Abstract
BackgroundProlonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). In order to investigate IPI influence on the transcriptional phenotype underlying RMTLE we comparatively analyzed the transcriptomic signatures of CA3 explants surgically obtained from RMTLE patients with (FS) or without (NFS) febrile seizure history. Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations.Methodology/Principal FindingsDNA microarray analysis revealed that CA3 global gene expression differed significantly between FS and NFS subgroups. An integrative functional genomics methodology was used for characterizing the relations between GO biological processes themes and constructing transcriptional interaction networks defining the FS and NFS transcriptomic signatures and its major gene-gene links (hubs). Co-expression network analysis showed that: i) CA3 transcriptomic profiles differ according to the IPI; ii) FS distinctive hubs are mostly linked to glutamatergic signalization while NFS hubs predominantly involve GABAergic pathways and neurotransmission modulation. Both networks have relevant hubs related to nervous system development, what is consistent with cell genesis activity in the hippocampus of RMTLE patients. Moreover, two candidate genes for therapeutic targeting came out from this analysis: SSTR1, a relevant common hub in febrile and afebrile transcriptomes, and CHRM3, due to its putative role in epilepsy susceptibility development. MRI texture analysis allowed an overall accuracy of 90% for pixels correctly classified as belonging to FS or NFS groups. Histological examination revealed that granule cell loss was significantly higher in FS hippocampi.Conclusions/SignificanceCA3 transcriptional signatures and dentate gyrus morphology fairly correlate with IPI in RMTLE, indicating that FS-RMTLE represents a distinct phenotype. These findings may shed light on the molecular mechanisms underlying refractory epilepsy phenotypes and contribute to the discovery of novel specific drug targets for therapeutic interventions.
Highlights
Epilepsy affects 50 million people worldwide, 80% of them living in developing countries, and about 30% of the patients did not achieve remission with the available anti-epileptic drugs [1]
The uniqueness of from RMTLE patients with (FS) genomic signature is supported by a recent epidemiologic survey on temporal lobe epilepsy (TLE) patients with (TLE-FS) or without (TLE-NFS) early childhood febrile seizures based on age of onset, seizure type and ictal symptoms and familial recurrence, that placed TLE-FS as phenotype distinct from afebrile TLE [61]
Similar conclusions came from a study of neuropathologic features of resected hippocampi from refractory mesial temporal lobe epilepsy (RMTLE) patients where morphological alterations such as cell genesis and granule cell dispersion correlate with febrile initial precipitating injury (IPI) [62]
Summary
Epilepsy affects 50 million people worldwide, 80% of them living in developing countries, and about 30% of the patients did not achieve remission with the available anti-epileptic drugs [1]. A large body of experimental data on how antecedent febrile seizures lead to MTLE emerged from studies on animal models of inflammation- and hyperthermia-induced seizures [6,7,8,9,10] Some of these studies combined in vitro and animal models in order to check for pre-existing factors, such as ion channel mutations, cortical dysplasia or brain injuries. These factors may explain some but not the vast majority of MTLE cases in which children without any identifiable predisposing factor had PFS and further developed epilepsy. Prolonged febrile seizures constitute an initial precipitating injury (IPI) commonly associated with refractory mesial temporal lobe epilepsy (RMTLE). Texture analyses on MRI images of dentate gyrus were conducted in a subset of surgically removed sclerotic hippocampi for identifying IPI-associated histo-radiological alterations
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