Disruption of prefrontal function and connectivity in individuals with phenylketonuria

Phenylketonuria (PKU) is a genetic disorder associated with disruption of prefrontal cortex (PFC) development and executive dysfunction. To date, however, there is little evidence directly linking these two sequelae of PKU. We utilized functional magnetic resonance imaging (fMRI) to evaluate prefrontal functioning in six individuals with early-treated PKU (ETPKU) during performance of an n-back working memory task and compared results with those of six age- and gender-matched neurologically intact individuals. In addition, we evaluated the possible presence of PKU-related disruptions in functional connectivity, as might be hypothesized based on prior reports of white matter injury in individuals with ETPKU. A number of brain regions, nearly half of which were located in the PFC, were found to show atypical neural activity in individuals with ETPKU during working memory performance. We also found decreased connectivity both within the PFC as well as between the PFC and other brain regions in individuals with ETPKU compared with controls. Results from this preliminary study suggest that both prefrontal dysfunction and disruptions in functional connectivity may contribute to PKU-related executive impairment. In addition to advancing our understanding of PKU, the current findings have a broader impact in that PKU is regularly used as a model of early prefrontal dysfunction in the study of other neurodevelopmental disorders (e.g., autism).