Relationships between Age and White Matter Integrity in Children with Phenylketonuria

Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder associated with cognitive compromise. Diffusion tensor imaging (DTI) has allowed detection of poorer microstructural white matter integrity in children with PKU, with decreased mean diffusivity (MD) in comparison with healthy children. However, very little research has been conducted to examine the trajectory of white matter development in this population. The present study investigated potential differences in the developmental trajectory of MD between children with early- and continuously-treated PKU and healthy children across a range of brain regions. Methods: Children with PKU (n = 31, mean age = 12.2 years) were recruited through metabolic clinics, and their MD findings across 10 brain regions of interest (ROIs) were compared with those of healthy control children (n = 51, mean age = 12.0 years). Hierarchical linear regressions, including age, group, and the age by group interaction, were performed on MD for each ROI. For ROIs with significant interactions, Pearson correlations between age and MD were obtained and compared across groups. Results: The age by group interaction was significant for the splenium and genu of the corpus callosum, the optic radiation, and the hippocampus (p \u3c 0.05 in all instances). The relationship between MD and age was significant for all 4 of these ROIs within the PKU group but none within the control group. In all instances, MD decreased as a function of increasing age. The relationship between age and MD was significantly different between the PKU and control groups for the optic radiation, hippocampus, and genu of the corpus callosum (z \u3c -1.96 in all instances). Conclusions: A stronger age-related decrease in MD was identified for children with PKU in comparison with healthy children in 4 ROIs, indicating that the trajectory of white matter development is abnormal in children with PKU. Further research using longitudinal methodology is needed to fully elucidate our understanding of white matter development in PKU