Update on the treatment of phenylketonuria: long-term safety and efficacy of sapropterin dihydrochloride

Hilary Vernon^1,2
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, ²Kennedy Krieger Institute, Baltimore, MD, USA

Abstract: Phenylketonuria (PKU) is an inborn error of metabolism caused by a defect in the enzyme phenylalanine hydroxylase, which is responsible for converting phenylalanine to tyrosine. Untreated, this disorder will result in severe intellectual disability. However, with proper management, outcome is excellent. For many years, this disorder was managed exclusively with dietary measures which consisted of a phenylalanine-restricted diet. However, with the recent introduction of a stable, orally bioavailable form of tetrahydrobiopterin (BH4), the cofactor for phenylalanine hydroxylase, treatment in this disorder has been drastically altered. This stable form of BH4, sapropterin dihydrochloride, has a very good safety profile and is very effective in many patients with PKU in lowering plasma phenylalanine levels and allowing for liberalization of the phenylalanine-restricted diet. The introduction of BH4 has posed many new challenges in the treatment of PKU, including developing the best protocol to determine whether or not a patient will respond to BH4, and how to treat atypical populations including young children, fully affected, untreated adults, and pregnant patients. In this review, we will examine the history of treatment in PKU, the history of treatment with BH4, protocol options for determining if a patient is a drug responder, and considerations for treatment in special populations.

Keywords: sapropterin dihydrochloride, phenylketonuria, phenylalanine