The DOI matches its Crossref record; 84 of the 85 references it cites were found in a registry or an index; 45 of the 88 sources its claims cite were checked for support.
Progress in Understanding and Treating SCN2A-Mediated Disorders
Open accessAbstract
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.
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Claims the paper makes
24 Own interpretation · 23 No basis given · 20 Partly supported · 13 No full text of the sources · 6 Supported · 2 Supported so far · 2 Couldn’t confirm · 1 Sources not found · 1 Not checked yet · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Supportedcites [24] source
The Introduction identifies SCN2A associations with ASD and developmental delay, and with infantile seizures ranging from benign infantile familial seizures to epileptic encephalopathy. The Results distinguish those seizure phenotypes from an ASD and/or intellectual-disability group. The paper also describes a smaller additional phenotypic group, which does not undermine the claim that the three named associations are primary. (LLM, conf=0.89)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
- Not checked — no full text of the sourcecites [3] source
- Partly supportedcites [16] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [17] source
- Not checked — no full text of the sourcecites [18] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“To date, only about 20 of the hundreds of disorder-associated variants have been electrophysiologically assessed (summarized in [24,25]).”
§ Progress in understanding and treating SCN2A-mediated disorders > Linking disorders to changes in channel function
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Compartmental modeling can provide insight into the net effect on neuronal excitability in such conditions [24].”
§ Progress in understanding and treating SCN2A-mediated disorders > Linking disorders to changes in channel function
What the sources say
- Supportedcites [24] source
The Results describe incorporating SCN2A variants into a computational model of cortical pyramidal cells to test their effects on neuronal excitability. The model predicted reduced excitability for ASD-associated variants during early development but minimal changes in mature neurons, directly illustrating the claimed use of compartmental modeling. (LLM, conf=0.94)
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated infantile epileptic encephalopathy
What the sources say
- Could not verifycites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“A child with this variant developed seizures at 13 months with developmental regression and features of ASD [39].”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
What the sources say
- Partly supportedcites [39] sourceExperimental — accuracy not yet measured
The Case Report (page not specified) describes a child with seizure-like episodes between 4 and 6 months, flexor spasms at 12 months, and features suggestive of autism. It does not report seizure onset at 13 months or explicitly describe developmental regression. The Case Report’s genetic findings identify the child’s variant as K1422E. (LLM, conf=0.88)
plainSingle case- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, for infants with postnatal-onset seizures (≤3 months), non-selective sodium channel blockers, such as phenytoin and carbamazepine, are more effective [25], as would be expected based on a gain of function variant [24].”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
What the sources say
- Supportedcites [25] source
The treatment comparison (p. 10) reports significantly better responses to phenytoin, carbamazepine, and sodium channel blockers overall in children with early-onset SCN2A-related epilepsy. The discussion (p. 18) links early onset and blocker effectiveness to gain-of-function mutations, consistent with the citing sentence’s qualified explanation. (LLM, conf=0.90)
- Supportedcites [24] source
The citation to this paper [24] is attached to the gain-of-function explanation, not the treatment-effectiveness claim attributed to [25]. The Discussion states that SCN2A variants associated with infantile seizures produce gain of function in NaV1.2 and increased neuronal excitability. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“An integrated analysis of genetic and electrophysiological data led to a model to account for the three disorders associated with SCN2A (Figure 2) [24].”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
What the sources say
- Supportedcites [24] source
The Methods and Results describe incorporating electrophysiological measurements of SCN2A variants into computational models and comparing variants associated with autism spectrum disorder, benign infantile familial seizures (BIFS), and epileptic encephalopathy (EE). The Results report distinct predicted effects on neuronal excitability for all three, supporting the claim that the combined analysis produced a model accounting for their differences. Page numbers are unavailable in our copy. (LLM, conf=0.92)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The subsequent publication of 71 novel SCN2A patients from Europe [25] further support the model proposed in Ben-Shalom et al.. [26].”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
What the sources say
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
The Previously unpublished patients section (p. 4) reports 71 previously unreported patients with SCN2A mutations. The paper also reports findings consistent with the cited sentence’s model-supporting interpretation: early-onset epilepsy was associated with gain-of-function effects, and later-onset epilepsy with loss-of-function effects (p. 1; Functional studies, p. 18). Our copy does not establish that all 71 patients were from Europe; it says they were referred through a network of collaborators. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [26] source
plaincorrelationaln = 71- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Analysis of data from publications and clinical cohorts has already provided insights into genotype-phenotype relationships and appropriate antiepileptic drugs [24,25].”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards personalized therapeutics
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
The Results (page unavailable) describe a literature review of SCN2A variants in 148 families and group the variants by phenotype; the Discussion (page unavailable) links variant function to infantile seizures versus ASD/developmental delay. These passages support the genotype–phenotype part, but the retrieved text does not establish an analysis of clinical-cohort data or provide guidance on appropriate antiepileptic drugs. (LLM, conf=0.86)
