Phenylketonuria is an autosomal recessive disease caused by mutations in the gene coding for phenylalanine hydroxylase (chromosome 12q). Phenylalanine hydroxylase deficiency produces elevated phenylalanine concentrations in plasma, CSF, and urine as a direct result of the inability to convert phenylalanine to tyrosine. Mutations in the gene for PAH result in either failure to produce a PAH enzyme or production of an enzyme with decreased catalytic activity. This leads to an elevation of the blood phenylalanine (phe) level and to increased transport of phe into the brain. Phe itself is thought to be a direct cause of neurotoxicity in PKU. Neurotransmitter deficiency and decreased protein synthesis in the brain may be other mechanisms of neurotoxicity. Inhibition of the enzyme tyrosinase by elevated phe levels leads to decreased melanin synthesis in an untreated patient, resulting in hypo-pigmentation.