Elsevier

Pediatric Neurology

Volume 34, Issue 2, February 2006, Pages 116-120
Pediatric Neurology

Original article
Recurrent De Novo Mutations of SCN1A in Severe Myoclonic Epilepsy of Infancy

https://doi.org/10.1016/j.pediatrneurol.2005.07.009Get rights and content

Mutations in the voltage-gated sodium channel gene SCN1A are a major cause of severe myoclonic epilepsy of infancy (Dravet syndrome) and generalized epilepsy with febrile seizures plus. This study reports the identification of six de novo SCN1A mutations in patients with severe myoclonic epilepsy of infancy, including a tetranucleotide deletion in exon 26. The same deletion was previously observed in two unrelated patients and appears to result from slipped-strand mispairing of a direct repeat during deoxyribonucleic acid replication. Review of the literature indicates that recurrent mutations account for 25% of SCN1A mutations in severe myoclonic epilepsy of infancy, including six sites of deamination at CpG dinucleotides.

Introduction

Mutations in the voltage-gated sodium channel SCN1A are responsible for inherited epilepsy with a broad spectrum of clinical severity. Our initial report in 2000 described SCN1A mutations in two families with generalized epilepsy with febrile seizures plus (GEFS+) (OMIM 604233), a usually mild seizure disorder [1]. At the present time, more than 150 SCN1A mutations have been identified, most of them in patients with severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome (OMIM 607208) [2]. Ninety percent of severe myoclonic epilepsy of infancy mutations arise de novo in affected individuals [3], [4], [5]. Approximately 50% of these mutations result in truncated proteins, demonstrating haploinsufficiency for SCN1A, and several of the missense mutations in patients with severe myoclonic epilepsy of infancy also appear to cause loss of function [6]. Several distinct biophysical mechanisms have been associated with mutations in generalized epilepsy with febrile seizures plus, including impaired channel inactivation and reduced time spent in the inactivated state, both of which lead to increased persistent sodium current at the cellular level. A unique mechanism was observed for the missense mutation D1866Y in the C-terminal domain, which impairs interaction with the sodium channel β subunit [7]. The current paper describes the identification of five new SCN1A mutations and one recurrent mutation in patients with severe myoclonic epilepsy of infancy. The deoxyribonucleic acid (DNA) sequence context at the site of each recurrent mutation is also examined.

Section snippets

Patients

Six patients were selected for analysis on the basis of their clinical presentation. Five patients were consistent with the diagnosis of severe myoclonic epilepsy of infancy according to the International League Against Epilepsy guidelines [8]. Patient 4 was consistent with borderline severe myoclonic epilepsy of infancy (SMEB) [9]. The patients were identified at clinics in three different countries, Germany (n = 3), Canada (n = 1), and the United States (n = 2).

DNA Isolation and Analysis

DNA was extracted from blood

Clinical Data

The clinical features of the six patients are summarized in Table 1. A family history of epilepsy was only observed for Patient 2. The father and mother of Patient 2 had febrile seizures and absence epilepsy, respectively. Consanguinity was not present in any of the families.

Because severe myoclonic epilepsy of infancy is often refractory to pharmacologic intervention, we reviewed the medical records of each patient to determine which antiepileptic medications were most beneficial in reducing

Discussion

Five of the six mutations described in this paper have not previously been reported. R613X, P707fsX715, and S914fsX934 truncate >50% of the Nav1.1 protein, making it unlikely to generate a functional channel [11]. The mutation R1525X in the D3-D4 loop truncates the final 485 of the total of 2009 amino acids, and K1846fsX1856 removes the final 153 residues of the C-terminus (Fig 1A). Biophysical characterization of two similarly truncated Nav1.1 mutants, R712X and R1892X, demonstrated that both

References (14)

There are more references available in the full text version of this article.

Cited by (47)

  • Genetics and clinical correlation of Dravet syndrome and its mimics – experience of a tertiary center in Taiwan

    2021, Pediatrics and Neonatology
    Citation Excerpt :

    DS typically presents in the first year of life with core symptoms of prolonged, convulsive seizures which may or may not be related to fever or vaccinations, generalized clonic or hemiclonic seizure pattern, and no previous development delay. A previous study reported an age at seizure onset of between 5 and 8 months; however, an age older than 1 year has also been reported.17 The median age at seizure onset in our study was 7 months, and no patient had seizure onset after 1 year of age.

  • Rodent genetic models of neurodevelopmental disorders and epilepsy

    2020, European Journal of Paediatric Neurology
    Citation Excerpt :

    The syndrome is characterised by multiple seizure types including febrile generalized tonic-clonic and focal-clonic, tonic, status epilepticus, myoclonic and atypical absences. The epileptic symptoms are highly refractory to AEDs and the onset of the disease occurs within the first year of life [30]. As recently reviewed by Griffen at al. [31], multiple mouse models of Dravet with SCN1A loss of function exist.

  • Recurrent De Novo Dominant Mutations in SLC25A4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number

    2016, American Journal of Human Genetics
    Citation Excerpt :

    Mutation rates at CpG sites are estimated to be 18.2 times higher than at non-CpG sites due to spontaneous deamination of 5-methylcytosine nucleotides to thymine.65 Most reports of recurrent de novo mutations associated with disease occur in CpG sites causing substitution of arginine residues.66–70 The c.703C>G (p.Arg235Gly) mutation is not located at a CpG site, which may explain the less frequent recurrence.

  • De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome

    2013, American Journal of Human Genetics
    Citation Excerpt :

    Children with Dravet syndrome are prone to repetitive and prolonged epileptic seizures in the setting of fever.2 Although these fever-induced seizures start around the age of 6 months (range = 3–16 months),3 other seizure types occur during the course of the disease, and developmental plateauing is typical in the second year of life. Taking into account SCN1A abnormalities due to single or multiple exons deletions, de novo mutations in SCN1A (MIM 182389) are known to cause Dravet syndrome in ∼75% of affected probands.4

  • Seizure control in a patient with Dravet syndrome and cystic fibrosis

    2013, Epilepsy and Behavior Case Reports
    Citation Excerpt :

    An MRI scan of the brain at the age of three did not reveal any abnormality. Given the clinical course, DS was suspected, and DNA sequence analysis of the SCN1A gene proved a de novo missense mutation, p.S1231T in exon 18, which results in an amino acid substitution in the D3S1 segment [5]. After insufficient sustained effect of antiepileptic treatment with benzodiazepines, barbiturates, primidone, sultiame, and valproic acid in varying combinations, the patient received potassium bromide in addition to valproic acid, primidone, and sultiame, which finally led to a cessation of seizures at the age of 7 years except for rare fever-induced seizures.

View all citing articles on Scopus

The first two authors contributed equally to this work.

View full text