Mutations in SCN3A cause early infantile epileptic encephalopathy
Open accessAbstract
Objective: Voltage‐gated sodium (Na + ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A , and SCN8A , encoding the Na + channel pore‐forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B , encoding the accessory subunit β 1 , are established causes of genetic epilepsies. SCN3A , encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of 4 patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in 2 cases, p.Pro1333Leu, and p.Val1769Ala). Methods: All patients presented with treatment‐resistant epilepsy in the first year of life, severe to profound intellectual disability, and in 2 cases (both with the variant p.Ile875Thr), diffuse polymicrogyria. Results: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and for 2 of 3 mutants (p.Ile875Thr and p.Pro1333Leu), a leftward shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The antiseizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild‐type and mutant Nav1.3 channels. Interpretation: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain, while providing additional insight into mechanisms of slow inactivation of Nav1.3. Ann Neurol 2018;83:703–717
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75% of patients with SCN3A GOF variants have a malformation of cortical development (MCD), such as polymicrogyria.
“Intriguingly, 75% of patients with SCN3A GOF variants have a malformation of cortical development (MCD), such as polymicrogyria 36,37 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [36]
The Discussion reports polymicrogyria in two patients with the p.Ile875Thr variant and says it was not a consistent feature of the cohort. The paper links the severe epilepsy variants to gain of function, but does not support the claimed 75% rate of cortical malformations; one of the four patients with de novo variants did not have an MRI. (LLM, conf=0.88)
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Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
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- Authors
- Zaman, T., Helbig, I., Božović, I. B., DeBrosse, S. D., Bergqvist, A. C., Wallis, K., Medne, L., Maver, A., Peterlin, B., Helbig, K. L., Zhang, X., & Goldberg, E. M.
- Affiliations
- Children's Hospital of Philadelphia (US)
- Department of Biology and Medical Genetics, School of Medicine University of Rijeka Rijeka Croatia
- Case Western Reserve University (US)
- Division of Neurology, Department of Pediatrics Children's Hospital of Philadelphia Philadelphia PA
- Division of Human Genetics, Department of Pediatrics, Individualized Medical Genetics Center Children's Hospital of Philadelphia Philadelphia PA
- Ljubljana University Medical Centre (SI)
- Corresponding author
- Goldberg, Ethan M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2018-03-30
- Volume
- 83
- Issue
- 4
- Pages
- 703-717
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC5912987
- OpenAlex
- W2793002335
- Cited by
- 102
- References
- 59
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 13 · 2023: 7 · 2022: 12 · 2021: 19 · 2020: 16 · 2019: 13 · 2018: 3
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-04-19)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (K08 NS097633)
- Burroughs Wellcome Fund
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- SCN3A, Nav1.3, infantile epileptic encephalopathy, voltage-gated sodium channels, de novo missense variant, gain-of-function, drug-resistant epilepsy, intellectual disability, polymicrogyria, phenytoin, lacosamide, neuronal excitability, channel pharmacology
- MeSH terms
- Lacosamide, Adolescent, Adult, Analysis of Variance, Cell Line, Transformed, Child, Preschool, Electric Stimulation, Female, Humans, Magnetic Resonance Imaging, Male, Membrane Potentials, Models, Molecular, Mutation, Phenytoin, Spasms, Infantile, Transfection, Sodium Channels, Cohort Studies, Patch-Clamp Techniques, Voltage-Gated Sodium Channel Blockers, NAV1.3 Voltage-Gated Sodium Channel
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