The phenotype of
            <i>SCN8A</i>
            developmental and epileptic encephalopathy

Gardella, Elena; Marini, Carla; Trivisano, Marina; Fitzgerald, Mark P.; Alber, Michael; Howell, Katherine; Darra, Francesca; Siliquini, Sabrina; Bölsterli, Bigna K.; Masnada, Silva; Pichiecchio, Anna; Johannesen, Katrine M; Jepsen, Birgit; Fontana, Elena; Anibaldi, Gaia; Russo, Silvia; Cogliati, Francesca; Montomoli, Martino; Specchio, Nicola; Rubboli, Guido; Veggiotti, Pierangelo; Beniczky, Sándor; Wolff, Markus; Helbig, Ingo; Vigevano, Federico; Scheffer, Ingrid E.; Guerrini, Renzo; Møller, Rikke S.

doi:10.1212/wnl.0000000000006199

Cited by 119 publications

(178 citation statements)

References 35 publications

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“…However, it is important to note that many of the patients suffering from severe SCN8A DEE are unable to walk autonomously. Furthermore, the patients in this intermediate cohort do not suffer from the spasticity and paraplegia or the extrapyramidal/cerebellar symptoms that up to 50% of the severe DEE patients do . A few patients in this cohort (8%) had dyskinesia, which is also seen in both severe DEEs and BFIS families.…”

Section: Discussionmentioning

confidence: 77%

“…44,47 Green indicates intermediate epilepsy (this study). Red indicates DEE variants (previously published). Pink indicates recurrent variants: DEE and intermediate epilepsy…”

Section: Discussionmentioning

confidence: 99%

“…SCN8A ‐positive patients underwent a detailed clinical evaluation, and patients with severe DEE and BFIS were excluded from the study. The criteria for severe DEE were defined as severe, pharmacoresistant epilepsy, and developmental impairment, as previously reported . BFIS is a self‐limiting epilepsy syndrome characterized by afebrile seizures, typically in clusters, with onset between 4 and 8 months.…”

Section: Methodsmentioning

confidence: 99%

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The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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Summary Objective Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A‐related epilepsies. Methods A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results We found 36 probands who presented with an SCN8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance With this study, we explore the electroclinical features of an intermediate SCN8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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Section: Discussionmentioning

confidence: 77%

“…44,47 Green indicates intermediate epilepsy (this study). Red indicates DEE variants (previously published). Pink indicates recurrent variants: DEE and intermediate epilepsy…”

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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“…11 Both variants completely eliminate channel activity, indicating that the affected residues are essential for channel function. 7 It cannot be excluded that other rare genetic variants may contribute to the observed phenotypes. Depolarizing shifts of voltage-dependent activation in the R1638C mutation reduce the number of channels available to open at any membrane voltage and thereby reduce neuronal excitability.…”

Section: Discussionmentioning

confidence: 99%

“…1,7,8 Severe SCN8A DEE (Mendelian Inheritance in Man EIEE13) is characterized by intractable seizures with an average age at seizure onset of 4 months, cognitive deterioration, pyramidal/extrapyramidal signs, progressive cerebral atrophy, and visual impairment leading to cortical blindness. [7][8][9] All affected individuals described to date are monoallelic (heterozygous) carriers of a gain-of-function (GOF) or loss-of-function (LOF) variant in combination with a wild-type (WT) allele. Epileptic myoclonus, spasm-like episodes, and recurrent convulsive status epilepticus are frequently observed.…”

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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A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

Zaman

Tayoun

Goldberg

2019

Ann Clin Transl Neurol

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Objective Pathogenic variants in SCN8A, encoding the voltage‐gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single‐tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers. Methods SCN8A variants were identified via an exome‐based panel of epilepsy‐associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage‐clamp recordings of ionic currents in heterologous cells. Results We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity. Interpretation We present a comprehensive single‐center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.

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The phenotype of SCN8A developmental and epileptic encephalopathy

Cited by 119 publications

References 35 publications

The spectrum of intermediate SCN8A‐related epilepsy

The spectrum of intermediate SCN8A‐related epilepsy

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

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

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