Development and Adaptive Function in Individuals With SCN2A-Related Disorders

Beatrice Southby Goad¹, Jill Rodda^{1

2}, Meagan Allen¹, Daniel Bamborschke³, Isabella Overmars¹, Rachel J Kerr¹, Ittai Bushlin⁴, Saurabh Chopra⁵, Rohini Coorg^{6

7}, Gabriel Dabscheck^{1

8

9}, Jeremy L Freeman^{1

8}, Mark T Mackay^{1

8

9}, Orrin Devinsky¹⁰, Renzo Guerrini^{11

12}, Elena Parrini¹¹, Bigna Bölsterli^{13

14

15}, Inna Hughes¹⁶, Linda L Huh¹⁷, Mahesh Kamate¹⁸, Abby B Kunz¹⁹, Gia Melikishvili²⁰, Christina Miteff²¹, Kenneth Alexis Myers^{22

23

24}, Heather E Olson^{25

26}, Annapurna Poduri^{25

26}, Sekhar Pillai²⁷, Catherine Kate Riney^{28

29}, Adriane Sinclair²⁸, Sophie Calvert²⁸, Thomas Q Reynolds^{30

31}, Ana Roche Martinez³², Angelo Russo³³, Lynette Grant Sadleir³⁴, Iciar Sanchez-Albisua³⁵, Stefano Sartori³⁶, Stephanie Shea³⁷, Constance L Smith-Hicks³⁸, Claire G Spooner³⁹, Rhys H Thomas^{40

41}, Simone L Ardern-Holmes⁴², Richard Ian Webster⁴², Massimiliano Valeriani^{43

44}, Pierangelo Veggiotti^{45

46}, Silvia Masnada⁴⁵, Tyson L Ware⁴⁷, Michael Yoong^{48

49}, Geza Berecki⁵⁰, Angela De Dominicis⁵¹, Nicola Specchio⁵¹, Marina Trivisano⁵¹, Rikke Steensbjerre Møller^{52

53}, Markus Wolff⁵⁴, Walid Fazeli³, Ingrid Scheffer^{1

8

9

50

55}, Katherine B Howell^{1

8

9}

Affiliations

¹ Murdoch Children's Research Institute, Melbourne, Australia.
² Department of Physiotherapy, University of Melbourne, Australia.
³ Department of Pediatric Neurology, Children's Hospital, University Hospital, Bonn, Germany.
⁴ Division of Pediatric Neurology, Oregon Health and Science University, Portland.
⁵ Indraprastha Apollo Hospital, New Delhi, India.
⁶ Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX.
⁷ Texas Children's Hospital, Houston.
⁸ Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
⁹ Department of Paediatrics, University of Melbourne, Australia.
¹⁰ Comprehensive Epilepsy Centre, New York University Grossman School of Medicine, New York.
¹¹ Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
¹² University of Florence, Italy.
¹³ Department of Neuropediatrics and Child Development Centre, University Children's Hospital, Zurich, Switzerland.
¹⁴ University of Zurich, Switzerland.
¹⁵ Department of Pediatric Neurology, Children's Hospital of Eastern Switzerland, Sankt Gallen.
¹⁶ Department of Neurology, University of Rochester Medical Center, NY.
¹⁷ BC Children's Hospital, British Columbia, Canada.
¹⁸ Department of Pediatric Neurology, Jawaharlal Nehru Medical College, Belgaum, India.
¹⁹ Presbyterian Medical Group, Albuquerque, NM.
²⁰ Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia.
²¹ Department of Paediatric Neurology, John Hunter Children's Hospital, New Lambton Heights, Australia.
²² Division of Child Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Quebec, Canada.
²³ Research Institute of the McGill University Health Centre, Montreal, Canada.
²⁴ Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Quebec, Canada.
²⁵ Department of Neurology, Boston Children's Hospital, MA.
²⁶ National Institute of Neurological Disorders and Stroke, Bethesda, MD.
²⁷ Department of Neurology, Sydney Children's Hospital, Australia.
²⁸ Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Australia.
²⁹ School of Medicine, University of Queensland, Australia.
³⁰ Tufts University School of Medicine, Boston, MA.
³¹ Maine Health Neurology, Scarborough, ME.
³² Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació, Barcelona, Spain.
³³ IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria dell'età Pediatrica Bologna, Italy.
³⁴ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
³⁵ Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.
³⁶ Paediatric Neurology and Neurophysiology Unit - University Hospital of Padua, Padova, Italy.
³⁷ Department of Pediatric Neurology, Children's Hospital Colorado, Aurora, CO.
³⁸ Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD.
³⁹ Department of Paediatric Neurology, Starship Children's Hospital, Auckland, New Zealand.
⁴⁰ Newcastle Upon Tyne NHS Foundation Trust, United Kingdom.
⁴¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom.
⁴² TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, Australia.
⁴³ Developmental Neurology Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
⁴⁴ Systems Medicine Department, University of Tor Vergata, Rome, Italy.
⁴⁵ Pediatric Neurology Unit, Buzzi Children's Hospital, Milan, Italy.
⁴⁶ Neuroscience Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Italy.
⁴⁷ Department of Paediatrics, Royal Hobart Hospital, Australia.
⁴⁸ Barts Health NHS Trust, London, United Kingdom.
⁴⁹ Queen Mary University of London, United Kingdom.
⁵⁰ Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
⁵¹ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.
⁵² Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre (member of ERN EPICARE), Dianalund, Denmark.
⁵³ Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.
⁵⁴ Swiss Epilepsy Center, Klinik Lengg AG, Zürich, Switzerland; and.
⁵⁵ Epilepsy Research Centre, University of Melbourne, Austin Health, Australia.

