Abstracts

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

Abstract number : 3.18
Submission category : 2. Translational Research / 2A. Human Studies
Year : 2024
Submission ID : 766
Source : www.aesnet.org
Presentation date : 12/9/2024 12:00:00 AM
Published date :

Authors :
Presenting Author: Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes

Sindhu Viswanathan, MBChB – University of Melbourne
Karen Oliver, PhD – University of Melbourne
Brigid Regan, BSc(Hons) – University of Melbourne
Amy Schneider, MGenCouns – University of Melbourne
Candace Myers, PhD – University of Washington
Michele Mehaffey, MS – University of Washington
Amy LaCroix, BS – University of Washington
Jayne Antony, MD PhD – University of Sydney
Richard Webster, MBBS, MSc – University of Sydney
Michael Cardamone, MBBS, FRACP – Sydney Children's Hospital Network; University of New South Wales
Gopinath Subramanian, MBBS, MD – John Hunter Children’s Hospital
Annie TG Chiu, MBBS – University of Melbourne
Eugenia Roza, PhD, MD – Carol Davila University of Medicine and Pharmacy and Dr. Victor Gomoiu Children’s Hospital
Raluca Teleanu, PhD, MD – Carol Davila University of Medicine and Pharmacy and Dr. Victor Gomoiu Children’s Hospital
Stephen Malone, MBBS, PhD – University of Queensland and Queensland Children's Hospital
Richard Leventer, MBBS, PhD – University of Melbourne and Murdoch Children’s Research Institute
Deepak Gill, MRCPCH – The Children’s Hospital at Westmead Clinical School, Department of Neurology, Kids Neuroscience Centre, The University of Sydney, Sydney, NSW, Australia
Samuel Berkovic, MD, FRS – University of Melbourne
Michael Hildebrand, PhD – University of Melbourne
Beatrice Goad, BS – University of Melbourne and Murdoch Children’s Research Institute
Katherine Howell, MBBS, PhD – Department of Neurology, Royal Children's Hospital, Melbourne, Australia
Joseph Symonds, PhD – University of Glasgow and Royal Hospital for Children
Andreas Brunklaus, MD – Royal Hospital for Children
Lynette Sadleir, MBChB, MD – University of Otago Wellington
Sameer Zuberi, MBChB, MD – Paediatric Neurosciences Research Group, Royal Hospital for Children
Heather C. Mefford, MD, PhD – University of Washington and St. Jude Children's Research Hospital

Rationale: To understand the etiological landscape and phenotypic differences between the developmental and epileptic encephalopathy (DEE) syndromes of DEE with spike-wave activation in sleep (DEE-SWAS) and epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS).


Methods: All patients fulfilled ILAE DEE-SWAS or EE-SWAS criteria with a Core cohort (n=91) from our Epilepsy Genetics research program, and 10 additional patients from collaborators in the Expanded cohort (n=101) in whom the etiology was known. Detailed phenotyping and analysis of molecular genetic and imaging findings 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%) of the Core cohort. Structural etiologies occurred in 12/91 (13%) individuals. We identified 10 novel genes for D/EE-SWAS: ATP1A2, CACNA1A, FOXP1, GRIN1, KCNMA1, KCNQ3, PPFIA3, PUF60, SETD1B and ZBTB18, and 2 novel copy number variants, 17p11.2 duplication and 5q22 deletion. D/EE-SWAS genes were highly co-expressed in brain, highlighting the importance of channelopathies and transcriptional regulators. Although developmental regression patterns and seizure types were similar in both syndromes, DEE-SWAS was associated with a longer duration of epilepsy and poorer intellectual outcome than EE-SWAS.


Conclusions: DEE-SWAS and EE-SWAS have highly heterogeneous genetic and structural etiologies. Phenotypic analysis highlights valuable clinical differences between the syndromes of DEE-SWAS and EE-SWAS which inform clinical care and prognostic counselling. Our etiological findings pave the way for the development of precision therapies for these severe DEE syndromes.


Funding: Australian National Health and Medical Research Council of Australia and Medical Research Future Fund (GNT1091593, GNT1196637, GNT1172897, GNT2006841)


Translational Research