Phenylalanine hydroxylase (PAH) deficiency is an inherited metabolic disorder that impacts the body’s ability to process a specific amino acid. This condition is more widely recognized as phenylketonuria, often abbreviated as PKU. Individuals with this disorder cannot properly break down phenylalanine, an amino acid found in many protein-rich foods and some artificial sweeteners. If not managed, phenylalanine can accumulate in the body to harmful levels.
Genetic Origins of PAH Deficiency
PAH deficiency stems from specific changes, known as mutations, within the PAH gene. This gene provides the instructions for producing the phenylalanine hydroxylase enzyme, which is responsible for converting phenylalanine into another amino acid called tyrosine.
The inheritance pattern for this condition is autosomal recessive. This means an individual must inherit a non-working copy of the PAH gene from both parents to develop the disorder. Parents who carry one mutated copy of the gene typically do not exhibit symptoms themselves but can pass the gene to their children. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit two affected genes and develop PAH deficiency.
Impact on the Body
Without a properly functioning phenylalanine hydroxylase enzyme, phenylalanine from the diet builds up to potentially toxic concentrations in the blood and brain. Untreated infants may gradually develop profound intellectual disability over their first few months of life.
Beyond cognitive impairment, other symptoms can manifest. These include developmental delays, seizures, and behavioral challenges such as hyperactivity or anxiety. A distinct musty or mousy odor may be present in the breath, skin, or urine. Individuals with untreated PAH deficiency might also have lighter skin, hair, and eye color, as phenylalanine plays a part in melanin production.
Diagnosis Through Screening
PAH deficiency is most commonly identified through routine newborn screening programs. This screening typically involves a simple blood test, often referred to as a heel prick test. A few drops of blood are collected from the infant’s heel within the first few days of life.
The blood sample is then analyzed in a laboratory to measure phenylalanine levels. Elevated phenylalanine levels indicate a possible diagnosis of PAH deficiency. If the initial screening result is positive, follow-up blood and sometimes urine tests are conducted to confirm the diagnosis and determine the specific type and severity of the deficiency. Early detection through these screening programs is important, allowing treatment to commence before irreversible neurological damage occurs.
Lifelong Management Strategies
The primary approach to managing PAH deficiency involves a strict, lifelong dietary regimen that limits phenylalanine intake. This dietary control aims to prevent phenylalanine from accumulating to harmful levels in the body. Individuals must carefully avoid high-protein foods such as meat, fish, eggs, dairy products, nuts, and legumes.
Instead, their diet heavily relies on fruits, most vegetables, and specially formulated low-protein foods like breads and pastas. A phenylalanine-free medical formula provides the necessary protein and other essential nutrients that cannot be obtained from the restricted diet. This formula is a central part of the daily management plan and must be consumed regularly throughout life.
Medical therapies can supplement dietary management for some patients. Sapropterin dihydrochloride, sold under brand names like Kuvan or Javygtor, is an oral medication that can help certain individuals with PAH deficiency break down phenylalanine more effectively. This medication works by enhancing the activity of the remaining phenylalanine hydroxylase enzyme in responsive patients, potentially increasing their tolerance for dietary phenylalanine.
Another treatment option for adults with uncontrolled phenylalanine levels, typically above 600 micromol/L, is enzyme substitution therapy using pegvaliase, marketed as Palynziq. This injectable medication introduces a different enzyme, phenylalanine ammonia-lyase, which directly breaks down phenylalanine in the body. Regular blood tests are a continuous part of management to monitor phenylalanine levels and adjust the diet and medication as needed to maintain optimal health and cognitive function.