Mutations in <i>SCN3A</i> cause early infantile epileptic encephalopathy

Zaman, Tariq; Helbig, Ingo; Božović, Ivana Babić; DeBrosse, Suzanne D.; Bergqvist, A. Christina; Wallis, Kimberly; Medne, Līvija; Maver, Aleš; Peterlin, Borut; Helbig, Katherine L.; Zhang, Xiaohong; Goldberg, Ethan M.

doi:10.1002/ana.25188

Cited by 80 publications

(84 citation statements)

References 59 publications

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“…By comparison, variants in familial SCN disease such as SCN4A periodic paralysis/myotonia or SCN9/10/11A ‐related pain disorders are better tolerated for both truncating and missense variants (Figure ) . Our analysis further supports the emerging evidence that SCN3A , which shows strong depletion for PTV and missense variants, is a good candidate gene for epilepsy, although only a few patients have been reported to date …”

Section: Discussionsupporting

confidence: 80%

“…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 . Recent case series of patients with SCN8A variants clearly demonstrate how variants associated with NDDs showed LoF effects, whereas those associated with epilepsy showed GoF effects with good response to SCBs …”

Section: Discussionmentioning

confidence: 99%

“…43 Our analysis further supports the emerging evidence that SCN3A, which shows strong depletion for PTV and missense variants, is a good candidate gene for epilepsy, although only a few patients have been reported to date. 27,28 Additionally, the variant constraint results indicate that, besides SCN1A/2A/3A/8A, other members of the SCN gene family are unlikely to be associated with severe epilepsy/ NDDs. For example, SCN9A has an established role in familial pain disorders 43 ; however, its pathogenicity in severe forms of epilepsy has never been confirmed.…”

Section: Scn Constraint Analysis Aids Variant Interpretationmentioning

confidence: 99%

“…[15][16][17][18]40 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. 28 Recent case series of patients with SCN8A variants clearly demonstrate how variants associated with NDDs showed LoF effects, whereas those associated with epilepsy showed GoF effects with good response to SCBs. 19,24,26,53 This study presents clinical and experimental evidence that GoF SCN2/3/8A variants and copy number duplications respond well to sodium channel blockage.…”

Section: Clinical Relevance and Implications For Precision Medicinementioning

confidence: 99%

“…25,26 SCN3A-associated epilepsies are clinically heterogeneous, presenting with mainly GoF missense variants, early onset seizures, epileptic encephalopathy, polymicrogyria, and developmental impairment. 27,28 To better understand the biology of seizure susceptibility in SCN-related epilepsies, our aim was to determine similarities and differences between sodium channel disorders and apply variant constraint analysis to identify severe sodium channel disease. This approach allowed us to develop a broader perspective on precision treatment than on an individual gene or variant level and to recognize common patterns among SCNrelated disorders informing clinical practice.…”

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: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Scn Constraint Analysis Aids Variant Interpretationmentioning

confidence: 99%

Section: Clinical Relevance and Implications For Precision Medicinementioning

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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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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Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

Hull

O’Malley²,

Chen

et al. 2020

Ann Clin Transl Neurol

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Objective: Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked to DEEs. While these VGSC-linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that Scn2a-, Scn3a-, and Scn8a-linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (I Na) and pyramidal neuron hyperexcitability. In contrast, Scn1a-linked DEE variants, in general, are loss-of-function, resulting in decreased I Na and hypoexcitability of fast-spiking interneurons. VGSC β1 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology. Methods: We investigated excitability defects in pyramidal and parvalbumin-positive (PV +) interneurons in the Scn1b −/− model of EIEE52. We also used Scn1b FL/FL mice to delete Scn1b in specific neuronal populations. Results: Scn1b −/− cortical PV + interneurons were hypoexcitable, with reduced I Na density. Scn1b −/− cortical pyramidal neurons had population-specific changes in excitability and impaired I Na density. Scn1b deletion in PV + neurons resulted in 100% lethality, whereas deletion in Emx1 + or Camk2a + neurons did not affect survival. Interpretation: This work suggests that SCN1B-linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.

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Mutations in SCN3A cause early infantile epileptic encephalopathy

Cited by 80 publications

References 59 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

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

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

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