- Supportedcites [25] source
The paper reports phenotypes from 71 patients and reviews 130 previously reported patients (p. 1). It also links SCN2A mutation properties and age at epilepsy onset to differing responses to sodium channel blockers (p. 1), supporting the claim about genotype–phenotype relationships and antiepileptic drug selection. (LLM, conf=0.92)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
- Probably not a substantial claim. 17
- It may state two separate claims as one. 44
- The quote only partly states this claim. 2
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“NaV1.2 is widely expressed throughout the human central nervous system, but not in peripheral tissues [7,8].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
- Could not verifycites [7] sourceExperimental — accuracy not yet measured
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)
- Could not verifycites [8] sourceExperimental — accuracy not yet measured
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)
- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“3) autism spectrum disorder/intellectual disability (ASD/ID), characterized by global developmental delay, particularly of social and language milestones.”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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;”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Not checked — no full text of the sourcecites [26] source
- Not checked — no full text of the sourcecites [27] source
- Not checked — no full text of the sourcecites [28] source
- Not checked — no full text of the sourcecites [29] source
- Not checked — no full text of the sourcecites [30] source
- Not checked — no full text of the sourcecites [31] source
- Supportedcites [33] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Supportedcites [34] sourceExperimental — accuracy not yet measured
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay;”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“While exceptions have been noted, sodium channels typically must go through all three steps to be available for subsequent activation [5].”
§ Progress in understanding and treating SCN2A-mediated disorders > The structure and function of SCN2A / NaV1.2
What the sources say
- Supportedcites [5] source
The Abstract describes activation followed by inactivation as the usual sequence and identifies closed-state inactivation as an exception. It also says channels recover from inactivation on repolarization and return to the resting state, consistent with becoming available for subsequent activation. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
- Supportedcites [9] source
The Introduction (page not provided) says NaV1.1 is highly expressed in many GABAergic inhibitory neurons and accounts for essentially all sodium current in hippocampal interneuron cell bodies. It describes NaV1.2 primarily in axons and dendrites, supporting the first clause, to which this source is cited. The mouse interneuron-subtype exception is cited to [11], not to this paper. (LLM, conf=0.87)
- Partly supportedcites [10] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [11] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
What the sources say
- Could not verifycites [53] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [54] sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [55] sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
What the sources say
- Partly supportedcites [45] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [46] source
- Not checked — no full text of the sourcecites [47] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated infantile epileptic encephalopathy
What the sources say
- Partly supportedcites [25] sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
What the sources say
- Supportedcites [52] source
The Cardiac sodium channelopathies section identifies SCN5A as encoding the principal cardiac sodium-channel subunit and links its mutations to long QT syndrome and ventricular arrhythmias. The Disorders of cardiac conduction section also links SCN5A mutations to heart block, Brugada syndrome, and dilated cardiomyopathy occurring with conduction disorders and arrhythmia. The paper treats cardiomyopathy as an associated condition, not itself an arrhythmia. (LLM, conf=0.90)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
What the sources say
- Supportedcites [56] source
The Patients section reports that a girl with neonatal epileptic encephalopathy was “partially rescued using lidocaine,” supporting the lidocaine-improvement claim. This citation is attached to the lidocaine example, not the ethosuximide or acetazolamide examples; the report of one patient is consistent with the stated uncertainty about generalizability. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [57] source
- Supportedcites [25] source
For this source, the citation is attached to ethosuximide for late-onset seizures, not to the lidocaine or acetazolamide examples. The treatment table (p. 11) lists ESM (ethosuximide) under seizure reduction, and the infantile/childhood epilepsy section (p. 6) describes this group as having seizure onset after 3 months. The paper reports a limited treatment observation, consistent with the sentence’s caution about generalizability. (LLM, conf=0.82)
- Not checked — no full text of the sourcecites [28] source
- Not checked — no full text of the sourcecites [29] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For seizures starting between 3 months and 12 months there are limited SCN2A-specific data, so standard AED guidelines are recommended [53].”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
What the sources say
- Partly supportedcites [53] sourceExperimental — accuracy not yet measured
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)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
What the sources say
- Not checked — no full text of the sourcecites [42] source
- Partly supportedcites [43] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [44] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
What the sources say
- Partly supportedcites [48] sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [49] source
- Not checked — no full text of the sourcecites [50] source
- Supportedcites [51] source
The Abstract states that SCN1A haploinsufficiency causes Dravet syndrome, which includes autism-spectrum behaviors, and that Scn1a-haploinsufficient mice display autistic-like behaviors. The Discussion also reports an association between SCN1A mutations and autism. These passages support the ASD association for which this paper is cited. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
