Phenylketonuria: modelling cerebral amino acid and neurotransmitter metabolism

Objective Phenylketonuria (PKU) is a metabolic disorder characterised by deficient hepatic phenylalanine hydroxylase activity, leading to elevated phenylalanine levels. Despite adherence to a phenylalanine-restricted diet, many adult PKU patients continue to experience executive function deficits, likely linked to high cerebral phenylalanine concentrations and deficiencies in monoaminergic neurotransmitters. Given the complexity of the interaction between diet and brain neurotransmitter metabolism, we employed computational metabolic modelling alongside experimental data from dietary intervention studies in PKU mice to identify key metabolic drivers underlying these deficits. Our goal was to provide a mechanistic, model-based foundation to support and optimise dietary therapies in PKU. Method We developed a computational model simulating large neutral amino acid (LNAA) transport across the blood-brain barrier and the subsequent metabolism of cerebral amino acids and monoaminergic neurotransmitters. The model was validated using direct measurements of brain amino acid concentrations in PKU mice subjected to various dietary regimens. Results The model predicts that cerebral amino acid levels are primarily influenced by their plasma concentrations and, to a lesser extent, by competition among LNAAs for transport mechanisms. Notably, it suggests that cerebral monoaminergic neurotransmitter levels are more significantly affected by elevated phenylalanine levels, likely through non-competitive inhibition of hydroxylase enzymes, than by the availability of precursor amino acids. Consequently, the model indicates that reducing phenylalanine levels, in conjunction with supplementing tyrosine and tryptophan, is more effective in restoring neurotransmitter levels than precursor supplementation alone. Conclusion This study presents the first comprehensive model integrating LNAA transport and cerebral neurotransmitter metabolism in PKU. The model enhances our understanding of the disease’s pathophysiology and highlights the importance of combined therapeutic strategies that target both phenylalanine reduction and precursor amino acid supplementation. Furthermore, it identifies knowledge gaps in LNAA transport mechanisms and offers a framework applicable to other neurological disorders involving diet-gene-neurotransmitter interactions.