University of Groningen Genotyping and phenotyping epilepsies of childhood Vlaskamp, Danique IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Vlaskamp, D. (2018). Genotyping and phenotyping epilepsies of childhood. Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license. More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne- amendment. Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 02-10-2021 Genotyping and phenotyping epilepsies of childhood Danique Vlaskamp 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 1 Layout Douwe Oppewal Cover design Christien Rondaan Printed by Ipskamp Printing, Enschede, the Netherlands ISBN 978-94-034-1144-6 (printed version) 978-94-034-1143-9 (e-book) © Copyright 2018 D.R.M. Vlaskamp, Groningen, the Netherlands All rights reserved. No part of this publication may be reproduced or transmitted in any forms or by any means, without prior written permission of the author. This research was funded by the Junior Scientifi c Masterclass. Unrestricted travel grants were received from the Dutch Society of Child Neurology, Jo Kolk Foundation (VVAO), the Research School of Behavioural and Cognitive Neurosciences (BCN). Conference attendances were fi nancially supported by the BCN. Printing of this thesis was fi nancially supported by the the University of Groningen and the BCN. 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 2 Genotyping and phenotyping epilepsies of childhood Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 05 december 2018 om 14.30 uur door Danique Rienke Maria Vlaskamp geboren op 15 mei 1991 te Raalte 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 3 Promotores Prof. dr. C.M.A. van Ravenswaaij-Arts Prof. dr. O.F. Brouwer Copromotores Dr. P.M.C. Callenbach Dr. P. Rump Beoordelingscommissie Prof. dr. V.V.A.M. Knoers Prof. dr. H.P.H. Kremer Prof. dr. K.P.J. Braun 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 4 COVER The tree on the cover of this thesis symbolizes the relationship between the genotype and the phenotype of epilepsies of childhood. The beautiful tree has deeply anchored, widely spreading roots (genotype) that grow a new flowering tree with a unique pattern of branches, leaves and blossoms (phenotype). Painted by Christien Rondaan 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 5 6 Paranimfen Nienke te Grootenhuis Wieke Eggink 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 6 7 CONTENTS Chapter 1 Introduction 9 PART I - THE YIELD OF GENETIC TESTING Chapter 2 Copy number variation in a hospital-based cohort of children with epilepsy 27 Published as: Epilepsia Open. 2017; 2: 244–254. Chapter 3 Empowerment and anxiety of patients and parents 49 during genetic counseling for epilepsy Manuscript ready to submit PART II - GENOTYPE-PHENOTYPE STUDIES Chapter 4 SYNGAP1 encephalopathy: a distinctive generalized 71 developmental and epileptic encephalopathy Accepted for publication in Neurology Chapter 5 Genotype-phenotype correlation of 248 individuals with 95 GRIN2A-related disorders identifies two distinct phenotypic subgroups associated with different classes of variants, protein domains and functional consequences Accepted for publication in Brain Chapter 6 Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy 123 Revised version under review Chapter 7 Haploinsufficiency of the STX1B gene is associated with 145 myoclonic astatic epilepsy Published as: European Journal of Paediatric Neurology. 2016; 20: 489-492 Chapter 8 PRRT2-related phenotypes in patients with a 16p11.2 deletion 157 Published as: European Journal of Medical Genetics. 2018, in press. Chapter 9 Positive effect of sodium channel blocking anti-epileptic 177 drugs on neonatal infantile epilepsy due to a SCN2A mutation Translated from the Dutch paper published as: Epilepsie. 2017; Periodiek voor Professionals 15, nr.3 Chapter 10 General discussion and a proposal for a diagnostic algorithm 185 for genetic testing for epilepsy Chapter 11 Nederlandse samenvatting 201 Dankwoord 208 Curriculum vitae 213 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 7 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 8 9 Chapter 1 Introduction 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 9 10 CHAPTER 1 I am about to discuss the disease called “sacred.” It is not, in my opinion, any more divine or more sacred than any other diseases, but has a natural cause… Its origin, like that of other diseases, lies in heredity... The fact is that the cause of this affection is... the brain... My own view is that those who first attributed a sacred character to this malady were like the magicians, purifiers, charlatans, and quacks of our own day... So that there is no need to put the disease in a special class and to consider it more divine than the others... Each has a nature and a power of its own; none is hopeless or incapable of treatment.1 Hippocrates, 460–370 BC, on epilepsy Hippocrates was revolutionary for his time in arguing that the origin of epilepsy lies in ‘heredity’. Although hereditary does not always equal genetic, we now have robust evidence that genetic variants can cause or contribute to epilepsy. However, we still have a long way to go to fully understand the intriguing role of genetics in epilepsy. To comprehend the current challenges in epilepsy genetics addressed in this thesis, it is helpful to learn more about epilepsy phenotyping and genotyping. Whereas epilepsy phenotyping concentrates on describing the clinical presentation, epilepsy genotyping focuses on identifying the underlying genetic cause. Integration of information on epilepsy phenotype and genotype is important in clinical practice and research settings in order to find new genes and risk factors for epilepsy, to better understand the disease and its presentation and to improve its management and outcome. 525699-L-sub01-bw-Vlaskamp Processed on: 29-10-2018 PDF page: 10 INTRODUCTION 11 EPILEPSY PHENOTYPING 1 An epileptic seizure is defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.2 Seizures can be provoked by acute disturbances in the body, such as hypoglycemia or acute infection, or can occur unprovoked. Patients are diagnosed with epilepsy if they present with any of the following three conditions: 1. at least two unprovoked seizures occurring >24 hours apart, 2. one unprovoked (or reflex) seizure and a probability of further seizures in the next 10 years similar to the general recurrence risk after two unprovoked seizures (at least 60%), or 3. a diagnosis of an epilepsy syndrome.3 Epilepsy is diagnosed in 41-87 children per 100,000 children each year.4 Epilepsy is not a single disease entity, but should be considered as a group of disorders. Its presentation, etiology, management and prognosis can vary significantly for the different epilepsies. Epilepsy therefore warrants further classification for clinical and research purposes. The International League Against Epilepsy (ILAE) has made several classification guidelines.5–11 In the most recent guideline from 2017, they recommended classifying epilepsy at three consecutive levels: 1. seizure type, 2. epilepsy type, and 3. epilepsy syndrome.12 The flowchart in Figure 1 demonstrates how to classify epilepsies using this three-step method. Depending on the availability of clinical information, epilepsy can be classified up to level 1, 2 or 3. 1. Seizure type. Epileptic seizures should be classified based on their onset as focal, generalized or unknown.12,13 Epilepsy is a disorder involving neuronal networks and all seizures are hypothesized to occur somewhere within a network.14,15 Focal seizures are limited to networks within one hemisphere, while generalized seizures rapidly engage bilaterally distributed networks.16 Both clinical and electroencephalogram (EEG) data can help to distinguish focal and generalized seizures. If more detailed clinical information on the seizures is available, they can be further classified based on the level of awareness (for focal seizures only) and by describing their first feature.12,13 Focal seizures can evolve to bilateral tonic-clonic seizures (previously called ‘secondary generalized seizures’).12,13,17 2. Epilepsy type. Since individuals can have both focal and generalized seizures, a second level of classification has been introduced: epilepsy type. Epilepsy type can be focal, generalized or combined generalized and focal.12 3. Epilepsy syndrome. To diagnose the epilepsy syndrome, one should also consider the setting in which seizures occur. This setting includes the patient’s gender, age at seizure onset, developmental course, family history, and results from additional investigations such as EEG and imaging.