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Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.

ABSTRACT: We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of voltage-gated sodium (Na_V ) channel function, we examined the effects of human SCN1B^R46C (β1^R46C ), SCN1B^R60C (β1^R60C ), and SCN1B^V158M (β1^V158M ) on the three predominant brain Na_V channel subtypes Na_V 1.1 (SCN1A), Na_V 1.2 (SCN2A), and Na_V 1.6 (SCN8A). We observed a shift toward more depolarizing potentials of conductance-voltage relationships (Na_V 1.2/β1^R46C , Na_V 1.2/β1^R60C , Na_V 1.6/β1^R46C , Na_V 1.6/β1^R60C , and Na_V 1.6/β1^V158M ) and channel availability (Na_V 1.1/β1^R46C , Na_V 1.1/β1^V158M , Na_V 1.2/β1^R46C , Na_V 1.2/β1^R60C , and Na_V 1.6/β1^V158M ), and detected a slower recovery from fast inactivation for Na_V 1.1/β1^V158M . Combined with modeling data indicating perturbation-induced structural changes in β1, these results suggest that the SCN1B variants reported here can disrupt normal Na_V channel function in the brain, which may contribute to EIEE52.

SUBMITTER: Scala M

PROVIDER: S-EPMC8585727 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.

Scala Marcello M Efthymiou Stephanie S Sultan Tipu T De Waele Jolien J Panciroli Marta M Salpietro Vincenzo V Maroofian Reza R Striano Pasquale P Van Petegem Filip F Houlden Henry H Bosmans Frank F

Epilepsia 20210426 6

We identified nine patients from four unrelated families harboring three biallelic variants in SCN1B (NM_001037.5: c.136C>T; p.[Arg46Cys], c.178C>T; p.[Arg60Cys], and c.472G>A; p.[Val158Met]). All subjects presented with early infantile epileptic encephalopathy 52 (EIEE52), a rare, severe developmental and epileptic encephalopathy featuring infantile onset refractory seizures followed by developmental stagnation or regression. Because SCN1B influences neuronal excitability through modulation of ...[more]

PMID: 33901312

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Project description:ObjectiveEpileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the fact that thousands of genes are involved in neurodevelopment. Therefore, high-throughput next-generation sequencing (NGS) was used to investigate the genetic causes of non-syndromic cryptogenic neonatal/infantile EE (NIEE).MethodsWe have selected a cohort of 31 patients with seizure cryptogenic NIEE and seizure onset before 24 months. All investigations including metabolic work-up, were negative. Using NGS, we distinguished a panel of 430 epilepsy-associated genes by NGS was utilized to identify possible pathogenic variants in the patients. Segregation analysis and multiple silico analysis prediction tools were used for pathogenicity assessment. The identified variants were classified as "pathogenic," "likely pathogenic" and "uncertain significance," according to the American College of Medical Genetics (ACMG) guidelines.ResultsPathogenic or likely pathogenic variants were identified in six genes (ALG13 [1], CDKL5 [2], KCNQ2 [2], PNPO [1], SCN8A [1], SLC9A6 [2]) in 9 NIEE patients (9/31; 29%). Variants of uncertain significance (VUS) were found in DNM1 and TUBA8 in 2 NIEE patients (2/31; 6%). Most phenotypes in our cohort matched with those reported cases.SignificanceThe diagnostic rate (29%) of pathogenic and likely pathogenic variants was comparable to the recent studies of early-onset epileptic encephalopathy, indicating that gene panel analysis through NGS is a powerful tool to investigate cryptogenic NIEE in patients. Six percent of patients had neurometabolic disorders. Some of our diagnosed cases illustrated that successful molecular investigation may allow a better treatment strategy and avoid unnecessary and even invasive investigations. Functional analysis could be performed to further study the pathogenicity of the VUS identified in DNM1 and TUBA8.

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Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.

Publications

Homozygous SCN1B variants causing early infantile epileptic encephalopathy 52 affect voltage-gated sodium channel function.

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