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Novartis Found Symp. 2007;288:260-72; discussion 272-81.

Focal brain malformations: a spectrum of disorders along the mTOR cascade.

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  • 1PENN Epilepy Center, Department of Neurology, University of Pennsylvania Medical Center, 3 West Gates Bldg, 3400 Spruce St., Philadelphia, PA 19104, USA.


Focal cortical dysplasia with balloon cells (FCDIIB), hemimegalencephaly (HMEG), and ganglioglioma (GG) are sporadic focal malformations of cortical development that are highly associated with epilepsy. Histologically, all three malformations are characterized by disordered cortical lamination and the presence of markedly enlarged cell types known as balloon cells in FCDIIB and HMEG and atypical ganglion cells (AGCs) in GG. These cells are similar to giant cells in the tuberous sclerosis complex (TSC). Recent work has shown that there is enhanced activation of the mTOR cascade in TSC, FCD, HMEG and GG, suggesting a common pathogenesis for these disorders. We propose that these malformation types reflect a spectrum of disorders along the mTOR cascade. The mTOR pathway is known to regulate cell growth and thus is an ideal candidate to study in malformations associated with aberrant cell size. We hypothesize that focal brain malformations form as a consequence of a somatic gene mutation occurring within a progenitor cell during brain development. Our work has implemented several strategies to investigate FCD, HMEG and GG. First, we use single nucleotide polymorphism (SNP) arrays and gene sequencing to identify mutations in candidate genes that would lead to activation of the mTOR cascade. Second, we are using gene and protein expression profile techniques to understand how mTOR activation affects the developing cortex.

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