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. K E Y W O R D S Doose syndrome, epilepsy/seizures, genetics, myoclonic astatic epilepsy SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: Tang S, Addis L, Smith A, et al; EuroEPINOMICS-RES Consortium. Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures. Epilepsia. 2020;61:995-1007. https://

Complex Mosaicism of Two Distinct Mutations in a Female Patient With KCNA2-Related Encephalopathy: A Case Report

“…The great majority of the mutations were missense and located in exon 3. Two main phenotypes emerged from the described cases (Syrbe et al, 2015;Masnada et al, 2017). A milder phenotype associated with loss-of-function mutations comprised infantile/early childhood seizure onset, frequent febrile and afebrile focal seizures.…”

“…A more severe phenotype carrying gain-of-function mutations presented as epilepsy, ataxia and intellectual disability. The c.1120A > G mutation was the most common gain-of-function mutation (Syrbe et al, 2015). Masnada et al (2017) found that some of the gain-of-function mutations also showed some additional loss-offunction effects and proposed to subgroup those patients carrying mutations with similar electrophysiological properties (Masnada et al, 2017).…”

“…In 2015, mutation in KCNA2 (MIM#176262) was firstly identified as a novel cause of developmental and epileptic or epileptic encephalopathy (Syrbe et al, 2015). The KCNA2 gene encoded the voltagegate K + channel K V 1.2 that belonged to the K V 1 family with eight members expressed in the central nervous system (Long et al, 2005).…”

Epilepsy With Myoclonic Atonic Seizures: Why Is the Yield of Genetic Testing for a “Presumed Genetic” Epilepsy Low?

“…10 However, focal seizures have been reported in children with EMAS, including in the recent study. 7 Finally, most studies agree there is a variable course for children with EMAS. Doose noted onset in the first or second year of life, absence status epilepticus, and tonic seizures were poor prognostic indicators.…”

“…9 However, 21% of patients in the study by Tang et al were reported to have developmental delay prior to epilepsy onset. 7 Similarly, a recent survey of diagnosis and treatment of EMAS showed only 50% to 79% of respondents felt developmental delay prior to seizure onset was an exclusionary criterion for the diagnosis of EMAS. 10 Initial seizure types included myoclonic, atonic-astatic, myoclonic-astatic (now known as myoclonic atonic), absence, absence or nonconvulsive status epilepticus, and generalized tonic clonic seizures.…”