Hyperphenylalaninemia (HPA) is a metabolic disorder defined by elevated levels of the amino acid phenylalanine (Phe) circulating in the blood. Phenylalanine is obtained through the diet as a building block of protein. In individuals with HPA, the body cannot process this amino acid effectively, causing it to accumulate to potentially toxic concentrations. This buildup requires swift and continuous medical intervention because early detection and diligent management are necessary to prevent serious, long-term health complications.
The Spectrum of Hyperphenylalaninemia
HPA is a range of disorders categorized by the degree of phenylalanine elevation in the body. The severity is determined by the amount of residual enzyme activity an individual possesses. Classic Phenylketonuria (PKU) represents the most severe form, typically involving plasma phenylalanine concentrations greater than 1200 µmol/L without treatment.
Less severe forms are referred to as non-PKU HPA or mild PKU, where blood phenylalanine levels are lower. Mild PKU is defined by concentrations between 360 and 1200 µmol/L, while benign HPA is considered 120 to 360 µmol/L. This specific classification directly informs the required level of dietary restriction and overall medical management plan.
Genetic Basis and Inheritance
The primary cause of HPA is a defect in the gene responsible for creating the enzyme Phenylalanine Hydroxylase (PAH). This PAH enzyme, found in the liver, converts phenylalanine into the amino acid tyrosine. When the PAH gene contains mutations, the resulting enzyme is non-functional or has reduced activity, leading to phenylalanine accumulation.
HPA is inherited in an autosomal recessive pattern. This means a child must inherit two copies of the non-working PAH gene, one from each parent, to develop the condition. Inheriting only one mutated copy makes the individual a carrier who typically does not exhibit symptoms. The specific nature of the gene mutation determines the amount of residual PAH enzyme activity, which dictates the clinical severity.
Detecting HPA: Newborn Screening and Diagnosis
Universal newborn screening programs detect HPA within days of birth, before symptoms develop. This mandated procedure involves collecting a few drops of blood from the baby’s heel, often referred to as a heel prick test. For accurate results, the sample is typically collected after the newborn has been feeding for at least 24 hours.
The blood sample is analyzed using advanced laboratory techniques, such as tandem mass spectrometry, to measure the concentration of phenylalanine. An elevated level in the initial screen requires immediate follow-up testing. Confirmatory diagnosis involves further blood and urine tests, and often genetic testing to identify specific mutations in the PAH gene.
Lifelong Management through Diet and Medication
Management of HPA focuses on maintaining blood phenylalanine concentrations within a target range (generally 120 to 360 µmol/L) for optimal neurological outcomes. The cornerstone of treatment is a strict, lifelong diet that severely restricts the intake of natural protein, the primary source of phenylalanine. Foods high in protein, such as meat, fish, dairy, eggs, and nuts, must be largely eliminated.
Patients consume specialized medical foods or protein substitutes that are phenylalanine-free but supply essential amino acids and nutrients necessary for growth and health. These formulas ensure the body receives adequate protein without contributing to the buildup of phenylalanine. The total daily allowance of natural protein is carefully calculated by a metabolic dietitian.
Medication Options
For a subset of patients, medication can be an important part of the treatment plan. The drug sapropterin dihydrochloride, a synthetic version of the cofactor tetrahydrobiopterin (BH4), is effective for individuals classified as BH4-responsive. This medication enhances the residual activity of the defective PAH enzyme, allowing some individuals to better process phenylalanine and potentially increase their dietary tolerance.
The management plan requires frequent monitoring, particularly during periods of rapid growth. Regular blood spot testing ensures phenylalanine levels remain within the therapeutic range, and the metabolic team adjusts the diet and medication dosage as needed. Adherence to this strict regimen requires the continuous support of specialized physicians, dietitians, and social workers.
Potential Health Consequences of Untreated HPA
The neurotoxic effect of persistently high phenylalanine levels on the developing brain is the primary concern. If the condition is left undiagnosed or untreated in early life, the excess phenylalanine interferes with brain development. The most severe outcome of untreated HPA is profound intellectual disability.
Untreated individuals may also experience neurological problems, including tremors and seizures. Other symptoms include microcephaly (an unusually small head size) and behavioral issues such as hyperactivity and irritability. Physical signs like a musty odor in the breath or urine and patches of eczema may also become noticeable. Timely diagnosis and adherence to the prescribed management plan are necessary to prevent these severe, long-term consequences.