In the ILAE epilepsy classification framework the identification of the etiology of epilepsy is included as a fundamental element and it is divided into the following categories: structural, genetic, infectious, metabolic, immune, or of unknown cause. Combined etiologies are increasingly emerging in the complex pathophysiology of epilepsy. For example, in recent years, the close relationship between structural and genetic causes has been gaining ground.
For some types of focal epileptogenic lesions, gene-disease associations have already been identified, e.g. focal cortical dysplasia II considered a mosaic mTORopathy. So-called somatic< variants, post-zygotically acquired genetic variants that arise during cortical development, have been investigated in recent years to assess their role in the etiology of focal lesional epilepsies (LFE), in particular in developmental cortical malformations (1) (2). Boßelmann et al. examined the brain tissue of 1386 individuals undergoing epilepsy surgery in order to detect somatic variants in these patients by ultra-deep targeted sequencing or deep whole-exome sequencing (3). The patients included had a histopathological diagnosis of long-term epilepsy-associated tumour (LEAT) or malformation of cortical development (MCD) including any focal-cortical dysplasia (FCD type I-III). The analysis confirmed already known associations, such as BRAF, SLC35A2, MTOR, PTPN11, and supported the statistical plausibility of a further 8 associations already identified through histopathological reviews and comprehensive in silico analyses including structural modelling and interaction analysis. Two genes were associated with LFE for the first time: DYRK1A and EGFR. DYRK1A is involved in mTOR pathway activation, EGFR on the other hand has been shown to be related to more malignant growth patterns and proliferative activity. The specific mechanism by which they might cause LFE requires further study. Identifying genetic associations in patients with focal epileptogenic lesions could be helpful in developing target therapies, similar to the mTOR-inhibitor everolimus in mTORpathies or to the galactose supplementary diet in SLC35A2-related patients. Follow-up studies in the matter could provide further treatments for patients not eligible for surgery or after an incomplete resection (when seizure freedom is not achieved) or before surgery in patients with mosaic variants in peripheral samples.
Key Points:
- Investigating gene-disease associations in epileptogenic brain lesions may aid the development of future targeted therapies
- Some gene-disease associations (such as BRAF, SLC35A2, MTOR, PTPN11) are established and confirmed in recent studies
- There is statistical plausibility for other potential diagnostic biomarkers (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS) and for two novel associations (DYRK1A and EGFR)
References:
- Lai D, Gade M, Yang E, Koh HY, Lu J, Walley NM, Buckley AF, Sands TT, Akman CI, Mikati MA, McKhann GM, Goldman JE, Canoll P, Alexander AL, Park KL, Von Allmen GK, Rodziyevska O, Bhattacharjee MB, Lidov HGW, Vogel H, Grant GA, Porter BE, Poduri AH, Crino PB, Heinzen EL. Somatic variants in diverse genes leads to a spectrum of focal cortical malformations. Brain. 2022 Aug 27;145(8):2704-2720. doi: 10.1093/brain/awac117. PMID: 35441233; PMCID: PMC9612793.
- Baldassari S, Ribierre T, Marsan E, Adle-Biassette H, Ferrand-Sorbets S, Bulteau C, Dorison N, Fohlen M, Polivka M, Weckhuysen S, Dorfmüller G, Chipaux M, Baulac S. Dissecting the genetic basis of focal cortical dysplasia: a large cohort study. Acta Neuropathol. 2019 Dec;138(6):885-900. doi: 1007/s00401-019-02061-5. Epub 2019 Aug 23. PMID: 31444548; PMCID: PMC6851393.
- Boßelmann, C.M., Leu, C., Brünger, T. et al. Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR. Nat Commun 15, 10429 (2024). doi.org/10.1038/s41467-024-54911-w
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