria (PKU) is a rare inherited metabolic disorder characterized by the inability to properly metabolize phenylalanine, an amino acid found in many protein-containing foods. Here’s a detailed overview of PKU, its causes, and treatment options.

What is Phenylketonuria (PKU)?

PKU is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, which leads to a deficiency or absence of the enzyme phenylalanine hydroxylase. This enzyme is crucial for converting phenylalanine into tyrosine, another amino acid. When the enzyme is deficient or inactive, phenylalanine accumulates in the blood and can reach toxic levels, particularly affecting the brain and leading to serious health problems if not managed properly.

Causes of PKU

1. Genetic Mutations:
   • PKU results from mutations in the PAH gene located on chromosome 12. These mutations impair the production or function of the phenylalanine hydroxylase enzyme, preventing the body from breaking down phenylalanine effectively.
2. Inheritance Pattern:
   • PKU follows an autosomal recessive inheritance pattern, meaning that an individual must inherit two copies of the mutated gene (one from each parent) to develop the disorder. If both parents are carriers of the mutation, there is a 25% chance with each pregnancy that their child will have PKU.
3. Dietary Triggers:
   • Individuals with PKU cannot metabolize phenylalanine found in protein-rich foods (e.g., meat, dairy products, nuts) and artificial sweeteners like aspartame. Consumption of these substances can lead to dangerous increases in blood phenylalanine levels.

Consequences of Untreated PKU

If left untreated, high levels of phenylalanine can lead to severe intellectual disability, developmental delays, behavioral problems, seizures, and other neurological issues due to its neurotoxic effects on brain cells .

Treatment of PKU

1. Dietary Management:
   • The cornerstone of PKU treatment involves a strict low-phenylalanine diet that limits protein intake. This typically includes avoiding high-protein foods and using special low-protein formulas designed for individuals with PKU to ensure adequate nutrition without excess phenylalanine.
2. Medications:
   • Sapropterin dihydrochloride (Kuvan): This medication acts as a cofactor for the residual activity of the PAH enzyme in some individuals with mild forms of PKU. It can help lower blood phenylalanine levels and may allow for a less restricted diet .
   • Pegvaliase-pqpz (Palynziq): An injectable enzyme substitution therapy used for adults with uncontrolled high levels of phenylalanine despite dietary management. It helps break down excess phenylalanine  .
3. Monitoring:
   • Regular monitoring of blood phenylalanine levels is essential to ensure they remain within safe limits. This monitoring helps adjust dietary intake and medication dosages as needed throughout life .
4. Ongoing Research:
   • Research into new therapies such as gene therapy and large neutral amino acid supplementation is ongoing, aiming to improve treatment outcomes for individuals with PKU