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Cited by 338Epilepsy research and treatmentIon channel regulation and functionGenetics and Neurodevelopmental Disorders

Progress in Understanding and Treating SCN2A-Mediated Disorders

Open access
Sanders, Stephan J., Campbell, Arthur J., Cottrell, Jeffrey R., Moller, Rikke S., Wagner, Florence F., Auldridge, Angie L., Bernier, Raphael A., Catterall, William A. +17 more·2018·Trends in Neurosciences
DOI 10.1016/j.tins.2018.03.011PMC PMC6015533
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Abstract

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel Na V 1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders.

Integrity signals

Registry

Crossref · 10.1016/j.tins.2018.03.011

Cites

84 of 84 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

45 of 88 cited sources checked · 15 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    SCN2A variants are primarily associated with three distinct disorders: infantile epileptic encephalopathy, benign familial infantile seizures, and autism spectrum disorder/intellectual disability.

    “Variants in SCN2A are primarily associated with three distinct disorders [24,25]: 1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay; 2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-t”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [24] source
    • cites [25] source

      The classification in ‘Previously unpublished patients’ (p. 4) supports the broad association with benign neonatal/infantile seizures, epileptic encephalopathy, and intellectual disability or autism without epilepsy. But it distinguishes four groups, including a separate encephalopathy group with infantile or childhood epilepsy; the source does not limit that group to infantile onset. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Early in development, NaV1.2 is the only sodium channel isoform expressed in the axon initial segment, the site of action potential initiation.

    “Early on, NaV1.2 is the only sodium channel isoform expressed in the axon initial segment (AIS) [3,16,17], an axonal subcompartment located proximal to the soma that is the site of action potential initiation [18].”
    Quote in the paperSubstantial claim1 of 4 sources checked
    • cites [3] source
    • cites [16] source

      The Discussion states that before NaV1.6 appeared, only NaV1.2 was observed at initial segments. The study examined developing retinal ganglion cells, so it does not establish that this is true of axon initial segments generally. The action-potential-initiation clause has a separate citation and is not attributed to this paper here. (LLM, conf=0.83)

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    • cites [17] source
    • cites [18] source
  • Premisecitation

    Only about 20 of the hundreds of disorder-associated SCN2A variants have been electrophysiologically assessed to date.

    “To date, only about 20 of the hundreds of disorder-associated variants have been electrophysiologically assessed (summarized in [24,25]).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [24] source

      The Results (page unavailable) report that seven BIFS and three epileptic-encephalopathy variants had been characterized electrophysiologically, and the Methods report electrophysiological examination of 11 ASD-associated variants—about 20 in total. But the paper’s literature review identified 148 disorder-associated SCN2A variants (117 unique), not the claimed hundreds. (LLM, conf=0.86)

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    • cites [25] source

      The Functional studies discussion (p. 17) says that only a small number of identified SCN2A mutations had been studied functionally, and reports four additional analyses. It does not establish that the number electrophysiologically assessed was about 20. The Results (p. 5) count 201 patients, not hundreds of distinct variants, so that denominator is also unsupported by this copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Compartmental modeling can provide insight into the net effect on neuronal excitability in such conditions.

    “Compartmental modeling can provide insight into the net effect on neuronal excitability in such conditions [24].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
  • Premisecitation

    Although epileptic encephalopathy often presents with neonatal seizures, seizure onset after three months probably occurs in 20%-40% of cases.

    “While epileptic encephalopathy frequently presents with seizures in the neonatal period, with some families retrospectively reporting rhythmic movements in utero, it is likely that seizure onset after three months occurs in 20%-40% of cases [24,25].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [24] source

      The Results (page not provided) describe SCN2A-associated epileptic encephalopathy as characterized by infantile seizures, but do not give a neonatal-onset frequency. Searches for seizure onset after three months and the 20%–40% estimate found no passage addressing either figure. (LLM, conf=0.74)

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    • cites [25] source

      The encephalopathy sections (pp. 5–6) report 71 patients with seizure onset before three months and 58 with onset at three months or later, supporting the point that later onset occurs. Among patients with known onset in those groups, the latter is about 45%, not the claimed 20%–40%; the passages also do not establish how often onset was specifically neonatal. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 17
  • May combine two claims. 44
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NaV1.2 is widely expressed throughout the human central nervous system but not in peripheral tissues.

