Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders
Open accessAbstract
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.
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Benign familial infantile seizures are characterized by infantile-onset seizures before 12 months of age that resolve by 2 years of age without overt long-term neuropsychiatric sequelae.
“2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-term neuropsychiatric sequelae;”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The Benign (familial) neonatal/infantile seizures section (p. 5) reports seizure freedom by age 2 and normal cognitive development in most cases. But onset ranged up to 23 months, one patient had isolated seizures at age 14, and another developed partial cognitive deterioration. The categorical age limits and absence of long-term sequelae therefore overstate the source. (LLM, conf=0.88)
Experimental — accuracy not yet measuredInfantile epileptic encephalopathy is characterized by infantile-onset seizures before 12 months of age followed by neurodevelopmental delay.
“1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay;”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The classification in “Previously unpublished patients” (p. 4) links early infantile epilepsy to seizures before 3 months and impaired cognitive development; the patient description (p. 5) likewise reports onset within 3 months and intellectual disability. These passages support early seizures and developmental impairment, but they do not establish that delay followed the seizures or define this group by a before-12-month cutoff. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAutism spectrum disorder/intellectual disability is characterized by global developmental delay, particularly in social and language milestones.
“3) autism spectrum disorder/intellectual disability (ASD/ID), characterized by global developmental delay, particularly of social and language milestones.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The section “Intellectual disability and/or autism without epilepsy” (p. 7) reports SCN2A-related cases with autism and moderate to severe intellectual disability. It does not characterize this subgroup as having global developmental delay, particularly in social and language milestones; searches for those developmental features found no supporting passage. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSCN2A variants are primarily associated with three distinct disorders: infantile epileptic encephalopathy, benign familial infantile seizures, and autism spectrum disorder/intellectual disability.
“Variants in SCN2A are primarily associated with three distinct disorders [24,25]: 1) infantile epileptic encephalopathy (IEE), characterized by infantile-onset seizures, before 12 months of age, followed by neurodevelopmental delay; 2) benign (familial) infantile seizures (BIS), characterized by infantile-onset seizures, before 12 months of age, that resolve by 2 years of age without overt long-t”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The classification in ‘Previously unpublished patients’ (p. 4) supports the broad association with benign neonatal/infantile seizures, epileptic encephalopathy, and intellectual disability or autism without epilepsy. But it distinguishes four groups, including a separate encephalopathy group with infantile or childhood epilepsy; the source does not limit that group to infantile onset. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA subsequent publication of 71 novel SCN2A patients from Europe further supports the model proposed by Ben-Shalom et al.
“The subsequent publication of 71 novel SCN2A patients from Europe [25] further support the model proposed in Ben-Shalom et al.. [26].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
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)
Experimental — accuracy not yet measured
Only about 20 of the hundreds of disorder-associated SCN2A variants have been electrophysiologically assessed to date.
“To date, only about 20 of the hundreds of disorder-associated variants have been electrophysiologically assessed (summarized in [24,25]).”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The Functional studies discussion (p. 17) says that only a small number of identified SCN2A mutations had been studied functionally, and reports four additional analyses. It does not establish that the number electrophysiologically assessed was about 20. The Results (p. 5) count 201 patients, not hundreds of distinct variants, so that denominator is also unsupported by this copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeizure onset after three months often meets criteria for West syndrome, with infantile spasms and hypsarrhythmia on EEG, and can evolve to Lennox-Gastaut syndrome with multiple seizure types as the child ages.
“In contrast, onset after three months often meets criteria for West Syndrome, with infantile spasms and a hypsarrhythmia pattern on EEG, evolving to Lennox-Gastaut syndrome with multiple seizure types as the child gets older [25].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The infantile/childhood epilepsy section (p. 6) reports 16 patients with West syndrome or infantile spasms, five of whom later developed Lennox-Gastaut syndrome. The seizure-outcome section (p. 17) reports hypsarrhythmia on EEG in children with West syndrome. But the paper says the majority of the remaining patients with onset after three months had unclassifiable epilepsies, so the claim overstates how commonly that onset leads to West syndrome and subsequent Lennox-Gastaut syndrome. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAlthough epileptic encephalopathy often presents with neonatal seizures, seizure onset after three months probably occurs in 20%-40% of cases.
