Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

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http://hdl.handle.net/10138/325005

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EuroEPINOMICS- RES Consortium , Tang , S , Addis , L , Smith , A , Pal , D K & Lehesjoki , A-E 2020 , ' Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures ' , Epilepsia , vol. 61 , no. 5 , pp. 995-1007 . https://doi.org/10.1111/epi.16508

Title: Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures
Author: EuroEPINOMICS- RES Consortium; Tang, Shan; Addis, Laura; Smith, Anna; Pal, Deb K.; Lehesjoki, Anna-Elina
Contributor: University of Helsinki, Department of Medical and Clinical Genetics
Date: 2020-05
Language: eng
Number of pages: 13
Belongs to series: Epilepsia
ISSN: 0013-9580
URI: http://hdl.handle.net/10138/325005
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.
Subject: Doose syndrome
epilepsy
seizures
genetics
myoclonic astatic epilepsy
DE-NOVO MUTATIONS
OF-FUNCTION MUTATIONS
ASTATIC EPILEPSY
INTELLECTUAL DISABILITY
FEBRILE SEIZURES
GENERALIZED EPILEPSY
AUTISM
VARIANTS
PROGNOSIS
PROTEIN
3112 Neurosciences
3124 Neurology and psychiatry
3111 Biomedicine
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