Electroclinical features of epileptic encephalopathy caused by <i><scp>SCN8A</scp></i> mutation

Takahashi, Satoru; Yamamoto, Shigeo; Okayama, Akie; Araki, Akiko; Saitsu, Hirotomo; Matsumoto, Naomichi; Azuma, Hiroshi

doi:10.1111/ped.12622

Cited by 14 publications

(14 citation statements)

References 12 publications

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“…1A). Two missense mutations of Arg1872 were described in seven patients1, 3, 11, 18 and we describe a third substitution in two patients, making this the most frequently mutated residue. The CpG dinucleotides in the codons for Arg1617 and Arg1872 are mutational hotspots (Fig.…”

Section: Introductionmentioning

confidence: 69%

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Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

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ObjectiveThe early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage‐gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.MethodsClinical exome sequencing was carried out on patients with early‐onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G‐protein subunit Gβγ, and sodium channel subunit β1 were assessed by coimmunoprecipitation.ResultsWe identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady‐state inactivation. Protein interactions were not affected.InterpretationRecurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain‐of‐function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss‐of‐function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene‐ and mutation‐specific treatments.

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Section: Introductionmentioning

confidence: 69%

“…Clinical features include seizure onset before 18 months of age, intellectual disability, and developmental delay 1, 2, 3, 4, 5. Movement disorders are common and 50% of affected individuals are nonambulatory 1, 3, 6, 7, 8, 9, 10, 11, 12. SUDEP (sudden unexpected death in epilepsy) is reported in 10% of cases 1, 2, 4, 5…”

Section: Introductionmentioning

confidence: 99%

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

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“…To date, more than 100 SCN8A mutations have been reported, an overwhelming majority of which were de novo [12, 14, 17–29]. Only few inherited SCN8A mutations were reported.…”

Section: Discussionmentioning

confidence: 99%

“…Among these mutations, Arg 1872 and Arg 1617 might be two mutational hotspots, which had been identified in more than ten independent patients [14, 17, 23, 26]. In vitro functional analysis proved that both of the mutations Arg 1872 and Arg 1617 impaired the Na v 1.6 channel transition from open state to inactivated state, resulting in channel hyperactivity [30].…”

Section: Discussionmentioning

confidence: 99%

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

et al. 2017

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Background SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.MethodsTo identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.ResultsA heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.ConclusionsOur findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s12881-017-0460-1) contains supplementary material, which is available to authorized users.

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“…The majority of the functionally tested SCN8A mutations result in gain-of-function (GOF), causing the Na v 1.6 channel to be hyperactive, leading to increased neuronal firing [1,[4][5][6]. Thus, it appears that neuronal hyperexcitability caused by GOF mutations is the predominant mechanism underlying epilepsy in SCN8A encephalopathy.…”

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confidence: 99%