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.









Disease Name
 GeneGuaranteed Exons 
 Inheritance Ethnicity
 Carrier Frequency
 Detection Rate
Residual Risk

Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARCaucasian1 in 5075%0.0050761421319797
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARAfrican1 in 15841%0.00374531835205993
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARAsian1 in 7841%0.00757575757575758
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARAshkenazi Jewish1 in 22517%0.003690036900369
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARWorldwide1 in 6566%0.00529100529100529
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARTurkey1 in 3263%0.0117647058823529
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARIreland1 in 3470%0.00900900900900901
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARSicily1 in 2648%0.0204081632653061
Phenylalanine Hydroxylase Deficiency PAH1-13 [13] (*29)ARSephardic Jewish – Iranian, Bukharian, Kavkazi, Tunisian and Moroccan 1 in 1852%0.0277777777777778