AUTHOR=Gelot Antoinette Bernabe , Represa Alfonso 

TITLE=Progression of Fetal Brain Lesions in Tuberous Sclerosis Complex

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 14 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2020.00899

DOI=10.3389/fnins.2020.00899

ISSN=1662-453X

ABSTRACT=Tuberous sclerosis (TSC) is a multisystem autosomal dominant genetic disorder due to loss of function of TSC1/TSC2 resulting in increased mTOR (mammalian target of rapamycin) signaling. In the brain, TSC is characterized by the formation of specific lesions that include subependymal and white matter nodules and cortical tubers. Cells that constitute TSC lesions are mainly balloon cells and dysmorphic neurons and astrocytes, but normal cells also populate the tubers. Although considered as a developmental disorder, the histopathological features of brain lesions have been described in only a limited number of fetal cases, providing little information on how these lesions develop. In this report we characterized the development of TSC lesions in fetal brains ranging from 19 gestational weeks (GW) to 8th postnatal month. Our data indicate that subcortical lesions, forming within and at the vicinity of germinative zones, are the first alterations (already detected in 19GW brains), characterized by the presence of numerous dysmorphic astrocytes and balloon cells. Our data show that cortical tuber formation is a long process that initiates with the presence of dysmorphic astrocytes (by 19-21GW), followed by the apparition of balloon cells (by 24GW) and acquiring dysmorphic neurons only by the end of gestation (by 36GW). Furthermore, the typical tuberal aspect of cortical lesions is only reached when bundles of neurofilament positive extensions delineate the bottom of the cortical lesion by 36GW. In addition, our study reveals the presence of balloon cells and dysmorphic neurons immunopositive for interneuron markers such as calbindin and parvalbumin, suggesting that TSC lesions would be mosaic lesions generated from different classes of progenitors.