PMID: 40694750
PMCID: PMC12522044 (available on 2026-08-12)
DOI: 10.1212/WNL.0000000000213868

Development and Adaptive Function in Individuals With SCN2A-Related Disorders

Beatrice Southby Goad et al. Neurology. 2025.

. 2025 Aug 12;105(3):e213868.

doi: 10.1212/WNL.0000000000213868. Epub 2025 Jul 22.

Authors

Affiliations

¹ Murdoch Children's Research Institute, Melbourne, Australia.
² Department of Physiotherapy, University of Melbourne, Australia.
³ Department of Pediatric Neurology, Children's Hospital, University Hospital, Bonn, Germany.
⁴ Division of Pediatric Neurology, Oregon Health and Science University, Portland.
⁵ Indraprastha Apollo Hospital, New Delhi, India.
⁶ Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX.
⁷ Texas Children's Hospital, Houston.
⁸ Department of Neurology, Royal Children's Hospital, Melbourne, Australia.
⁹ Department of Paediatrics, University of Melbourne, Australia.
¹⁰ Comprehensive Epilepsy Centre, New York University Grossman School of Medicine, New York.
¹¹ Neuroscience Department, Meyer Children's Hospital IRCCS, Florence, Italy.
¹² University of Florence, Italy.
¹³ Department of Neuropediatrics and Child Development Centre, University Children's Hospital, Zurich, Switzerland.
¹⁴ University of Zurich, Switzerland.
¹⁵ Department of Pediatric Neurology, Children's Hospital of Eastern Switzerland, Sankt Gallen.
¹⁶ Department of Neurology, University of Rochester Medical Center, NY.
¹⁷ BC Children's Hospital, British Columbia, Canada.
¹⁸ Department of Pediatric Neurology, Jawaharlal Nehru Medical College, Belgaum, India.
¹⁹ Presbyterian Medical Group, Albuquerque, NM.
²⁰ Department of Pediatrics, MediClubGeorgia Medical Center, Tbilisi, Georgia.
²¹ Department of Paediatric Neurology, John Hunter Children's Hospital, New Lambton Heights, Australia.
²² Division of Child Neurology, Department of Pediatrics, Montreal Children's Hospital, McGill University Health Centre, Quebec, Canada.
²³ Research Institute of the McGill University Health Centre, Montreal, Canada.
²⁴ Department of Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Quebec, Canada.
²⁵ Department of Neurology, Boston Children's Hospital, MA.
²⁶ National Institute of Neurological Disorders and Stroke, Bethesda, MD.
²⁷ Department of Neurology, Sydney Children's Hospital, Australia.
²⁸ Neurosciences Unit, Queensland Children's Hospital, South Brisbane, Australia.
²⁹ School of Medicine, University of Queensland, Australia.
³⁰ Tufts University School of Medicine, Boston, MA.
³¹ Maine Health Neurology, Scarborough, ME.
³² Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació, Barcelona, Spain.
³³ IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria dell'età Pediatrica Bologna, Italy.
³⁴ Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand.
³⁵ Division of Neuropaediatrics, Development and Rehabilitation, Department of Paediatrics, Inselspital, Bern University Hospital, University of Bern, Switzerland.
³⁶ Paediatric Neurology and Neurophysiology Unit - University Hospital of Padua, Padova, Italy.
³⁷ Department of Pediatric Neurology, Children's Hospital Colorado, Aurora, CO.
³⁸ Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD.
³⁹ Department of Paediatric Neurology, Starship Children's Hospital, Auckland, New Zealand.
⁴⁰ Newcastle Upon Tyne NHS Foundation Trust, United Kingdom.
⁴¹ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom.
⁴² TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Sydney, Australia.
⁴³ Developmental Neurology Unit, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
⁴⁴ Systems Medicine Department, University of Tor Vergata, Rome, Italy.
⁴⁵ Pediatric Neurology Unit, Buzzi Children's Hospital, Milan, Italy.
⁴⁶ Neuroscience Research Center, Department of Biomedical and Clinical Sciences, University of Milan, Italy.
⁴⁷ Department of Paediatrics, Royal Hobart Hospital, Australia.
⁴⁸ Barts Health NHS Trust, London, United Kingdom.
⁴⁹ Queen Mary University of London, United Kingdom.
⁵⁰ Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
⁵¹ Neurology, Epilepsy and Movement Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.
⁵² Department of Epilepsy Genetics and Personalized Treatment, The Danish Epilepsy Centre (member of ERN EPICARE), Dianalund, Denmark.
⁵³ Department for Regional Health Research, University of Southern Denmark, Odense, Denmark.
⁵⁴ Swiss Epilepsy Center, Klinik Lengg AG, Zürich, Switzerland; and.
⁵⁵ Epilepsy Research Centre, University of Melbourne, Austin Health, Australia.

