Search

Myoclonic astatic epilepsy (MAE) is a rare generalised childhood epilepsy with variable but poorly described neurodevelopmental outcome. Family studies suggest a major genetic influence as up to two thirds of relatives have seizures, or electroencephalographic (EEG) abnormalities. MAE is associated with 10 different genes, yet these genes account for less than 20% of the genetic aetiology of MAE leaving the majority unexplained. The aims of this thesis were (1) describe the epilepsy and neurodevelopmental phenotype of MAE cases, (2) perform EEG studies on first degree family members for familial EEG abnormalities and compare occurrence of epileptiform features to population prevalence and (3) to collect DNA and identify MAE causative genetic variants through exome sequencing. I assembled the largest MAE cohort (n=123) to date. The epilepsy phenotype is remarkably similar to previously published cohorts. I identified a severe neurodevelopmental phenotype: intellectual disability was reported in 64.9%, autism spectrum disorder in 21.3% and attention deficit hyperactivity symptoms in 41.0%. Additionally, extremely low adaptive behavioural scores were identified in 69.4% of cases. I performed EEG studies on 38 first-degree relatives of 13 MAE families, and found an excess of epileptiform EEG features in adults (>16 years), compared to controls (P=0.05, RR 6.82). I identified likely pathogenic or candidate variants in 11 of 109 cases. This comprised known genes associated with MAE: CHD2 n=1, SYNGAP1 n=2, SLC6A1 n=1, KIAA2022 n=1; epilepsy associated genes novel for MAE: KCNB1 n=1, MECP2 n=1, KCNH5 n=1, and three new candidate genes; SMARCA2 n=1, ASH1L n=1 and CHD4 n=1. Lastly, I highlight phenotypic features which help correlate with known and novel specific gene associations, discuss that MAE is a phenotypic and genetic nosological bridge between genetic generalised epilepsy and epileptic encephalopathy, and discussion applications and future directions leading on from this project.