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

Viswanathan, S; Oliver, KL; Regan, BM; Schneider, AL; Myers, CT; Mehaffey, MG; LaCroix, AJ; Antony, J; Webster, R; Cardamone, M; Subramanian, GM; Chiu, ATG; Roza, E; Teleanu, RI; Malone, S; Leventer, RJ; Gill, D; Berkovic, SF; Hildebrand, MS; Goad, BS; Howell, KB; Symonds, JD; Brunklaus, A; Sadleir, LG; Zuberi, SM; Mefford, HC; Scheffer, IE

Author(s): Viswanathan, S; Oliver, KL; Regan, BM; Schneider, AL; Myers, CT; Mehaffey, MG; LaCroix, AJ; Antony, J; Webster, R; Cardamone, M; Subramanian, GM; Chiu, ATG; Roza, E; Teleanu, RI; Malone, S; Leventer, RJ; Gill, D; Berkovic, SF; Hildebrand, MS; Goad, BS; Howell, KB; Symonds, JD; Brunklaus, A; Sadleir, LG; Zuberi, SM; Mefford, HC; Scheffer, IE;
Details: Publication Year 2024-08-02,Volume 96,Issue #5,Page 932-943
Journal Title: Annals of Neurology
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.
Publisher: WIley
Keywords: Humans; Female; Male; Child, Preschool; Child; Infant; *Spasms, Infantile/genetics/physiopathology; Adolescent; Electroencephalography; Sleep/physiology/genetics; Cohort Studies; Phenotype; Adult; Young Adult
Research Division(s): Population Health And Immunity
PubMed ID: 39096015
Publisher's Version: https://doi.org/10.1002/ana.27041
Open Access at Publisher's Site: https://doi.org/10.1002/ana.27041
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-14 09:49:46

Last Modified: 2024-10-25 10:50:51