What the sources say
- Partly supportedcites [35] sourceExperimental — accuracy not yet measured
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“SCN2A expression begins early in gestation [8], and channel dysfunction may alter brain development.”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
What the sources say
- Could not verifycites [8] sourceExperimental — accuracy not yet measured
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)
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
What the sources say
- Supportedcites [59] source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
What the sources say
- Partly supportedcites [24] sourceExperimental — accuracy not yet measured
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)
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
What the sources say
- Partly supportedcites [60] sourceExperimental — accuracy not yet measured
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)
- Not matchedcites [61]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked — no full text of the sourcecites [62] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Partly supported
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
direct- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > The structure and function of SCN2A / NaV1.2
What the sources say
- Not checked — no full text of the sourcecites [4] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > The SCN2A gene
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > The role of SCN2A in neurodevelopmental disorders
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
- Not checked — no full text of the sourcecites [22] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > The structure and function of SCN2A / NaV1.2
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
- Not checked — no full text of the sourcecites [21] source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Developmental and cell-type specific patterns of NaV1.2 expression across brain regions
What the sources say
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > The structure and function of SCN2A / NaV1.2
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § The role of SCN2A in neurodevelopmental disorders · plain
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“About a third of documented cases develop seizures, often between the age of 18 months and 4 years.”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated autism spectrum disorder/intellectual disability
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated infantile epileptic encephalopathy
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Seizure type varies widely between individuals, with most experiencing more than one type of seizure.”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated infantile epileptic encephalopathy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one. The quote only partly states this claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of note, the variant p.K1422E, described earlier (Table 2), reverts the NaV1.2 filter to the ancestral state.”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Development varies from moderate to profound global developmental delay, often with comorbid hypotonia, microcephaly, cerebral and/or cerebellar atrophy, and cortical visual impairment.”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated infantile epileptic encephalopathy
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“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].”
§ Progress in understanding and treating SCN2A-mediated disorders > Linking disorders to changes in channel function
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Linking disorders to changes in channel function
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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”
§ Progress in understanding and treating SCN2A-mediated disorders > Towards a model of SCN2A pathophysiology
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated autism spectrum disorder/intellectual disability
What the sources say
- Not matchedcites unpublished observations, scn2a.org family group
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Not matched
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A homology in animal models and other channels
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Children with SCN2A-associated autism spectrum disorder/intellectual disability
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We would also expect the incidence of loss of function cases to be ~5-fold higher than gain of function cases (Table 1).”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the gain of function nature of these variants suggest sodium channel inhibitors would be more efficacious.”
§ Progress in understanding and treating SCN2A-mediated disorders > Existing treatments
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > SCN2A-mediated disorders
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Concluding remarks
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Concluding remarks
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Progress in understanding and treating SCN2A-mediated disorders > Future treatments
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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
Experimental — accuracy not yet measured
Citations
Cites
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Synaptic, transcriptional and chromatin genes disrupted in autism
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“Nonconducting Missense Often clustered in the pore loop N/A N/A N/A Prevents sodium flux through channel R379H 25363760 [83]; 28256214 [24]”
Self-citationSpatio-temporal transcriptome of the human brain
Kang, H. J., Kawasawa, Y. I., Cheng, F., Zhu, Y., Xu, X., Li, M., Sousa, A. M. M., Pletikos, M., Meyer, K. A., Sedmak, G., et al. (2011) · Nature · doi:10.1038/nature10523 · Cited by 2,084 · cited 2×
“SCN2A expression begins early in gestation [8], and channel dysfunction may alter brain development.”
BackgroundDe novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · cited 2×
“Year SCN2A association documented 2009 [56] 2002 [77] 2012 [78] N[360_TD$DIFF]/A”
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De novo mutations in schizophrenia implicate synaptic networks
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“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], BISs with late-onset episodic ataxia [28–31], childhood-onset epileptic encephalopathy [32], and schizophrenia [33,34].”