    “NaV1.2 is widely expressed throughout the human central nervous system, but not in peripheral tissues [7,8].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [7] source

      The “Gene expression across tissues” section describes broad expression patterns across brain and other tissues, but does not report NaV1.2 expression. Searches for “NaV1.2,” “SCN2A,” and the claimed CNS-versus-peripheral pattern found no passage addressing that specific claim. (LLM, conf=0.76)

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    • cites [8] source

      The Global transcriptome dynamics section describes gene expression across human brain regions, but the passages in our copy do not address NaV1.2 or its distribution outside the brain. Searches for NaV1.2, SCN2A, and peripheral-tissue expression found no passage supporting the claimed CNS-versus-peripheral distinction. (LLM, conf=0.75)

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Autism spectrum disorder/intellectual disability is characterized by global developmental delay, particularly in social and language milestones.

    “3) autism spectrum disorder/intellectual disability (ASD/ID), characterized by global developmental delay, particularly of social and language milestones.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [24] source

      The Results (page not provided) report that many individuals with ASD have co-existing intellectual disability and developmental delay. The paper does not characterize that delay as global or say it particularly affects social and language milestones. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [25] source

      The section “Intellectual disability and/or autism without epilepsy” (p. 7) reports SCN2A-related cases with autism and moderate to severe intellectual disability. It does not characterize this subgroup as having global developmental delay, particularly in social and language milestones; searches for those developmental features found no supporting passage. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Benign familial infantile seizures are characterized by infantile-onset seizures before 12 months of age that resolve by 2 years of age without overt long-term neuropsychiatric sequelae.

    “2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-term neuropsychiatric sequelae;”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [24] source

      The Introduction says BIFS seizures resolve before age two, and the Discussion describes their resolution without further apparent neurological impairment. The paper calls them infantile seizures but does not specify onset before 12 months, so that age cutoff is not supported by our copy. (LLM, conf=0.84)

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    • cites [25] source

      The Benign (familial) neonatal/infantile seizures section (p. 5) reports seizure freedom by age 2 and normal cognitive development in most cases. But onset ranged up to 23 months, one patient had isolated seizures at age 14, and another developed partial cognitive deterioration. The categorical age limits and absence of long-term sequelae therefore overstate the source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Most children with SCN2A variants fit one of the three main categories, but exceptions include epileptic encephalopathy with choreoathetoid movements, benign infantile seizures with late-onset episodic ataxia, childhood-onset epileptic encephalopathy, and schizophrenia.

    “While most children with SCN2A variants fit into one of these three categories, there are some exceptions, including epileptic encephalopathy with choreoathetoid movements [26,27], benign infantile seizures with late-onset episodic ataxia [28–31], childhood-onset epileptic encephalopathy [32], and schizophrenia [33,34].”
    Quote in the paperNot a substantial claim2 of 8 sources checked
    • cites [26] source
    • cites [27] source
    • cites [28] source
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    • cites [33] source
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    • cites [34] source
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Infantile epileptic encephalopathy is characterized by infantile-onset seizures before 12 months of age followed by neurodevelopmental delay.

    “1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay;”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [24] source

      The Results describe SCN2A-associated epileptic encephalopathy as involving infantile seizures and moderate to severe developmental delay. Our copy does not specify seizure onset before 12 months or establish that developmental delay follows the seizures; it also describes a group of SCN2A cases rather than all infantile epileptic encephalopathy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [25] source

      The classification in “Previously unpublished patients” (p. 4) links early infantile epilepsy to seizures before 3 months and impaired cognitive development; the patient description (p. 5) likewise reports onset within 3 months and intellectual disability. These passages support early seizures and developmental impairment, but they do not establish that delay followed the seizures or define this group by a before-12-month cutoff. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sodium channels typically must complete activation, inactivation, and recovery to be available for subsequent activation, though exceptions exist.

    “While exceptions have been noted, sodium channels typically must go through all three steps to be available for subsequent activation [5].”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Inhibitory interneurons largely express NaV1.1 rather than NaV1.2, though NaV1.2 has been found in some multipolar and bouquet-class interneurons in mouse.

    “Inhibitory interneurons largely express NaV1.1 instead of NaV1.2 [9,10], though NaV1.2 channels have been identified in some multipolar and bouquet-class interneurons in mouse [11].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] source
    • cites [10] source

      The developing mouse hippocampus results (page unavailable) report NaV1.1 in nearly all examined parvalbumin-positive interneurons, supporting the NaV1.1 expression portion. The cited paper does not establish that inhibitory interneurons generally express NaV1.1 instead of NaV1.2. The multipolar and bouquet-class exception is attached to a different citation, [11], so it is not assessed here. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [11] source

  • May combine two claims.

