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Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features

  • Author Footnotes
    † These authors contributed equally and shared co-first authors.
    Nadine Morrison-Levy
    Footnotes
    † These authors contributed equally and shared co-first authors.
    Affiliations
    Department of Pediatrics, Queen’s University, Kingston, Ontario, Canada
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  • Author Footnotes
    † These authors contributed equally and shared co-first authors.
    Felippe Borlot
    Footnotes
    † These authors contributed equally and shared co-first authors.
    Affiliations
    Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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  • Puneet Jain
    Affiliations
    Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
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  • Robyn Whitney
    Correspondence
    Communications should be addressed to: Dr. Whitney; Division of Neurology; McMaster Children’s Hospital McMaster University; 1200 Main Street West; Hamilton, Ontario, L8N3Z5, Canada.
    Affiliations
    Division of Neurology, Department of Paediatrics, McMaster University, Hamilton, Ontario, Canada
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  • Author Footnotes
    † These authors contributed equally and shared co-first authors.

      Abstract

      Our current knowledge of genetically determined forms of epilepsy has shortened the diagnostic pathway usually experienced by the families of infants diagnosed with early-onset developmental and epileptic encephalopathies. Genetic causes can be found in up to 80% of infants presenting with early-onset developmental and epileptic encephalopathies, often in the context of an uneventful perinatal history and with no clear underlying brain abnormalities. Although current disease-specific therapies remain limited and patient outcomes are often guarded, a genetic diagnosis may lead to early therapeutic intervention using new and/or repurposed therapies. In this review, an overview of epilepsy genetics, the indications for genetic testing in infants, the advantages and limitations of each test, and the challenges and ethical implications of genetic testing are discussed. In addition, the following causative genes associated with early-onset developmental and epileptic encephalopathies are discussed in detail: KCNT1, KCNQ2, KCNA2, SCN2A, SCN8A, STXBP1, CDKL5, PIGA, SPTAN1, and GNAO1. The epilepsy phenotypes, comorbidities, electroencephalgraphic findings, neuroimaging findings, and potential targeted therapies for each gene are reviewed.

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