Relationship of electrophysiological dysfunction and clinical severity in<i>SCN2A</i>-related epilepsies

Lauxmann, Stephan; Verbeek, Nienke E.; Liu, Yuanyuan; Zaichuk, Mariana; Müller, Stephan; Lemke, Johannes R.; Kempen, Marjan J. A. van; Lerche, Holger; Hedrich, Ulrike B. S.

doi:10.1002/humu.23619

Cited by 31 publications

(51 citation statements)

References 38 publications

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“…Epilepsy patients with distinct types of SCN2A variants present with seizures at different ages; those with GoF missense variants usually present within the first 2 months after birth, whereas those with LoF missense variants present on average 9 months later. Those with PTVs exhibit seizures typically after 3 years . Furthermore, CNV duplications covering SCN2A are associated with neonatal onset seizures.…”

Section: Discussionmentioning

confidence: 99%

“…Among SCN2A variant carriers, the responsiveness to medication appears to be more complex and directly linked to variant function. Those with early onset seizures (<3 months) due to GoF effects appear to respond well to SCBs, whereas those with later onset epilepsy and NDDs due to LoF variants often remain treatment resistant . 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 .…”

Section: Discussionmentioning

confidence: 99%

“…Those with PTVs exhibit seizures typically after 3 years. 15,16 Furthermore, CNV duplications covering SCN2A are associated with neonatal onset seizures. This mirrors Allen Brain Atlas data illustrating that SCN2A is highly expressed in the prenatal stage, in particular at the mid/ late fetal-neonatal stage.…”

Section: Age-specific Expression Of Sodium Channelsmentioning

confidence: 99%

“…Variants in SCN2A have been identified in different forms of infantile epilepsy, including benign infantile seizures, developmental and epileptic encephalopathies (DEEs), Ohtahara syndrome, and West syndrome . Recent studies propose that GoF missense variants in SCN2A are associated with neonatal or early infantile seizures presenting at <3 months of age, whereas LoF missense and PTVs are associated with later onset epilepsy and autism spectrum disorder (ASD)/NDDs . SCN8A encephalopathy presents in infancy with multiple seizure types including focal, tonic, clonic, myoclonic absence seizures, and epileptic spasms .…”

Section: Introductionmentioning

confidence: 99%

“…[11][12][13] Recent studies propose that GoF missense variants in SCN2A are associated with neonatal or early infantile seizures presenting at <3 months of age, whereas LoF missense and PTVs are associated with later onset epilepsy and autism spectrum disorder (ASD)/NDDs. [14][15][16][17][18] SCN8A encephalopathy presents in infancy with multiple seizure types including focal, tonic, clonic, myoclonic absence seizures, and epileptic spasms. [19][20][21][22] The developmental outcome is poor, and many patients have motor manifestations, including hypotonia and movement disorders.…”

Section: Introductionmentioning

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: 99%

Section: Discussionmentioning

confidence: 99%

Section: Age-specific Expression Of Sodium Channelsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Brunklaus

Steckler

et al. 2020

Epilepsia

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Further delineation of phenotypic spectrum of SCN2A‐related disorder

Richardson

Baralle

Bennett

et al. 2021

American J of Med Genetics Pt A

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SCN2A‐related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype–genotype association in SCN2A‐related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype–phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel‐blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.

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Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy

Miao

Tang

Jia

et al. 2020

Molec Gen & Gen Med

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BackgroundTo investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A‐related developmental epileptic encephalopathy (DEE).MethodsWe enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole‐cell patch‐clamp recording.ResultsThe phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast‐inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature.ConclusionThese findings provided the insights into the phenotype–genotype–funotype relationships of SCN2A‐related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.

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Relationship of electrophysiological dysfunction and clinical severity inSCN2A-related epilepsies

Cited by 31 publications

References 38 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

Further delineation of phenotypic spectrum of SCN2A‐related disorder

Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy

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