Phenylketonuria (PKU) is inherited in an autosomal recessive pattern, meaning a child must receive a faulty copy of the responsible gene from both parents to develop the condition. If only one parent passes on the variant, the child becomes a carrier but won’t have PKU themselves. Both parents of an affected child are carriers, and they typically have no symptoms or any idea they carry the gene.
The Gene Behind PKU
PKU is caused by variants in a gene called PAH, located on chromosome 12. This gene tells the body how to make an enzyme that converts the amino acid phenylalanine into other compounds the body needs. When both copies of the PAH gene carry a variant, the enzyme either doesn’t work well or doesn’t work at all. Phenylalanine then builds up to toxic levels in the blood and brain instead of being processed normally.
Hundreds of different variants in the PAH gene have been identified. That’s why PKU can range from severe to mild. A person with two severely damaging variants will have classic PKU, with blood phenylalanine levels above 1,200 micromoles per liter. Someone with milder variants may have moderate PKU (600 to 1,200 micromoles per liter) or a very mild form sometimes called non-PKU hyperphenylalaninemia, where levels stay below 600. The specific combination of variants a child inherits from each parent determines where they fall on that spectrum.
How Two Carriers Have an Affected Child
Everyone carries two copies of the PAH gene, one from each parent. Carriers have one working copy and one faulty copy. The working copy produces enough enzyme to keep phenylalanine at normal levels, so carriers feel perfectly healthy and would never know without genetic testing.
When two carriers have a child together, each pregnancy has:
- A 25% chance the child inherits two faulty copies and has PKU
- A 50% chance the child inherits one faulty copy and becomes a carrier like the parents
- A 25% chance the child inherits two working copies and is neither affected nor a carrier
These odds reset with every pregnancy. Having one child with PKU doesn’t change the probability for the next. A couple could have four children and all four could be affected, or none could be.
Who Is More Likely to Carry the Gene
In the United States, PKU is most common in people of European or Native American ancestry. It is much less common among people of African, Hispanic, or Asian descent. This doesn’t mean it can’t occur in those populations, just that the carrier frequency is lower. Because carriers show no outward signs, many people have no family history of PKU and are surprised when a child is diagnosed.
A Rarer Form With Different Genes
About 2% of cases that look like PKU are actually caused by a different problem. The PAH enzyme needs a helper molecule called BH4 to function. Variants in the genes responsible for producing or recycling BH4 can cause the same buildup of phenylalanine, but the condition behaves differently and is more severe. BH4 deficiency is also inherited in an autosomal recessive pattern, but it involves different genes on different chromosomes, and it cannot be managed with the standard PKU dietary approach alone. Newborn screening programs test for this distinction because the treatment path is different.
How PKU Is Detected at Birth
Every baby born in the United States is screened for PKU within the first day or two of life, usually between 24 and 48 hours after birth. A healthcare provider pricks the baby’s heel and collects a few drops of blood onto a special filter paper card. The blood is tested for elevated phenylalanine levels. Most states screen once, though 13 states use a two-screen model, testing again at one to two weeks of age.
The test works best after the baby has had some protein in their diet, which is why it’s done after at least 24 hours of feeding. If the initial screen comes back abnormal, follow-up blood tests confirm the diagnosis and determine severity.
Genetic Testing for Parents and Pregnancies
If you already have a child with PKU or know you’re a carrier, genetic testing can provide more information for future family planning. Carrier screening is available for partners to find out whether they also carry a PAH variant. If both partners are confirmed carriers and the family’s specific gene variants are known, prenatal genetic testing through procedures like chorionic villus sampling or amniocentesis can determine whether a fetus is affected.
The American College of Obstetricians and Gynecologists recommends that prepregnancy carrier screening and prenatal testing be offered when relevant. Cell-free DNA testing from the mother’s blood, which is used for some other conditions, is not currently recommended for detecting PKU variants in a fetus.