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Gene expression analysis in human focal cortical dysplasia and tuberous sclerosis

ABSTRACT: Focal cortical dysplasia (FCD), a focal brain malformation, is the most common cause of intractable epilepsy. One of the related disorders is tuberous sclerosis (TS). The dysplasia appears to result from a defect in cortical development, however, this disorder is heterogeneous, and FCD seizure therapy is non-specific and failure-prone. As a final recourse, patients may undergo multiple surgical resections to control seizures. Thus, there is a clinical need to characterize this disorder with respect to structural, molecular, and electrophysiological profiles, which will lead to development of animal models and pilot therapies that we will then apply to humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62019 | GEO | 2015/06/01

SECONDARY ACCESSION(S): PRJNA262955

REPOSITORIES: GEO

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Project description:Focal Cortical Dysplasia (FCD) is a frequent cause of drug-resistant focal epilepsy in children and young adults. The international FCD classifications of 2011 and 2022 have identified several clinico-pathological subtypes, either occurring isolated, i.e., FCD ILAE Type 1 or 2, or in association with a principal cortical lesion, i.e., FCD Type 3. Here, we addressed the DNA methylation signature of a previously described new subtype of FCD 3D occurring in the occipital lobe of very young children and microscopically defined by neuronal cell loss in cortical layer 4. We studied the DNA methylation profile using 850K BeadChip arrays in a retrospective cohort of 104 patients with FCD 1A, 2A, 2B, 3D, TLE without FCD, and 16 postmortem specimens without neurological disorders as controls, operated in China or in Germany. DNA was extracted from formalin-fixed paraffin-embedded tissue blocks with microscopically confirmed lesions, and DNA methylation profiles were bioinformatically analyzed with a recently developed deep learning algorithm. Our results revealed a distinct position of FCD 3D in the DNA methylation map of common FCD subtypes, also different from non-FCD epilepsy surgery controls or non-epileptic postmortem controls. Within the FCD 3D cohort, the DNA methylation signature separated three histopathology subtypes, i.e., fibrotic scarring around porencephalic cysts, loss of layer 4, and Rasmussen encephalitis. Differential methylation in FCD 3D with loss of layer 4 specifically mapped to biological pathways related to neurodegeneration, biogenesis of ECM components, axon guidance, and regulation of the actin cytoskeleton. Our data suggest that DNA methylation signatures in cortical malformations are not only of diagnostic value but also phenotypically relevant, providing the molecular underpinnings of structural and histopathological features associated with epilepsy. Further studies will be necessary to confirm these results and clarify their functional relevance and epileptogenic potential in these difficult-to-treat children.

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Gene expression analysis in human focal cortical dysplasia and tuberous sclerosis

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