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Molecular Genetic Investigation of Autosomal Recessive Neurodevelopmental Disorders

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Molecular Genetic Investigation of Autosomal Recessive Neurodevelopmental Disorders MOLECULAR GENETIC INVESTIGATION OF AUTOSOMAL RECESSIVE NEURODEVELOPMENTAL DISORDERS by MANJU ANN KURIAN A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Clinical and Experimental Medicine The Medical School University of Birmingham July 2010 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Men ought to know that from the brain and from the brain only arise our pleasures, joys, laughter, and jests as well as our sorrows, pains, griefs and tears. ... It is the same thing which makes us mad or delirious, inspires us with dread and fear, whether by night or by day, brings us sleeplessness, inopportune mistakes, aimless anxieties, absent-mindedness and acts that are contrary to habit... Hippocrates (Fifth century B.C.) Abstract Development of the human brain occurs in a number of complex pre- and postnatal stages which are governed by both genetic and environmental factors. Aberrant brain development due to inherited defects may result in a wide spectrum of neurological disorders which are commonly encountered in the clinical field of paediatric neurology. In the work for this thesis, I have investigated the molecular basis and defined the clinical features of three autosomal recessive neurological syndromes. I studied a cohort of children with early onset epileptic encephalopathy and, in one family, identified a novel homozygous pathogenic mutation of PLCB1. I have also utilised autozygosity mapping techniques to study consanguineous families with a complex motor disorder, infantile parkinsonism-dystonia, and identified loss-of-function mutations in the gene encoding the dopamine transporter (SLC6A3). Subsequent acquisition of a cohort of similarly affected children allowed detailed clinical and molecular characterisation of this novel disorder, dopamine transporter deficiency syndrome. Finally I have delineated the clinical and genetic features of PLA2G6-associated neurodegeneration. The identification of disease-causing genes contributes greatly to understanding the disease mechanisms underlying such early-onset disorders, and also provides novel insights into normal human neurodevelopment. I would like to dedicate this thesis to my husband, David and our beautiful daughter, Imogen. I am forever indebted to you both for your constant love and support which has enabled me to bring this work to completion. Over the years, I have been privileged to work with a number of neurologically impaired children and their families, who have taught me so much, and continue to be a constant source of inspiration. Given the nature of this thesis, no dedication would be complete without a tribute to their courage, patience and perseverance. Acknowledgements It is with great pleasure that I acknowledge the help and encouragement given to me during this period of research. Firstly, I cannot thank my supervisor Eamonn Maher enough for truly inspiring me, and for all the encouragement and support over the last few years. Thank you also to Paul Gissen for being a fantastic mentor and kindred spirit, and for the many helpful academic discussions. I am grateful to my laboratory colleagues in the Section of Medical and Molecular Genetics, especially Neil Morgan and Esther Meyer (for excellent laboratory training and also for kindly proof reading this thesis) and to Fatimah Rahman and Louise Tee (for kindly undertaking SNP arrays). Thank you also to the West Midlands Regional Genetic Laboratory for all their practical assistance, including the diagnostic screening of PLA2G6 for referred patients. I have had the great pleasure of working with some wonderful clinicians and I would especially like to thank Evangeline Wassmer for her incredible support and clinical input into this research. A thesis of this nature would not have been possible without excellent training in the semiology of movement disorders, and I am indebted to Martin Smith and Hardev Pall for providing this. Many thanks to Mary King for all the support and continuous teaching over the years, and for guiding me in how to become a paediatric neurologist. I am particularly thankful to my collaborators, who have facilitated this work. Firstly, I would like to especially thank Maarten Reith and his group at NYU who performed all functional investigations on mutant hDAT (Chapter 4, 5 and Appendix 2) and provided Figure 4-9 (Page 147). Thank you also to the many clinicians and