Brain molecular mechanisms in Rasmussen encephalitis

Abstract

Objective This study was undertaken to identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non‐RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. Methods Frozen brain tissue (ages = 2–19 years) was obtained from control autopsy (n = 14), surgical PWE (n = 10), and surgical RE cases (n = 27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p < .05) and label‐free quantitative mass spectrometry (false discovery rate < 5%) in the three groups. Results WES revealed no common pathogenic variants in RE, but several rare and likely deleterious variants of unknown significance (VUS; ANGPTL7/MTOR, SCN1A, FCGR3B, MTOR) and more common HLA VUS in >25% of RE cases (HLA‐DRB1, HLA‐DQA2), all with allele frequency < 5% in the general population. RNAseq in RE versus PWE (1516 altered transcripts) revealed significant activation of crosstalk between dendritic and natural killer cells (p = 7.94 × 10−6, z = 2.65), in RE versus control (7466 transcripts) neuroinflammation signaling activation (p = 6.31 × 10−13, z = 5.07), and in PWE versus control (945 transcripts) phagosome formation activation (p = 2.00 × 10−13, z = 5.61). Proteomics detected fewer altered targets. Significance In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow‐up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients

“…A comparison of the significant proteins common to each pairwise comparison was evaluated by a Venn diagram generated from InteractiVenn (78). Celltype annotations for each protein were evaluated in comparison to a reference choroid plexus dataset (79), as we have similarly done previously in other brain regions with enrichment evaluated by a Fisher's exact test (54,70,71,73,80,81). The signaling pathways associated with the differentially expressed proteins were assessed by Ingenuity Pathway Analysis (IPA, Qiagen).…”

Immune Mechanisms in Epileptogenesis: Update on Diagnosis and Treatment of Autoimmune Epilepsy Syndromes

“…Recent findings examining 27 surgical specimens with control autopsies and people with non-RE-related epilepsy by whole exome sequencing did not reveal common pathogenic variants in RE but detected many variants of unknown significance in genes associated with severe epilepsies, as well as an accumulation of rare allelic HLA variants (HAL-DRB1 and HLA-DQA2) in > 25% of RE patients, which are represented in < 5% of the general population. Ribonucleic acid (RNA) sequencing additionally detected significant activation of the crosstalk between dendritic and NK cells, of neuroinflammatory signalling, and of phagosome formation [ 99 ]. This exciting new data may pave the way for new therapeutic alternatives in RE, especially TNFα blockers, and caspase-1 inhibitors, like belnacasan (VX-765).…”