The lack of clear correlations between the concentration of Trp and Tyr and its metabolites, are in agreement with observations published by Harding et al., argued that the most likely cause of brain DA and 5-HT deficiency in PKU is Phe-mediated inhibition of brain Tyr hydroxylase (TH) and Trp hydroxylase (TPH) activities rather than decreased substrate availability [35]. This evidence concerns the gene TH and phenylketonuria.