title: Long-term treatment and diagnosis of tetrahydrobiopterin-responsive hyperphenylalaninemia with a mutant phenylalanine hydroxylase gene.
abstract: A novel therapeutic strategy for phenylketonuria (PKU) has been initiated in Japan. A total of 12 patients who met the criteria for tetrahydrobiopterin (BH(4))-responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) (EC 1.14.16.1) gene were recruited at 12 medical centers in Japan between June 1995 and July 2001. Therapeutic efficacy of BH(4) was evaluated in single-dose, four-dose, and 1-wk BH(4) loading tests followed by long-term BH(4) treatment, and also examined in relation to the PAH gene mutations. The endpoints were determined as the percentage decline in serum phenylalanine from initial values after single-dose (>20%), four-dose (>30%), and 1-wk BH(4) (>50%) loading tests. Patients with mild PKU exhibiting decreases in blood phenylalanine concentrations of >20% in the single-dose test also demonstrated decreases of >30% in the four-dose test. The 1-wk test elicited BH(4) responsiveness even in patients with poor responses in the shorter tests. Patients with mild HPA, many of whom carry the R241C allele, responded to BH(4) administration. No clear correlation was noted between the degree of decrease in serum phenylalanine concentrations in the single- or four-dose tests and specific PAH mutations. The 1-wk test (20 mg/kg of BH(4) per day) is the most sensitive test for the diagnosis of BH(4)-responsive PAH deficiency. Responsiveness apparently depends on mutations in the PAH gene causing mild PKU, such as R241C. BH(4) proved to be an effective therapy that may be able to replace or liberalize the phenylalanine-restricted diets for a considerable number of patients with mild PKU.
authors.affiliation: Department of Pediatrics, Osaka City University Graduate School of Medicine,1-4-3, Asahimachi, abeno-ku, Osaka 545-8585, Japan. shintakuh@med.osaka-cu.ac.jp
authors.forename: Haruo
authors.initials: H
authors.lastname: Shintaku
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Ohura
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Okano
authors.forename: Misao
authors.initials: M
authors.lastname: Ohwada
authors.forename: Naruji
authors.initials: N
authors.lastname: Sugiyama
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sakura
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yoshida
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshino
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Ken
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kikumaro
authors.initials: K
authors.lastname: Aoki
authors.forename: Teruo
authors.initials: T
authors.lastname: Kitagawa
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D009154:Mutation; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000175:diagnosis* / Q000188:drug therapy* / Q000235:genetics
chemical_list: D001708:Biopterins; D010651:Phenylalanine Hydroxylase; C003402:sapropterin