SCN2A-related disorders

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SCN2A-related disorders are a group of rare neurodevelopmental disorders caused by pathogenic variants in the SCN2A gene, which encodes a subunit of the voltage-gated sodium channel NaV1.2. [1] Mutations in the SCN2A gene can cause a broad spectrum of disorders collectively referred to as SCN2A-related disorders. These include cases of autism, self-limited epilepsy, early infantile developmental and epileptic encephalopathy, later onset developmental and epileptic encephalopathy, infantile spasms, SCN2A-related disorders without epilepsy, episodic ataxia, and further movement disorders.

Contents

Clinical significance

Mutations in the SCN2A gene can cause a broad spectrum of disorders collectively referred to as SCN2A-related disorders. These include cases of autism [2] , self-limited epilepsy, early infantile developmental and epileptic encephalopathy, later onset developmental and epileptic encephalopathy, infantile spasms, SCN2A-related disorders without epilepsy, episodic ataxia, and further movement disorders. [1] Two major groups of SCN2A mutations can be distinguished based on their functional consequences and response to seizure medication: gain of function mutations, typically associated with seizure onset within the first three months of life, and loss of function mutations, in which seizures begin after the first three months or may never occur. The former group tends to benefit from treatment with sodium channel blockers, whereas in the latter, such treatment is often ineffective or may even exacerbate seizures. [3] Notably, SCN2A is known to be the most prominent genetic risk factor for autism-spectrum-disorders. [2]

SCN2A gene mutations have also been identified in bitemporal glucose hypometabolism [4] , and bipolar disorder. [5]

February 24th - International SCN2A Awareness Day

International SCN2A Awareness Day is globally recognized as February 24 each year. The goal is to raise awareness of disorders caused by pathological variants in the SCN2A gene, including epilepsy, autism, intellectual disability, and self-limited familial infantile epilepsy (SelFIE). Advocacy goals for SCN2A Awareness Day include improving care, funding research and community support efforts, and promoting early genetic testing and counseling.

ICD-10-CM Code

Effective October 1, 2025, the ICD-10-CM code for SCN2A-related neurodevelopmental disorder is QA0.0101. [6]

SCN2A Patient Advocacy Organizations (PAOs / PAGs)

Further reading

Review Articles

Genotype/Phenotype

Treatment (Current and Emerging)

