Hyperphenylalaninemia, or HPA, is a metabolic condition where the body cannot properly break down phenylalanine, an amino acid obtained from protein in food. This impairment leads to elevated levels of phenylalanine in the blood. The condition is most often identified through newborn screening programs shortly after birth.
Understanding the Spectrum of Phenylalanine Levels
Hyperphenylalaninemia exists on a spectrum, with severity determined by blood phenylalanine (Phe) concentration. These variations result from different activity levels of the enzyme phenylalanine hydroxylase (PAH), which processes Phe. The two primary classifications are non-PKU hyperphenylalaninemia and the more severe Phenylketonuria (PKU), with blood Phe levels guiding the management approach.
Non-PKU HPA is the milder form of the condition. The PAH enzyme is partially functional, allowing it to process some phenylalanine. Blood Phe levels are elevated but do not reach concentrations high enough to cause neurological damage, and individuals may require little to no dietary intervention.
Classic PKU is the most severe form of HPA, where the PAH enzyme is severely deficient or completely absent. This prevents the body from breaking down phenylalanine, leading to a significant buildup in the blood with levels that can exceed 20 mg/dL. Without strict management, these toxic levels can cause irreversible intellectual disability and seizures. The difference in enzyme function can be compared to a slow-draining sink versus one that is completely clogged.
Genetic Origins of Hyperphenylalaninemia
Hyperphenylalaninemia is an inherited genetic disorder caused by mutations in the PAH gene. This gene provides the instructions for making the phenylalanine hydroxylase (PAH) enzyme. Over 1,000 different mutations in this gene have been identified, which alter the enzyme’s function and lead to different severities of HPA.
The condition follows an autosomal recessive inheritance pattern, meaning a child must inherit two copies of the mutated PAH gene—one from each parent—to develop HPA. Individuals with only one copy are carriers and do not show symptoms, as their functional gene produces enough PAH enzyme. If both parents are carriers, there is a 25 percent chance with each pregnancy that their child will have HPA.
While most HPA cases involve PAH gene mutations, a small percentage results from a different genetic issue. In these rare instances, the disorder is caused by a deficiency in tetrahydrobiopterin (BH4). BH4 is a cofactor, or “helper” molecule, that the PAH enzyme needs to function, so without enough BH4, the enzyme cannot process phenylalanine.
The Diagnostic Process
The primary method for diagnosing hyperphenylalaninemia is newborn screening, a mandatory public health program in many countries. The process involves a heel prick test, usually within 24 to 48 hours of birth, where a few drops of a baby’s blood are collected on filter paper. This sample is then sent to a laboratory for analysis.
Laboratories use tandem mass spectrometry to measure the phenylalanine in the blood sample. If the screening detects an elevated phenylalanine level, it is considered a presumptive positive result. This initial finding indicates that further investigation is necessary to confirm a diagnosis.
An out-of-range screening result prompts immediate follow-up with more definitive diagnostic tests. These confirmatory tests involve a detailed analysis of the infant’s blood and urine. This follow-up confirms the diagnosis and helps determine the specific type and severity of HPA.
Core Management Strategies
Managing hyperphenylalaninemia, particularly classic PKU, centers on controlling blood phenylalanine levels through a lifelong, low-phenylalanine diet. This diet involves strictly limiting or avoiding high-protein foods, as nearly all dietary protein contains phenylalanine. Restricted foods include:
- Meat
- Poultry
- Fish
- Dairy products
- Eggs
- Nuts
- Legumes
- Soy
To ensure proper nutrition, individuals rely on special medical formulas. These formulas provide all necessary amino acids for protein synthesis, minus phenylalanine, along with required vitamins and minerals. The formula is a consistent part of the daily diet and is adjusted based on age, weight, and metabolic needs to ensure nutritional completeness.
Regular blood tests are a constant part of HPA management to measure phenylalanine concentration and assess the diet’s effectiveness. Based on these results, dietary adjustments are made to keep Phe levels within a safe target range, between 2 and 6 mg/dL. This balance prevents the neurological risks of high Phe levels and potential nutritional deficiencies.
A medication called sapropterin dihydrochloride (Kuvan) may be used with the diet for some patients. Sapropterin is a pharmaceutical form of the BH4 cofactor that helps the PAH enzyme function better. For responsive patients, it can enhance residual PAH enzyme activity, lower blood Phe levels, and potentially allow for a less restrictive diet. A trial period determines if the medication effectively reduces blood phenylalanine.
Lifelong Health Considerations
With early diagnosis and consistent, lifelong management, individuals with HPA can lead healthy lives with normal cognitive development. Adherence to a “diet-for-life” is necessary to maintain blood phenylalanine levels in the target range. This prevents neurological and cognitive problems, such as deficits in executive function, attention, and processing speed.
Living with a highly restrictive diet presents ongoing challenges, including social situations, the financial cost of medical foods, and the psychological burden of monitoring. Careful planning is needed for the transition from pediatric to adult healthcare to ensure individuals remain engaged with their management plan. Access to a multidisciplinary team of specialists is a feature of long-term care.
Maternal PKU is a specific consideration for women with HPA, who must maintain strict dietary control and low blood Phe levels before and during pregnancy. High maternal phenylalanine levels are teratogenic (harmful to a developing fetus) and can cross the placenta. This can lead to a high risk of:
- Miscarriage
- Intellectual disability
- Microcephaly (an abnormally small head)
- Congenital heart defects in the baby