title: Effect of BH(4) supplementation on phenylalanine tolerance.
abstract: BACKGROUND
  Tetrahydrobiopterin (BH(4)) is a potential new orphan drug for the treatment of some patients with phenylketonuria (PKU), mostly mild forms. Numerous studies have confirmed this finding and BH(4)-responsiveness may be predicted to some extent from the corresponding genotype.
  
  
  OBJECTIVE
  To investigate the response to BH(4) loading test, the phenylalanine hydroxylase (PAH) mutations and the long-term therapeutic efficacy of BH(4) in patients with PKU, and to better define BH(4)-responsive patients according to phenylalanine (Phe) levels and dietary phenylalanine tolerance.
  
  
  METHODS
  30 Italian PKU patients (age range: 6 months-24 years; 12 female, 18 male) were included in this retrospective study. Eleven out of 30 patients presented with Phe levels below 450 micromol/L and 19 patients with Phe levels between 450 and 900 micromol/L. In the second group, we investigated the effect of long-term (6 months-7 years) oral administration of BH(4) on blood Phe levels and daily Phe tolerance.
  
  
  RESULTS
  In all patients with initial blood Phe levels <450 micromol/L (n = 11), BH(4) loading test was positive, but no treatment was introduced. In 12 out of 19 patients with blood Phe levels >450 micromol/L and positive at BH(4) loading, the treatment with BH(4) (10 mg/kg per day) was initiated. Before BH(4) treatment, Phe tolerance was less than 700 mg/day in all patients except for one (patient no. 9), increasing to 2-3-fold (from 498 +/- 49 to 1475 +/- 155 mg/day) on BH(4) treatment. In these patients the amino acid mixture supplementation was stopped and the diet was a combination of low-protein foods and natural proteins, mostly from animal sources.
  
  
  CONCLUSIONS
  Long-term BH(4) substitution (up to 7 years) in a group of moderate PKU patients allowed a substantial relaxation of the dietary restrictions or even replacement of the diet with BH(4) without any adverse effects.
authors.affiliation: Metabolic Unit, Division of Metabolic Diseases, Department of Pediatrics, University Hospital, Padua, Italy. burlina@pediatria.unipd.it
authors.forename: A
authors.initials: A
authors.lastname: Burlina
authors.forename: N
authors.initials: N
authors.lastname: Blau
mesh_terms: D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004361:Drug Tolerance; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D010649:Phenylalanine / Q000097:blood / Q000494:pharmacology*; D010651:Phenylalanine Hydroxylase / Q000235:genetics; D010661:Phenylketonurias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D017354:Point Mutation / Q000502:physiology; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin