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Cited by 17Epilepsy research and treatmentAutoimmune Neurological Disorders and TreatmentsMultiple Sclerosis Research Studies

Brain molecular mechanisms in Rasmussen encephalitis

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Leitner, Dominique F., Lin, Ziyan, Sawaged, Zacharia, Kanshin, Evgeny, Friedman, Daniel, Devore, Sasha, Ueberheide, Beatrix, Chang, Julia W. +5 more·2023·Epilepsia
DOI 10.1111/epi.17457PMC PMC9852002
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Abstract

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.

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Cited by

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Authors
Leitner, D. F., Lin, Z., Sawaged, Z., Kanshin, E., Friedman, D., Devore, S., Ueberheide, B., Chang, J. W., Mathern, G. W., Anink, J. J., Aronica, E., Wisniewski, T., & Devinsky, O.
Affiliations
  • New York University (US)
  • University of California, Los Angeles (US)
  • Amsterdam Neuroscience (NL)
  • Center for Cognitive Neurology, Department of Neurology NYU Grossman School of Medicine New York New York USA
Corresponding author
Devinsky, Orrin
ORCID
Venue
Epilepsia
Publisher
Wiley
Published
2022-11-16
Volume
64
Issue
1
Pages
218-230
ISSN
  • 0013-9580 (ISSN-L)
  • 1528-1167
DOI
10.1111/epi.17457
PMC
PMC9852002
OpenAlex
W4308373401
Cited by
17
References
2
Citations by year
2026: 4 · 2025: 3 · 2024: 7 · 2023: 3
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Epilepsia (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
Funders
  • Finding A Cure for Epilepsy and Seizures
  • National Institutes of Health (P01AG060882, P30AG066512)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Health Sciences › Medicine › Neurology › Autoimmune Neurological Disorders and Treatments
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
Rasmussen encephalitis, molecular mechanisms, brain tissue, epilepsy, natural killer cells, dendritic cells, neuroinflammation, innate immune response, adaptive immune response, HLA variants, variants of uncertain significance, mTOR, ANGPTL7, SCN1A, phagosome formation, immune signaling pathways
MeSH terms
Angiopoietin-like Proteins, Angiopoietin-Like Protein 7, Adolescent, Adult, Brain, Child, Child, Preschool, Encephalitis, Epilepsy, Humans, Inflammation, Young Adult, TOR Serine-Threonine Kinases

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