Phenylketonuria

Phenylketonuria (PKU) is a severe form of inherited phenylalanine hydroxylase (PAH) deficiency, a disorder of phenylalanine metabolism. PAH normally converts the amino acid phenylalanine into tyrosine in a reaction that requires the cofactor tetrahydrobiopterin. When PAH activity is deficient, phenylalanine accumulates in the blood and tissues .^1,2

PAH deficiency is caused by pathogenic variants in both copies of the PAH gene and is inherited in an autosomal recessive pattern. Persistently high phenylalanine concentrations are particularly harmful to the developing brain. Without effective control beginning early in life, severe PAH deficiency can cause irreversible intellectual disability and other neurological and behavioral abnormalities .^1,2

PAH deficiency exists along a spectrum because different genetic variants can leave different amounts of residual enzyme activity. In current clinical terminology, PAH deficiency is often used as the broader name for this spectrum. Historically, phenylketonuria has referred particularly to severe PAH deficiency with very high untreated phenylalanine concentrations, while milder elevations have been described as hyperphenylalaninemia .¹

The name phenylketonuria comes from phenylketones, alternative products of phenylalanine metabolism that can accumulate when the usual pathway is impaired and be excreted in urine. Elevated phenylalanine is not always caused by PAH deficiency, however. Disorders affecting tetrahydrobiopterin metabolism and other rare conditions can also produce hyperphenylalaninemia, so the terms are not interchangeable .¹