Research Readiness, Clinical Outcome Assessments, and Clinical Trial Design

References

  1. 1 2 3 George, Alfred L., ed. (2024). SCN2A-related disorders. Cambridge elements. Elements in genetics in epilepsy. Cambridge, United Kingdom New York, NY: Cambridge University Press. ISBN   978-1-009-53036-1.
  2. 1 2 Sanders, Stephan J.; Murtha, Michael T.; Gupta, Abha R.; Murdoch, John D.; Raubeson, Melanie J.; Willsey, A. Jeremy; Ercan-Sencicek, A. Gulhan; DiLullo, Nicholas M.; Parikshak, Neelroop N.; Stein, Jason L.; Walker, Michael F.; Ober, Gordon T.; Teran, Nicole A.; Song, Youeun; El-Fishawy, Paul (May 2012). "De novo mutations revealed by whole-exome sequencing are strongly associated with autism" . Nature. 485 (7397): 237–241. Bibcode:2012Natur.485..237S. doi:10.1038/nature10945. ISSN   1476-4687.
  3. ↑ Wolff, Markus; Johannesen, Katrine M.; Hedrich, Ulrike B. S.; Masnada, Silvia; Rubboli, Guido; Gardella, Elena; Lesca, Gaetan; Ville, Dorothée; Milh, Mathieu; Villard, Laurent; Afenjar, Alexandra; Chantot-Bastaraud, Sandra; Mignot, Cyril; Lardennois, Caroline; Nava, Caroline (2017-05-01). "Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders". Brain. 140 (5): 1316–1336. doi:10.1093/brain/awx054. hdl: 1765/100043 . ISSN   0006-8950. PMID   28379373.
  4. ↑ Sundaram, Senthil K.; Chugani, Harry T.; Tiwari, Vijay N.; Huq, A. H. M. M. (2013-07-01). "SCN2A Mutation Is Associated With Infantile Spasms and Bitemporal Glucose Hypometabolism". Pediatric Neurology. 49 (1): 46–49. doi:10.1016/j.pediatrneurol.2013.03.002. ISSN   0887-8994. PMC   3868437 . PMID   23827426.
  5. ↑ Stahl, Eli A.; Breen, Gerome; Forstner, Andreas J.; McQuillin, Andrew; Ripke, Stephan; Trubetskoy, Vassily; Mattheisen, Manuel; Wang, Yunpeng; Coleman, Jonathan R. I.; Gaspar, Héléna A.; de Leeuw, Christiaan A.; Steinberg, Stacy; Pavlides, Jennifer M. Whitehead; Trzaskowski, Maciej; Byrne, Enda M. (May 2019). "Genome-wide association study identifies 30 loci associated with bipolar disorder". Nature Genetics. 51 (5): 793–803. doi:10.1038/s41588-019-0397-8. ISSN   1546-1718. PMC   6956732 . PMID   31043756.
  6. ↑ "ICD-10 Code for SCN2A-related neurodevelopmental disorder- QA0.0101- Codify by AAPC". www.aapc.com. Retrieved 2025-12-03.
  7. ↑ Berg, Anne T; Thompson, Christopher H; Myers, Leah Schust; Anderson, Erica; Evans, Lindsey; Kaiser, Ariela J E; Paltell, Katherine; Nili, Amanda N; DeKeyser, Jean-Marc L; Abramova, Tatiana V; Nesbitt, Gerry; Egan, Shawn M; Vanoye, Carlos G; George, Alfred L (2024-08-01). "Expanded clinical phenotype spectrum correlates with variant function in SCN2A -related disorders". Brain. 147 (8): 2761–2774. doi:10.1093/brain/awae125. ISSN   0006-8950. PMC   11292900 . PMID   38651838.
  8. ↑ Berg, Anne T.; Nili, Amanda N.; Evans, Lindsey; Paltell, Katherine C.; Kaiser, Ariela J.E.; Anderson, Erica L.; Egan, Shawn M.; Kaat, Aaron J.; Nesbitt, Gerry; Myers, Leah S. (February 2025). "Assessing Communication Impairments in a Rare Neurodevelopmental Disorder". Neurology Clinical Practice. 15 (1) e200391. doi:10.1212/CPJ.0000000000200391. PMC  11492899. PMID   39439575.
  9. ↑ DiStefano, Nicholas; Cooper, Jaimee N.; Elisha, David H.; Zalta, Max; Mittal, Jeenu; Cohen, David; Monterrubio, Andrea; Hossain, Ryan; Sangadi, Akhila; Mittal, Rahul; Eshraghi, Adrien A. (2025-05-28). "Decoding SCN2A Variants: Bridging Genetics and Phenotypes in Autism Spectrum Disorder". Journal of Clinical Medicine. 14 (11): 3790. doi: 10.3390/jcm14113790 . ISSN   2077-0383. PMC   12156426 . PMID   40507552.
