Early white-matter abnormalities of the ventral frontostriatal pathway in fragile X syndrome

Aim Fragile X syndrome is associated with cognitive deficits in inhibitory control and with abnormal neuronal morphology and development. Method In this study, we used a diffusion tensor imaging (DTI) tractography approach to reconstruct white-matter fibers in the ventral frontostriatal pathway in young males with fragile X syndrome (n=17; mean age 2y 9mo, SD 7mo, range 1y 7mo-3y 10mo), and two age-matched comparison groups: (1) typically developing (n=13; mean age 2y 3mo, SD 7mo, range 1y 7mo-3y 6mo) and (2) developmentally delayed (n=8; mean age 3y, SD 4mo, range 2y 9mo-3y 8mo). Results We observed that young males with fragile X syndrome exhibited increased density of DTI reconstructed fibers than those in the typically developing (p=0.001) and developmentally delayed (p=0.001) groups. Aberrant white-matter structure was localized in the left ventral frontostriatal pathway. Greater relative fiber density was found to be associated with lower IQ (Mullen composite scores) in the typically developing group (p=0.008). Interpretation These data suggest that diminished or absent fragile X mental retardation 1 protein expression can selectively alter white-matter anatomy during early brain development and, in particular, neural pathways. The results also point to an early neurobiological marker for an important component of cognitive dysfunction associated with fragile X syndrome.