Progress in Understanding and Treating SCN2A-Mediated Disorders

Stephan J Sanders; Arthur J Campbell; Jeffrey R Cottrell; Rikke S Moller; Florence F Wagner; Angie L Auldridge; Raphael A Bernier; William A Catterall; Wendy K Chung; James R Empfield; Alfred L George Jr; Joerg F Hipp; Omar Khwaja; Evangelos Kiskinis; Dennis Lal; Dheeraj Malhotra; John J Millichap; Thomas S Otis; Steven Petrou; Geoffrey Pitt; Leah F Schust; Cora M Taylor; Jennifer Tjernagel; John E Spiro; Kevin J Bender

doi:10.1016/j.tins.2018.03.011

Progress in Understanding and Treating SCN2A-Mediated Disorders

Trends Neurosci. 2018 Jul;41(7):442-456. doi: 10.1016/j.tins.2018.03.011. Epub 2018 Apr 23.

Authors

Stephan J Sanders¹, Arthur J Campbell², Jeffrey R Cottrell², Rikke S Moller³, Florence F Wagner², Angie L Auldridge⁴, Raphael A Bernier⁵, William A Catterall⁶, Wendy K Chung⁷, James R Empfield⁸, Alfred L George Jr⁹, Joerg F Hipp¹⁰, Omar Khwaja¹⁰, Evangelos Kiskinis¹¹, Dennis Lal², Dheeraj Malhotra¹⁰, John J Millichap¹², Thomas S Otis¹³, Steven Petrou¹⁴, Geoffrey Pitt¹⁵, Leah F Schust⁴, Cora M Taylor¹⁶, Jennifer Tjernagel¹⁷, John E Spiro¹⁷, Kevin J Bender¹⁸

Affiliations

¹ Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: stephan.sanders@ucsf.edu.
² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA.
³ The Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark.
⁴ FamilieSCN2a Foundation, P.O. Box 82, East Longmeadow, MA 01028, USA.
⁵ Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
⁶ Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA.
⁷ Simons Foundation, New York, NY 10010, USA; Department of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
⁸ Xenon Pharmaceuticals Inc., 3650 Gilmore Way, Burnaby, BC V5G 4W8, Canada.
⁹ Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹⁰ Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
¹¹ Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹² Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Epilepsy Center and Division of Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, IL 60611, USA; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
¹³ Sainsbury Wellcome Centre for Neural Circuits and Behaviour, University College London, 25 Howland Street, London W1T 4JG, UK.
¹⁴ Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
¹⁵ Cardiovascular Research Institute, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.
¹⁶ Geisinger Health System, 100 North Academy Avenue, Danville, PA 17822, USA.
¹⁷ Simons Foundation, New York, NY 10010, USA.
¹⁸ Department of Neurology, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: kevin.bender@ucsf.edu.

Abstract

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na_V1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

Keywords: Na(V)1.2; autism spectrum disorder; developmental delay; epilepsy; intellectual disability; neurodevelopment; neurodevelopmental disorder; sodium channel.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Humans
NAV1.2 Voltage-Gated Sodium Channel / genetics*
NAV1.2 Voltage-Gated Sodium Channel / metabolism*
Neurodevelopmental Disorders / drug therapy
Neurodevelopmental Disorders / genetics*
Neurodevelopmental Disorders / metabolism*

Substances

NAV1.2 Voltage-Gated Sodium Channel
SCN2A protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding