Authors :
Xingyu Wang, BS – Department of Neurology, Xuanwu Hospital, Capital Medical University
Lin-ai Guo, PhD – Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing
Yuexin Zhang, BS – Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing
Qiang Guo, MD – Department of Neurosurgery, Guangdong Sanjiu Brain Hospital
Presenting Author: Yicong Lin, MD – Xuanwu Hospital, Capital Medical University, Beijing, China
Yueshan Piao, MD – Xuanwu Hospital, Capital Medical University, Beijing, China
Yuping Wang, MD – Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing
Rationale:
The 2022 ILAE diagnostic guidelines incorporated mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) as a novel pathological entity characterized by an increase in heterotopic neurons and oligodendroglial cells in the white matter and associated with somatic SLC35A2 mutations, while the relationship between these features remains unclear. Prior studies detected SLC35A2 mutations in about half of patients, so other potential pathogenic somatic variants (PPSVs) beyond SLC35A2 may exist. This study aimed to investigate the correlation between SLC35A2 mutations and oligodendroglial hyperplasia and their association with phenotypes, and to detect PPSVs.
Methods:
Clinical data including onset age, epilepsy duration, seizure types, neurodevelopmental status, interictal scalp electroencephalography (EEG), magnetic resonance imaging (MRI), positron emission tomography (PET), and magnetoencephalography (MEG) were retrospectively reviewed for patients with histologically confirmed MOGHE who underwent epilepsy surgery at two comprehensive epilepsy centers in China from 2021 to 2024. Tissue samples were processed using EnVision immunohistochemistry with antibodies against Olig2. Oligodendrocyte density in white matter was quantified using ImageJ software. DNA next-generation sequencing was performed determining variant allele frequency (VAF) of SLC35A2, and pathogenicity was assessed using Polyphen and ClinVar. Correlations were evaluated with linear regression for VAF and oligodendrocyte density, Fisher’s exact test for SLC35A2 mutation-clinical features, and Kruskal-Wallis/Mann-Whitney U for oligodendrocyte density and clinical features.
Results:
29 cases met histopathological criteria for MOGHE. Among 25 cases with genetic testing, 52.0% (13/25) harbored somatic SLC35A2 variants, and VAF demonstrated a positive correlation with oligodendroglial density. Pathogenic mutations of NBN, LZTR1, RAF1, and 19p13.3 and 16p13.3 duplications were detected. Higher oligodendroglial density was associated with epileptic spasms and trended toward earlier onset age. SLC35A2 mutations did not correlate with epileptic spasms, unilateral interictal EEG discharges, neurodevelopment retardation, MRI abnormalities, MEG dipole clustering, PET unilateral hypometabolism, onset age, epilepsy duration, or surgical outcomes.
Conclusions:
This study demonstrates a positive correlation between SLC35A2 VAF and oligodendroglial density in human brain tissue, reinforcing the role of SLC35A2 somatic variants in driving oligodendroglial hyperplasia. Elevated oligodendroglial density correlates with epileptic spasms and trends toward earlier epilepsy onset. PPSVs in MOGHE samples were detected. These findings enrich the understanding of relationship among genotype, pathology and phenotype in MOGHE pathogenesis.
Funding:
This work was supported by Beijing Natural Science Foundation [Grant No. Z200024], Beijing Hospitals Authority [Grant No. PX2023032]