This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Expanding the phenotype and genetic spectrum of myoclonic astatic epilepsy Tang, Shan Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 10. Oct. 2021 EXPANDING THE PHENOTYPE AND GENETIC SPECTRUM OF MYOCLONIC ASTATIC EPILEPSY Dr. Shan Tang MBBS, MRCPCH Institute of Psychiatry, Psychology & Neuroscience King’s College London A Thesis submitted for the Degree of Doctor of Philosophy to the University of London February 2017 1 Abstract 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. 2 Table of Contents Abstract ..................................................................................................................... 2 Table of Contents ....................................................................................................... 3 Table of Figures ......................................................................................................... 8 Table of Tables ........................................................................................................ 11 Acknowledgements ................................................................................................. 13 Publications ............................................................................................................. 14 Declaration .............................................................................................................. 15 Abbreviations .......................................................................................................... 16 Chapter 1 Introduction: The phenotype and genetic basis of myoclonic astatic epilepsy 17 1.1 Historical perspective ............................................................................................. 17 1.2 Phenotypic features ................................................................................................ 21 1.2.1 Clinical epidemiology ............................................................................................. 21 1.2.2 Pathology ............................................................................................................... 21 1.2.3 Seizures .................................................................................................................. 22 1.3 EEG ......................................................................................................................... 25 1.4 Neurological examination ....................................................................................... 25 1.5 Neurodevelopmental comorbidity .......................................................................... 25 1.6 Course and Prognosis .............................................................................................. 27 1.7 Genetic Aetiology .................................................................................................. 28 1.7.1 Twin studies ........................................................................................................... 28 1.7.2 Family studies – seizures ........................................................................................ 29 1.7.3 Family studies – EEG ............................................................................................... 29 1.7.4 Gene mutation studies ........................................................................................... 31 1.7.5 Copy number variants ............................................................................................ 40 1.8 Challenges and Strategies ....................................................................................... 41 1.9 Project Aims and Objectives ................................................................................... 43 Chapter 2 Methods: Recruitment and Phenotyping ............................................. 44 2.1 Study setup ............................................................................................................ 44 2.2 Participant recruitment .......................................................................................... 44 2.3 Collaborators .......................................................................................................... 45 3 2.3.1 UK Clinical Collaborators ........................................................................................ 45 2.3.2 International Clinical Collaborators ........................................................................ 45 2.4 UK cohort: Recruitment and phenotyping pathway ................................................ 45 2.5 Deep Phenotyping .................................................................................................. 47 2.6 Phenotyping Instruments for the UK cohort ............................................................ 47 2.6.1 General medical information ................................................................................. 47 2.6.2 Cognition ................................................................................................................ 48 2.6.3 Language ................................................................................................................ 48 2.6.4 Autism spectrum disorder ...................................................................................... 49 2.6.5 The Strength and Difficulties questionnaire ........................................................... 50 2.6.6 The Conner’s Comprehensive Behaviour Rating Scale ........................................... 50 2.6.7 The Adaptive Behaviour Assessment System ......................................................... 51 2.7 Data collection for the Euroepinomics and Italian cohort ........................................ 52 Chapter 3 Results: The epilepsy and neurodevelopmental phenotype of MAE ..... 53 3.1 MAE cohorts ........................................................................................................... 53 3.2 Epilepsy phenotype ................................................................................................ 53 3.3 Intellectual disability and Language ........................................................................ 56 3.4 Autism .................................................................................................................... 58 3.5 Strength and Difficulties Questionnaire .................................................................