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Cited by 1,292Epilepsy research and treatmentIon channel regulation and functionPharmacological Effects and Toxicity Studies

De Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy

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Claes, Lieve, Del-Favero, Jurgen, Ceulemans, Berten, Lagae, Lieven, Van Broeckhoven, Christine, De Jonghe, Peter·2001·The American Journal of Human Genetics
DOI 10.1086/320609PMC PMC1226119
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Abstract

Severe myoclonic epilepsy of infancy (SMEI) is a rare disorder that occurs in isolated patients. The disease is characterized by generalized tonic, clonic, and tonic-clonic seizures that are initially induced by fever and begin during the first year of life. Later, patients also manifest other seizure types, including absence, myoclonic, and simple and complex partial seizures. Psychomotor development stagnates around the second year of life. Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+). GEFS+ is a mild type of epilepsy associated with febrile and afebrile seizures. Because both GEFS+ and SMEI involve fever-associated seizures, we screened seven unrelated patients with SMEI for mutations in SCN1A. We identified a mutation in each patient: four had frameshift mutations, one had a nonsense mutation, one had a splice-donor mutation, and one had a missense mutation. All mutations are de novo mutations and were not observed in 184 control chromosomes.

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  • Loss-of-function variants of NaV1.1 cause Dravet syndrome and generalized epilepsy with febrile seizures plus, and have also been associated with ASD.

    “Loss of function variants of NaV1.1 cause Dravet syndrome [48], generalized epilepsy with febrile seizures plus [49], and have also been associated with ASD [50,51].”

    From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [48]

    The paper identifies de novo SCN1A mutations in seven patients with severe myoclonic epilepsy of infancy (Dravet syndrome; Discussion, p. 4). It proposes loss of function as one possible mechanism but also considers a toxic increase in function and says the exact mechanism requires further analysis (Discussion, pp. 4–5). This citation is attached to the Dravet-syndrome portion of the sentence, not the separately cited GEFS+ or ASD claims. (LLM, conf=0.88)

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  • As one-third of patients with Dravet syndrome present with febrile status epilepticus, either a hemiclonic or generalized tonic-clonic seizure, the diagnosis of Dravet syndrome may be considered from age 6 months when development and the EEG are typically normal.

    “As one-third of patients present with febrile status epilepticus, either a hemiclonic or generalized tonicclonic seizure, the diagnosis of Dravet syndrome may be considered from age 6 months when development and the EEG are typically normal 12,158 .”

    From Developmental and epileptic encephalopathies (2024) · cites this paper as [158]

    The Introduction (p. 1) describes early seizures as often prolonged and fever-associated, with normal early development. The Phenotype section (p. 3) reports onset at 2–6 months in seven patients. Our copy does not establish that one-third present with febrile status epilepticus, describe hemiclonic presentation or normal early EEG findings, or give a diagnostic recommendation from age 6 months. (LLM, conf=0.88)

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  • Genomic sequencing data indicate that a number of mutations in the Scn1a gene contribute to a spectrum of different epileptic disorders affecting children, including de novo as well as missense, frame-shift, and nonsense mutations.

    “Genomic sequencing data indicate that a number of mutations in the Scn1a gene contribute to a spectrum of different epileptic disorders affecting children, including de novo (Claes et al., 2001; Fujiwara et al., 2003) as well as missense, frame-shift, and nonsense mutations (Fujiwara et al., 2003).”

    From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Claes et al., 2001

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Authors
Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P.
Affiliations
  • University of Antwerp (BE)
  • Antwerp University Hospital (BE)
  • Universitair Ziekenhuis Leuven (BE)
ORCID
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2001-06
Volume
68
Issue
6
Pages
1327-1332
ISSN
0002-9297 (ISSN-L)
DOI
10.1086/320609
PMC
PMC1226119
OpenAlex
W2157702138
Cited by
1,292
References
14
Citations by year
2026: 47 · 2025: 50 · 2024: 49 · 2023: 44 · 2022: 64 · 2021: 74 · 2020: 63 · 2019: 64 · 2018: 40 · 2017: 58 · 2016: 53 · 2015: 48 · 2014: 64 · 2013: 54 · 2012: 55
FWCI
26.08
Type
journal article
Language
en
Open access
Licence
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Document Server@UHasselt (UHasselt) (submittedVersion)
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 › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
Keywords
Dravet syndrome, SCN1A, sodium channel alpha subunit, de novo mutations, frameshift mutation, nonsense mutation, splice donor mutation, missense mutations, febrile seizures, generalized epilepsy with febrile seizures plus
MeSH terms
Amino Acid Sequence, Base Sequence, Belgium, Child, Child, Preschool, DNA Mutational Analysis, Epilepsies, Myoclonic, Exons, Female, Humans, Infant, Introns, Male, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Paternity, Phenotype, Polymorphism, Restriction Fragment Length, Sodium Channels, Frameshift Mutation, Conserved Sequence, Codon, Nonsense, Microsatellite Repeats, Mutation, Missense, NAV1.1 Voltage-Gated Sodium Channel

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