Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Tang, Shan; Addis, Laura; Smith, Anna; Topp, Simon D.; Pendziwiat, Manuela; Mei, Davide; Parker, Alasdair; Agrawal, Shakti; Hughes, Elaine; Lascelles, Karine; Williams, Ruth E.; Fallon, Penny; Robinson, Robert; Cross, Helen J.; Hedderly, Tammy; Eltze, Christin; Kerr, Tim; Desurkar, Archana; Hussain, Nahin; Kinali, Maria; Bagnasco, Irene; Vassallo, Grace; Whitehouse, William; Goyal, Sushma; Absoud, Michael; EuroEPINOMICS?RES Consortium; M�ller, Rikke S.; Helbig, Ingo; Weber, Yvonne G.; Marini, Carla; Guerrini, Renzo; Simpson, Michael A.; Pal, Deb K.

Abstract

Objective: We aimed to describe the extent of neurodevelopmental impairments and
identify the genetic etiologies in a large cohort of patients with epilepsy with myoclonic
atonic seizures (MAE).
Methods: We deeply phenotyped MAE patients for epilepsy features, intellectual
disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder
using standardized neuropsychological instruments. We performed exome analysis
(whole exome sequencing) filtered on epilepsy and neuropsychiatric gene sets to
identify genetic etiologies.
Results: We analyzed 101 patients with MAE (70% male). The median age of seizure
onset was 34 months (range = 6-72 months). The main seizure types were myoclonic
atonic or atonic in 100%, generalized tonic-clonic in 72%, myoclonic in 69%, absence
in 60%, and tonic seizures in 19% of patients. We observed intellectual disability in
62% of patients, with extremely low adaptive behavioral scores in 69%. In addition,
24% exhibited symptoms of autism and 37% exhibited attention-deficit/hyperactivity
symptoms. We discovered pathogenic variants in 12 (14%) of 85 patients, including
five previously published patients. These were pathogenic genetic variants in
SYNGAP1 (n = 3), KIAA2022 (n = 2), and SLC6A1 (n = 2), as well as KCNA2,
SCN2A, STX1B, KCNB1, and MECP2 (n = 1 each). We also identified three new
candidate genes, ASH1L, CHD4, and SMARCA2 in one patient each.
Significance: MAE is associated with significant neurodevelopmental impairment.
MAE is genetically heterogeneous, and we identified a pathogenic genetic etiology
in 14% of this cohort by exome analysis. These findings suggest that MAE is a manifestation
of several etiologies rather than a discrete syndromic entity.

Citation

Tang, S., Addis, L., Smith, A., Topp, S. D., Pendziwiat, M., Mei, D., Parker, A., Agrawal, S., Hughes, E., Lascelles, K., Williams, R. E., Fallon, P., Robinson, R., Cross, H. J., Hedderly, T., Eltze, C., Kerr, T., Desurkar, A., Hussain, N., Kinali, M., …Pal, D. K. (2020). Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia, 61(5), 995-1007. https://doi.org/10.1111/epi.16508

• Journal Article Type: Article
• Acceptance Date: Mar 27, 2020
• Online Publication Date: May 29, 2020
• Publication Date: May 29, 2020
• Deposit Date: Jun 16, 2020
• Publicly Available Date: Jun 16, 2020
• Journal: Epilepsia
• Print ISSN: 0013-9580
• Electronic ISSN: 1528-1167
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 61
• Issue: 5
• Pages: 995-1007
• DOI: https://doi.org/10.1111/epi.16508
• Keywords: Doose syndrome, epilepsy/seizures, genetics, myoclonic astatic epilepsy
• Public URL: https://nottingham-repository.worktribe.com/output/4661060
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16508?af=R
• Additional Information: Tang, S., Addis, L., Smith, A., Topp, S. D., Pendziwiat, M., … Mei, D. (2020). Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia, 61(5), 995–1007. https://doi.org/10.1111/epi.16508