“While epileptic encephalopathy frequently presents with seizures in the neonatal period, with some families retrospectively reporting rhythmic movements in utero, it is likely that seizure onset after three months occurs in 20%-40% of cases [24,25].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
The encephalopathy sections (pp. 5–6) report 71 patients with seizure onset before three months and 58 with onset at three months or later, supporting the point that later onset occurs. Among patients with known onset in those groups, the latter is about 45%, not the claimed 20%–40%; the passages also do not establish how often onset was specifically neonatal. (LLM, conf=0.86)
Experimental — accuracy not yet measuredSeizure onset under age 3 months in SCN2A DEEs and 6 months in SCN8A DEEs is associated with GOF, and SCBs are efficacious in these phenotypes.
“Seizure onset under age 3 months in SCN2A DEEs and 6 months in SCN8A DEEs, is associated with GOF 34,35 , and SCBs are efficacious in these phenotypes 34 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [34]
The Discussion (p. 13) associates SCN2A epilepsy onset before 3 months with gain-of-function mutations and a relatively good response to sodium-channel blockers. The treatment section (p. 17) cautions that this response is based on retrospective observations. Our copy does not establish the claimed 6-month threshold, gain-of-function association, or blocker efficacy for SCN8A DEEs (searched: SCN8A). (LLM, conf=0.90)
Experimental — accuracy not yet measuredDosing of gene therapy requires a delicate balance to ensure that a GOF phenotype is not turned into a LOF phenotype, as many genes demonstrate severe phenotypes with both types of dysfunction.
“Dosing is an important issue, which requires a delicate balance to ensure that a GOF phenotype is not turned into a LOF phenotype, as many genes demonstrate severe phenotypes with both types of dysfunction 34 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [34]
The Functional studies section (p. 13) identifies both gain-of-function and loss-of-function SCN2A mutations in children with epilepsy. The Seizure outcome and treatment effects section (p. 17) discusses possible seizure aggravation when sodium-channel blockers further reduce activity in a loss-of-function disorder. The paper does not address gene-therapy dosing or show that treatment can turn a gain-of-function phenotype into a loss-of-function phenotype; its evidence concerns SCN2A rather than many genes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredFor infants with postnatal-onset seizures at 3 months or earlier, non-selective sodium channel blockers such as phenytoin and carbamazepine are more effective, as expected for a gain-of-function variant.
“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].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
Some reports describe clinical improvement with less mainstream medications, including lidocaine for infantile epileptic encephalopathy, ethosuximide for late-onset seizures, and acetazolamide for episodic ataxia, though data on generalizability are limited.
“Some reports have described clinical improvement with less mainstream medications, including lidocaine in children with infantile epileptic encephalopathy [56,57], ethosuximide for late-onset seizures [25], and acetazolamide for episodic ataxia [28,29], though data on the generalizability of these effects are limited.”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
Analysis of data from publications and clinical cohorts has already provided insights into genotype-phenotype relationships and appropriate antiepileptic drugs.
“Analysis of data from publications and clinical cohorts has already provided insights into genotype-phenotype relationships and appropriate antiepileptic drugs [24,25].”
From Progress in Understanding and Treating SCN2A-Mediated Disorders (2018) · cites this paper as [25]
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Genetic modifiers affecting severity of epilepsy caused by mutation of sodium channelScn2a
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Novel de novo SCN2A Mutation in a Child With Migrating Focal Seizures of Infancy
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Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings
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Compromised function in the Nav1.2 Dravet syndrome mutation R1312T
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SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet
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A case of recurrent encephalopathy with SCN2A missense mutation
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Letter to the editor: confirming neonatal seizure and late onset ataxia in SCN2A Ala263Val
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Progress in Understanding and Treating SCN2A-Mediated Disorders
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“For children with ASD/ID and childhood-onset seizures ( 12 months), the opposite is true, with nonsodium channel inhibiting AEDs offering the best options, including levetiracetam,benzodiazepines,andvalproate.”
