Phenylketonuria: Current Treatments and Future Developments

Abstract

Phenylalanine hydroxylase (PAH) deficiency is an inborn error of metabolism that results in elevated phenylalanine levels in blood. The classical form of the disease with phenylalanine level > 1200 µmol/L in blood is called phenylketonuria (PKU) and is associated with severe intellectual disability when untreated. In addition, phenylalanine levels above the therapeutic range in pregnant female patients lead to adverse fetal effects. Lowering the plasma phenylalanine level prevents intellectual disability, maintaining the level in the therapeutic range of 120–360 µmol/L is associated with good outcome for patients as well as their pregnancies. Patient phenotypes are on a continuous spectrum from mild hyperphenylalaninemia to mild PKU, moderate PKU, and severe classic PKU. There is a good correlation between the biochemical phenotype and the patient’s genotype. For over four decades the only available treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy which is effective in up to 55% of patients depending on the population. Cofactor therapy typically is more effective in patients with milder forms of the disease and less effective in classical PKU. A new therapy has just been approved that can be effective in all patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. This article reviews the mainstay therapy, adjunct enzyme cofactor therapy, and the newly available enzyme substitution therapy for hyperphenylalaninemia. It also provides an outlook on emerging approaches for hyperphenylalaninemia treatment such as recruiting the microbiome into the therapeutic endeavor as well as therapies under development such as gene therapy.