    Interpretationreasoning

    The effectiveness of sodium channel blockers in early-onset SCN2A seizures is opposite to current guidelines for empiric neonatal seizure treatment and is a compelling reason for rapid genetic testing.

    “Of note, this is the opposite of current guidelines for empiric neonatal seizure treatment [53] and is a compelling reason for rapid genetic testing for this condition [54,55].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [53] source

      The cited paper’s Summary and Table 6 (page not available in our copy) discuss treatment of infantile seizures, but do not give an empiric neonatal treatment recommendation to compare with sodium-channel blockers. A search for neonatal treatment and SCN2A found no passage establishing the claimed opposition; the separate rapid-testing rationale is cited to other sources [54,55]. (LLM, conf=0.74)

      Experimental — accuracy not yet measured
    • cites [54] source

      The Discussion (page not available) recommends comprehensive genetic testing during the initial evaluation of early-life epilepsy because a genetic diagnosis could help identify targeted treatments. It does not establish that sodium channel blockers are effective for early-onset SCN2A seizures or specifically call for rapid testing for that condition; it describes SCN2A treatment recommendations as anecdotal and reports no SCN2A cases in its cohort. The guideline comparison is cited separately to [53]. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [55] source

      The Discussion (page not provided) supports genetic testing for newborns with epilepsy because it may guide targeted treatment, and the Results identify three infants with SCN2A variants. The paper does not establish that rapid testing for SCN2A specifically is warranted by sodium-channel blocker effectiveness. The guideline comparison is attached to a different citation, [53], so it is not assessed here. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The ten human voltage-gated sodium channels derive from this ancestral NaV1 channel, and different model organisms reflect stages in this differentiation.

    “The ten voltage-gated sodium channels in humans are derived from this NaV1 channel (Figure 3) [45–47] with different model organisms reflecting stages in this differentiation (Table 3).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [45] source

      The Abstract and Discussion (pages unavailable) trace the human SCN gene family to a single ancestral vertebrate gene and compare duplications across vertebrate lineages, supporting the evolutionary account. But the Introduction says the tenth human gene, SCN7A, produces Naₓ, which is not voltage-gated; the source therefore does not support calling all ten human channels voltage-gated. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [46] source
    • cites [47] source

  • May combine two claims.

    Premisecitation

    Seizure onset after three months often meets criteria for West syndrome, with infantile spasms and hypsarrhythmia on EEG, and can evolve to Lennox-Gastaut syndrome with multiple seizure types as the child ages.

    “In contrast, onset after three months often meets criteria for West Syndrome, with infantile spasms and a hypsarrhythmia pattern on EEG, evolving to Lennox-Gastaut syndrome with multiple seizure types as the child gets older [25].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] source

      The infantile/childhood epilepsy section (p. 6) reports 16 patients with West syndrome or infantile spasms, five of whom later developed Lennox-Gastaut syndrome. The seizure-outcome section (p. 17) reports hypsarrhythmia on EEG in children with West syndrome. But the paper says the majority of the remaining patients with onset after three months had unclassifiable epilepsies, so the claim overstates how commonly that onset leads to West syndrome and subsequent Lennox-Gastaut syndrome. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    NaV1.5 is expressed in the heart, and its disruption can cause cardiac arrhythmias including heart block, long QT, Brugada syndrome, and cardiomyopathy.

    “NaV1.5 is expressed in the heart, and its disruption can lead to cardiac arrhythmias, including heart block, long QT, Brugada syndrome, and cardiomyopathy [52].”
    Quote in the paperSubstantial claim1 of 1 sources checked

  • May combine two claims.

    Premisecitation

    Some reports describe clinical improvement with less mainstream medications, including lidocaine for infantile epileptic encephalopathy, ethosuximide for late-onset seizures, and acetazolamide for episodic ataxia, though data on generalizability are limited.

    “Some reports have described clinical improvement with less mainstream medications, including lidocaine in children with infantile epileptic encephalopathy [56,57], ethosuximide for late-onset seizures [25], and acetazolamide for episodic ataxia [28,29], though data on the generalizability of these effects are limited.”
    Quote in the paperNot a substantial claim2 of 5 sources checked
    • cites [56] source
    • cites [57] source
    • cites [25] source
    • cites [28] source
    • cites [29] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    For seizures starting between 3 and 12 months, SCN2A-specific data are limited, so standard AED guidelines are recommended.