BackgroundInfluentialSelf-citationIon Channels in Genetic Epilepsy: From Genes and Mechanisms to Disease-Targeted Therapies
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Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies
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Elkhateeb, N., Issa, M. Y., Elbendary, H. M., Elnaggar, W., Ramadan, A., Rafat, K., Kamel, M., Abdel‐Ghafar, S. F., Amer, F., Hassaan, H. M., et al. (2024) · Clinical Genetics · doi:10.1111/cge.14481 · Cited by 7 · see citing works
Self-citation
- Authors
- Wolff, M., Johannesen, K. M., Hedrich, U. B. S., Masnada, S., Rubboli, G., Gardella, E., Lesca, G., Ville, D., Milh, M., Villard, L., Afenjar, A., Chantot-Bastaraud, S., Mignot, C., Lardennois, C., Nava, C., Schwarz, N., Gérard, M., Perrin, L., Doummar, D., Auvin, S., Miranda, M. J., Hempel, M., Brilstra, E., Knoers, N., Verbeek, N., van Kempen, M., Braun, K. P., Mancini, G., Biskup, S., Hörtnagel, K., Döcker, M., Bast, T., Loddenkemper, T., Wong-Kisiel, L., Baumeister, F. M., Fazeli, W., Striano, P., Dilena, R., Fontana, E., Zara, F., Kurlemann, G., Klepper, J., Thoene, J. G., Arndt, D. H., Deconinck, N., Schmitt-Mechelke, T., Maier, O., Muhle, H., Wical, B., Finetti, C., Brückner, R., Pietz, J., Golla, G., Jillella, D., Linnet, K. M., Charles, P., Moog, U., Õiglane-Shlik, E., Mantovani, J. F., Park, K., Deprez, M., Lederer, D., Mary, S., Scalais, E., Selim, L., Van Coster, R., Lagae, L., Nikanorova, M., Hjalgrim, H., Korenke, G. C., Trivisano, M., Specchio, N., Ceulemans, B., Dorn, T., Helbig, K. L., Hardies, K., Stamberger, H., de Jonghe, P., Weckhuysen, S., Lemke, J. R., Krägeloh-Mann, I., Helbig, I., Kluger, G., Lerche, H., & Møller, R. S.
- Affiliations
- University Children's Hospital Tübingen (DE)
- University of Southern Denmark (DK)
- Hertie Institute for Clinical Brain Research (DE)
- University of Pavia (IT)
- University of Copenhagen (DK)
- 7 Department of Genetics, Lyon University Hospital, Lyon, France
- 10 Department of Pediatric Neurology and Reference Center for Rare Children Epilepsy and Tuberous Sclerosis, Hôpital Femme Mere Enfant, Centre Hospitalier Universitaire de Lyon, HCL, France
- Inserm (FR)
- Hôpital Armand-Trousseau (FR)
- 13 AP-HP, Unité de Gènètique Clinique, Hôpital Armand Trousseau, Groupe Hospitalier Universitaire de l’Est Parisien, Paris, France
- Assistance Publique – Hôpitaux de Paris (FR)
- 15 Service de Pediatrie neonatale et Réanimation - Neuropediatrie, 76000 Rouen, France
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Caen Normandie (FR)
- Herlev Hospital (DK)
- University Medical Center Hamburg-Eppendorf (DE)
- University Medical Center Utrecht (NL)
- 25 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
- Erasmus MC (NL)
- CeGaT (Germany) (DE)
- Diakonie Kork (DE)
- Boston Children's Hospital (US)
- 31 Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic, Rochester MN, USA
- RoMed Kliniken (DE)
- University Hospital Cologne (DE)
- Istituto Giannina Gaslini (IT)
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- 36 Centro di Diagnosi e Cura delle Epilessie Infantili, Azienda Ospedaliera -Policlinico Gianbattista Rossi, Verona, Italy
- University of Münster (DE)
- Klinikum Aschaffenburg (DE)
- University of Michigan (US)
- Oakland University (US)
- Université Libre de Bruxelles (BE)
- 43 Children’s Hospital Lucerne, Luzerner Kantonsspital, Kinderspital Luzern, CH-6000 Luzern 16, Switzerland
- Ostschweizer Kinderspital (CH)
- Christian-Albrechts-Universität zu Kiel (DE)
- Gillette Children's Specialty Healthcare (US)
- Elisabeth-Krankenhaus Essen (DE)
- 48 Wangen, Germany
- University Hospital Heidelberg (DE)
- Klinikum Lippe (DE)
- Aarhus University Hospital (DK)
- 55 Children’s Clinic, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia
- Sisters of Mercy Health System (US)
- Children's Hospital Colorado (US)
- Institute of Pathology and Genetics (BE)
- Centre Hospitalier de Luxembourg (LU)
- Cairo University (EG)
- 61 Department of Pediatrics, Division of Pediatric Neurology and Metabolism, Ghent University Hospital, Ghent, Belgium
- Universitair Ziekenhuis Leuven (BE)
- 2 The Danish Epilepsy Centre, Dianalund, Denmark
- 63 Zentrum für Kinder- und Jugendmedizin (Elisabeth Kinderkrankenhaus), Klinik für Neuropädiatrie u. Angeborene, Stoffwechselerkrankungen, Oldenburg, Germany
- Bambino Gesù Children's Hospital (IT)
- University of Antwerp (BE)
- Swiss Epilepsy Center (CH)
- Ambry Genetics (United States) (US)
- 68 Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
- University Hospital Leipzig (DE)
- 1 Department of Pediatric Neurology and Developmental Medicine, University Children’s Hospital, Tübingen, Germany
- Children's Hospital of Philadelphia (US)
- Schön Klinik Vogtareuth (DE)
- ORCID
- Wolff, Markus
- Johannesen, Katrine M.
