Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS)

Sindhu Viswanathan; Karen L Oliver; Brigid M Regan; Amy L Schneider; Candace T Myers; Michele G Mehaffey; Amy J LaCroix; Jayne Antony; Richard Webster; Michael Cardamone; Gopinath M Subramanian; Annie T G Chiu; Eugenia Roza; Raluca I Teleanu; Stephen Malone; Richard J Leventer; Deepak Gill; Samuel F Berkovic; Michael S Hildebrand; Beatrice S Goad; Katherine B Howell; Joseph D Symonds; Andreas Brunklaus; Lynette G Sadleir; Sameer M Zuberi; Heather C Mefford; Ingrid E Scheffer

doi:10.1002/ana.27041

Solving the Etiology of Developmental and Epileptic Encephalopathy with Spike-Wave Activation in Sleep (D/EE-SWAS)

Ann Neurol. 2024 Nov;96(5):932-943. doi: 10.1002/ana.27041. Epub 2024 Aug 2.

Authors

Sindhu Viswanathan^{1

2}, Karen L Oliver^{1

3

4}, Brigid M Regan¹, Amy L Schneider¹, Candace T Myers⁵, Michele G Mehaffey^{5

6}, Amy J LaCroix⁶, Jayne Antony⁷, Richard Webster⁷, Michael Cardamone⁸, Gopinath M Subramanian⁹, Annie T G Chiu¹, Eugenia Roza^{10

11}, Raluca I Teleanu^{10

11}, Stephen Malone^{12

13}, Richard J Leventer^{14

15}, Deepak Gill^{7

16}, Samuel F Berkovic¹, Michael S Hildebrand^{1

15}, Beatrice S Goad^{14

15}, Katherine B Howell^{14

15}, Joseph D Symonds^{17

18}, Andreas Brunklaus^{17

18}, Lynette G Sadleir¹⁹, Sameer M Zuberi^{17

18}, Heather C Mefford^{6

20}, Ingrid E Scheffer^{1

14

15

21}

Affiliations

¹ Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
² Department of Paediatrics, Hospital Pulau Pinang, George Town, Malaysia.
³ Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
⁴ Department of Medical Biology, the University of Melbourne, Melbourne, Australia.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington, USA.
⁶ Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.
⁷ T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
⁸ Department of Paediatric Neurology, Sydney Children's Hospital, Randwick; School of Clinical Medicine, UNSW Sydney, Sydney, Australia.
⁹ Department of Paediatric Neurology, John Hunter Children's Hospital, New Lambton Heights, Australia.
¹⁰ Faculty of Medicine, Clinical Neurosciences Department, Paediatric Neurology, Carol Davila University of Medicine and Pharmacy, București, Romania.
¹¹ Pediatric Neurology Department, Dr. Victor Gomoiu Children's Hospital, București, Romania.
¹² Centre for Advanced Imaging, University of Queensland, St Lucia, Australia.
¹³ Neurosciences Department, Queensland Children's Hospital, South Brisbane, Australia.
¹⁴ Department of Neurology, Royal Children's Hospital, University of Melbourne, Melbourne, Australia.
¹⁵ Neuroscience Research Group, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁶ Kids Neuroscience Centre, Kids Research Institute, Sydney, Australia.
¹⁷ School of Health and Wellbeing, University of Glasgow, Glasgow, UK.
¹⁸ The Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
¹⁹ Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand.
²⁰ Centre for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
²¹ The Florey Institute of Neurosciences and Mental Health, Melbourne, Australia.

PMID: 39096015
PMCID: PMC11496008 (available on 2025-11-01)
DOI: 10.1002/ana.27041

Abstract

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.

MeSH terms

Adolescent
Adult
Child
Child, Preschool
Cohort Studies
Electroencephalography
Female
Humans
Infant
Male
Phenotype
Sleep / genetics
Sleep / physiology
Spasms, Infantile* / genetics
Spasms, Infantile* / physiopathology
Young Adult

Abstract

MeSH terms

Grants and funding