<i><scp>SCN</scp>8A</i> mutations in Chinese children with early onset epilepsy and intellectual disability

Fung, Lai-Wah Eva; Kwok, Sui-Lam Jamie; Tsui, Stephen Kwok‐Wing

doi:10.1111/epi.13016

Cited by 10 publications

(5 citation statements)

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“…Associated epilepsy syndromes can include Lennox-Gastaut, West, Dravet and Ohtahara. To date epileptic encephalopathy associated with a de novo SCN8A pathogenic variant has been reported in the literature in about 50 individuals (0.6-2.4% of cases with early infantile epileptic encephalopathy) [5,7,83,91,154,[309][310][311][312][313][314][315][316][317][318][319][320][321][322][323]. In most tested cases, SCN8A mutations showed a gain-of-function effect [309,324].…”

Section: Scn8a-related Epileptic Encephalopathymentioning

confidence: 99%

10.2174/1381612823666170809115827

Balestrini

Sisodiya

2018

CPD

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Section: Scn8a-related Epileptic Encephalopathymentioning

confidence: 99%

10.2174/1381612823666170809115827

Balestrini

Sisodiya

2018

CPD

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“…Since the first pathogenic SCN8A variant was discovered in an affected individual with epilepsy 1 , a wide clinical spectrum of neurodevelopmental phenotypes has been reported. The spectrum ranges from benign familial infantile epilepsy (BFIE) with self-limiting seizures and typical cognitive development [2][3][4] , over an intermediate phenotype with variable seizure onset, treatable seizures and mild intellectual disability (ID) 5 to early onset developmental and epileptic encephalopathies (DEE) with moderate to severe ID [6][7][8][9][10] , often with movement disorders, cortical visual impairment, severe gastrointestinal symptoms and increased risk of premature death 7,[10][11][12][13][14][15] . Furthermore, rare clinical presentations with ID, autism spectrum disorder (ASD) and movement disorders without epilepsy have been described [16][17][18][19] .…”

Section: Introductionmentioning

confidence: 99%

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

Johannesen

Liu

Koko

et al. 2021

Brain

103

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We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel NaV1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups could be identified: 1) Benign familial infantile epilepsy (BFIE) (n = 15, normal cognition, treatable seizures), 2) intermediate epilepsy (n = 33, mild ID, partially pharmaco-responsive), 3) developmental and epileptic encephalopathy (DEE, n = 177, severe ID, majority pharmaco-resistant), 4) generalized epilepsy (n = 20, mild to moderate ID, frequently with absence seizures), 5) unclassifiable epilepsy (n = 127), and 6) neurodevelopmental disorder without epilepsy (n = 20, mild to moderate ID). Groups 1–3 presented with focal or multifocal seizures (median age of onset: four months) and focal epileptiform discharges, whereas the onset of seizures in group 4 was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human NaV1.6 channels and whole-cell patch-clamping. Two variants causing DEE showed a strong gain-of-function (GOF, hyperpolarising shift of steady-state activation, strongly increased neuronal firing rate), and one variant causing BFIE or intermediate epilepsy showed a mild GOF (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (LOF, reduced current amplitudes, depolarising shift of steady-state activation, reduced neuronal firing). Including previous studies, functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested GOF variant had either focal (97, groups 1–3), or unclassifiable epilepsy (39), whereas 34 with a LOF variant had either generalized (14), no (11) or unclassifiable (6) epilepsy; only three had DEE. Computational modeling in the GOF group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. GOF variant carriers responded significantly better to sodium channel blockers (SCBs) than to other anti-seizure medications, and the same applied for all individuals of groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of LOF variant carriers and the extent of the electrophysiological dysfunction of the GOF variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that SCBs present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

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“…In the mammalian brain, the most highly expressed VGSC α subunits are SCN1A , SCN2A , SCN3A , and SCN8A, which encode Na v 1.1, Na v 1.2, Na v 1.3, and Na v 1.6 respectively. Mutations in these VGSCs are responsible for an increasing number of epilepsy syndromes (Escayg et al, 2000; Estacion et al, 2014; Fung et al, 2015; Howell et al, 2015; Schwarz et al, 2016; Sugawara et al, 2001; Surovy et al, 2016). Mutations in SCN1A have been established as the main cause of Dravet syndrome and have also been identified in some families with generalized epilepsy with febrile seizures plus (GEFS+) (Escayg and Goldin, 2010; Scheffer et al, 2009; Volkers et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

SCN3A deficiency associated with increased seizure susceptibility

Lamar

Vanoye

Calhoun

et al. 2017

Neurobiology of Disease

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Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction. Voltage clamp analysis showed no detectable sodium current in a heterologous expression system expressing the SCN3A-L247P variant. Furthermore, cell surface biotinylation demonstrated a reduction in the amount of SCN3A-L247P at the cell surface, suggesting the SCN3A-L247P variant is a trafficking-deficient mutant. To further explore the possible clinical consequences of reduced SCN3A activity, we investigated the effect of a hypomorphic Scn3a allele (Scn3aHyp) on seizure susceptibility and behavior using a gene trap mouse line. Heterozygous Scn3a mutant mice (Scn3a+/Hyp) did not exhibit spontaneous seizures nor were they susceptible to hyperthermia-induced seizures. However, they displayed increased susceptibility to electroconvulsive (6 Hz) and chemiconvulsive (flurothyl and kainic acid) induced seizures. Scn3a+/Hyp mice also exhibited deficits in locomotor activity and motor learning. Taken together, these results provide evidence that loss-of-function of SCN3A caused by reduced protein expression or deficient trafficking to the plasma membrane may contribute to increased seizure susceptibility.

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SCN8A mutations in Chinese children with early onset epilepsy and intellectual disability

Cited by 10 publications

References 4 publications

10.2174/1381612823666170809115827

10.2174/1381612823666170809115827

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

SCN3A deficiency associated with increased seizure susceptibility

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