The purpose of this study is to determine if Amish patients with PKU show responsiveness
after a high dose, prolonged Saproterin trial. The population of interest has a high
frequency of a specific splice site mutation, the 1066-11G>A mutation. This splice site
mutation activates a cryptic splice site resulting in an in frame insertion of 9 nucleotides
preceding exon 11. This leads to protein conformational changes and abrogation of function.
Previous studies of this genotype have indicated <1% residual activity of the PAH enzyme and
an insignificant responsiveness to Saproterin. However, in this specific study Phe levels
were evaluated only over 24 hours after a single-dose BH4 challenge at the standard dose of
20mg/kg.
Based on new clinical information, the investigators hypothesize that if given a prolonged
trial of Saproterin at a higher dose, Amish patients with PKU, specifically those homozygous
for the c.1066-11G>A mutation, will have a significant reduction in Phe levels or an increase
in Phe tolerance and/or improvement in executive functioning and quality of life.