Abstract
Phenylketonuria (PKU) is a recessive disorder characterized by disruption in the metabolism of the amino acid phenylalanine (Phe). Prior research indicates that individuals with PKU have substantial white matter (WM) compromise. Much less is known about gray matter (GM) in PKU, but a small body of research suggests volumetric differences compared to controls. To date, developmental trajectories of GM structure in individuals with PKU have not been examined, nor have trajectories of WM and GM been examined within a single study. To address this gap in the literature, we compared longitudinal brain development over a three-year period in individuals with PKU (n = 35; 18 male) and typically-developing controls (n = 71; 35 male) aged 7-21 years. Using diffusion tensor imaging (DTI) and structural magnetic resonance imaging (MRI), we observed whole-brain and regional WM differences between individuals with PKU and controls, which were often exacerbated with increasing age. In marked contrast with trajectories of WM development, trajectories of GM development did not differ between individuals with PKU and controls, indicating that neuropathology in PKU is more prominent in WM than GM. Within individuals with PKU, mediation analyses revealed that whole-brain mean diffusivity (MD) and regional MD in the corpus callosum and centrum semiovale mediated the relationship between dietary treatment compliance (i.e., Phe control) and executive abilities, suggesting a plausible neurobiological mechanism by which Phe control may influence cognitive outcomes. Our findings clarify the specificity, timing, and cognitive consequences of whole-brain and regional WM pathology, with implications for treatment and research in PKU.