Similarity of Balloon Cells in Focal Cortical Dysplasia to Giant Cells in Tuberous Sclerosis

To the Editor: In a very recent article in Epilepsia (2005; 46:1716–1723), Ying et al. studied balloon cells from focal cortical dysplasia (FCD), coming to the conclusion that the cells form a heterogeneous group with differential expression of glial/astrocytic markers [microtubule-associated protein 2 (MAP2), glial fibrillary acidic protein (GFAP)] and several other tissue-specific proteins. Such a result resembles our and other authors' conclusions from immunohistochemical and ultrastructural research on giant cells in tuberous sclerosis (TS). We found characteristic cells present in all three types of TS-associated lesions: subependymal giant cell astrocytoma (SEGA), cortical tubers, and subependymal nodules (SENs) share a similar profile of protein expression and are a group of undifferentiated cells that, depending on individual determination, can show neural or glial features (Jozwiak et al. Immunohistochemical and microscopic studies on giant cells in tuberous sclerosis. HistolHistopathol 2005;20:1321–1326). Thus we recently evaluated the presence of two TS-associated proteins, hamartin and tuberin, in FCD type I (in which balloon cells are not found) and IIB (with balloon cells). Hamartin and tuberin are products of tumor-suppressor genes TSC1 and TSC2, inevitable for proper development of tissues and lethal if both alleles are subject to germ-line mutation. Inactivating mutation of TSC1 or TSC2, found in TS, leads to upregulation of mTOR (mammalian target of rapamycin), the kinase being a central regulator of protein transcription and subsequent uncontrolled cell proliferation. As a result, the clinical manifestation of TS is associated with tumor development in the brain, heart, kidneys, lungs, liver, and/or skin. Based on similarities between balloon and giant cells, our hypothesis was that FCD may be a form of focal TS, limited to selected regions of the brain tissue. According to our expectations, in an immunohistochemical study, we found loss of tuberin and hamartin expression, as well as strong immunoreactivity for mTOR in FCD type IIB. Specific kinases implicated in TS progression (pS6K1, pAkt, and pErk) also were hyperactivated in the same samples. Cortical balloon cells in these samples were NSE positive, whereas most subcortical giant cells were labeled with GFAP. In FCD type I and normal brain tissue, tuberin and hamartin were detected, but immunoreactivity for mTOR, the active form of S6K1, Akt, and Erk was subtle. Nestin expression in all samples was weak or absent. These findings suggest activation of the same pathways underlying both FCD IIB and TS and argue for recognition of the similarities in both pathologies and for considering FCD IIB as a focal form of TS. Such a conclusion could also potentially have a practical outcome: current research with the application of rapamycin as an effective drug limiting activity of mTOR kinase are under way and, in animal models of TS, show effectiveness of this therapy. Nevertheless, further elucidation of accompanying mutiations that probably predispose patients to FCD must be performed.