title: Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype.
abstract: BACKGROUND
  How to efficiently diagnose tetrahydrobiopterin (BH4) responsiveness in patients with phenylketonuria remains unclear. This study investigated the positive predictive value (PPV) of the 48-hour BH4 loading test and the additional value of genotype.
  
  
  METHODS
  Data of the 48-hour BH4 loading test (20 mg BH4/kg/day) were collected at six Dutch university hospitals. Patients with ≥30% phenylalanine reduction at ≥1 time points during the 48 hours (potential responders) were invited for the BH4 extension phase, designed to establish true-positive BH4 responsiveness. This is defined as long-term ≥30% reduction in mean phenylalanine concentration and/or ≥4 g/day and/or ≥50% increase of natural protein intake. Genotype was collected if available.
  
  
  RESULTS
  177/183 patients successfully completed the 48-hour BH4 loading test. 80/177 were potential responders and 67/80 completed the BH4 extension phase. In 58/67 true-positive BH4 responsiveness was confirmed (PPV 87%). The genotype was available for 120/177 patients. 41/44 patients with ≥1 mutation associated with long-term BH4 responsiveness showed potential BH4 responsiveness in the 48-hour test and 34/41 completed the BH4 extension phase. In 33/34 true-positive BH4 responsiveness was confirmed. 4/40 patients with two known putative null mutations were potential responders; 2/4 performed the BH4 extension phase but showed no true-positive BH4 responsiveness.
  
  
  CONCLUSIONS
  The 48-hour BH4 loading test in combination with a classified genotype is a good parameter in predicting true-positive BH4 responsiveness. We propose assessing genotype first, particularly in the neonatal period. Patients with two known putative null mutations can be excluded from BH4 testing.
authors.forename: Karen
authors.initials: K
authors.lastname: Anjema
authors.forename: Margreet
authors.initials: M
authors.lastname: van Rijn
authors.forename: Floris C
authors.initials: FC
authors.lastname: Hofstede
authors.forename: Annet M
authors.initials: AM
authors.lastname: Bosch
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.forename: Estela
authors.initials: E
authors.lastname: Rubio-Gozalbo
authors.forename: Maaike C
authors.initials: MC
authors.lastname: de Vries
authors.forename: Mirian C H
authors.initials: MC
authors.lastname: Janssen
authors.forename: Carolien C A
authors.initials: CC
authors.lastname: Boelen
authors.forename: Johannes G M
authors.initials: JG
authors.lastname: Burgerhof
authors.forename: Nenad
authors.initials: N
authors.lastname: Blau
authors.forename: M Rebecca
authors.initials: MR
authors.lastname: Heiner-Fokkema
authors.forename: Francjan J
authors.initials: FJ
authors.lastname: van Spronsen
mesh_terms: D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010661:Phenylketonurias / Q000188:drug therapy* / Q000235:genetics; D055815:Young Adult
chemical_list: D001708:Biopterins; C003402:sapropterin