Phenylketonuria: A guide through the complex maze of its neurological pathophysiology providing a new perspective on treatment strategies

Abstract

Phenylketonuria (PKU), an autosomal recessive disease caused by a deficiency in the phenylalanine-4-hydroxylase enzyme or its cofactor tetrahydrobiopterin, is characterized by excessive phenylalanine (Phe) and reduced tyrosine (Tyr) levels and typically manifests neurologically. Even early treated PKU patients with proper metabolic control, obtained immediately after birth upon diagnosis of the disease, show late-onset neurological complications. Although the disease has already been researched for over 90 years, the complexity of its neurological pathophysiology has only recently been unraveled. Where it was initially thought that the neurological phenotype could be attributed to the increased Phe and decreased Tyr levels resulting in impaired neurotransmitter synthesis, it is now hypothesized that other processes including alterations in protein synthesis, oxidative stress, changes in bioenergetics and white matter disturbances play an important role in the development of these neurological manifestations. In this review, we aim to guide you through the complex maze of the brain pathophysiology observed in PKU while providing a new perspective on future treatment strategies in order to completely overcome symptom onset.