Neuronal mechanisms of mutations in <i>SCN8A</i> causing epilepsy or intellectual disability

Liu, Yuanyuan; Schubert, Julian; Sonnenberg, Lukas; Helbig, Ingo; Hoei‐Hansen, Christina E.; Koko, Mahmoud; Rannap, Maert; Lauxmann, Stephan; Huq, Mahbubul; Schneider, Michael; Johannesen, Katrine M; Kurlemann, Gerhard; Gardella, Elena; Becker, Felicitas; Weber, Yvonne G.; Benda, Jan; Møller, Rikke S.; Lerche, Holger

doi:10.1093/brain/awy326

Cited by 103 publications

(191 citation statements)

References 43 publications

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“…By contrast, the majority of SCN2A/3A/8A ‐associated early onset epilepsies including benign epilepsies and epileptic encephalopathies are caused by GoF missense variants and full gene duplications. The PTVs in SCN2A/3A/8A do not lead to a clinically defined epilepsy syndrome but to heterogeneous NDDs, including autism with or without later onset seizures . Moreover, in the SCN CNV cohort, we observed that patients with duplications presented with significantly earlier seizure onset and responded better to SCBs compared to patients with deletions.…”

Section: Discussionmentioning

confidence: 68%

“…There are only limited reports on pathogenic SCN3A variants; however, most of these present within the first days of life due to GoF effects and there is evidence to show that mutant channels may respond to SCBs . Recent case series of patients with SCN8A variants clearly demonstrate how variants associated with NDDs showed LoF effects, whereas those associated with epilepsy showed GoF effects with good response to SCBs …”

Section: Discussionmentioning

confidence: 99%

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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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Objective Voltage‐gated sodium channels (SCNs) share similar amino acid sequence, structure, and function. Genetic variants in the four human brain‐expressed SCN genes SCN1A/2A/3A/8A have been associated with heterogeneous epilepsy phenotypes and neurodevelopmental disorders. To better understand the biology of seizure susceptibility in SCN‐related epilepsies, our aim was to determine similarities and differences between sodium channel disorders, allowing us to develop a broader perspective on precision treatment than on an individual gene level alone. Methods We analyzed genotype‐phenotype correlations in large SCN‐patient cohorts and applied variant constraint analysis to identify severe sodium channel disease. We examined temporal patterns of human SCN expression and correlated functional data from in vitro studies with clinical phenotypes across different sodium channel disorders. Results Comparing 865 epilepsy patients (504 SCN1A, 140 SCN2A, 171 SCN8A, four SCN3A, 46 copy number variation [CNV] cases) and analysis of 114 functional studies allowed us to identify common patterns of presentation. All four epilepsy‐associated SCN genes demonstrated significant constraint in both protein truncating and missense variation when compared to other SCN genes. We observed that age at seizure onset is related to SCN gene expression over time. Individuals with gain‐of‐function SCN2A/3A/8A missense variants or CNV duplications share similar characteristics, most frequently present with early onset epilepsy (<3 months), and demonstrate good response to sodium channel blockers (SCBs). Direct comparison of corresponding SCN variants across different SCN subtypes illustrates that the functional effects of variants in corresponding channel locations are similar; however, their clinical manifestation differs, depending on their role in different types of neurons in which they are expressed. Significance Variant function and location within one channel can serve as a surrogate for variant effects across related sodium channels. Taking a broader view on precision treatment suggests that in those patients with a suspected underlying genetic epilepsy presenting with neonatal or early onset seizures (<3 months), SCBs should be considered.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Brunklaus

Steckler

et al. 2020

Epilepsia

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“…10,[13][14][15] The less severe familial SCN8A-related disorders show an autosomal dominant pattern of inheritance, whereas the large majority of EIEE13 cases occur de novo. 1,10-12 A small number of heterozygous LOF variants have been found in patients with ID, autism spectrum disorder (ASD), or movement disorders who do not necessarily have epilepsy.…”

Section: Introductionmentioning

confidence: 99%

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

Wengert

Tronhjem²,

Wagnon

et al. 2019

Epilepsia

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Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. Methods: We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results: We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. Significance: These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants 2278 | WENGERT ET al.

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“…Substitution of arginine 1872 by the uncharged amino acids leucine, glutamine, or tryptophan impairs inactivation of the Na v 1.6 channel. [8][9][10] We generated a conditional mouse model of p.Arg1872Trp that recapitulates the early seizure onset and susceptibility to premature death that are characteristic of DEE. 11 Because the pathogenic mechanism of SCN8A encephalopathy is neuronal hyperexcitability due to gainof-function mutations, reduction of transcript abundance is a logical therapeutic strategy.…”

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confidence: 99%

Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

Lenk

Jafar‐Nejad

Hill

et al. 2020

Annals of Neurology

104

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Objective SCN8A encephalopathy is a developmental and epileptic encephalopathy (DEE) caused by de novo gain‐of‐function mutations of sodium channel Nav1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug‐resistant seizures, developmental delay, and cognitive impairment. This study was carried out to determine whether reducing the abundance of the Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure onset and prolong survival in a mouse model of SCN8A encephalopathy. Methods ASO treatment was tested in a conditional mouse model with Cre‐dependent expression of the pathogenic patient SCN8A mutation p.Arg1872Trp (R1872W). This model exhibits early onset of seizures, rapid progression, and 100% penetrance. An Scn1a +/− haploinsufficient mouse model of Dravet syndrome was also treated. ASO was administered by intracerebroventricular injection at postnatal day 2, followed in some cases by stereotactic injection at postnatal day 30. Results We observed a dose‐dependent increase in length of survival from 15 to 65 days in the Scn8a‐R1872W/+ mice treated with ASO. Electroencephalographic recordings were normal prior to seizure onset. Weight gain and activity in an open field were unaffected, but treated mice were less active in a wheel running assay. A single treatment with Scn8a ASO extended survival of Dravet syndrome mice from 3 weeks to >5 months. Interpretation Reduction of Scn8a transcript by 25 to 50% delayed seizure onset and lethality in mouse models of SCN8A encephalopathy and Dravet syndrome. Reduction of SCN8A transcript is a promising approach to treatment of intractable childhood epilepsies. Ann Neurol 2020;87:339–346

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Neuronal mechanisms of mutations in SCN8A causing epilepsy or intellectual disability

Cited by 103 publications

References 43 publications

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

Scn8a Antisense Oligonucleotide Is Protective in Mouse Models of SCN8A Encephalopathy and Dravet Syndrome

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