Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study

Abstract

We report an autopsy case of tuberous sclerosis complex (TSC) in a 20-week gestational age female fetus. The brain showed lesions suggestive of early cortical tubers and subependymal hamartomatous nodules. The large cells within these nodular clusters were variably immunoreactive for glial fibrillary acidic protein (GFAP) and vimentin and negative for synaptophysin and neurofilament. Subependymal radial glia expressed both vimentin and GFAP, but subpial radial glia either did not express these markers (in contrast to an age-matched control) or were absent. Tuberin expression was noted in heterotopic neurons in the white matter and brain cells consistent with Cajal Retzius cells in the neocortical molecular layer, very weakly in superficial cortical neurons, neurons in the basal ganglia, Purkinje cells and external granular cells of cerebellum, cranial nerve nuclei neurons, occasional germinal matrix cells, ependymal cells, choroid plexus epithelium, and pituitary gland neuroendocrine cells; it was not seen within the cells of subependymal nodules. The pattern of tuberin immunoreactivity was similar to that which we have observed in older TSC patients. Proliferating cell labeling indexes were comparable in the germinal matrix of the TSC patient and an age-matched control. Abnormal subpial radial glia may be responsible for some of the neuronal migration abnormalities that appear to result in neocortical tubers.

Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex

“…To mimic the timing of cortical tuber development in late-stage TSC fetuses (1,(12)(13)(14), we treated pregnant dams whose pups bore doxycycline regulable neural progenitor cell-specific cre alleles and a Tsc1 homozygous conditional allele (Tsc1 cc Nestin-rtTA-IRES-eGFP + TetOp-cre + ) with doxycycline in feed on various gestational days. Doxycycline given on embryonic day 8 (E8) induced cre expression in a small proportion of cells in the thalamus, brainstem, and spinal cord (Fig.…”

“…Interestingly, this extended developmental period required for giant cell development in this model is similar to what is seen in the fetus with TSC. Focal brain lesions have been noted in fetuses with TSC as early as 19-20 wk of gestation, but they lack balloon-like giant cells (13,14). Instead, giant cells have been observed in the brain of the fetus with TSC to some extent at 24 wk of gestation and more robustly at 30 wk of gestation (12).…”

“…Severe epilepsy is seen in most patients with TSC, and the number and size of tubers correlate with an increased risk for intractable seizures (3,5), which are associated with poor cognitive outcome (6). Because tubers have been identified in the developing neocortex of patients with TSC as early as 20 wk of gestation (12)(13)(14), it is thought that giant cells develop at some point during neural progenitor cell proliferation, neuronal differentiation, and migration. However, the cellular and genetic mechanisms of giant cell development are poorly understood because of the absence of a mouse model that replicates giant cells.…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…With the recent advances in both fetal ultrasonography and magnetic resonance imaging, tubers can be detected during the prenatal period in TSC patients [194][195][196]. Tubers have been detected as early as 20 weeks gestation [197,198], indicating that tubers form during embryonic brain development, probably between week 10 and 20 of human gestation.…”

Normal and Abnormal Development of the Human Cerebral Cortex

“…Several gene products have been found to be crucial for corticogenesis based on the findings from experimental studies on mutant animals. These products include reelin, LIS-1, doublecortin, fukutin, tuberin and EMX2, and their mutations cause the mouse reeler phenotype, human Miller-Dieker syndrome (MDS), X-linked subcortical laminar heterotopia/ lissencephaly syndrome (XLSCLH), Fukuyama-type congenital muscular dystrophy (FCMD), tuberous sclerosis and schizencephaly, respectively [81][82][83][84][85][86][87][88][89][90]. These gene products are expressed in normally developing brains during periods of corticogenesis, predominantly in the neuronal cell population, including the CR cells of the marginal layer.…”