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

Juliet K. Knowles*, Ingo Helbig, Cameron S. Metcalf, Laura S Lubbers, Lori L. Isom, Scott Demarest, Ethan M. Goldberg, Alfred L. George, Holger Lerche, Sarah Weckhuysen, Vicky Whittemore, Samuel F. Berkovic, Daniel H. Lowenstein

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

60 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2461-2475
Number of pages15
JournalEpilepsia
Volume63
Issue number10
DOIs
StatePublished - Oct 2022

Funding

Many ideas in this review were inspired by the Epilepsy Precision Medicine Meeting in Washington, DC, September 2019, and we are grateful to the attendees for stimulating discussion. We gratefully acknowledge organizations who supported the meeting, including: CURE Epilepsy Foundation, Dravet Syndrome Foundation, Epilepsy Foundation, GeneDx, Invitae, Jonathan Mugar, Knopp Biosciences, Lennox Gastaut Syndrome Foundation, Praxis Precision Medicines, Syngap Research Fund, TESS Research Foundation, UCB, and Xenon. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH) or the NIH Institutes and Centers. We would like to thank Eryn Fitch and Michael Kaufman for their efforts in coordination and contribution to the manuscript. I.H. was supported by the Hartwell Foundation through an Individual Biomedical Research Award. This work was also supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS; K02 NS112600), including support through the Channelopathy‐Associated Epilepsy Research Center Without Walls (U54 NS108874), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center at Children's Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984), and intramural funds of the Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative. Research reported in this publication was also supported by the NIH National Center for Advancing Translational Sciences under award number UL1TR001878. This project was also supported in part by the Institute for Translational Medicine and Therapeutics' Transdisciplinary Program in Translational Medicine and Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. C.S.M. is supported by HHSN271201600048C, Screening of Investigational Compounds to Treat, Modify or Prevent Epilepsy for the NIH/NINDS Epilepsy Therapy Screening Program. J.K.K. is supported by NIH/NINDS K08NS119800, NIH/NINDS K12NS098482, the Taking Flight and Research Continuity awards from the CURE Epilepsy Foundation, the Elterman Award from the Child Neurology Society/Child Neurology Foundation, and the Stanford Maternal and Child Health Research Institute. E.M.G. is supported by NIH/NINDS K08 NS097633 and the Burroughs Wellcome Fund Career Award for Medical Scientists. A.L.G. is supported by NIH/NINDS U54 NS108874. L.L.I. is supported by NIH/NINDS R37 NS076752 and by a research grant to the University of Michigan from Stoke Therapeutics. H.L. is supported by grants from the German Research Foundation (Research Unit For‐2715, grant Le1030/23‐1), and the Federal Ministry of Education and Research in Germany (Treat‐ION, 01GM1907A). S.F.B. is supported by a National Health and Medical Research Council Program Grant (ID: 1091593). S.D. has funding from NIH/NINDS U01NS114312, International Foundation for CDKL5 Research, Project 8P Foundation, and Mila's Miracle Foundation. S.W. is supported by grants from the Fonds Wetenschappelijk Onderzoek Fund and European Joint Program on Rare Diseases (1861419 N, G041821N, TreatKCNQ). L.S.L, V.W., and D.H.L. have no funding sources to report.

Keywords

  • epilepsy
  • exome sequencing
  • genomic medicine
  • personalized medicine
  • precision medicine

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

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