Sapropterin dihydrochloride for phenylketonuria and tetrahydrobiopterin deficiency

10.1586/EEM.10.39 Phenylketonuria Phenylketonuria (PKU; Online Mendelian Inheritance in Man No. 262600) is a genetic disorder characterized by a deficiency of the hepatic enzyme phenylalanine-4-hydroxylase (PAH; EC 1.14.16.1), causing elevated concentrations of phenylalanine (Phe) in the blood and brain. Hyperphenylalaninemia (HPA) can also be caused by a deficiency of tetrahydrobiopterin (BH4), a cofactor of PAH (BH4 deficiency). Phe is an essential amino acid, which is not synthesized de novo and must be obtained by diet. PAH converts Phe to tyrosine, an important precursor for catecholamines and melanine [1]. PKU is an inherited, autosomal recessive disease caused by mutations in the PAH gene. More than 550 disease-causing mutations have been identified in patients with PKU or HPA [101,102]. The majority of genetic alterations in the PAH gene are missense mutations, but splice-site, nonsense and silent mutations, as well as frame shifts and larger deletions and insertions, may also occur. Different mutations affect the activity of the PAH enzyme to different extents, and this may account for the wide variation in blood Phe concentrations among patients with PKU [2,3]. The location and type of mutations in the PAH gene cannot yet be used to fully predict clinical phenotype and, currently, genotyping of the PAH gene has limited value in the diagnosis of PKU phenotypes [1]. Almost all cases of PKU in industrialized countries are detected via newborn screening programs, used across Europe since the 1960s. Higher blood Phe concentrations are associated with more severe disease and a greater risk of neurological impairment and, as such, require more urgent treatment. A general classification of PKU disease severity as a function of Phe concentrations is shown in Table 1 [4,5]. However, several classifications exist and they vary depending on the practices carried out in individual countries. The increased circulating concentration of Phe resulting from PKU and HPA is thought to have a neurotoxic effect in the brain [4]. If left untreated from birth, PKU leads to white matter abnormalities [6] and severe mental retardation [7], with losses of cognitive and executive function [8,9]. Although early intervention to Nenad Blau