Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike–Wave Activation in Sleep (D/EE‐SWAS )
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Objective: To understand the etiological landscape and phenotypic differences between 2 developmental and epileptic encephalopathy (DEE) syndromes: DEE with spike–wave activation in sleep (DEE‐SWAS) and epileptic encephalopathy with spike–wave activation in sleep (EE‐SWAS). Methods: All patients fulfilled International League Against Epilepsy (ILAE) DEE‐SWAS or EE‐SWAS criteria with a Core cohort (n = 91) drawn from our Epilepsy Genetics research program, together with 10 etiologically solved patients referred by collaborators in the Expanded cohort (n = 101). Detailed phenotyping and analysis of molecular genetic results were performed. We compared the phenotypic features of individuals with DEE‐SWAS and EE‐SWAS. Brain‐specific gene co‐expression analysis was performed for D/EE‐SWAS genes. Results: We identified the etiology in 42/91 (46%) patients in our Core cohort, including 29/44 (66%) with DEE‐SWAS and 13/47 (28%) with EE‐SWAS. A genetic etiology was identified in 31/91 (34%). D/EE‐SWAS genes were highly co‐expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Structural etiologies were found in 12/91 (13%) individuals. We identified 10 novel D/EE‐SWAS genes with a range of functions: ATP1A2 , CACNA1A , FOXP1 , GRIN1 , KCNMA1 , KCNQ3 , PPFIA3 , PUF60 , SETD1B, and ZBTB18 , and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. Although developmental regression patterns were similar in both syndromes, DEE‐SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE‐SWAS. Interpretation: DEE‐SWAS and EE‐SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between DEE‐SWAS and EE‐SWAS which inform clinical care and prognostic counseling. Our etiological findings pave the way for the development of precision therapies. ANN NEUROL 2024;96:932–943
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An EEG during sleep often provides additional findings that guide epilepsy syndrome classification, such as generalized paroxysmal fast activity in LGS and spike-wave activation in sleep in EE-SWAS and DEE-SWAS, directing therapy selection.
“Often, an EEG during sleep provides additional findings that guide epilepsy syndrome classification (such as generalized paroxysmal fast activity in LGS and spike-wave activation in sleep in the syndromes of epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) and DEE-SWAS), directing therapy selection 170 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [170]
The Introduction identifies sleep-activated spike-wave activity as the EEG signature of EE-SWAS and DEE-SWAS. The Results report that paroxysmal fast activity emerged in three patients who evolved from DEE-SWAS to LGS, and the Discussion links syndrome differentiation to different therapeutic approaches. The paper does not establish that sleep EEG often provides these additional findings across epilepsy syndromes, specify that the LGS activity was generalized or detected during sleep, or show that these particular EEG findings direct therapy selection. Page numbers were not available in our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measuredCognitive decline may indicate the need for sleep EEG studies to identify a, so far, unrecognised epileptic encephalopathy, such as DEE-SWAS or EE-SWAS.
“Cognitive decline may indicate the need for sleep EEG studies to identify a, so far, unrecognised epileptic encephalopathy, such as DEE-SWAS or EE-SWAS 170 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [170]
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References 42 · Cited by 23
- Authors
- Viswanathan, S., Oliver, K. L., Regan, B. M., Schneider, A. L., Myers, C. T., Mehaffey, M. G., LaCroix, A. J., Antony, J., Webster, R., Cardamone, M., Subramanian, G. M., Chiu, A. T. G., Roza, E., Teleanu, R. I., Malone, S., Leventer, R. J., Gill, D., Berkovic, S. F., Hildebrand, M. S., Goad, B. S., Howell, K. B., Symonds, J. D., Brunklaus, A., Sadleir, L. G., Zuberi, S. M., Mefford, H. C., & Scheffer, I. E.
- Affiliations
- The University of Melbourne (AU)
- University of Washington (US)
- The University of Sydney (AU)
- UNSW Sydney (AU)
- John Hunter Children's Hospital (AU)
- Carol Davila University of Medicine and Pharmacy (RO)
- The University of Queensland (AU)
- Royal Children's Hospital (AU)
- Royal Hospital for Children (GB)
- University of Otago (NZ)
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Scheffer, Ingrid E.
- ORCID
- Viswanathan, Sindhu
- Oliver, Karen L.
- Regan, Brigid M.
- Schneider, Amy L.
- Myers, Candace T.
- Cardamone, Michael
- Subramanian, Gopinath M.
- Chiu, Annie T.G.
- Roza, Eugenia
- Teleanu, Raluca I.
- Malone, Stephen
- Leventer, Richard J.
- Gill, Deepak
- Berkovic, Samuel F.
- Hildebrand, Michael S.
- Goad, Beatrice S.
- Howell, Katherine B.
- Symonds, Joseph D.
- Brunklaus, Andreas
- Sadleir, Lynette G.
- Zuberi, Sameer M.
- Mefford, Heather C.
- Scheffer, Ingrid E.
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2024-08-02
- Volume
- 96
- Issue
- 5
- Pages
- 932-943
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC11496008
- OpenAlex
- W4401300450
- Cited by
- 23
- References
- 42
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 2
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Annals of Neurology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- Funders
- Health Research Council of New Zealand
- National Health and Medical Research Council (GNT1091593, GNT1196637, 2019/GNT1172897, 2021/GNT2006841)
- National Institutes of Health (R01NS069605)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- developmental and epileptic encephalopathy, genetic etiology, novel genes, copy number variation, 17p11.2 duplication, channelopathies, transcription factors, developmental regression, cognitive outcomes
- MeSH terms
- Adolescent, Adult, Child, Child, Preschool, Electroencephalography, Female, Humans, Infant, Male, Phenotype, Sleep, Spasms, Infantile, Cohort Studies, Young Adult
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