    “For seizures starting between 3 months and 12 months there are limited SCN2A-specific data, so standard AED guidelines are recommended [53].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [53] source

      The Approach to therapy and interventions section recommends early AED treatment for infants, and the Discussion says evidence for specific treatments in infants is limited. Neither passage addresses SCN2A-specific data or singles out seizures beginning between 3 and 12 months; the report offers general infantile-seizure recommendations rather than the stated SCN2A-specific rationale. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Voltage-gated sodium channels evolved from a calcium channel early in animal evolution, and the DEKA ion selectivity filter in NaV1 derives from the ancestral DEEA filter.

    “Voltage-gated sodium channels (NaV) are derived from a calcium channel (CaV3) early in the evolution of animals [42–44] with the DEKA ion selectivity filter in NaV1 being derived from the ancestral DEEA filter (Figure 3, Table 3).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [42] source
    • cites [43] source

      The “Evolutionary history and sodium channel genes” section says four-domain sodium channels evolved from calcium channels and appeared around the evolution of metazoans. It does not identify CaV3 as the ancestor. “Molecular basis of function” identifies DEKA as the sodium-channel selectivity-filter residues and compares them with EEEE in calcium channels, but does not say that DEKA derives from an ancestral DEEA filter. Page numbers are unavailable in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [44] source

  • May combine two claims.

    Premisecitation

    Loss-of-function variants of NaV1.1 cause Dravet syndrome and generalized epilepsy with febrile seizures plus, and have also been associated with ASD.

    “Loss of function variants of NaV1.1 cause Dravet syndrome [48], generalized epilepsy with febrile seizures plus [49], and have also been associated with ASD [50,51].”
    Quote in the paperNot a substantial claim2 of 4 sources checked
    • cites [48] source

      The paper identifies de novo SCN1A mutations in seven patients with severe myoclonic epilepsy of infancy (Dravet syndrome; Discussion, p. 4). It proposes loss of function as one possible mechanism but also considers a toxic increase in function and says the exact mechanism requires further analysis (Discussion, pp. 4–5). This citation is attached to the Dravet-syndrome portion of the sentence, not the separately cited GEFS+ or ASD claims. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [49] source
    • cites [50] source
    • cites [51] source

  • May combine two claims.

    Interpretationcitation

    Widespread adoption of genetic testing in IEE, ASD, and ID is expected to increase the frequency of known SCN2A cases to hundreds per year, similar to the incidence of SCN1A-mediated Dravet syndrome at 6.4 per 100,000 births.

    “Widespread adoption of genetic testing in IEE, ASD, and ID is expected to increase the frequency of known SCN2A cases to hundreds per year, similar to the incidence of SCN1A-mediated Dravet Syndrome at 6.4 per 100,000 births [35].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] source

      The Abstract and Discussion report clinical Dravet syndrome at 1 in 15,700 births, approximately 6.4 per 100,000. But they report SCN1A-associated Dravet syndrome at 1 in 20,900 births, approximately 4.8 per 100,000. The cited rate is therefore for all clinical cases, not SCN1A-mediated cases; the paper does not assess the projected number of SCN2A cases. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    SCN2A expression begins early in gestation, and channel dysfunction may alter brain development.

    “SCN2A expression begins early in gestation [8], and channel dysfunction may alter brain development.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] source

      The citation is attached to the claim that SCN2A expression begins early in gestation, not to the subsequent statement about channel dysfunction. The Expression trajectories of neurodevelopment and Spatiotemporal gene expression sections discuss prenatal gene expression, but the passages found by searching for SCN2A and early fetal sodium-channel expression do not identify SCN2A or establish its onset. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    At least in cortical regions, NaV1.1 channels affected in Dravet are more commonly expressed in inhibitory neurons, and NaV1.1 loss of function may have opposing effects on brain networks compared with NaV1.2 loss of function in excitatory neurons.

    “When considering such treatments, it is critical to remember that, at least in cortical regions, NaV1.1 channels affected in Dravet are more commonly expressed in inhibitory neurons [59], and that loss of function with NaV1.1 may have opposing effects on brain networks compared to NaV1.2 loss of function in excitatory neurons.”
    Quote in the paperNot a substantial claim1 of 1 sources checked

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Computational modeling of loss-of-function variants suggests that neuronal excitability is restored in the mature brain as NaV1.6 replaces NaV1.2 as the critical channel for action potential generation at two years of age.

