Enhanced slow inactivation contributes to dysfunction of a recurrent <i>SCN2A</i> mutation associated with developmental and epileptic encephalopathy

Ganguly, Surobhi; Thompson, Christopher H.; George, Alfred L.

doi:10.1113/jp281834

Cited by 13 publications

(15 citation statements)

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“…The mother of Patient 48 carried a mosaic SCN2A variant R853Q with a ratio of about 20% in the peripheral blood. R853Q is a recurrent variation that has been reported repeatedly in the literature ( Ganguly et al, 2021 ). Both the Patient 48 and two other patients with the same variant in our study, as well as patients with the same variant reported in the literature, were diagnosed with West syndrome.…”

Section: Discussionmentioning

confidence: 95%

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Zeng

Yang

Duan

et al. 2022

Front. Mol. Neurosci.

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ObjectiveThe aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.MethodsThe SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.ResultsIn 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.ConclusionThe phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

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Section: Discussionmentioning

confidence: 95%

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Zeng

Yang

Duan

et al. 2022

Front. Mol. Neurosci.

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“…Conversely, R853Q patient iPSC-derived neurons showed no significant differences in electrophysiological properties at DIV 21, despite a LoF phenotype described in heterologous expression systems and in silico prediction of reduced neuronal firing (7,8,11). However, examination at an earlier (DIV 13-15) and later (DIV 28-31) time points revealed an increase in membrane capacitance and neuronal excitability at rest, respectively.…”

Section: Discussionmentioning

confidence: 87%

“…Conversely, patients with the de novo missense SCN2A variant R853Q present with late-onset (>3 months) seizures with neurodevelopmental delay are resistant to treatment with SCBs or other anti-epileptic drugs (4)(5)(6). A LoF has been reported as the principle biophysical mechanism for this variant (7,8,11).…”

Section: Introductionmentioning

confidence: 99%

Distinctivein vitrophenotypes in iPSC-derived neurons from patients with gain- and loss-of-functionSCN2Adevelopmental and epileptic encephalopathy

Mao

Mattei

Rollo

et al. 2023

Preprint

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SCN2Aencodes Nav1.2, an excitatory neuron voltage-gated sodium channel and major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with nature ofSCN2Avariant dysfunction with gain-of-function (GoF) cases presenting with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age. Here, we established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrentSCN2ADEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Patient-derived iPSC lines were differentiated using aNeurogenin-2overexpression yielding populations of cortical-like glutamatergic neurons. Electrophysiological and transcriptomic profiles were assessed after 2-4 weeks in culture. Increased neuronal activity at both cellular and network level was observed for R1882Q iPSC-derived neurons at three weeks of differentiation. In contrast, R853Q neurons showed only subtle changes in excitability after four weeks in vitro. In alignment with the reported efficacy in some GoFSCN2Apatients, phenytoin (sodium channel blocker) reduced excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways pointed at the shared mechanisms underlyingSCN2ADEE.

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“…S3). Population variants were chosen based on minor allele frequency greater than 0.0001 in gnomAD (19), while pathogenic variants were chosen to represent either gain-and loss-of-function effects based on previously published data (10,18,(20)(21)(22).…”

Section: Analytical Validity Of Automated Patch Clamp For Nav12mentioning

confidence: 99%

Epilepsy-associatedSCN2A(Na_V1.2) Variants Exhibit Diverse and Complex Functional Properties

Thompson¹,

Potet²,

Abramova³

et al. 2023

Preprint

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Pathogenic variants in neuronal voltage-gated sodium (NaV) channel genes including SCN2A, which encodes NaV1.2, are frequently discovered in neurodevelopmental disorders with and without epilepsy. SCN2A is also a high confidence risk gene for autism spectrum disorder (ASD) and non-syndromic intellectual disability (ID). Previous work to determine the functional consequences of SCN2A variants yielded a paradigm in which predominantly gain-of-function (GoF) variants cause epilepsy whereas loss-of-function (LoF) variants are associated with ASD and ID. However, this framework is based on a limited number of functional studies conducted under heterogenous experimental conditions whereas most disease-associated SCN2A variants have not been functionally annotated. We determined the functional properties of more than 30 SCN2A variants using automated patch clamp recording to assess the analytical validity of this approach and to examine whether a binary classification of variant dysfunction is evident in a larger cohort studied under uniform conditions. We studied 28 disease-associated variants and 4 common population variants using two distinct alternatively spliced forms of NaV1.2 that were heterologously expressed in HEK293T cells. Multiple biophysical parameters were assessed on 5,858 individual cells. We found that automated patch clamp recording provided a valid high throughput method to ascertain detailed functional properties of NaV1.2 variants with concordant findings for a subset of variants that were previously studied using manual patch clamp. Additionally, many epilepsy-associated variants in our study exhibited complex patterns of gain- and loss-of-function properties that are difficult to classify overall by a simple binary scheme. The higher throughput achievable with automated patch clamp enables study of a larger number of variants, greater standardization of recording conditions, freedom from operator bias, and enhanced experimental rigor valuable for accurate assessment of NaV channel variant dysfunction. Together, this approach will enhance our ability to discern relationships between variant channel dysfunction and neurodevelopmental disorders.

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Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy

Abstract: support-information-section).

Cited by 13 publications

References 51 publications

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Distinctivein vitrophenotypes in iPSC-derived neurons from patients with gain- and loss-of-functionSCN2Adevelopmental and epileptic encephalopathy

Epilepsy-associatedSCN2A(Na_V1.2) Variants Exhibit Diverse and Complex Functional Properties

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Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy

Abstract: support-information-section).

Cited by 13 publications

References 51 publications

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Distinctivein vitrophenotypes in iPSC-derived neurons from patients with gain- and loss-of-functionSCN2Adevelopmental and epileptic encephalopathy

Epilepsy-associatedSCN2A(NaV1.2) Variants Exhibit Diverse and Complex Functional Properties

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Epilepsy-associatedSCN2A(Na_V1.2) Variants Exhibit Diverse and Complex Functional Properties