Abstract

Phenylketonuria (PKU) is a genetic disorder caused by a deficiency of the liver enzyme phenylalanine hydroxylase, resulting in the accumulation of neurotoxic phenylalanine (Phe) in the brain and body fluids. Although early studies highlighted reduced biogenic amines in untreated PKU patients, later research revealed that even early-treated individuals experience significant neurotransmitter imbalances, particularly affecting serotonin and dopamine. The most consistent findings across clinical studies are reduced levels of serotonin, dopamine, norepinephrine, and their metabolites in both peripheral (urine, plasma, platelets) and central (cerebrospinal fluid) biological samples.

Preclinical studies using PKU mouse models have confirmed persistent abnormalities in brain neurotransmitters, particularly serotonin, alongside elevated Phe levels. Additionally, serotonin precursor supplementation has been shown to improve behavioral alterations and the associated neuropathological background in the affected mouse model.

Two main hypotheses have been proposed to explain these imbalances. The first suggests that neurotransmitter depletion results from reduced brain levels of tryptophan (Trp) and tyrosine (Tyr) due to competition with Phe at the blood-brain barrier (BBB). Although a single, unconfirmed clinical study suggested that large neutral amino acid (LNAA) supplementation might reduce brain Phe uptake, this has not been confirmed in animal studies. Another mechanism suggests that high Phe interferes with Trp and Tyr hydroxylation, impairing neurotransmitter synthesis.

The clinical relevance of these neurotransmitter deficits remains unclear. A direct effect on IQ has not been established. Studies are lacking in early infancy, when brain neurotransmitter levels peak. In adults with early-treated PKU, serotonin metabolite depletion has been associated with specific neuropsychological impairments and brain structure alterations. Importantly, not all patients show reduced neurotransmitter levels, indicating interindividual variability in susceptibility to Phe-related neurochemical changes.