BackgroundInsights into autism spectrum disorder genomic architecture and biology from 71 risk loci
Sanders, S. J., He, X., Willsey, A. J., Ercan-Sencicek, A. G., Samocha, K. E., Cicek, A. E., Murtha, M. T., Bal, V. H., Bishop, S. L., Dong, S., et al. (2015) · Neuron · doi:10.1016/j.neuron.2015.09.016 · Cited by 1,430
Self-citationAssembly of functionally integrated human forebrain spheroids
Birey, F., Andersen, J., Makinson, C. D., Islam, S., Wei, W., Huber, N., Fan, H. C., Metzler, K. R. C., Panagiotakos, G., Thom, N., et al. (2017) · Nature · doi:10.1038/nature22330 · Cited by 1,365 · cited 1×
“Patientderived induced pluripotent stem cell-based approaches including neuronal cultures [64,65] and organoids [66,67] hold great promise in this regard, as they would allow researchers to probe for the functional effects of SCN2A genetic variants on many levels including neuronal excitability, developmental progress…”
BackgroundCell diversity and network dynamics in photosensitive human brain organoids
Quadrato, G., Nguyen, T., Macosko, E. Z., Sherwood, J. L., Min Yang, S., Berger, D. R., Maria, N., Scholvin, J., Goldman, M., Kinney, J. P., et al. (2017) · Nature · doi:10.1038/nature22047 · Cited by 1,321 · cited 1×
“Patientderived induced pluripotent stem cell-based approaches including neuronal cultures [64,65] and organoids [66,67] hold great promise in this regard, as they would allow researchers to probe for the functional effects of SCN2A genetic variants on many levels including neuronal excitability, developmental progress…”
BackgroundDe Novo Mutations in the Sodium-Channel Gene SCN1A Cause Severe Myoclonic Epilepsy of Infancy
Claes, L., Del-Favero, J., Ceulemans, B., Lagae, L., Van Broeckhoven, C., & De Jonghe, P. (2001) · The American Journal of Human Genetics · doi:10.1086/320609 · Cited by 1,292 · cited 1×
“1 cause Dravet syndrome [48], generalized epilepsy with febrile seizures plus [49], and have also been associated with ASD [50,51].”
Background
Research works printed but not linked: 1
- Campbell, 2016, Improving our structural understanding of NaV1.2 missense mutations, FamilieSCN2A Foundation Conference
Cited by
Sorted by citations
Neurodevelopmental disorders—the history and future of a diagnosticconcept
Morris-Rosendahl, D. J., & Crocq, M. (2020) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2020.22.1/macrocq · Cited by 607
Spratt, P. W. E., Ben-Shalom, R., Keeshen, C. M., Burke, K. J., Clarkson, R. L., Sanders, S. J., & Bender, K. J. (2019) · Neuron · doi:10.1016/j.neuron.2019.05.037 · Cited by 244
“Heterozygous loss-offunction variants (haploinsufficiency) in SCN2A that diminish or eliminate channel function are strongly associated with ASD as well as intellectual disability (ID), whereas gain-of-function missense variants are strongly associated with infantile epilepsy of varying severity (Begemann et al., 2019…”
BackgroundSelf-citationEvolutionary constraint and innovation across hundreds of placental mammals
Christmas, M. J., Kaplow, I. M., Genereux, D. P., Dong, M. X., Hughes, G. M., Li, X., Sullivan, P. F., Hindle, A. G., Andrews, G., Armstrong, J. C., et al. (2023) · Science · doi:10.1126/science.abn3943 · Cited by 292
“Among the genes that are evolving faster in hibernators are HSPD1 [involved in stress adaptation underlying mammalian torpor (152)], the mTor pathway inhibitor ADAMST9 [also implicated in longevity based on sequence convergence inmicrobats and nakedmole rats (153)], and two genes connected to neurodevelopmental disord…”
BackgroundSelf-citationAge-dependent instability of mature neuronal fate in induced neurons from Alzheimer’s patients
Mertens, J., Herdy, J. R., Traxler, L., Schafer, S. T., Schlachetzki, J. C. M., Böhnke, L., Reid, D. A., Lee, H., Zangwill, D., Fernandes, D. P., et al. (2021) · Cell Stem Cell · doi:10.1016/j.stem.2021.04.004 · Cited by 240
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“In 50% of patients diagnosed with SCN2A syndrome, symptoms are similar to the more familiar forms of ASD, including reduced social interaction and repeated behaviors [83].”
BackgroundDevelopmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum
Guerrini, R., Conti, V., Mantegazza, M., Balestrini, S., Galanopoulou, A. S., & Benfenati, F. (2023) · Physiological Reviews · doi:10.1152/physrev.00063.2021 · Cited by 196
Sodium channelopathies in neurodevelopmental disorders
Meisler, M. H., Hill, S. F., & Yu, W. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-020-00418-4 · Cited by 210
Developmental and epileptic encephalopathies: what we do and do not know
Specchio, N., & Curatolo, P. (2020) · Brain · doi:10.1093/brain/awaa371 · Cited by 173
Autism Spectrum Disorder Genetics and the Search for Pathological Mechanisms
Manoli, D. S., & State, M. W. (2021) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2020.20111608 · Cited by 159
Sestan, N., & State, M. W. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.015 · Cited by 127
Predicting functional effects of missense variants in voltage-gated sodium and calcium channels
Heyne, H. O., Baez-Nieto, D., Iqbal, S., Palmer, D. S., Brunklaus, A., May, P., Collaborative, E., Johannesen, K. M., Lauxmann, S., Lemke, J. R., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay6848 · Cited by 140
Self-citationEpilepsy-Related Voltage-Gated Sodium Channelopathies: A Review
Menezes, L. F. S., Júnior, E. F. S., Tibery, D. V., Carneiro, L. D. A., & Schwartz, E. F. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01276 · Cited by 143
“…costs associated with genetic epilepsy diagnosis, since traditional August 2020 | Volume 11 | Article 1276 cytogenetic and microarray-based tests are lengthy, expensive, and diagnostic yield is incredibly low (Veeramah et al., 2013; Allen et al., 2016; Sands and Choi, 2017; Orsini et al., 2018).”
