Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
Issue number5
Pages (from-to)995-1007
Publication statusPublished - May 2020

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