Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures.
Age of Onset
Attention Deficit Disorder with Hyperactivity
/ complications
Autism Spectrum Disorder
/ complications
Child
Child, Preschool
Electroencephalography
Epilepsies, Myoclonic
/ complications
Epilepsy, Generalized
/ complications
Female
Humans
Infant
Intellectual Disability
/ complications
Male
Neuroimaging
Phenotype
Seizures
/ genetics
Exome Sequencing
Doose syndrome
epilepsy/seizures
genetics
myoclonic astatic epilepsy
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
07
08
2019
revised:
24
02
2020
accepted:
27
03
2020
pubmed:
30
5
2020
medline:
1
12
2020
entrez:
30
5
2020
Statut:
ppublish
Résumé
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). 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. 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. 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.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
995-1007Subventions
Organisme : Medical Research Council
ID : MC_PC_19009
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J011231/1
Pays : United Kingdom
Investigateurs
Dana Craiu
(D)
Carol Davila
(C)
Alexandru Obregia
(A)
Peter De Jonghe
(P)
Anna-Elina Lehesjoki
(AE)
Hiltrud Muhle
(H)
Bernd Neubauer
(B)
Kaja Selmer
(K)
Ulrich Stephani
(U)
Katalin Sterbova
(K)
Pasquale Striano
(P)
Tiina Talvik
(T)
Sarah von Spiczak
(S)
Sarah Weckhuysen
(S)
Hande Caglayan
(H)
Dorota Hoffman-Zacharska
(D)
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
Références
Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia. 2010;51:676-85.
Doose H, Gerken H, Leonhardt R, Völzke E, Völz C. Centrencephalic myoclonic-astatic petit mal. Clinical and genetic investigation. Neuropadiatrie. 1970;2:59-78.
Kaminska A, Ickowicz A, Plouin P, et al. Delineation of cryptogenic Lennox-Gastaut syndrome and myoclonic astatic epilepsy using multiple correspondence analysis. Epilepsy Res. 1999;36:15-29.
Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics. 2002;33:122-32.
Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children's Hospital of Philadelphia. Epilepsia. 2007;48:1703-7.
Trivisano M, Specchio N, Cappelletti S, et al. Myoclonic astatic epilepsy: an age-dependent epileptic syndrome with favorable seizure outcome but variable cognitive evolution. Epilepsy Res. 2011;97:133-41.
Nolte R, Wolff M. Behavioural and developmental aspects of primary generalized myoclonic-astatic epilepsy. Epilepsy Res Suppl. 1992;6:175-83.
Nabbout R. Absence of mutations in major GEFS+ genes in myoclonic astatic epilepsy. Epilepsy Res. 2003;56:127-33.
Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B. Nat Genet. 1998;19:366-70.
Escayg A, Heils A, MacDonald BT, et al. A novel SCN1A mutation associated with generalized epilepsy with febrile seizures plus-and prevalence of variants in patients with epilepsy. Am J Hum Genet. 2001;68:866-73.
Mullen SA. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Ann Neurol. 2011;68:1152-5.
Carvill GL, Heavin SB, Yendle SC, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat Genet. 2013;45:825-30.
Mignot C, von Stulpnagel C, Nava C, et al. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy. J Med Genet. 2016;53:511-22.
Syrbe S, Hedrich UBS, Riesch E, et al. De novo loss- or gain-of-function mutations in KCNA2 cause epileptic encephalopathy. Nat Genet. 2015;47:393-9.
Schubert J, Siekierska A, Langlois M, et al. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet. 2014;46:1327-32.
Carvill G, McMahon J, Schneider A, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet. 2015;96:808-15.
Balestrini S, Milh M, Castiglioni C, et al. TBC1D24 genotype-phenotype correlation: epilepsies and other neurologic features. Neurology. 2016;87:77-85.
de Lange IM, Helbig KL, Weckhuysen S, et al. De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy. J Med Genet. 2016;53:850-8.
Wolff M, Johannesen KM, Hedrich UBS, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain. 2017;140:1316-36.
