Initially developed to stimulate phenylalanine hydroxylase (PAH) activity in individuals who have PKU because of a metabolic defect in the synthesis or regeneration of BH4 that is a cofactor of PAH, BH4 has proven beneficial even in a significant proportion of individuals who have mutations in the PAH gene itself ("classical" PKU) [24]. Here, PAH is linked to pulmonary arterial hypertension.