The progression of white matter abnormalities in individuals with early-treated phenylketonuria (PKU)
[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Phenylketonuria (PKU) is a rare autosomal recessive disorder characterized by a disruption in the ability to metabolize phenylalanine (phe) into tyrosine, a precursor for dopamine and other catecholamines. Even with early and continuous treatment, those with PKU exhibit cognitive and neurological sequelae, the most prominent of which is abnormalities of cortical white matter (WM). Past studies suggest that posterior WM is generally more compromised than anterior WM, but little is known regarding how this pattern of findings translates to potential impact along the spatial extent of individual WM tracts. The present study utilizes a new analysis approach called Automated Fiber-Tract Quantification (AFQ) to advance our understanding of the tract-specific progression of WM abnormalities in individuals with early-treated PKU (ETPKU). Diffusion Tensor Imaging (DTI) data from a sample of 22 individuals with ETPKU and a demographically-matched sample of 21 healthy individuals without PKU was analyzed using AFQ. In addition, a subsample of 8 individuals with ETPKU was reevaluated six months later after demonstrating a significant reduction in blood phe levels related to sapropterin treatment. Within-tract AFQ analyses revealed location-by-group interactions for several WM tracts throughout the brain. In most cases, ETPKU-related disruptions in mean diffusivity (MD) were more apparent in posterior (as compared to anterior) aspects of a given tract. This finding was more pronounced with increased age and higher phe levels. Significant reduction in blood phe levels was associated with a similar pattern of improvement (posterior-to-anterior) within most tracts. Taken together, these findings suggest that there is a systematic progression of WM abnormalities in individuals with ETPKU in a posterior-to-anterior manner along individual WM tracts that mirrors the previously observed pattern of progression through the brain.