  10. ↑ Berg, Anne T; Thompson, Christopher H; Myers, Leah Schust; Anderson, Erica; Evans, Lindsey; Kaiser, Ariela J E; Paltell, Katherine; Nili, Amanda N; DeKeyser, Jean-Marc L; Abramova, Tatiana V; Nesbitt, Gerry; Egan, Shawn M; Vanoye, Carlos G; George, Alfred L (2024-08-01). "Expanded clinical phenotype spectrum correlates with variant function in SCN2A -related disorders". Brain. 147 (8): 2761–2774. doi:10.1093/brain/awae125. ISSN   0006-8950. PMC   11292900 . PMID   38651838.
  11. ↑ Brunklaus, Andreas; Feng, Tony; Brünger, Tobias; Perez-Palma, Eduardo; Heyne, Henrike; Matthews, Emma; Semsarian, Christopher; Symonds, Joseph D; Zuberi, Sameer M; Lal, Dennis; Schorge, Stephanie (2022-12-19). "Gene variant effects across sodium channelopathies predict function and guide precision therapy". Brain. 145 (12): 4275–4286. doi:10.1093/brain/awac006. ISSN   0006-8950. PMC   9897196 . PMID   35037686.
  12. ↑ Crawford, Katherine; Xian, Julie; Helbig, Katherine L.; Galer, Peter D.; Parthasarathy, Shridhar; Lewis-Smith, David; Kaufman, Michael C.; Fitch, Eryn; Ganesan, Shiva; O'Brien, Margaret; Codoni, Veronica; Ellis, Colin A.; Conway, Laura J.; Taylor, Deanne; Krause, Roland (2021-07-01). "Computational analysis of 10,860 phenotypic annotations in individuals with SCN2A-related disorders". Genetics in Medicine. 23 (7): 1263–1272. doi:10.1038/s41436-021-01120-1. ISSN   1098-3600. PMC   8257493 . PMID   33731876.
  13. ↑ Satterstrom, F. Kyle; Kosmicki, Jack A.; Wang, Jiebiao; Breen, Michael S.; Rubeis, Silvia De; An, Joon-Yong; Peng, Minshi; Collins, Ryan; Grove, Jakob; Klei, Lambertus; Stevens, Christine; Reichert, Jennifer; Mulhern, Maureen S.; Artomov, Mykyta; Gerges, Sherif (2020-02-06). "Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism". Cell. 180 (3): 568–584.e23. doi:10.1016/j.cell.2019.12.036. ISSN   0092-8674. PMC   7250485 . PMID   31981491.
  14. ↑ Wolff, Markus; Brunklaus, Andreas; Zuberi, Sameer M. (2019). "Phenotypic spectrum and genetics of SCN2A-related disorders, treatment options, and outcomes in epilepsy and beyond". Epilepsia. 60 (S3): S59 –S67. doi:10.1111/epi.14935. ISSN   1528-1167. PMID   31904126.
  15. ↑ Goldstein, Jonathan; Ross, David A.; Luca, Daniel Moreno De (2019-04-01). "Found in Translation: Autism Genetics and the Quest for Its Rosetta Stone". Biological Psychiatry. 85 (7): e29 –e30. doi:10.1016/j.biopsych.2019.02.001. ISSN   0006-3223. PMC   6698908 . PMID   30871690.
  16. ↑ Sanders, Stephan J.; Campbell, Arthur J.; Cottrell, Jeffrey R.; Moller, Rikke S.; Wagner, Florence F.; Auldridge, Angie L.; Bernier, Raphael A.; Catterall, William A.; Chung, Wendy K.; Empfield, James R.; George, Alfred L.; Hipp, Joerg F.; Khwaja, Omar; Kiskinis, Evangelos; Lal, Dennis (2018-07-01). "Progress in Understanding and Treating SCN2A-Mediated Disorders". Trends in Neurosciences. 41 (7): 442–456. doi:10.1016/j.tins.2018.03.011. ISSN   0166-2236. PMC   6015533 . PMID   29691040.
  17. ↑ Wolff, Markus; Johannesen, Katrine M.; Hedrich, Ulrike B. S.; Masnada, Silvia; Rubboli, Guido; Gardella, Elena; Lesca, Gaetan; Ville, Dorothée; Milh, Mathieu; Villard, Laurent; Afenjar, Alexandra; Chantot-Bastaraud, Sandra; Mignot, Cyril; Lardennois, Caroline; Nava, Caroline (2017-05-01). "Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders". Brain. 140 (5): 1316–1336. doi:10.1093/brain/awx054. hdl: 1765/100043 . ISSN   0006-8950. PMID   28379373.
  18. ↑ Dechene, Elizabeth (2016-03-21). "SCN2A – a 2016 update". Beyond the Ion Channel. Retrieved 2025-10-16.
  19. ↑ Helbig, Ingo (2014-01-05). "Story of a genetic shape-shifter: SCN2A in benign seizures, autism and epileptic encephalopathy". Beyond the Ion Channel. Retrieved 2025-10-16.