    “In keeping with this concern, computational modeling of loss of function variants suggests that neuronal excitability is restored in the mature brain as NaV1.6 replaces NaV1.2 as the critical channel underlying action potential generation at two years of age [24].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] source

      The Results and Discussion report that modeled loss-of-function variants reduce excitability during development but have minimal effects on excitability in the mature model as NaV1.6 replaces NaV1.2 in the distal axon initial segment. The Introduction links this transition to seizure resolution before two years of age; it does not establish that the channel replacement or restoration of excitability occurs at two years. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationcitation

    Because small molecule compounds that enhance or diminish ion channel activity already exist, it is conceivable to develop drugs that modulate NaV1.2 activity to treat IEE and ASD/ID.

    “Since there is precedent for small molecule compounds that either enhance or diminish ion channel activity [60–62], it is conceivable to develop drugs for modulating NaV1.2 activity to treat IEE and ASD/ID.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [60] source

      The introductory section and the NaV1.3 characterization section (pages unavailable) establish a precedent for small molecules that diminish sodium-channel activity. The paper describes channel-enhancing agents as polypeptide toxins, not small molecules, so it does not support the enhancing half of the cited precedent. The proposed NaV1.2 treatment for IEE and ASD/ID is the citing authors’ inference, not a finding attributed to this source. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [61]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [62] source

  • May combine two claims.

    Premisenone given

    SCN2A dysfunction is a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability.

    “Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability.”
    • Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
      “disruption of the gene SCN2A has been identified as a prominent cause of a wide range of neurodevelopmental disorders, including autism spectrum disorder (ASD), intellectual disability (ID), and infantile-onset seizures (before the first year of life) of varying severity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Gain-of-function SCN2A variants lead to IEE and BIS, whereas loss-of-function variants lead to ASD/ID.

    “Variants associated with greater NaV1.2 channel activity (i.e., gain of function) lead to IEE and BIS, while those associated with diminished channel activity (i.e., loss of function) lead to ASD/ID (Figure 2).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Sodium channels are pseudo-heterotetrameric proteins with four similar domains (I-IV), each containing six membrane-spanning segments S1-S6; S1-S4 form voltage-sensing domains and S5-S6 form pore loops and the DEKA selectivity filter.

    “Sodium channels are pseudo-heterotetrameric protein structures consisting of four highly similar domains, termed I, II, III, and IV (Figure 1). Each domain contains 6 membrane-spanning segments S1-S6 (Figure 1) [4] with S1-S4v forming the voltage-sensing domains and S5-S6 forming the pore loops and DEKA selectivity filter.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    NaV1.2 has two major developmentally regulated splice isoforms that use mutually exclusive copies of the fifth coding exon and differ by one amino acid at position 209: Asn (5N) and Asp (5A).

    “There are two major developmentally regulated splice isoforms of NaV1.2 that use mutually exclusive copies of the fifth coding exon and differ by one amino acid at position 209: Asparagine (Asn/N; termed 5N) vs. Aspartic acid (Asp/D; 5A) [2,3] (Figure 1A).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] source
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  • May combine two claims.

    Premisenone given

    Ion channels such as NaV1.2 are druggable targets, and small molecule compounds can be developed to directly and selectively increase or decrease channel function as potential treatments.

    “ion channels such as NaV1.2 are “druggable” targets, and small molecule compounds can be developed to directly and selectively increase or decrease channel function as the basis for potential treatments.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    NaV1.2 is prominently expressed in the cerebellar cortex, where it is co-expressed with NaV1.6 in unmyelinated axons of excitatory granule cells that form parallel fiber synapses on Purkinje neurons.

    “Another prominent site of NaV1.2 expression is the cerebellar cortex [22]. Here, NaV1.2 channels are co-expressed with NaV1.6 in unmyelinated axons of excitatory granule cells that form parallel fiber synapses on Purkinje neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] source

  • May combine two claims.

    Premisecitation

    The 5N and 5A splice isoforms of SCN2A are developmentally regulated: 5N is co-expressed with 5A in fetal brain, and neurons predominantly express 5A after the second postnatal week in mouse.

    “The 5N and 5A splice isoforms of SCN2A are developmentally regulated, with 5N co-expressed with 5A in the fetal brain, eventually transitioning to neurons predominantly expressing 5A after the second postnatal week in mouse [2,14].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] source
    • cites [14] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    NaV1.2 is one of four sodium channel paralogs expressed throughout the central nervous system, along with NaV1.1, NaV1.3, and NaV1.6.

