Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Juliet K Knowles¹, Ingo Helbig^{2

3

4

5

6

7}, Cameron S Metcalf⁸, Laura S Lubbers⁹, Lori L Isom¹⁰, Scott Demarest¹¹, Ethan M Goldberg^{2

3

5}, Alfred L George Jr¹², Holger Lerche¹³, Sarah Weckhuysen^{14

15

16

17}, Vicky Whittemore¹⁸, Samuel F Berkovic¹⁹, Daniel H Lowenstein²⁰

Affiliations

¹ Department of Neurology, Division of Child Neurology, Stanford University School of Medicine, Stanford, California, USA.
² Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³ Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁵ Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁶ Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
⁷ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁸ Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
⁹ Citizens United for Research in Epilepsy, Chicago, Illinois, USA.
¹⁰ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
¹¹ Department of Pediatrics and Neurology, University of Colorado, School of Medicine, Aurora, Colorado, USA.
¹² Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁴ Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁵ Applied and Translational Neurogenomics Group, Vlaams Instituut voor Biotechnologie Center for Molecular Neurology, Antwerp, Belgium.
¹⁶ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
¹⁷ μNEURO Research Center of Excellence, University of Antwerp, Antwerp, Belgium.
¹⁸ Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, USA.
¹⁹ Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia.
²⁰ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

PMID: 35716052
PMCID: PMC9561034
DOI: 10.1111/epi.17332

Review

Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Juliet K Knowles et al. Epilepsia. 2022 Oct.

. 2022 Oct;63(10):2461-2475.

doi: 10.1111/epi.17332. Epub 2022 Jul 17.

Authors

Affiliations

¹ Department of Neurology, Division of Child Neurology, Stanford University School of Medicine, Stanford, California, USA.
² Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
³ Epilepsy NeuroGenetics Initiative, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁴ Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁵ Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁶ Institute of Clinical Molecular Biology, University of Kiel, Kiel, Germany.
⁷ Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany.
⁸ Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA.
⁹ Citizens United for Research in Epilepsy, Chicago, Illinois, USA.
¹⁰ Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
¹¹ Department of Pediatrics and Neurology, University of Colorado, School of Medicine, Aurora, Colorado, USA.
¹² Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
¹³ Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁴ Division of Neurology, University Hospital Antwerp, Antwerp, Belgium.
¹⁵ Applied and Translational Neurogenomics Group, Vlaams Instituut voor Biotechnologie Center for Molecular Neurology, Antwerp, Belgium.
¹⁶ Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Antwerp, Belgium.
¹⁷ μNEURO Research Center of Excellence, University of Antwerp, Antwerp, Belgium.
¹⁸ Division of Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, Maryland, USA.
¹⁹ Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia.
²⁰ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.

PMID: 35716052
PMCID: PMC9561034
DOI: 10.1111/epi.17332

Abstract

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

Keywords: epilepsy; exome sequencing; genomic medicine; personalized medicine; precision medicine.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

L.L.I. serves as cochair of the scientific advisory board of the Dravet Syndrome Foundation and served on the Board of the American Epilepsy Society. A portion of her research is funded by a grant to the University of Michigan from Stoke Therapeutics. S.D. has consulted for Upsher-Smith, BioMarin, Neurogene, Marinus, Tysha, and Ovid Therapeutics. S.D. also serves on the advisory board for the nonprofit foundations SLC6A1 Connect, Ring14 USA, Project 8P, and FamilieSCN2A. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

**FIGURE 1**
Overview of genetic testing results from large-scale diagnostic studies in >25 000 individuals.^- The 50 most common genetic etiologies across all three studies are shown. lpath, likely pathogenic; path, pathogenic.

**FIGURE 2**
Following discovery of *SCN8A*-related disorders, these were modeled, supported by patient advocacy, and translated into potential treatments, providing an example of relatively efficient progression through the “pipeline” from gene discovery to novel precision medicine approaches. ASO, antisense oligonucleotide.

See this image and copyright information in PMC

References

1. National Research Council of the National Academies. Toward precision medicine: building a knowledge network for biomedical research and a new taxonomy of disease. Washington, DC: The National Academies Press; 2011. - PubMed
1. Niestroj LM, Perez-Palma E, Howrigan DP, Zhou Y, Cheng F, Saarentaus E, et al. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. Brain. 2020;143:2106–18. - PMC - PubMed
1. Leu C, Stevelink R, Smith AW, Goleva SB, Kanai M, Ferguson L, et al. Polygenic burden in focal and generalized epilepsies. Brain. 2019;142:3473–81. - PMC - PubMed
1. Sisodiya SM. Precision medicine and therapies of the future. Epilepsia. 2021;62(Suppl 2):S90–S105. - PMC - PubMed
1. Kearney H, Byrne S, Cavalleri GL, Delanty N. Tackling epilepsy with high-definition precision medicine: a review. JAMA Neurol. 2019;76:1109–16. - PubMed

Publication types

Actions
Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Affiliations

Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous