Phenylalanine Hydroxylase Deficiency (PAH)

Phenylalanine hydroxylase deficiency is an autosomal recessive disorder caused by pathogenic variants in the gene PAH. While it is found in many different ethnicities, it is particularly prevalent in Sephardic Jewish, Sicilian, Irish, and Turkish individuals, as well as Caucasians. Pathogenic PAH variants result in loss of function of the phenylalanine hydroxylase enzyme, which breaks down the amino acid phenylalanine. The most severe form of the disease is called phenylketonuria. If untreated, buildup of phenylalanine will result in irreversible brain damage and severe intellectual disability. Treatment involves the removal of phenylalanine from the diet. Even with strict adherence to the treatment, some neurologic deficiencies have been noticed in long-term survivors. Psychological problems, including anxiety, depression, phobias and panic attacks may occur in adults who do not comply well to their treatment. Some patients have a milder form of hyperphenylalaninemia and may tolerate higher levels of phenylalanine in their diet. Depending on the genotype, patients may be responsive to BH4, which can direct their treatment. However, it is not always possible to predict the severity of the disease based on genotype.

For information about carrier frequency and residual risk, please see the residual risk table.

This gene is included on the following panel(s):