The Effectiveness of High-Dose Synthetic BH4 (Saproterin Dihydrochloride or "Kuvan") in Amish PKU Patients

Phenylketonuria (PKU) is caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). PAH is responsible for the rate limiting step in phenylalanine catabolism. This reaction is dependent on tetrahydrobiopterin (BH4). BH4 is a catalytic cofactor for the enzyme PAH. Supplementation with synthetic BH4 (saproterin dihydrochloride or KuvanTm) has been shown to activate residual PAH activity and lower Phe levels in certain patients. It may also have a chaperone effect by binding abnormal PAH protein and decreasing its degradation. Saproterin is an approved oral drug developed to reduce blood Phenylalanine (Phe) levels and increase Phe tolerance in BH4 responsive patients with hyperphenylalaninemia.

Certain genotypes have been found to be good predictors of Saproterin responsiveness; however, these correlations are imperfect. Therefore the standard of care is to perform a trial of Saproterin therapy to assess responsiveness in every PAH patient regardless of genotype. Currently this recommendation does not include patients with two null mutations.

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 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.

Recently, observation in several Amish patients suggests some promise that these patients may be responsive to Saproterin after a longer trial of the medication (Personal comment - Samuel Yang, MD). In addition, studies evaluating PAH enzyme activity in these patients, have found evidence that this genotype may need higher cofactor concentrations for optimal enzyme activity and therefore may require a higher dose of Saproterin then the currently recommended 20mg/kg (9). To date, no formal clinical trial has been done.

To answer the question of whether this genotype is responsive to Saproterin at higher doses, over a prolonged period, the investigators propose a randomized clinical trial comparing blood Phe levels in patients treated with standard-dose Saproterin to those treated with high-dose Saproterin. The results of this study could reveal a new population of Saproterin responsive PKU patients. This could call into question other null mutations of the PAH gene and their responsiveness to Saproterin. This may lead to the investigation of genotypes previously thought to be unresponsive to Saproterin. Further, diet treatment alone has proven to be difficult for the Amish population for cultural and economic reasons.