Testing for tetrahydrobiopterin responsiveness in patients with hyperphenylalaninemia due to phenylalanine hydroxylase deficiency

INTRODUCTION: Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin (BH4), reduce plasma phenylalanine levels in some patients with phenylketonuria (PKU), providing the first pharmacological therapy for PKU. Responsiveness to this therapy must be determined empirically through a BH4 loading test or trial. The authors have analyzed the loading tests currently in use in light of the numerous factors that can influence their results. Sapropterin dihydrochloride is a stable, synthetic form of BH4 approved for treatment of PKU in responsive patients. METHODS: An expert panel identified evidence from published reports of clinical experience. Reports of research involving at least 25 patients and published in English were considered. RESULTS: In all, 14 studies met both criteria; eight employing the sapropterin dihydrochloride preparation from Schircks Laboratories and six the sapropterin dihydrochloride preparation from Biomarin/Merck Serono. CONCLUSION: The arbitrary responsiveness definition of a >30% reduction in blood phenylalanine appears to be a good compromise between sensitivity and specificity for the initial screening test. However, individual patient characteristics should be considered when interpreting results, especially in patients with low baseline phenylalanine levels.