PMID: 40694750
PMCID: PMC12522044 (available on 2026-08-12)
DOI: 10.1212/WNL.0000000000213868

Abstract

Background and objectives: Developmental impairment is common in individuals with SCN2A-related disorders, although descriptions are limited. We aimed to determine trajectories and outcomes of development and adaptive function.

Methods: This was a mixed retrospective cross-sectional study of individuals from an international SCN2A Natural History Study, who had neurologic/neurodevelopmental disorders due to an SCN2A variant. Individuals with SCN2A intragenic variants were grouped into early-onset (EO) and late-onset (LO) phenotypic groups; those with SCN2A-containing 2q24.3 copy number variants (CNVs) were considered separately. We collected medical and developmental history from parents/caregivers and medical records. Adaptive function and behavior were characterized using functional classification system levels and Vineland Adaptive Behavior Scales-3 (VABS-3) Parent/Caregiver Form. We repeated analyses on individuals with variants known to result in gain-of-function (GOF, typically EO phenotypes) or loss-of-function (LOF, typically LO phenotypes).

Results: A total of 100 individuals (age 0.1-21.9 years, 39% female) were studied. Phenotypic groups were EO (n = 44), LO (n = 48), and 2q24.3 CNV (n = 8). Developmental delay/intellectual disability was present in 91 of 100, and 23 of 80 individuals (29%) older than 2 years had autism spectrum disorder. Of people older than the typical age for skill attainment, 59 of 95 (62%) could sit and 48 of 88 (55%) could walk. In addition, 27 of 86 individuals (31%) spoke more than 1-5 single words, and 24 of 74 (32%) followed two-step commands. Median VABS-3 Adaptive Behavior Composite (ABC) scores were as follows: the EO phenotypic group had a score of 56 (range 21-110), the LO phenotypic group had a score of 45 (range 20-89), and 5 of 6 with a 2q24.3 CNV had an ABC score of <45. The EO phenotypic group had 3 distinct subgroups, consistent with "benign," "intermediate," and "severe" definitions previously published. The LO phenotypic group showed a continuum of severity, without distinct clusters. However, clinically relevant differences in motor function were evident when subgrouped by seizure-onset age; a lower proportion with earlier seizure onset (age <18 months) were independently ambulant than those with later onset or no seizures (5/15 [33%] vs 10/12 [83%] vs 14/15 [93%], p < 0.01). Analyses of individuals with confirmed GOF/LOF variants (n = 57) showed similar results to the EO/LO analyses.

