Pku Board

Purpose: 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. Conclusion: The data presented suggest higher than anticipated number of PKU mutations
respond to BH4, and such mutations are on all the domains of PAH. Genet Med 2004:6(1):27–32.
Key Words: Phenylketonuria, PKU, Tetrahydrobiopterin, BH4, phenylalanine,