    “NaV1.2 is one of four sodium channel paralogs expressed throughout the central nervous system, along with NaV1.1 (SCN1A), NaV1.3 (SCN3A), and NaV1.6 (SCN8A).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The 5N and 5A isoforms influence channel voltage dependence; the adult 5A channel activates at lower depolarization voltages and increases neuronal activity.

    “These isoforms influence channel voltage dependence; results indicate that the adult 5A encodes a channel that activates at lower depolarization voltages, resulting in increased neuronal activity [3,15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] source
    • cites [15] source

  • May combine two claims.

    Premisecitation

    In mature neurons, NaV1.2 is restricted to the proximal axon initial segment, where it acts as a reserve pool and is thought to help action potentials backpropagate into the somatodendritic compartment.

    “NaV1.2 is at this point restricted to the region of AIS most proximal to the soma, where it functions as a reserve pool of channels, right next to the cell body. Once action potentials are initiated in the AIS by NaV1.6, NaV1.2 is thought to help action potentials backpropagate into the somatodendritic compartment [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] source

  • May combine two claims.

    Premisecitation

    Unlike cortical myelinated axons, where NaV1.2 is lost during development, cerebellar NaV1.2 expression persists throughout development, with an apparent peak in density in the second and third postnatal weeks in mice.

    “In contrast to the developmental loss of NaV1.2 in cortical myelinated axons, NaV1.2 expression persists throughout development in the cerebellum, with an apparent peak in density within the second and third postnatal weeks in mice [22,23].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] source
    • cites [23] source

  • May combine two claims.

    Premisenone given

    SCN2A encodes the neuronal voltage-gated sodium channel NaV1.2, which participates in action potential initiation and propagation in several neuron classes.

    “SCN2A encodes the neuronal sodium channel NaV1.2.”
    • Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
      “SCN2A encodes the neuronal voltage-gated sodium channel NaV1.2, which is involved in the initiation and propagation of action potentials in a range of neuron classes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Missense variants can alter the biophysical properties of the channel, especially when they occur in regions important for voltage sensing or ion flux.

    “Similarly, missense variants can conceivably alter the biophysical properties of the channel, especially if such variants are in parts of the protein that are important for sensing voltage (e.g., within the voltage sensing domain) or permitting ion flux (e.g., within the pore domain) (Figure 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Functional assays show a strong correlation between genotype and phenotype, and the effect of disease-associated variants on protein function can predict the nature and severity of the phenotype.

    “Functional assays demonstrate strong correlation between genotype and phenotype.”
    • Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
      “the consequences of disease-associated variants on protein function can predict the nature and severity of the resulting phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    About one third of documented SCN2A-associated ASD/ID cases develop seizures, often between 18 months and 4 years of age.

    “About a third of documented cases develop seizures, often between the age of 18 months and 4 years.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Some children with the earliest seizure onset are classified as having Ohtahara syndrome, based on tonic seizures and EEG burst suppression, or epilepsy of infancy with migrating focal seizures.

    “Some of the children with the earliest age of seizure onset are classified as having Ohtahara syndrome, based on tonic seizures and electroencephalography (EEG) burst suppression, or epilepsy of infancy with migrating focal seizures (EIMFS).”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisenone given

    Seizure type varies widely between individuals, and most experience more than one type of seizure.

    “Seizure type varies widely between individuals, with most experiencing more than one type of seizure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The variant K1422E alters the third residue of the DEKA ion selectivity filter and is predicted to produce both loss-of-function and gain-of-function effects.

    “At least one has come to light: the variant K1422E alters the third residue in the DEKA ion selectivity filter (Figure 1) and is predicted to produce both loss of function and gain of function effects [37,38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [37] source
    • cites [38] source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The p.K1422E variant reverts the NaV1.2 ion selectivity filter to the ancestral state.

    “Of note, the variant p.K1422E, described earlier (Table 2), reverts the NaV1.2 filter to the ancestral state.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Development in SCN2A-associated IEE varies from moderate to profound global delay, often with hypotonia, microcephaly, cerebral and/or cerebellar atrophy, and cortical visual impairment.

    “Development varies from moderate to profound global developmental delay, often with comorbid hypotonia, microcephaly, cerebral and/or cerebellar atrophy, and cortical visual impairment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The p.K1422E variant converts the channel into a non-selective cation channel with increased persistent, Ca2+-dominated current and reduced non-selective conductance when activated.

    “This variant converts the channel into a non-selective cation channel with increased persistent, Ca2+-dominated current and reduced, non-selective conductance when activated [37,38].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] source
    • cites [38] source

  • May combine two claims.