BackgroundSodium channelopathies of skeletal muscle and brain
Mantegazza, M., Cestèle, S., & Catterall, W. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00025.2020 · Cited by 137
Self-citationIon Channel Functions in Early Brain Development
Smith, R. S., & Walsh, C. A. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2019.12.004 · Cited by 133
“Cell-type susceptibility represents a key avenue for future research on EE pathophysiology, as well as on developmental psychiatric diseases classified as interneuronopathies, such as SCN2A in autism and epilepsy syndromes [82].”
BackgroundThe phenotypic spectrum of SCN2A-related epilepsy
Reynolds, C., King, M. D., & Gorman, K. M. (2019) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2019.12.016 · Cited by 124
A framework for the investigation of rare genetic disorders in neuropsychiatry
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Self-citationImpaired cortico-striatal excitatory transmission triggers epilepsy
Miyamoto, H., Tatsukawa, T., Shimohata, A., Yamagata, T., Suzuki, T., Amano, K., Mazaki, E., Raveau, M., Ogiwara, I., Asaka-Oba, A., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09954-9 · Cited by 124
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“Intriguingly, an estimated 20%–30% of individuals with Na V 1.2 deficiency-associated ASD/ID develop “late-onset” seizures (Sanders et al., 2018; Wolff et al., 2017).”
InfluentialIqbal, S., Pérez‐Palma, E., Jespersen, J. B., May, P., Hoksza, D., Heyne, H., Ahmed, S. S., Rifat, Z. T., Rahman, M. S., Lage, K., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2002660117 · Cited by 123
Self-citationIdentifying mutations in epilepsy genes: Impact on treatment selection
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Autism and developmental disability caused by KCNQ3 gain‐of‐function variants
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“Interestingly, a parallel but reverse genotype–phenotype correlation has been reported for SCN2A-related disorders, where GoF results in early epilepsy and LoF imparts neurodevelopmental disability with autistic features and more variable epilepsy phenotypes with later onset.(34) This similarity may not be coincidenta…”
ResultWolff, M., Brunklaus, A., & Zuberi, S. M. (2019) · Epilepsia · doi:10.1111/epi.14935 · Cited by 105
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“This is one of the most recurrent pathogenic variants for this form of SCN2A DEE, with 6 cases reported to date (12).”
BackgroundSelf-citationParadoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells
Spratt, P. W. E., Alexander, R. P. D., Ben‐Shalom, R., Sahagun, A., Kyoung, H., Keeshen, C. M., Sanders, S., & Bender, K. J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109483 · Cited by 107
Self-citationDysfunction of the corticostriatal pathway in autism spectrum disorders
Li, W., & Pozzo‐Miller, L. D. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24560 · Cited by 114
“2 have been identified as a prominent cause of ASD (Sanders et al., 2018).”
BackgroundGene variant effects across sodium channelopathies predict function and guide precision therapy
Brunklaus, A., Feng, T., Brünger, T., Pérez‐Palma, E., Heyne, H., Matthews, E. L., Semsarian, C., Symonds, J. D., Zuberi, S. M., Lal, D., et al. (2022) · Brain · doi:10.1093/brain/awac006 · Cited by 104
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Biological concepts in human sodium channel epilepsies and their relevance in clinical practice
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Self-citationImpact of predictive, preventive and precision medicine strategies in epilepsy
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Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy
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“Despite the lack of personalized treatment options in LoF SCN2A cases (other than avoiding sodium channel blockers), GoF variants in SCN2A might respond to sodium channel blockers [83,84].”
BackgroundSelf-citationDisentangling glial diversity in peripheral nerves at single-nuclei resolution
Yim, A. K., Wang, P. L., Bermingham, J. R., Hackett, A. R., Strickland, A. M., Miller, T. M., Ly, C. V., Mitra, R. D., & Milbrandt, J. (2022) · Nature Neuroscience · doi:10.1038/s41593-021-01005-1 · Cited by 88
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“2 is 2,005 amino acids long and coding mutations associated with IEE, BIS and ASD/ID have been identified along the entire length of the protein.”
InfluentialShin, W., Kweon, H., Kang, R., Kim, D., Kim, K., Kang, M., Kim, S. Y., Hwang, S. N., Kim, J. Y., Yang, E., et al. (2019) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2019.00145 · Cited by 83
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“2, a major sodium channel expressed in the central nervous system (CNS) mediating the action potential initiation, propagation, and backpropagation [6 – 8].”
