Phenylketonuria (PKU) is a rare, inherited metabolic disorder that affects the body’s ability to process a specific amino acid. This condition is present from birth and requires immediate and lifelong management to prevent serious health complications. PKU is caused by a genetic defect that disrupts a normal chemical process in the body.
The Biological Mechanism of Phenylketonuria
PKU is caused by a defect in the PAH gene, which provides instructions for creating the liver enzyme Phenylalanine Hydroxylase. This enzyme converts the amino acid Phenylalanine (Phe) into Tyrosine. In individuals with PKU, this enzyme is non-existent or severely deficient, meaning the conversion cannot happen efficiently.
Phenylalanine is an essential amino acid obtained through the diet and found in nearly all proteins. When the body cannot process it, Phe builds up to toxic levels in the blood and brain tissue. This accumulation leads to the severe neurological damage and intellectual disability characteristic of untreated PKU.
The condition is inherited in an autosomal recessive pattern. A child must inherit a non-working copy of the PAH gene from both parents. If both parents are carriers, they show no symptoms but have a one-in-four chance of having a child with PKU.
Screening and Diagnosis in Newborns
Screening for PKU is mandatory for all newborns in the United States because early detection is vital. This standardized process, now part of the heel prick test, is performed shortly after birth. A few drops of blood are collected from the infant’s heel and analyzed for elevated Phenylalanine levels.
The screening is performed after the baby is 24 hours old and has consumed some protein, which is necessary to raise Phe levels for an accurate result. If the initial screening suggests high levels, a second, more detailed blood test is immediately ordered to confirm the diagnosis. Genetic sequencing may also be used to identify the specific mutation in the PAH gene.
Diagnosis usually occurs within the first few days of life, allowing for immediate intervention before neurological damage can occur. Prompt initiation of treatment ensures that individuals with PKU can avoid the severe consequences of the disorder.
Dietary and Medical Management
The cornerstone of PKU management is a lifelong, strictly controlled diet that severely restricts Phenylalanine intake while ensuring adequate nutrition. This requires limiting or eliminating all high-protein foods, which are the primary sources of Phenylalanine.
Foods that must be avoided include:
- Meat
- Fish
- Eggs
- Dairy products
- Nuts
- Legumes
- The artificial sweetener aspartame
To prevent protein deficiency and ensure proper growth, individuals rely on specialized medical foods, often referred to as synthetic protein substitutes or amino acid mixtures. These formulas are Phenylalanine-free and provide the necessary protein building blocks, vitamins, and minerals that the restricted diet lacks. The formula must be consumed multiple times daily.
Medical management may also include adjunct therapies for some patients with residual enzyme activity. The medication sapropterin dihydrochloride (Kuvan) is a synthetic form of the cofactor tetrahydrobiopterin (BH4). This compound enhances the limited function of the defective Phenylalanine Hydroxylase enzyme, allowing some individuals to tolerate a slightly higher amount of natural protein.
Regular monitoring of blood Phenylalanine levels is required throughout life to ensure the diet effectively keeps levels within the target range (typically 120 to 360 micromoles per liter). Frequent blood spot tests are crucial for making necessary adjustments to the dietary allowance or medication dosage.
Long-Term Health and Adherence
When treatment is initiated immediately following newborn screening and maintained consistently, individuals with PKU typically achieve normal cognitive development and lead healthy lives. However, lifelong dietary adherence presents unique challenges, especially during adolescence and adulthood. Social pressures and the palatability of the medical formula can lead to non-adherence as individuals gain independence.
A relaxation of the diet and subsequent high Phenylalanine levels can lead to symptoms including impaired executive function, slower processing speed, and mood disorders like anxiety and depression. Even short-term elevations in Phe levels can cause reversible changes in brain structure and function, highlighting the need for continuous control.
Maternal PKU represents a distinct and serious risk. Women with PKU must maintain extremely strict metabolic control before and throughout pregnancy. High Phenylalanine levels in the mother’s blood cross the placenta and are toxic to the developing fetus, regardless of whether the baby has inherited PKU. Poor control is associated with severe complications for the baby, including:
- Intellectual disability
- Microcephaly
- Heart defects