Moller RS, Wuttke TV, Helbig I, et al. Mutations in GABRB3: from febrile seizures to epileptic encephalopathies. Neurology. 2017;88:483-92.
Routier L, Verny F, Barcia G, et al. Exome sequencing findings in 27 patients with myoclonic-atonic epilepsy: is there a major genetic factor? Clin Genet. 2019;96:254-60.
Helbig I, Lopez-Hernandez T, Shor O, et al. A recurrent missense variant in AP2M1 impairs clathrin-mediated endocytosis and causes developmental and epileptic encephalopathy. Am J Hum Genet. 2019;104:1060-72.
Tang S, Hughes E, Lascelles K, EuroEPINOMICS RES Myoclonic Astatic Epilepsy Working Group, Simpson MA, Pal DK. New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy. Am J Med Genet A. 2017;173:195-9.
Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389-99.
Oguni H, Fukuyama Y, Tanaka T, et al. Myoclonic-astatic epilepsy of early childhood-clinical and EEG analysis of myoclonic-astatic seizures, and discussions of the nosology of the syndrome. Brain Dev. 2001;23:757-64.
Eom S, Fisher B, Dezort C, Berg AT. Routine developmental, autism, behavioral, and psychological screening in epilepsy care settings. Dev Med Child Neurol. 2014;56:1100-5.
Meltzer HG, Goodman R, Ford F. Mental health of children and adolescents in Great Britain. London, UK: The Stationery Office, 2000.
Suls A, Jaehn J, Kecskés A, et al. De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet. 2013;93:967-75.
de Ligt J, Willemsen MH, van Bon BWM, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012;367:1921-9.
Hamdan FF, Srour M, Capo-Chichi J-M, et al. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014;10:e1004772.
Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674-82.
Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015;519:223-8.
Allen AS, Berkovic SF, Cossette P, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217-21.
O’Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246-50.
Neale BM, Kou Y, Liu LI, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485:242-5.
Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485:237-41.
de Kovel CGF, Syrbe S, Brilstra EH, et al. Neurodevelopmental disorders caused by de novo variants in KCNB1 genotypes and phenotypes. JAMA Neurol. 2017;74:1228-36.
Saitsu H, Akita T, Tohyama J, et al. De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci Rep. 2015;5(1):15199.
Zhu T, Liang C, Li D, et al. Histone methyltransferase Ash1L mediates activity-dependent repression of neurexin-1alpha. Sci Rep. 2016;6:26597.
Eschbach K, Moss A, Joshi C, et al. Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures. Epilepsy Res. 2018;147:95-101.
Caraballo RH, Chamorro N, Darra F, Fortini S, Arroyo H. Epilepsy with myoclonic atonic seizures: an electroclinical study of 69 patients. Pediatr Neurol. 2013;48:355-62.
Inoue T, Ihara Y, Tomonoh Y, et al. Early onset and focal spike discharges as indicators of poor prognosis for myoclonic-astatic epilepsy. Brain Dev. 2014;36:613-9.
Heyne HO, Singh T, Stamberger H, et al. De novo variants in neurodevelopmental disorders with epilepsy. Nat Genet. 2018;50:1048-53.
Parrini E, Marini C, Mei D, et al. Diagnostic targeted resequencing in 349 patients with drug-resistant pediatric epilepsies identifies causative mutations in 30 different genes. Hum Mutat. 2017;38:216-25.
De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209-15.
Stessman HAF, Xiong BO, Coe BP, et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017;49:515-26.
Weiss K, Terhal PA, Cohen L, et al. De novo mutations in CHD4, an ATP-dependent chromatin remodeler gene, cause an intellectual disability syndrome with distinctive dysmorphisms. Am J Hum Genet. 2016;99:934-41.
Mefford HC, Muhle H, Ostertag P, et al. Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalised and focal epilepsies. PLoS Genet. 2010;6:e1000962.
Mefford HC, Yendle SC, Hsu C, et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann Neurol. 2011;70:974-85.
Møller RS, Liebmann N, Larsen LHG, et al. Parental mosaicism in epilepsies due to alleged de novo variants. Epilepsia. 2019;60:e63-6.