Epigenomic diversity of cortical projection neurons in the mouse brain
Zhang, Z., Zhou, J., Tan, P., Pang, Y., Rivkin, A. C., Kirchgessner, M. A., Williams, E., Lee, C.-T., Liu, H., Franklin, A. D., et al. (2021) · Nature · doi:10.1038/s41586-021-03223-w · Cited by 73
Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders
Crawford, K., Xian, J., Helbig, K. L., Galer, P. D., Parthasarathy, S., Lewis‐Smith, D., Kaufman, M. C., Fitch, E., Ganesan, S., O’Brien, M., et al. (2021) · Genetics in Medicine · doi:10.1038/s41436-021-01120-1 · Cited by 58
“The SCN2A gene encodes the α -subunit of the neuronally expressed type II voltage-gated sodium channel, also known as Na V 1.2 6,7 .”
BackgroundInfluentialEpilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties
Thompson, C. H., Potet, F., Abramova, T. V., DeKeyser, J., Ghabra, N. F., Vanoye, C. G., Millichap, J. G., & George, A. L. (2023) · The Journal of General Physiology · doi:10.1085/jgp.202313375 · Cited by 68
“2 channels, and because earlier studies of missense variants associated with epilepsy demonstrated gain-of-function (GoF), a general genotype–phenotype correlation emerged (Sanders et al., 2018).”
BackgroundSelf-citationBegemann, A., Acuña, M. A., Zweier, M., Vincent, M., Steindl, K., Bachmann‐Gagescu, R., Hackenberg, A., Abela, L., Plecko, B., Kroell-Seger, J., et al. (2019) · Molecular Medicine · doi:10.1186/s10020-019-0073-6 · Cited by 66
“…is due to usually inherited missense variants that lead to a small but relevant gain of channel function and 3) epileptic encephalopathies are the result of profound and lasting gating changes due to de novo missense variants (Ben-Shalom et al. 2017, Sanders et al. 2018, Berecki et al. 2018).”
InfluentialGenetic Landscape of Rett Syndrome Spectrum: Improvements and Challenges
Vidal, S., Xiol, C., Pascual‐Alonso, A., O’Callaghan, M., Pineda, M., & Armstrong, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20163925 · Cited by 65
“Pathogenic variants in the SCN2A gene that produce loss-of-function of the protein lead to ASD/ID and increased channel activity that lead to epileptic encephalopathy early infantile 11 (EEIE11) and benign familial neonatal-infantile seizures (BFIS) [52].”
BackgroundThe landscape of early infantile epileptic encephalopathy in a consanguineous population
Nashabat, M., Qahtani, X. A., Makdob, S. A., Altwaijri, W. A., Baarmah, D., Hundallah, K. J., Alhashem, A. M., Tala, S. A., Maddirevula, S., Alkuraya, F. S., et al. (2019) · Seizure · doi:10.1016/j.seizure.2019.04.018 · Cited by 65
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Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders
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“2 prevails in excitatory neurons [11] and Glutamatergic neurons [12].”
BackgroundDegeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair
Stöber, T. M., Batulin, D., Triesch, J., Narayanan, R., & Jedlička, P. (2023) · Communications Biology · doi:10.1038/s42003-023-04823-0 · Cited by 65
“This is also the case for those with a loss-of-function mutation in the SCN2A subunit, whereas patients with a gain-of-function mutation in the SCN2A subunit usually bene fi t greatly from sodium channel blockers 168,169 ; see also ref.”
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“Such conditions could mimic cases of SCN2A haploinsufficiency, associated with autism spectrum disorder and intellectual disability [13, 58, 59].”
BackgroundSelf-citationMeasurement of genetic diseases as a cause of mortality in infants receiving whole genome sequencing
Kingsmore, S. F., Henderson, A. J., Owen, M. J., Clark, M. M., Hansen, C., Dimmock, D., Chambers, C., Jelliffe‐Pawlowski, L. L., & Hobbs, C. A. (2020) · npj Genomic Medicine · doi:10.1038/s41525-020-00155-8 · Cited by 58
Calcium and activity-dependent signaling in the developing cerebral cortex
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Clinical and genetic spectrum of SCN2A-associated episodic ataxia
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Dendritic Integration Dysfunction in Neurodevelopmental Disorders
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Self-citationMechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
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Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants
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“The standard AED guidelines are usually applied to patients indiscriminately (Wilmshurst et al., 2015; Sanders et al., 2018).”
BackgroundIon Channels Involvement in Neurodevelopmental Disorders
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SCN 2A channelopathies: Mechanisms and models
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“SCN2A associated LoF in these populations of neurons may further contribute to the emergence of later phenotypes, such as autism.(40) Evidence from rodent models suggests that developmentally regulated alternative splicing results in neonatal and adult Scn2a isoforms with different characteristics.”
