De novo mutations of voltage-gated sodium channel α II gene SCN2A in intractable epilepsies
Open accessAbstract
BACKGROUND: Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances. METHODS: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations. RESULTS: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18-mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation. CONCLUSIONS: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels.
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Some reports describe clinical improvement with less mainstream medications, including lidocaine for infantile epileptic encephalopathy, ethosuximide for late-onset seizures, and acetazolamide for episodic ataxia, though data on generalizability are limited.
“Some reports have described clinical improvement with less mainstream medications, including lidocaine in children with infantile epileptic encephalopathy [56,57], ethosuximide for late-onset seizures [25], and acetazolamide for episodic ataxia [28,29], though data on the generalizability of these effects are limited.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [56]
The observation of seizure improvement is based only on retrospective clinical review.
“While the observation of seizure improvement is based only on retrospective clinical review, this finding reinforces previous observations of drug response: withdrawal of phenytoin provoking status epilepticus in one case, status treated with fosphenytoin in another, 2 seizure-free on lamotrigine, and one with seizure control on lidocaine.6,12,14”
From <i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures (2015) · cites this paper as [6]
SCN2A is the second strongest overall association, with two truncating mutations in ASD cases and three in ID cases.
“The second strongest overall association, with two truncating mutations in ASD cases and three such mutations in ID cases, is SCN2A, a gene previously associated with epilepsy and seizure disorders [52,53].”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [53]
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- Authors
- Ogiwara, I., Ito, K., Sawaishi, Y., Osaka, H., Mazaki, E., Inoue, I., Montal, M., Hashikawa, T., Shike, T., Fujiwara, T., Inoue, Y., Kaneda, M., & Yamakawa, K.
- Affiliations
- Akita University (JP)
- Venue
- Neurology
- Published
- 2009-09-29
- Volume
- 73
- Issue
- 13
- Pages
- 1046-1053
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC2754324
- OpenAlex
- W2061682874
- Cited by
- 205
- References
- 30
- Citations by year
- 2026: 8 · 2025: 4 · 2024: 5 · 2023: 10 · 2022: 8 · 2021: 16 · 2020: 14 · 2019: 18 · 2018: 14 · 2017: 15 · 2016: 12 · 2015: 18 · 2014: 21 · 2013: 14 · 2012: 11
- FWCI
- 5.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare
- Fukuoka University
- Hirosaki University
- National Institutes of Health
- RIKEN
- National Institute of General Medical Sciences (GM-49711, R01GM049711)
- RIKEN Brain Science Institute
- 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
- SCN2A, de novo mutations, drug-resistant epilepsy, infantile spasms, Dravet syndrome, neonatal epileptic encephalopathy, voltage dependence of activation, channel inactivation, recovery from inactivation, genotype-phenotype correlation
- MeSH terms
- Amino Acid Sequence, Cell Line, DNA Mutational Analysis, Epilepsies, Myoclonic, Female, Haplotypes, Humans, Infant, Newborn, Kidney, Male, Nerve Tissue Proteins, Severity of Illness Index, Spasms, Infantile, Transfection, Sodium Channels, Conserved Sequence, Protein Structure, Tertiary, Fatal Outcome, Patch-Clamp Techniques, Mutation, Missense, Young Adult, NAV1.2 Voltage-Gated Sodium Channel
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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