Discussion: The spectrum of developmental impairments and adaptive function in SCN2A-related disorders is extremely broad. Phenotypic subgroups provide prognostic information and critically inform clinical trial design.

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Conflict of interest statement

O. Devinsky receives grant support from the National Institute of Neurological Disorders and Stroke, NIMH, MURI, CDC, and NSF; has equity and/or compensation from the following companies: Tilray, Tevard Biosciences, Regel Biosciences, Script Biosciences, Actio Biosciences, Empatica, Ajna Biosciences, Blackrock Neurotech, and California Cannabis Enterprises; has received consulting fees or equity options from Emotiv, UCB Pharma, Ultragenyx, and Praxis Precision Therapeutics; holds patents for the use of cannabidiol in treating neurologic disorders that are owned by GW and Jazz Pharmaceuticals (he has waived all financial interests); holds other patents in molecular biology; and is the managing partner of the PhiFund Ventures. R. Guerrini and E. Parrini are supported by the Current Research funds 2023 of the Italian Ministry of Health. I. Hughes has received funding from Neurelis, Neurocrine, Marinus, and the University of Rochester Medical Center for clinical trials in which she was the principal investigator. K. Riney has received honoraria for educational symposia, advisory boards, and/or consultancy work from Eisai, LivaNova, Medlink Neurology, Novartis, and UCB Australia Ltd; K. Riney's institution has supported clinical trials for Biogen Idec Research Ltd., DSLP, Eisai Inc., Epigenyx Therapeutics Inc., GW Research Ltd, Janssen-Cilag, Longboard Pharmaceuticals, Marinus Pharmaceuticals Inc., Medicure International Inc., LivaNova, Neurocrine Biosciences Inc., Noema Pharma, Novartis, SK Lifesciences Inc., Takeda Pharmaceutical Company Limited, UCB Australia Ltd.; UCB Biopharma SRL and Zogenix Inc. A. Russo has received speaker honoraria from Eisai and LivaNova; and has received speaker honoraria from Eisai and LivaNova. L.G. Sadleir has served on scientific advisory boards for Takeda Pharmaceuticals and Eisai Pharmaceuticals; has received funding for travel from Seqirus and Nutricia; has served as an investigator and consultant for Zynerba; is a consultant for the Epilepsy Study Consortium; and has received funding from the Health Research Council of New Zealand and Cure Kids New Zealand. R.H. Thomas has received honoraria from Angelini, Bial, Biocodex, Eisai, Jazz, LivaNova, Paladin Labs, Neuraxpharm, Sanofi, Takeda, and UCB Pharma; and unrestricted funding support from Angelini Joint working partnership with UCB Pharma. N. Specchio has served on scientific advisory boards for GW Pharma, BioMarin, Arvelle, Marinus, and Takeda; has received speaker honoraria from Eisai, Biomarin, Livanova, and Sanofi; and has served as an investigator for Zogenix, Marinus, Biomarin, UCB, and Roche. M. Trivisano has received speaker's fees or funding or has participated in advisory boards for BioMarin, Orion, and Biocodex. I. Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, Cerecin, Longboard Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, Stoke Therapeutics, Eisai, and Akumentis; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, Stoke Therapeutics, and Eisai; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc., Epygenyx, ES Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, SK Life Science, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix and Zynerba; has consulted for Care Beyond Diagnosis, the Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics, and Biohaven Pharmaceuticals; and is a non-executive director of Bellberry Ltd and a director of the Australian Academy of Health and Medical Sciences and the Royal Society (Australia). I. Scheffer may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc. and licensed to various diagnostic companies; and has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (PRRT2) 2011904493 and 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). K.B. Howell is supported by a clinician-scientist fellowship from the MCRI (the MCRI is supported by a Victorian State Government Operational Infrastructure Support Program). All other authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

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Development and Adaptive Function in Individuals With SCN2A-Related Disorders

Affiliations

Development and Adaptive Function in Individuals With SCN2A-Related Disorders

Authors

Affiliations

Abstract

Conflict of interest statement

References

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Medical