Phenylketonuria, commonly known as PKU, is a genetic disorder caused by a problem in the body’s ability to process an amino acid called phenylalanine. Phenylalanine is a building block of proteins found in many foods, including meat, dairy, eggs, and some artificial sweeteners. Normally, the body uses an enzyme called phenylalanine hydroxylase (PAH) to convert phenylalanine into another amino acid called tyrosine, which the body needs for making important substances like neurotransmitters and pigments in the skin, hair, and eyes.
In people with PKU, the gene responsible for producing the PAH enzyme is mutated or defective. This means the enzyme either does not work properly or is missing altogether. Because of this, phenylalanine cannot be broken down efficiently and starts to build up to toxic levels in the blood and other body fluids. This excess phenylalanine can cross into the brain and interfere with normal brain development and function, leading to intellectual disabilities, behavioral problems, and other neurological issues if untreated.
PKU is inherited in an autosomal recessive pattern, which means a child must inherit two defective copies of the PAH gene—one from each parent—to develop the disorder. Parents who each carry one defective gene usually do not show symptoms themselves but can pass the gene to their children. When both parents are carriers, there is a 25% chance with each pregnancy that the child will have PKU.
The mutations in the PAH gene are diverse, with thousands of different variants identified worldwide. Some mutations cause a complete loss of enzyme activity, leading to classical PKU, which is the most severe form. Others result in partial enzyme activity, causing milder forms of the disorder. Occasionally, structural changes in the gene, such as duplications of certain exons, can alter the enzyme’s shape and function, further affecting how well it works.
Because the enzyme PAH is mainly active in the liver, its deficiency primarily disrupts liver metabolism of phenylalanine. When phenylalanine accumulates, it not only remains in the bloodstream but also leads to the formation of abnormal byproducts, including phenylketones, which are harmful to brain cells. These toxic substances can damage the brain’s neurons and interfere with neurotransmitter production, which is crucial for normal cognitive and behavioral development.
The severity of PKU symptoms depends on how much the enzyme activity is reduced. Without treatment, high phenylalanine levels can cause severe intellectual disability, seizures, behavioral problems, and psychiatric disorders. However, early diagnosis through newborn screening and strict dietary management to limit phenylalanine intake can prevent these complications.
The diet for people with PKU involves avoiding high-protein foods and artificial sweeteners containing phenylalanine, such as aspartame. Instead, they consume special medical foods that provide protein without phenylalanine, often in the form of amino acid mixtures or specially designed low-phenylalanine peptides. This diet must be maintained lifelong to keep phenylalanine levels within a safe range.
In some cases, additional treatments are used to help reduce phenylalanine levels. For example, enzyme substitution therapies aim to provide alternative ways to break down phenylalanine. Research is ongoing to develop oral forms of these enzymes that can survive the digestive system and work effectively in the gut.
In summary, PKU is caused by inherited mutations in the gene for phenylalanine hydroxylase, leading to a deficiency of this enzyme. This deficiency prevents the normal conversion of phenylalanine to tyrosine, causing phenylalanine to accumulate to toxic levels, which can damage the brain and cause serious developmental problems if not managed properly. The disorder’s genetic nature, enzyme deficiency, and resulting metabolic imbalance form the core of what causes PKU.
