Abstract

In untreated phenylketonuria (PKU), deficiency of phenylalanine hydroxylase (PAH) results in elevated blood phenylalanine (Phe) concentrations and severe mental retardation. Current dietary treatment prevents mental retardation, but cognitive outcome remains suboptimal. The mechanisms by which elevated blood Phe concentrations disturb cerebral metabolism and cognitive function have not been fully elucidated. In this review, we discuss different hypotheses on the pathogenesis of PKU, focusing on the effects of disturbed large neutral amino acid (LNAA) transport from blood to brain on cerebral neurotransmitter and protein synthesis. Although the definitive roles of these processes in PKU pathogenesis are not fully understood yet, both substantially influence clinical outcome.