title: Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients.
abstract: BACKGROUND
  Hyperphenylalaninemia (HPA) is an inherited metabolic disorder due to deficiency of the enzyme phenylalanine hydroxylase (PAH) or its cofactor tetrahydrobiopterin (BH4). BH4-responsiveness in PAH-deficient HPA is a recently described characteristic of most milder phenotypes. BH4-responsive patients show reduction of plasma phenylalanine (phe) levels after oral administration of BH4.
  
  
  OBJECTIVE
  Determination of the incidence of BH4-responsiveness among a non-selected, cohort population of PAH-deficient hyperphenylalaninemic patients and evaluation of phenotype-genotype correlations.
  
  
  METHODS
  All patients born in Lombardy (Italy) between January 2000 and December 2004, and affected by HPA (107 patients) were classified after BH4 loading test, analysis of urinary pterins, and determination of DHPR activity in blood, and investigated for BH4-responsiveness. 6R-BH4 (20 mg/kg) was administered orally as a single dose and plasma samples were obtained at time-points 0, 4, 8, and 24 h after BH4 administration. In patients with basal plasma phe levels <or=360 mmol/L a combined phe (100 mg phe/kg) and BH4 (20 mg/kg) loading test was performed. Patients were defined "responsive to BH4" when plasma phe levels decreased by 30% 8h after oral BH4 administration.
  
  
  RESULTS
  BH4 significantly lowered blood phe levels in 91 (85%) of 107 patients affected by PAH-deficient HPA. Most responsive patients were affected by mild HPA (77%), a smaller percentage by mild (7%) and moderate (7%) phenylketonuria (PKU). One patient with classical PKU was responsive to BH4. Eighteen mutations were found to be associated to the BH4-responsive phenotype.
  
  
  CONCLUSIONS
  BH4-responsiveness is shown by a consistent number of PAH-deficient hyperphenylalaninemic patients and seems to be common in milder phenotypes. Genotype is not the only factor determining BH4-responsiveness.
authors.affiliation: Department of Paediatrics, San Paolo Hospital, University of Milan, Italy. l.fiori@libero.it
authors.forename: Laura
authors.initials: L
authors.lastname: Fiori
authors.forename: Betina
authors.initials: B
authors.lastname: Fiege
authors.forename: Enrica
authors.initials: E
authors.lastname: Riva
authors.forename: Marcello
authors.initials: M
authors.lastname: Giovannini
mesh_terms: D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005838:Genotype; D006801:Humans; D007223:Infant; D007558:Italy; D009154:Mutation; D010649:Phenylalanine / Q000097:blood*; D010651:Phenylalanine Hydroxylase / Q000172:deficiency*; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin