title: Efficacy and safety of BH4 before the age of 4 years in patients with mild phenylketonuria.
abstract: BACKGROUND
  Sapropterin dihydrochloride, an EMEA-approved synthetic formulation of BH4, has been available in Europe since 2009 for PKU patients older than 4 years, but its use with younger children is allowed in France based on an expert recommendation. We report the cases of 15 patients treated under the age of 4 years and demonstrate the safety and efficacy of this treatment for patients in this age group.
  
  
  METHODS
  We report the use of BH4 in 15 PKU patients treated before the age of 4 years.
  
  
  RESULTS
  Fifteen patients were enrolled in this retrospective study. Mean phenylalaninemia at diagnosis was 542 ± 164 μM and all patients had mild PKU (maximal phenylalaninemia: 600-1200 μM). BH4 responsiveness was assessed using a 24-hour BH4 loading test (20 mg/kg), performed during the neonatal period (n = 11) or before 18 months of age (n = 4). During the test, these patients exhibited an 80 ± 12% decrease in phenylalaninemia. Long-term BH4 therapy was initiated during the neonatal period (n = 7) or at the age of 13 ± 12 months (n = 8). The median duration of treatment was 23 months [min 7; max 80]. BH4 therapy drastically improved dietary phenylalanine tolerance (456 ± 181 vs 1683 ± 627 mg/day, p < 0.0001) and allowed a phenylalanine-free amino acid mixture to be discontinued or not introduced in 14 patients. Additionally, in the eight patients treated after a few months of diet therapy, BH4 treatment significantly decreased mean phenylalaninemia (352 ± 85 vs 254 ± 64 μM, p < 0.05), raised the percentage of phenylalaninemia tests within therapeutic targets [120-300 μM] (35 ± 25 vs 64 ± 16%, p < 0.05), and reduced phenylalaninemia variance (130 ± 21 vs 93 ± 27 μM, p < 0.05). No side effects were reported.
  
  
  CONCLUSIONS
  BH4-therapy is efficient and safe before the age of 4 years in mild PKU, BH4-responsive patients.
authors.affiliation: Médecine Pédiatrique & INSERM U921, CHRU de Tours, Université François Rabelais, Tours, France.
authors.forename: Oriane
authors.initials: O
authors.lastname: Leuret
authors.forename: Magalie
authors.initials: M
authors.lastname: Barth
authors.forename: Alice
authors.initials: A
authors.lastname: Kuster
authors.forename: Didier
authors.initials: D
authors.lastname: Eyer
authors.forename: Loïc
authors.initials: L
authors.lastname: de Parscau
authors.forename: Sylvie
authors.initials: S
authors.lastname: Odent
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.forename: François
authors.initials: F
authors.lastname: Feillet
authors.forename: François
authors.initials: F
authors.lastname: Labarthe
mesh_terms: D000367:Age Factors; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002675:Child, Preschool; D005260:Female; D005602:France; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010649:Phenylalanine / Q000008:administration & dosage / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000235:genetics; D010661:Phenylketonurias / Q000097:blood / Q000175:diagnosis / Q000178:diet therapy / Q000188:drug therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D001708:Biopterins; D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase; C003402:sapropterin