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Focal cortical dysplasia of Taylor's balloon cell type: Mutational analysis of the TSC1 gene indicates a pathogenic relationship to tuberous sclerosis
Author(s) -
Becker Albert J.,
Urbach Horst,
Scheffler Björn,
Baden Thomas,
Normann Sabine,
Lahl Rainer,
Pannek Heinz W.,
Tuxhorn Ingrid,
Elger Christian E.,
Schramm Johannes,
Wiestler Otmar D.,
Blümcke Ingmar
Publication year - 2002
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10251
Subject(s) - tuberous sclerosis , cortical dysplasia , tsc1 , loss of heterozygosity , pathology , tsc2 , exon , biology , epilepsy , medicine , allele , gene , genetics , apoptosis , pi3k/akt/mtor pathway , neuroscience
Focal cortical dysplasia (FCD) is characterized by a localized malformation of the neocortex and underlying white matter. Balloon cells, similar to those observed in tuberous sclerosis, are present in many cases (FCD bc ). In these patients, a hyperintense funnel‐shaped subcortical lesion tapering toward the lateral ventricle was the characteristic finding on fluid‐attenuated inversion recovery magnetic resonance imaging scans. Surgical lesionectomy results in complete seizure relief. Although the pathogenesis of FCD bc remains uncertain, histopathological similarities indicate that FCD bc may be related pathogenetically to tuberous sclerosis. Here, we studied alterations of the TSC1 and TSC2 genes in a cohort of patients with chronic, focal epilepsy and histologically documented FCD bc (n = 48). DNA was obtained after microdissection and laser‐assisted isolation of balloon cells, dysplastic neurons, and nonlesional cells from adjacent normal brain tissue. Sequence alterations resulting in amino acid exchange of the TSC1 gene product affecting exons 5 and 17 and silent base exchanges in exons 14 and 22 were increased in patients with FCD bc compared with 200 control individuals (exon 5, 2.3% FCD bc vs 0% C; exon 17, 35% FCD bc vs 1.0% C; exon 14, 37.8% FCD bc vs 15% C; exon 22, 45% FCD bc vs 23.8% C). Sequence alterations could be detected in FCD bc and in adjacent normal cells. In 24 patients, DNA was suitable to study loss of heterozygosity at the TSC1 gene locus in microdissected FCD bc samples compared with control tissue. Eleven FCD bc cases exhibited loss of heterozygosity. In the TSC2 gene, only silent polymorphisms were detected at similar frequencies as in controls. Our findings indicate that FCD bc constitutes a clinicopathological entity with distinct neuroradiological, neuropathological, and molecular genetic features. These data also suggest a role of the TSC1 gene in the development of FCD bc and point toward a pathogenic relationship between FCD bc and the tuberous sclerosis complex.