- Hedrich, Ulrike B. S.
- Masnada, Silvia
- Rubboli, Guido
- Gardella, Elena
- Milh, Mathieu
- Villard, Laurent
- Afenjar, Alexandra
- Mignot, Cyril
- Nava, Caroline
- Schwarz, Niklas
- Gérard, Marion
- Doummar, Diane
- Auvin, Stéphane
- Hempel, Maja
- Brilstra, Eva
- Knoers, Nine
- Braun, Kees P.
- Mancini, Grazia
- Hörtnagel, Konstanze
- Bast, Thomas
- Loddenkemper, Tobias
- Fazeli, Walid
- Striano, Pasquale
- Dilena, Robertino
- Fontana, Elena
- Zara, Federico
- Klepper, Joerg
- Thoene, Jess G.
- Arndt, Daniel H.
- Deconinck, Nicolas
- Jillella, Dinesh
- Charles, Perrine
- Moog, Ute
- Park, Kristen
- Lederer, Damien
- Scalais, Emmanuel
- Selim, Laila
- Lagae, Lieven
- Nikanorova, Marina
- Hjalgrim, Helle
- Korenke, G. Christoph
- Trivisano, Marina
- Specchio, Nicola
- Ceulemans, Berten
- Helbig, Katherine L.
- Stamberger, Hannah
- Weckhuysen, Sarah
- Lemke, Johannes R.
- Helbig, Ingo
- Kluger, Gerhard
- Lerche, Holger
- Møller, Rikke S
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-04-04
- Volume
- 140
- Issue
- 5
- Pages
- 1316-1336
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2604505267
- Cited by
- 600
- References
- 73
- Citations by year
- 2026: 64 · 2025: 56 · 2024: 60 · 2023: 67 · 2022: 63 · 2021: 84 · 2020: 59 · 2019: 79 · 2018: 45 · 2017: 20
- FWCI
- 45.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- HAL AMU (submittedVersion, other-oa)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Scopus (Elsevier) (submittedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- German Research Foundation (HE5415/3-1, DFG, HE5415/5-1, HE 5415/6-1)
- German Ministry for Education and Research (01DH12033, MAR 10/012)
- German chapter of the International League Against Epilepsy (DGfE)
- EU FP7 project EpiPGX (279062)
- European Science Foundation (DFG grant Le1030/11-2)
- German Ministry for Education and Research (BMBF) (01GM1105A)
- ESF/Euro-Epinomics (GA136.11.N, FWO/ESF-ECRP)
- Fund for Scientific Research Flanders (1125416N)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- SCN2A, Nav1.2, voltage-gated sodium channels, infantile epilepsy, West syndrome, sodium channel blockers, antiepileptic drug response, gain-of-function mutations, loss-of-function mutations, channel inactivation kinetics, persistent sodium current, phenotypic heterogeneity, neurodevelopmental disorders, epilepsy of infancy with migrating focal seizures, Ohtahara syndrome
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Denmark, Epilepsy, Female, Humans, Infant, Male, Mutation, Phenotype, Age of Onset, Sodium Channel Blockers, Young Adult, NAV1.2 Voltage-Gated Sodium Channel, Neurodevelopmental Disorders
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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