research groups who have sent us samples over the years, especially Birgit Assmann, Terry Sanger, Grace Vassallo, Ingrid Scheffer and the UKISS group. Collaboration with the BPNSU (British Paediatric Neurology Surveillance Unit) also contributed greatly to the acquisition of the infantile spasms cohort. Many thanks to Lesley MacPherson and Katherine Foster for their radiological expertise in analysing the MR/CT imaging of the PLAN cohort. Thank you also to Birgit Assmann for assistance with Figure 4-1 and Table 5-3. This PhD would not have been possible without generous funding from several organisations: the BCH Research Foundation, BDF NewLife and Action Medical Research. Special thanks must be given to my Mum for her unfailing love and never- ending support and encouragement in everything that I have wanted to do. I am also grateful to my brother, Matthew for all the help and support. Thank you to my late father for instilling a belief that I could achieve anything I put my mind to. I would hope that, had he been alive today, this work would have made him proud. Contents Listings Title Abstract Dedication Acknowledgements Table of Contents List of Illustrations List of Tables Abbreviations Table of Contents 1 General Introduction…………………………………………… 1 1.1 Introduction and overview............................................................. 2 1.2 Normal and abnormal brain development………………………… 4 1.2.1 Primary neurulation…………………..………………….……………… 7 1.2.2 Prosencephalic development……..………………….………............. 8 1.2.3 Development of the cerebellum……………………………………….. 9 1.2.4 Neuronal proliferation……………………………….….………………. 9 1.2.5 Neuronal migration……………………………….….………………….. 10 1.2.6 Organisation……………………………….….……………................... 11 1.2.7 Myelination……………………………….….……………..................... 13 1.2.8 Summary……………………………….….………..…………………… 13 1.3 Paediatric neurology……………………………….….……………… 14 1.4 Epilepsy……………………………….…………….….……………….. 15 1.4.1 Epidemiology……………………………….….…….….………………. 15 1.4.2 Definitions……………………………….…….…….….………………. 15 1.4.3 Classification of epileptic seizures……………………………………. 17 1.4.4 Classification of epilepsy syndromes…………………………………. 19 . 1.4.5 Mechanisms of epileptogenesis in the immature brain…………….. 21 1.4.5.1 Seizure susceptibility factors………………………………………….. 21 1.4.5.2 The epileptogenic cascade…………….…….…….….………............ 23 1.4.6 Genetics and epilepsy………………….…….…….….………………. 23 1.4.7 Summary………………….…….…….….……...….…………………… 25 1.5 Movement disorders and the basal ganglia…..….……………… 26 1.5.1 Introduction………………………….…….…….….…………………… 26 1.5.2 Neuroanatomy of the basal ganglia….…….…….….……………….. 28 1.5.3 Functional aspects of the basal ganglia.…….…….….……………… 29 1.5.3.1 Input connections to the basal ganglia….…….…….….……………. 29 1.5.3.2 Output connections from the basal ganglia….…….…….….………. 29 1.5.4 Basal ganglia disease mechanisms in motor disease….………….. 32 1.5.4.1 The firing rate model……………………………….….………………. 33 1.5.4.2 Firing pattern model……………………………….….………………… 33 1.5.5 Summary……………………………….….……………....................... 34 1.6 Gene identification……………………………….….……….............. 35 1.6.1 Why study rare recessive neurological diseases? …………………. 35 1.6.2 Approaches to gene identification…………………………………….. 37 1.6.2.1 Functional cloning……………………………….….…………………… 37 1.6.2.2 Positional cloning……………………………….….………………….. 38 1.6.3 Haplotypes and genetic markers…………………………………….. 39 1.6.4 Informativeness of markers……………………………….……………. 40 1.6.5 Maps……………………………….….……………...............................41 1.6.6 Linkage……………………………….………………………………….. 42 1.6.7 Recombination fraction……………………………….….……………... 42 1.6.8 LOD scores and critical values………………………………………… 43 1.6.9 Autozygosity mapping……………………………….….………………. 45 1.6.9.1 Introduction……………………………….….………………………….. 45 1.6.9.2 Consanguinity and the UK Pakistani population…………………….. 45 1.6.9.3 Principles of autozygosity mapping…………………………………… 48 1.6.9.4 Mathematical model for autozygosity mapping……………………… 49 1.6.9.5 The power of autozygosity mapping…………………………………... 50 1.6.9.6 Pitfalls of autozygosity mapping……………………………………….. 51 1.7 Conclusion……………………………….….…………….................... 53 2 General Methods ………………………….……………………. 54 2.1 Ascertainment of patients and control subjects…………………. 55 2.1.1 Patient recruitment…………………………………………………….... 55 2.1.2 Consent and ethics approval……………………………….………….. 56 2.1.3 Patient assessment and acquisition of blood samples……………… 56 2.1.4 DNA from control subjects……………………………….……............. 56 2.2 Materials……………………………….….……………........................ 57 2.2.1 Chemical reagents……………………………….….………………….
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