Phenylketonuria (PKU) is a rare, inherited metabolic disorder affecting the body’s ability to process the amino acid phenylalanine, a protein building block. The disorder is caused by a genetic change in the PAH gene, which creates the enzyme phenylalanine hydroxylase. Without this functional enzyme, phenylalanine accumulates in the blood and brain, leading to irreversible neurological damage, including intellectual disability, if not addressed quickly. Early diagnosis and immediate specialized treatment are paramount to ensuring a healthy developmental outcome.
Standard Newborn Screening
The diagnosis of PKU primarily relies on mandatory newborn screening conducted shortly after birth. This universal public health measure identifies the disorder before symptoms manifest. The procedure, sometimes referred to as a “heel stick,” is performed by a healthcare provider who gently warms the baby’s foot to increase blood flow.
A small, quick pinprick is then made on the baby’s heel to collect a few drops of blood. These drops are applied to a dried blood spot card, which is sent to a public health laboratory for analysis. The test is typically performed between 24 and 48 hours after birth, but sometimes up to seven days, to ensure the infant has consumed protein, which is necessary for phenylalanine to accumulate if the enzyme is missing.
The laboratory uses tandem mass spectrometry to measure the concentration of phenylalanine in the dried blood spot. This process also measures the level of tyrosine, the amino acid phenylalanine is converted into. If the initial sample is collected before 24 hours of age, or if the infant is discharged early, a repeat sample is often requested to ensure the test’s validity.
Interpreting Initial Screening Results
The newborn screening test is a preliminary measure, and a result flagged as “abnormal” or “positive” does not automatically confirm a PKU diagnosis. Laboratories establish specific cut-off values or reference ranges for the concentration of phenylalanine in the blood. If a baby’s phenylalanine level exceeds this established range, the result is considered out-of-range, requiring immediate follow-up.
Newborn screening has a high false-positive rate to ensure no affected infant is missed. This means many babies flagged with an abnormal result ultimately do not have the condition. Factors that can elevate phenylalanine levels include premature birth, certain medications, or receiving total parenteral nutrition (TPN).
The medical team contacts the family immediately following an abnormal screen. This rapid communication is essential because a definitive diagnosis must be established quickly to prevent brain damage, which can begin in the first few months of life. The next step involves performing specific and quantitative tests to confirm or rule out the disorder.
Confirmatory Testing Procedures
Following an abnormal newborn screening result, two primary types of tests are used to confirm the presence of PKU. The first and most critical test is the Quantitative Plasma Amino Acid Analysis. This procedure involves drawing a blood sample, usually after a short fasting period, to precisely measure the levels of phenylalanine and tyrosine in the plasma.
A confirmed diagnosis of classic PKU is typically indicated when untreated plasma phenylalanine levels exceed 1200 µmol/L (20 mg/dL). This quantitative test provides the precise biochemical evidence needed to start treatment protocols. The analysis also helps distinguish PKU from milder forms of the condition, collectively known as hyperphenylalaninemia, which may not require the same rigorous dietary management.
The second type of confirmatory test is genetic testing, which analyzes the baby’s DNA for mutations in the PAH gene. Genetic testing is not strictly necessary for initiating treatment. However, identifying the specific mutation in the PAH gene can provide valuable information for genetic counseling and may help predict the severity of the condition.
Identifying PKU in Older Individuals
While PKU is almost always diagnosed through universal newborn screening, a diagnosis in an older child or adult can occur in rare situations. This scenario is usually limited to individuals born in areas without routine screening or those missed due to a logistical error. Testing is typically prompted by the appearance of developmental or neurological concerns.
Symptoms that may trigger testing in older individuals include developmental delays, seizures, a musty body odor, or intellectual disability. The diagnostic process in these cases involves the same quantitative blood tests and genetic analysis used for confirmation in newborns. A physician may also recommend advanced imaging, such as a cranial magnetic resonance imaging (MRI), to look for white matter changes in the brain that are often associated with high phenylalanine levels.