title: Biopterin responsive phenylalanine hydroxylase deficiency.
abstract: OBJECTIVE
  Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. There have been more than 400 mutations identified in the PAH gene leading to variable degrees of deficiency in PAH activity, and consequently a wide spectrum of clinical severity. A pilot study was undertaken to examine the response to 6-R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4) in patients with atypical and classical PKU.
  
  
  METHODS
  PAH gene mutation analysis was performed using denaturing gradient gel electrophoresis and gene sequencing. Patients with classical, atypical, or mild PKU were orally given BH4 10 mg/kg. Blood phenylalanine and tyrosine levels were determined using tandem MS/MS at 0 hours, 4 hours, 8 hours, and 24 hours intervals.
  
  
  RESULTS
  Thirty-six patients were given a single oral dose of 10 mg/kg of BH4. Twenty one patients (58.33%) responded with a decrease in blood phenylalanine level. Of the patients that responded, 12 were classical, 7 atypical, and 2 mild. The mean decline in blood phenylalanine at 24 hours was > 30% of baseline. There were 15 patients who did not respond to the BH4 challenge, 14 of those had classical and one had atypical PKU. Mapping the mutations that responded to BH4 on the PAH enzyme showed that mutations were in the catalytic, regulatory, oligomerization, and BH4 binding domains. Five patients responding to BH4 had mutations not previously identified.
  
  
  CONCLUSIONS
  The data presented suggest higher than anticipated number of PKU mutations respond to BH4, and such mutations are on all the domains of PAH.
authors.affiliation: Department of Pediatrics and Microbiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.forename: Richard
authors.initials: R
authors.lastname: Koch
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Michals-Matalon
authors.forename: Kathryn
authors.initials: K
authors.lastname: Moseley
authors.forename: Sankar
authors.initials: S
authors.lastname: Surendran
authors.forename: Stephen
authors.initials: S
authors.lastname: Tyring
authors.forename: Heidi
authors.initials: H
authors.lastname: Erlandsen
authors.forename: Alejandra
authors.initials: A
authors.lastname: Gamez
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.forename: Anne
authors.initials: A
authors.lastname: Romstad
authors.forename: Lisbeth B
authors.initials: LB
authors.lastname: Møller
authors.forename: Flemming
authors.initials: F
authors.lastname: Guttler
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D001708:Biopterins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D010649:Phenylalanine / Q000097:blood*; D010661:Phenylketonurias / Q000188:drug therapy* / Q000235:genetics*; D014443:Tyrosine / Q000097:blood*
chemical_list: D001708:Biopterins; D014443:Tyrosine; D010649:Phenylalanine