  20. ↑ Tamura, Serena; Nelson, Andrew D.; Spratt, Perry W. E.; Hamada, Elizabeth C.; Zhou, Xujia; Kyoung, Henry; Li, Zizheng; Arnould, Coline; Barskyi, Vladyslav; Krupkin, Beniamin; Young, Kiana; Zhao, Jingjing; Holden, Stephanie S.; Sahagun, Atehsa; Keeshen, Caroline M. (2025-09-17). "CRISPR activation for SCN2A-related neurodevelopmental disorders" . Nature. 646 (8086): 983–991. doi:10.1038/s41586-025-09522-w. ISSN   1476-4687.
  21. ↑ Wagner, Matias; Berecki, Géza; Fazeli, Walid; Nussbaum, Claudia; Flemmer, Andreas W.; Frizzo, Silvana; Heer, Farina; Heinen, Florian; Horton, Robert; Jacotin, Henry; Motel, William; Spar, Brian; Klein, Christoph; Siegel, Corinna; Hübener, Christoph (July 2025). "Antisense oligonucleotide treatment in a preterm infant with early-onset SCN2A developmental and epileptic encephalopathy". Nature Medicine. 31 (7): 2174–2178. doi:10.1038/s41591-025-03656-0. ISSN   1546-170X. PMC   12283366 . PMID   40263630.
  22. ↑ Schust, Leah F.; Burke, Jennifer; SanInocencio, Christina; Bryan, Brad A.; Ho, Karen S.; Egan, Shawn M. (2024-05-01). "A patient organization perspective: charting the course to a cure for SCN2A-related disorders". Therapeutic Advances in Rare Disease. 5 26330040241292645. doi:10.1177/26330040241292645. ISSN   2633-0040. PMC   11555743 . PMID   39533986.
  23. ↑ Sevinc, Gunes; Knox, Kari; George, Michelle; Evans, Lindsey; Kaiser, Ariela; Paltell, Katherine Charlotte; Myers, Leah Schust; Ludwig, Natasha N.; Wojnaroski, Mary; Conecker, Gabrielle; Hecker, JayEtta; Downs, Jenny; Chapman, Chere A. T.; Berg, Anne T. (2025-03-01). "The Feasibility of Personalized Endpoints in Assessing Treatment Outcomes for Rare Diseases: A Pilot Study of Goal Attainment Scaling in SCN2A-Associated Developmental Epileptic Encephalopathy" . Value in Health. 28 (3): 441–448. doi:10.1016/j.jval.2024.12.004. ISSN   1098-3015. PMID   39733836.
  24. ↑ Kaat, Aaron J.; Evans, Lindsey; Nili, Amanda N.; Paltell, Katherine; Kaiser, Arielle; Anderson, Erica; Myers, Leah Schust; Berg, Anne T. (September 2025). "Vineland-3 Growth Scale Values: Psychometric Properties for Clinical Trial Readiness in SCN2A" . Journal of Child and Adolescent Psychopharmacology. 35 (7): 416–423. doi:10.1089/cap.2024.0107. ISSN   1044-5463.
  25. ↑ Downs, Jenny; Ludwig, Natasha N.; Wojnaroski, Mary; Keeley, Jessica; Schust Myers, Leah; Chapman, Chere A. T.; Hecker, JayEtta; Conecker, Gabrielle; Berg, Anne T. (2024-02-01). "What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy". Quality of Life Research. 33 (2): 519–528. doi:10.1007/s11136-023-03543-6. ISSN   1573-2649. PMC   10850209 . PMID   38064015.
  26. ↑ Ludwig, Natasha N.; Wojnaroski, Mary; Suskauer, Stacy J.; Slomine, Beth S.; Kaiser, Ariela; Paltell, Katherine; Evans, Lindsey; Tucker, Karis; Chapman, Chere A. T.; Conecker, Gabrielle; Hecker, JayEtta; Myers, Leah Schust; Downs, Jenny; Berg, Anne T. (2024-11-01). "Novel approaches to measuring cognition in individuals with severe to profound functional impairment: A pilot study in SCN2A-related disorder". Epilepsy & Behavior. 160 109975. doi:10.1016/j.yebeh.2024.109975. ISSN   1525-5050. PMID   39305725.
  27. ↑ Cohen, Stacey R.; Helbig, Ingo; Kaufman, Michael C.; Schust Myers, Leah; Conway, Laura; Helbig, Katherine L. (2022). "Caregiver assessment of quality of life in individuals with genetic developmental and epileptic encephalopathies". Developmental Medicine & Child Neurology. 64 (8): 957–964. doi:10.1111/dmcn.15187. ISSN   1469-8749. PMC   10305579 . PMID   35229292.
  28. ↑ Berg, Anne T.; Palac, Hannah; Wilkening, Greta; Zelko, Frank; Schust Meyer, Leah (January 2021). "SCN2A -Developmental and Epileptic Encephalopathies: Challenges to trial-readiness for non-seizure outcomes" . Epilepsia. 62 (1): 258–268. doi:10.1111/epi.16750. ISSN   0013-9580. PMID   33236786.
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