Are Functional Brain Networks Sensitive to High Phenylalanine in Adults With Phenylketonuria?

In early-treated adults with phenylketonuria (PKU), the effects of elevated phenylalanine (Phe) on functional brain networks remain poorly understood. While subacute structural brain changes have been reported, their functional significance remains unclear. Executive and attentional functions have been shown to be particularly sensitive to metabolic control in PKU. In this double-blind, randomized, placebo-controlled crossover trial, we investigated the effects of a 4-week high-Phe period on resting-state functional connectivity using seed-based analyses of the dorsal attention and frontoparietal networks, which are critically involved in executive and attentional functions. Twenty-three adults with PKU (median age 35.3 years [IQR 12.0]; 43% female) were included. When baseline connectivity was considered, no significant differences in functional connectivity were observed between the Phe and placebo periods. Without baseline adjustment, exploratory analyses revealed increased functional connectivity of the right frontal eye field within the dorsal attention network with frontal regions. Changes in functional connectivity were neither associated with changes in metabolite concentrations nor in working memory, attention, or executive function. These findings suggest that subacute increases in Phe may induce subtle and potentially transient changes in functional brain networks, although their functional relevance and persistence over longer exposure periods remain unclear.