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Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies

  • Epilepsy (C.W. Bazil, Section Editor)
  • Published:
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Abstract

Purpose of Review

Seizures can arise in neocortical, thalamocortical, limbic or brainstem networks. Here, we review recent genetic mechanisms implicated in focal and genetic generalized epilepsies (GGEs).

Recent Findings

Pathogenic variation in GAP activity toward RAGs 1 (GATOR1) complex genes (i.e., DEPDC5, NPRL2 and NPRL3) mainly result in focal epilepsies. They are associated with high rates of sudden unexpected death in epilepsy and malformations of cortical development (MCD), where “two-hits” in GATOR1-related pathways are also found in MCDs. Large-scale sequencing studies continue to reveal new genetic risk (germline or somatic) variants, and new genes relevant to epileptic encephalopathies (EEs). Genes previously associated with EEs, including GABAA receptor genes, are now known to play a role in both common focal and GGEs in individuals without intellectual disabilities. These findings suggest that there may be a common pathophysiological mechanism in GGEs and focal epilepsies. Finally, polygenic risk scores, based on common genetic variation, offer promise in helping to differentiate between GGEs and common forms of focal epilepsies.

Summary

Genetic abnormalities are a significant cause of common sporadic epilepsies, epilepsies associated with inflammatory markers, and focal epilepsies with or without MCD. Future studies using genome sequencing may provide more answers to the remaining unresolved epilepsy cases.

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Toronto, Toronto, Canada

    Farah Qaiser & Ryan K. C. Yuen

  2. Genetics & Genome Biology Program, The Hospital for Sick Children, Toronto, Canada

    Farah Qaiser & Ryan K. C. Yuen

  3. Division of Neurology, Department of Medicine, University of Toronto, Toronto, Canada

    Danielle M. Andrade

  4. Epilepsy Genetics Program, Krembil Brain Institute, University Health Network, University of Toronto, Toronto, Canada

    Danielle M. Andrade

  5. Division of Neurology, Toronto Western Hospital, Krembil Brain Institute, University of Toronto, 5W-445, 399 Bathurst St, Toronto, M5T 2S8, Canada

    Danielle M. Andrade

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DMA has received research grants from the McLaughlin Centre, EpLink and the Dravet Syndrome Foundation. DMA is a part of the MAB of Stoke Therapeutics and has received consulting fees from Eisai.

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Qaiser, F., Yuen, R.K.C. & Andrade, D.M. Genetics of Epileptic Networks: from Focal to Generalized Genetic Epilepsies. Curr Neurol Neurosci Rep 20, 46 (2020). https://doi.org/10.1007/s11910-020-01059-x

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