Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

EuroEPINOMICS RES Consortium

doi:10.1111/epi.16508

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

EuroEPINOMICS RES Consortium

GSTT Guy's and St Thomas' NHS Foundation Trust
King's College London
Eli Lilly & Co Ltd
University Hospital Schleswig-Holstein
Ospedale Pediatrico Meyer
Cambridge University Hospital NHS Foundation Trust
Birmingham Women's NHS Foundation Trust
King's College Hospital
Imperial College London; South West London & St George's NHS Mental Health Trust
Great Ormond Street Hospital for Children NHS Foundation Trust
UCL Great Ormond Street Institute of Child Health
Sheffield Children’s National Health Service Foundation Trust
University Hospitals of Leicester NHS Trust
Chelsea & Westminster Hospital NHS Foundation Trust
Martini Hospital
Manchester Children’s Hospital
University of Nottingham
The Danish Epilepsy Center Filadelfia
The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
University of Pennsylvania
Hertie-Institut fur klinische Hirnforschung
University of Tuebingen

Research output: Contribution to journal › Article › peer-review

48 Citations (Scopus)

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.

Original language	English
Pages (from-to)	995-1007
Number of pages	13
Journal	Epilepsia
Volume	61
Issue number	5
DOIs	https://doi.org/10.1111/epi.16508
Publication status	Published - 1 May 2020

Keywords

Doose syndrome
epilepsy/seizures
genetics
myoclonic astatic epilepsy

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10.1111/epi.16508

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@article{e852b29ea20440d0adbf64f84519beb5,

title = "Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures",

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.",

keywords = "Doose syndrome, epilepsy/seizures, genetics, myoclonic astatic epilepsy",

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

year = "2020",

month = may,

day = "1",

doi = "10.1111/epi.16508",

language = "English",

volume = "61",

pages = "995--1007",

journal = "Epilepsia",

issn = "0013-9580",

publisher = "Wiley-Blackwell",

number = "5",

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TY - JOUR

T1 - Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

AU - Tang, Shan

AU - Addis, Laura

AU - Smith, Anna

AU - Topp, Simon D.

AU - Pendziwiat, Manuela

AU - Mei, Davide

AU - Parker, Alasdair

AU - Agrawal, Shakti

AU - Hughes, Elaine

AU - Lascelles, Karine

AU - Williams, Ruth E.

AU - Fallon, Penny

AU - Robinson, Robert

AU - Cross, Helen J.

AU - Hedderly, Tammy

AU - Eltze, Christin

AU - Kerr, Tim

AU - Desurkar, Archana

AU - Hussain, Nahin

AU - Kinali, Maria

AU - Bagnasco, Irene

AU - Vassallo, Grace

AU - Whitehouse, William

AU - Goyal, Sushma

AU - Absoud, Michael

AU - Møller, Rikke S.

AU - Helbig, Ingo

AU - Weber, Yvonne G.

AU - Marini, Carla

AU - Simpson, Michael A.

AU - Guerrini, Renzo

AU - Pal, Deb K.

AU - EuroEPINOMICS RES Consortium

PY - 2020/5/1

Y1 - 2020/5/1

N2 - 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.

AB - 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.

KW - Doose syndrome

KW - epilepsy/seizures

KW - genetics

KW - myoclonic astatic epilepsy

UR - https://www.scopus.com/pages/publications/85085582268

U2 - 10.1111/epi.16508

DO - 10.1111/epi.16508

M3 - Article

C2 - 32469098

AN - SCOPUS:85085582268

SN - 0013-9580

VL - 61

SP - 995

EP - 1007

JO - Epilepsia

JF - Epilepsia

IS - 5

ER -

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

Abstract

Keywords

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