Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria

Abstract Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomized, placebo-controlled crossover trial, we investigated the impact of a 4-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19–48 years) underwent magnetic resonance imaging before and after the 4-week phenylalanine and placebo interventions (four time points). Structural T1-weighted images were preprocessed and evaluated using Direct Cortical Thickness Estimation using Deep Learning-based Anatomy Segmentation and Cortex Parcellation (DL+DiReCT), a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four time points, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441 µmol/l) than after the placebo period (873 µmol/l, P < 0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate = −0.095 mm, P < 0.001) and the left lingual gyrus (point estimate = −0.070 mm, P < 0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the phenylalanine-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs = 0.43 to 0.51, P ≤ 0.036) and decreased cortical thickness [rs = −0.62 to −0.39, not surviving false discovery rate (FDR) correction] after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs = −0.54 to −0.40, not surviving FDR correction). These findings provide evidence that a 4-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.