    Interpretationreasoning

    Some IEE-associated variants hyperpolarize the voltage dependence of activation so strongly that neurons may become less excitable over time, because sodium channels may activate at rest but the neuron never hyperpolarizes enough for them to recover from inactivation.

    “For example, some IEE-associated variants hyperpolarize the voltage dependence of activation to such a degree that neurons may end up being less excitable over time, as sodium channels may be activated at rest, but the neuron never hyperpolarizes to allow the same channels to recover from inactivation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The SCN2A genotype-phenotype model is supported by in vitro electrophysiology, the restriction of protein-truncating loss-of-function variants to ASD/ID, shared symptoms among individuals with recurrent missense variants, and the clustering of IEE/BIS variants near the voltage sensor domain while ASD/ID missense variants cluster near the pore loop regions.

    “This model is supported by several strands of evidence, including: 1) in vitro electrophysiology; 2) the restriction of protein truncating variants, resulting in loss of function, to ASD/ID cases; 3) shared symptoms between individuals with recurrent missense variants (Table S1); and 4) the clustering of IEE/BIS variants around the voltage sensor domain of the channel while the ASD/ID missense var”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Children with SCN2A-associated ASD/ID do not exhibit a distinctive syndrome, but several behavioral characteristics appear to be shared.

    “While children with SCN2A-associated ASD/ID do not exhibit a distinctive syndrome, several behavioral characteristics seem to be shared (unpublished observations, scn2a.org family group).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites unpublished observations, scn2a.org family group

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisenone given

    NaV1.2 has high homology to NaV1.1 and NaV1.3 and moderate homology to NaV1.4, NaV1.5, NaV1.6, and NaV1.7.

    “NaV1.2 retains a high degree of homology to both NaV1.1 and NaV1.3 and moderate homolog to NaV1.4, NaV1.5, NaV1.6, and NaV1.7 (Figure 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    In children with SCN2A-associated ASD/ID, early development is generally unremarkable until about 6 months of age, followed by moderate motor delay and pronounced verbal delay.

    “In children with ASD/ID, early development is generally unremarkable up to about 6 months of age, followed by moderate motor delay and pronounced verbal delay.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The incidence of loss-of-function SCN2A cases is expected to be about five times higher than that of gain-of-function cases.

    “We would also expect the incidence of loss of function cases to be ~5-fold higher than gain of function cases (Table 1).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Because these variants are gain-of-function, sodium channel inhibitors would likely be more efficacious for seizures starting between 3 and 12 months.

    “However, the gain of function nature of these variants suggest sodium channel inhibitors would be more efficacious.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    At present, the number of known SCN2A cases is roughly equal between IEE and ASD/ID, likely reflecting differences in the adoption of genetic testing.

    “At present the number of known SCN2A cases is roughly equal between IEE and ASD/ID, likely reflecting differences in the adoption of genetic testing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    SCN2A pathology will likely require normalizing NaV1.2 current while avoiding excessive enhancement or reduction of channel activity, which could cause IEE or ASD/ID symptoms, respectively.

    “Second, the SCN2A pathology will likely require normalizing the NaV1.2 channel current while avoiding overly enhancing or decreasing NaV1.2 channel activity that could result in IEE or ASD/ID symptoms, respectively.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Biophysical characterization of unknown patient-specific variants may be necessary to confirm the appropriate therapeutic intervention, especially when mixed gain- and loss-of-function characteristics are present.

    “In addition, biophysical characterization of unknown patient-specific variants may be necessary to confirm the appropriate therapeutic intervention, especially in cases where mixes of GoF and LoF characteristics are present (Table 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Normalizing NaV1.2 function has great potential to yield therapeutic benefit in both gain- and loss-of-function conditions, though therapeutic window and selectivity to other sodium channels must be addressed.

    “Normalization of NaV1.2 function has great potential to yield therapeutic benefit in both conditions, though the issues of therapeutic window and selectivity to other sodium channels must be addressed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationnone given

    SCN2A variants can lead to at least two severe disorders: gain of function leads to infantile-onset seizures and encephalopathy, and loss of function leads to autism spectrum disorder and/or intellectual disability.

    “SCN2A variants can lead to at least two severe disorders, with gain of function leading to infantile-onset seizures and encephalopathy, and loss of function leading to autism spectrum disorder and/or intellectual disability.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The high conservation between SCN2A/NaV1.2 and other voltage-gated sodium channels, including SCN5A/NaV1.5 whose disruption can cause cardiac arrhythmias, means that high selectivity for NaV1.2 will be essential to reduce side effects.

