Periventricular Heterotopia May Result from Radial Glial Fiber Disruption

Periventricular heterotopia (PVH) are collections of neurons and glia heterotopically located adjacent to the ventricles. The pathogenesis of periventricular heterotopia is believed to be a failure of cells to migrate from the ventricular zone. Mutations in filamin-1 (FLN1) have recently been identified as a genetic defect that results in an X-linked dominant form of PVH. In addition to this X-linked form, PVH may be found sporadically or occasionally as part of other syndromes. The pathogenesis(es) of PVH has not been entirely elucidated for patients with or without FLN1 mutation. In an attempt to better understand the pathogenesis of PVH, we examined 5 fetuses (gestational ages 21 to 34 wk), 3 females and 2 males, with PVH. Neuropathologic examination of these 5 fetuses revealed several to multiple periventricular nodules. No case showed the extensive periventricular heterotopia most commonly found in females with FLN1 mutations. By immunohistochemistry, neurofilament-positive cells were identified within the PVH in 3 of 5 cases and glial fibrillary acidic protein-positive cells surrounded the nodules in all 5 cases, but positive cells were only found within the nodules of 3 cases. Surprisingly, small collections of CD68-positive macrophages were found at the base of the nodules in 4 of the 5 cases. Moreover, in all cases, the radial glia highlighted with vimentin, showed disorganization specifically around the nodules. These data suggest that at least one pathogenesis for PVH is a disruption of the radial glial organization, resulting in a failure of cells to migrate from the ventricular zone.