BackgroundSelf-citationExpanded clinical phenotype spectrum correlates with variant function in SCN2A-related disorders
Berg, A. T., Thompson, C. H., Myers, L. S., Anderson, E. L., Evans, L. M., Kaiser, A. J. E., Paltell, K. C., Nili, A. N., DeKeyser, J., Abramova, T. V., et al. (2024) · Brain · doi:10.1093/brain/awae125 · Cited by 48
“6,7,12,13,18 Systematic characterization of the extent and nature of the developmental and functional impairments, however, has been inconsistent across studies.”
BackgroundResultSelf-citationA convergent molecular network underlying autism and congenital heart disease
Rosenthal, S. B., Willsey, H. R., Xu, Y., Yuan, M., Dea, J., Wang, S., Curtis, C., Sempou, E., Khokha, M. K., Chi, N. C., et al. (2021) · Cell Systems · doi:10.1016/j.cels.2021.07.009 · Cited by 41
“Of particular note was SCN2A, which had been previously reported to be expressed exclusively in the adult prefrontal cortex where it promotes the firing of mature excitatory neurons (Sanders et al., 2018; Spratt et al., 2019).”
BackgroundCRISPR activation for SCN2A-related neurodevelopmental disorders
Tamura, S., Nelson, A. D., Spratt, P. W. E., Hamada, E. C., Zhou, X., Kyoung, H., Li, Z., Arnould, C., Barskyi, V., Krupkin, B., et al. (2025) · Nature · doi:10.1038/s41586-025-09522-w · Cited by 52
“SCN2A -related NDDs are characterized by severe intellectual disability, global developmental delay, ASD and seizures that can be refractory to traditional treatment methods 2 .”
InfluentialSelf-citationRegulatory genes and pathways disrupted in autism spectrum disorders
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Zebrafish Modeling of Autism Spectrum Disorders, Current Status and Future Prospective
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“For instance, sodium channel blockers only work for KCNQ2 loss-of-function, and SCN2A and SCN8A gain-of-function mutations [51, 95].”
BackgroundCarvill, G. L., Matheny, T., Hesselberth, J. R., & Demarest, S. (2021) · Neurotherapeutics · doi:10.1007/s13311-021-01137-z · Cited by 39
“Meanwhile, pathogenic loss-of-function variants are one of the most common causes of autism spectrum disorder, and a small group of individuals also have childhood-onset epilepsy [39].”
BackgroundArnett, A. B., Trinh, S., & Bernier, R. (2018) · Current Opinion in Psychology · doi:10.1016/j.copsyc.2018.07.004 · Cited by 39
“Moreover, knowledge about the mechanism of impact in SCN2A disruptions has enormous potential to inform targeted neurodevelopmental research in other ASD populations, who may share common neurological differences despite differing etiology [37].”
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Axon initial segment structure and function in health and disease
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“LoF variants in both of the predominant Na V s in pyramidal neurons, Na V 1.2 and Na V 1.6, are associated with ASD and ID (148, 289, 311 – 313).”
InfluentialSelf-citationClinical Phenotypes of Carriers of Mutations in CHD8 or Its Conserved Target Genes
Beighley, J. S., Hudac, C. M., Arnett, A. B., Peterson, J. L., Gerdts, J. A., Wallace, A. S., Mefford, H. C., Hoekzema, K., Turner, T. N., O’Roak, B. J., et al. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.07.020 · Cited by 34
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Supplemental analyses found consistent results across medical conditions, even when considering the potential influence of a microcephaly-associated gene (i.e., DYRK1A, (29), SI Materials II) or a seizure-associated gene (i.e., SCN2A, (30)…”
BackgroundSelf-citationVoltage‐gated sodium channels in genetic epilepsy: up and down of excitability
Rusina, E., Simonti, M., Duprat, F., Cestèle, S., & Mantegazza, M. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15947 · Cited by 38
Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD
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“Children with SCN2A LoF variants typically have limited to no verbal repertoire and have difficulty following instructions, but often are very comfortable with caregivers ( 15 ).”
BackgroundInfluentialSelf-citationThe most recurrent monogenic disorders that overlap with the phenotype of Rett syndrome
Vidal, S., Brandi, N., Pacheco, P., Maynou, J., Fernández, G., Xiol, C., Pascual‐Alonso, A., Pineda, M., O’Callaghan, M., García‐Cazorla, À., et al. (2019) · European Journal of Paediatric Neurology · doi:10.1016/j.ejpn.2019.04.006 · Cited by 36
Data-driven historical characterization of epilepsy-associated genes
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Self-citationEfficient detection of copy‐number variations using exome data: Batch‐ and sex‐based analyses
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“2 ion selectivity on neuronal function Vertebrate voltage-gated sodium channels contain four highly conserved residues (DEKA) that confer selectivity for sodium (Dudev and Lim, 2014; Sanders et al., 2018).”
