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Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures
Author(s) -
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,
Møller Rikke S.,
Helbig Ingo,
Weber Yvonne G.,
Marini Carla,
Guerrini Renzo,
Simpson Michael A.,
Pal Deb K.
Publication year - 2020
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16508
Subject(s) - epilepsy , etiology , intellectual disability , exome sequencing , autism spectrum disorder , medicine , pediatrics , neurodevelopmental disorder , attention deficit hyperactivity disorder , cohort , neuropsychology , seizure types , epilepsy syndromes , candidate gene , psychiatry , copy number variation , autism , bioinformatics , genetics , phenotype , biology , gene , cognition , genome
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.