The PAH gene contains the biological instructions for creating an enzyme known as phenylalanine hydroxylase. This enzyme is produced primarily in the liver and plays a specific role in the body’s processing of an amino acid called phenylalanine. Phenylalanine is a building block of proteins and is obtained from the diet through protein-rich foods like meat, eggs, and milk, as well as some artificial sweeteners.
The Normal Function of the PAH Gene
The phenylalanine hydroxylase (PAH) enzyme’s main task is to initiate a chemical reaction that converts phenylalanine into a different amino acid, tyrosine. For this conversion to occur, the enzyme requires the assistance of another molecule called tetrahydrobiopterin, or BH4, which works as a cofactor to facilitate the process.
Once produced, tyrosine serves multiple functions within the body. It is a precursor for the synthesis of certain neurotransmitters, which are chemicals that transmit signals between nerve cells in the brain. Tyrosine is also used to produce melanin, the pigment that determines the color of skin and hair, and can be further broken down to create energy.
PAH Gene Mutations and Phenylketonuria (PKU)
A mutation in the PAH gene represents a change in the genetic instructions for making the phenylalanine hydroxylase enzyme. These mutations can alter the enzyme in several ways, such as changing a single amino acid in its structure, deleting a small segment of DNA, or interfering with how the gene’s instructions are read.
These genetic alterations can lead to a PAH enzyme that is either less efficient or completely non-functional. When the enzyme’s activity is reduced, it cannot effectively process phenylalanine, preventing its conversion into tyrosine. Consequently, phenylalanine begins to accumulate in the blood and other tissues.
This buildup of phenylalanine can become toxic, especially to the central nervous system. Nerve cells in the brain are particularly sensitive to high levels of this amino acid, and prolonged exposure can lead to brain damage. This metabolic disorder is known as Phenylketonuria (PKU). The specific type and combination of mutations determine the severity of the condition, resulting in a spectrum from mild to classic PKU.
Inheritance and Diagnosis
Phenylketonuria is classified as an autosomal recessive disorder. This means an individual must inherit two mutated copies of the PAH gene—one from each parent—to develop the condition. A person who inherits only one mutated copy is a carrier and typically shows no symptoms, as their functional gene produces enough enzyme to process phenylalanine.
The diagnosis of PKU almost universally occurs shortly after birth through routine newborn screening. This screening involves a blood test, often called a “heel prick,” where a small sample of blood is taken from the baby’s heel. The sample is analyzed to measure its phenylalanine level. Elevated levels suggest PKU and lead to further diagnostic testing for confirmation.
Managing Conditions Caused by PAH Mutations
Management of Phenylketonuria begins immediately after diagnosis and is a lifelong commitment. The foundation of treatment is a carefully controlled, low-phenylalanine diet. This diet involves severely restricting or eliminating high-protein foods, including:
- Meat, fish, and poultry
- Eggs
- Dairy products
- Nuts and legumes
Individuals must also avoid the artificial sweetener aspartame, which contains phenylalanine.
To ensure proper nutrition, individuals rely on a special medical formula that provides necessary amino acids, vitamins, and minerals without most phenylalanine. The dietary plan is tailored to each person based on their tolerance, which is monitored through regular blood tests.
Alongside diet, a medication known as sapropterin dihydrochloride can help some individuals. This drug is a synthetic form of the BH4 cofactor that assists the faulty PAH enzyme. For patients with certain mutations, this medication can improve enzyme activity and lower blood phenylalanine levels, potentially allowing for a less restrictive diet.