BackgroundMethodResultInfluentialSelf-citationPathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons
Asadollahi, R., Delvendahl, I., Muff, R., Tan, G., Rodríguez, D. G., Turan, S., Russo, M., Oneda, B., Joset, P., Boonsawat, P., et al. (2023) · Human Molecular Genetics · doi:10.1093/hmg/ddad048 · Cited by 31
“At about 1–2 years of age, Na V 1.2 in the distal part of the axon initial segment and the remaining axon is largely replaced by Na V 1.6, which takes over the process of AP initiation, whereas Na V 1.2 mainly contributes to back-propagation of APs to somato-dendritic compartments (1,2,4,5).”
InfluentialHeighway, J., Sedó, A., Garg, A., Eldershaw, L., Perreau, V. M., Berecki, G., Reid, C. A., Petrou, S., & Maljevic, S. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2022.105622 · Cited by 32
“CHANNEL COMPARTMENTALISATION AIS [5] Global AIS in neocortex, then shifts to proximal AIS [7] Cell bodies (neocortex) [11] Distal AIS and nodes of Ranvier [7, 10], dendrites [10] ASSOCIATED DISORDERS Epilepsy (Dravet Syndrome, GEFS+) [12], familial hemiplegic migraine [13] Epilepsy (DEE, B(F)NIS), ASD / ID [14, 15], a…”
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Self-citationArnett, A. B., Wang, T., Eichler, E. E., & Bernier, R. (2021) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-021-09371-4 · Cited by 33
“Gene had CHD8 binding sites but fold change was not statistically significant, as reported in [20].”
BackgroundSelf-citationPhenotypic complexities of rare heterozygous neurexin-1 deletions
Fernando, M. B., Fan, Y., Zhang, Y., Tokolyi, A., Murphy, A., Kammourh, S., Deans, P. J. M., Ghorbani, S., Onatzevitch, R., Pero, A., et al. (2025) · Nature · doi:10.1038/s41586-025-08864-9 · Cited by 30
“44) CACNA1D 45 , CACNA1C 46 , SCN1A 47 and SCN2A 48 ), as well as in neurodegenerative disease (for example, SOD1 (ref.”
Bi‐allelic VPS16 variants limit HOPS/CORVET levels and cause a mucopolysaccharidosis‐like disease
Sofou, K., Meier, K., Sanderson, L. E., Kaminski, D., Montoliu‐Gaya, L., Samuelsson, E., Blomqvist, M., Agholme, L., Gärtner, J., Mühlhausen, C., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202013376 · Cited by 29
Voltage-gated ion channels in epilepsies: circuit dysfunctions and treatments
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“Sodium channel neuronal type II alpha subunit (SCN2A; MIM 182390) [34,35]; ii.”
BackgroundInfluentialVenom-derived modulators of epilepsy-related ion channels
Chow, C. Y., Absalom, N. L., Biggs, K. A., King, G. F., & Ma, L. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114043 · Cited by 28
The phenotype and treatment of SCN2A ‐related developmental and epileptic encephalopathy
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“Interestingly, human ASD subjects with SCN2A mutations were reported to “enjoy physical contact with caregivers” (25).”
Self-citationA multi-omics approach for biomarker discovery in neuroblastoma: a network-based framework
Hussein, R., Abou‐Shanab, A. M., & Badr, E. (2024) · npj Systems Biology and Applications · doi:10.1038/s41540-024-00371-3 · Cited by 29
“Hsa-miR-137repressessomegenesinvolved inNBcellfatecommitment,survival,anddifferentiation,suchasGRN, GAD2,MEGF9,SLC1A5,SLC8A1,andSCN2AasillustratedinSupple-mentaryFig.5 80 – 84 .”
Waris, A., Siraj, M., Khan, A. A., Lin, J., Asim, M., & Alhumaydhi, F. A. (2024) · ACS Pharmacology & Translational Science · doi:10.1021/acsptsci.4c00494 · Cited by 30
Calcium Channel Dysfunction in Epilepsy: Gain of CACNA1E
Carvill, G. L. (2019) · Epiliepsy currents/Epilepsy currents · doi:10.1177/1535759719845324 · Cited by 26
“It should be noted, however, that there are examples of other ion channels implicated in DEE (eg, KCNQ2, SCN2A) that cause seizures by both loss and gain of function mechanisms, with some preliminary evidence of genotype–phenotype correlations.(20,21) For instance, individuals with loss of function KCNQ2 variants pres…”
Zaucha, J. M., Heinzinger, M., Kulandaisamy, A., Kataka, E. S., Llorián-Salvador, Ó., Popov, P. A., Rost, B., Gromiha, M. M., Zhorov, B. S., & Frishman, D. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbaa132 · Cited by 26
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Ganguly, S., Thompson, C. H., & George, A. L. (2021) · The Journal of Physiology · doi:10.1113/jp281834 · Cited by 24
Self-citation
Metadata
- 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)
- 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
- bronze
- doi.org
- 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 › Clinical Neurology › 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
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