    “First, the high degree of conservation (Figure 3B) between SCN2A/NaV1.2 and other voltage-gated sodium channels, including SCN5A/NaV1.5 that can induce cardiac arrhythmias if disrupted, demonstrates that high selectivity for NaV1.2 will be essential to reduce side effects.”
    Quote in the paperSubstantial claim
54 of 54

  • The paper relies on this without support.

    There is a clear unmet medical need for improved treatment options for SCN2A-associated disorders.

    “There is a clear unmet medical need for improved treatment options for SCN2A-associated disorders.”

  • The paper relies on this without support.

    SCN2A is a leading candidate for focused efforts to understand and treat neurodevelopmental disorders.

    “Thus, the well-defined biology describing NaV1.2 function, the strong genotype-phenotype correlations found within a genetically well-defined patient population, and the channel’s potential as a target for therapeutics all make SCN2A a leading candidate for focused efforts to understanding and treating neurodevelopmental disorders.”

  • The paper relies on this without support.

    SCN2A is an important test-case for investigating the neurobiology of neurodevelopmental disorders more generally.

    “The well-defined function of sodium channels makes SCN2A an important test-case for investigating the neurobiology of neurodevelopmental disorders more generally.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Adult brain-specific splicing of MAPT and SCN2A is seen exclusively in iNs and adult brain, whereas iPSC-iNs predominantly express the fetal isoforms.

    “In addition, adult brain-specific splicing of the microtubule-associated protein tau (MAPT) (Andreadis, 2005) and of the voltage-gated sodium channel gene SCN2A (Sanders et al., 2018) was seen exclusively in iNs and adult brain, whereas iPSC-iNs predominantly expressed the fetal isoforms (Figure S7).”

    From Age-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients (2021) · cites this paper as Sanders et al., 2018

Cites

Flagged first, then by citations

1 of the 85 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Campbell, 2016, Improving our structural understanding of NaV1.2 missense mutations, FamilieSCN2A Foundation Conference

Cited by

Sorted by citations

Related

Authors
Sanders, S. J., Campbell, A. J., Cottrell, J. R., Moller, R. S., Wagner, F. F., Auldridge, A. L., Bernier, R. A., Catterall, W. A., Chung, W. K., Empfield, J. R., George, A. L., Hipp, J. F., Khwaja, O., Kiskinis, E., Lal, D., Malhotra, D., Millichap, J. J., Otis, T. S., Petrou, S., Pitt, G., Schust, L. F., Taylor, C. M., Tjernagel, J., Spiro, J. E., & Bender, K. J.
Affiliations
  • University of California, San Francisco (US)
  • Broad Institute (US)
  • FamilieSCN2A Foundation (US)
  • University of Washington (US)
  • Simons Foundation (US)
  • Xenon Pharmaceuticals (Canada) (CA)
  • Northwestern University (US)
  • F. Hoffmann-La Roche AG (CH)
  • Sainsbury Wellcome Centre (GB)
  • The University of Melbourne (AU)
  • Cornell University (US)
  • Geisinger Health System (US)
Corresponding author
  • Sanders, Stephan J.
  • Bender, Kevin J.
ORCID
Venue
Trends in Neurosciences
Publisher
Elsevier BV
Published
2018-07
Volume
41
Issue
7
Pages
442-456
ISSN
0166-2236 (ISSN-L)
DOI
10.1016/j.tins.2018.03.011
PMC
PMC6015533
OpenAlex
W2800285111
Cited by
338
References
85
Citations by year
2026: 41 · 2025: 52 · 2024: 49 · 2023: 34 · 2022: 32 · 2021: 48 · 2020: 41 · 2019: 33 · 2018: 5
FWCI
5.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Neurosciences (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by-nc-nd)
  • UCL Discovery (University College London) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Institute of Mental Health (100047)
  • Broad Institute
  • National Institutes of Health
  • Simons Foundation Autism Research Initiative (513133, 402281, 491201, 349984)
  • Simons Foundation
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
SCN2A, Nav1.2 sodium channel, infantile seizures, autism spectrum disorder, intellectual disability, genotype-phenotype correlation, sodium channel modulators, neurodevelopmental disorders, drug development
MeSH terms
Animals, Humans, NAV1.2 Voltage-Gated Sodium Channel, Neurodevelopmental Disorders

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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