Biopterin responsive phenylalanine hydroxylase deficiency.
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.
Matalon
Reuben
R
Department of Pediatrics and Microbiology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Koch
Richard
R
Michals-Matalon
Kimberlee
K
Moseley
Kathryn
K
Surendran
Sankar
S
Tyring
Stephen
S
Erlandsen
Heidi
H
Gamez
Alejandra
A
Stevens
Raymond C
RC
Romstad
Anne
A
Møller
Lisbeth B
LB
Guttler
Flemming
F
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*
D001708:Biopterins; D014443:Tyrosine; D010649:Phenylalanine