Phenylketonuria (PKU) is a rare, inherited metabolic condition that affects how the body processes protein. The disorder occurs when a gene change impairs the body’s ability to break down a specific amino acid. If left untreated, the resulting buildup becomes toxic to the brain and nervous system, leading to severe, irreversible intellectual and developmental disabilities. Nearly all cases of PKU are identified through mandatory newborn screening programs, ensuring immediate treatment.
The Standard Newborn Screening Process
The process for diagnosing PKU begins with a universal public health measure known as newborn screening, which is performed on nearly all infants shortly after birth. This procedure involves collecting a small blood sample using the heel stick test. A healthcare provider gently pricks the baby’s heel to collect a few drops of blood onto specialized absorbent paper.
The sample is collected on a filter paper card, creating a Dried Blood Spot (DBS) specimen for laboratory analysis. The timing is important: the blood sample must be obtained after the newborn has been feeding for at least 24 hours, typically between 24 and 48 hours after birth.
This timing is necessary because phenylalanine only accumulates to detectable levels after the baby has ingested protein. If the screening is performed too early, the result may be falsely negative. If an infant is discharged before the 24-hour mark, a repeat test is usually scheduled within the first one to two weeks of life.
Understanding Phenylalanine Levels
The diagnostic screening focuses on measuring the concentration of the amino acid Phenylalanine (Phe) in the blood sample. Phe is an essential amino acid obtained through the diet and is a component of nearly all dietary proteins. In a healthy person, the enzyme Phenylalanine Hydroxylase (PAH) converts Phe into the amino acid tyrosine.
In individuals with PKU, the gene for the PAH enzyme is defective, leading to a partial or complete enzyme deficiency. This lack of functional PAH prevents the breakdown of Phe, causing it to rapidly accumulate in the bloodstream and tissues. The screening test detects this elevation of Phe concentration.
Laboratories analyze the DBS sample and compare the measured Phe level to a predetermined threshold. A normal blood phenylalanine level is typically below 120 \(\mu\)mol/L (2 mg/dL). A result above this cutoff is considered a “positive screen” and suggests the possibility of PKU or a milder form, hyperphenylalaninemia. This initial positive result requires immediate follow-up testing, as the screening is highly sensitive and designed to catch all potential cases.
Confirmatory Testing and Next Steps
It is important to understand that a positive result from the initial newborn screen is an indication, not a definitive diagnosis of PKU. Because the screening test has a high rate of false-positives, a second, more precise round of testing is required immediately. This follow-up process is treated with urgency due to the time-sensitive nature of the disorder.
The confirmatory testing typically involves a repeat blood draw, often analyzed using specialized techniques such as tandem mass spectrometry. This provides a more accurate measure of Phe levels. If the phenylalanine levels remain significantly elevated, the diagnosis is considered highly probable. In classic PKU, untreated plasma levels are often consistently over 1,200 \(\mu\)mol/L (20 mg/dL).
The diagnosis is often solidified by genetic testing, which involves sequencing the PAH gene on chromosome 12 to identify the specific mutations responsible for the enzyme deficiency. This analysis helps confirm the type and severity of PKU, guiding the long-term treatment plan. Once the diagnosis is confirmed, a low-phenylalanine diet and specialized medical formula are initiated without delay, as early treatment is the only way to prevent the severe neurotoxic effects of the condition.