PATHOGENESIS OF GILLES DE LA TOURETTE SYNDROME CLUES FROM CLINICAL PHENOTYPES by Valsamma Eapen MDBS., DPM., MRCPsych A thesis submitted to the University of London for the degree of PhD 1996 University College London Gower Street London ProQuest Number: 10017202 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10017202 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 TO MY PARENTS ABSTRACT Gilles de la Tourette Syndrome (GTS) is a developmental neuro­ psychiatrie disorder characterised by multiple motor and vocal tics. More than a century after its original description, there are still controversies about the essential clinical features of GTS, and, the failure as yet to find the putative gene(s) for the disorder may be a reflection of incorrect definition of the phenotypes. In this thesis, genetic data and neuroimaging techniques have been used to elucidate the phenotypic expressions of GTS. A total of 168 First Degree Relatives (FDRs) ascertained through 40 GTS probands and 66 FDRs ascertained through 20 Obsessive Compulsive Disorder (CCD) probands were studied. Findings from the segregation analyses were consistent with an autosomal dominant gene transmission with high penetrance, and sex dependent differences in the expression of GTS. There was also evidence to suggest the existence of a single major gene in the transmission of CCD. A genomic imprinting study of 437 GTS family members showed that maternally transmitted offsprings had a significantly earlier age at onset. There was evidence to suggest that Obsessive Compulsive Behaviour (OCR) forms an alternative phenotypic expression of the putative GTS gene(s). Analysis for GTS and Attention Deficit Hyperactivity Disorder (ADHD) failed to support a similar hypothesis. With regard to tics, it appears that not all cases are genetically related to GTS, and that some may be phenocopies. Single Photon Emission Tomography (SPET) showed that the affected family members of GTS probands had 'hypoperfusion' in the different brain areas. There were no distinctions based on the clinical phenotypes (GTS, Tics or OCB). Phenomenological analysis revealed differences in the obsessive compulsive symptom profile between GTS and OCD probands, but the familial OCD probands shared a similar profile to that of GTS. Implications of these findings in the aetiology and pathogenesis of GTS are discussed. ACKNOWLEDGEMENTS I owe special thanks to many people whose assistance made this work possible. I am indebted to Dr Mary Robertson, my primary supervisor, who helped clarify my ideas and supervised the project. I am particularly grateful for the encouragement and support she gave during the entire period. Professor David Pauls supervised the genetic section of this thesis and I am especially grateful for his assistance in the data analysis. My thanks are also due to Dr George John for the challenge. Professor Michael Trimble for the inspiration. Professor Harry Zeitlin for the encouragement. Professor Philip Graham for the support and guidance, and his helpful comments on the draft. I also wish to thank the staff at the OCD clinic, St Mary's Hospital, London, for their assistance in identifying patients, and Ms A. McGowen for her help with the pilot study. I would like to thank my family, colleagues and friends for their continuing encouragement and help. Finally my thanks are due to all the patients and their families who participated in the study and made this possible. STATEMENT The collection, collation and analysis of the data presented in this thesis were carried out by the author herself, except in the following areas. The data for the section on "genomic imprinting" was collected by the author along with five other investigators (Dr Mary M Robertson; Dr Jeremy Stern; Dr Allison Gourdie; Dr Vivienne Schneiden; Dr Gary Jackson) as part of another study on clinical phenomenology and linkage analysis. However, the data used in the analysis reported in this thesis was collated solely by the author. Support for statistical analysis was provided by Dr Jane O'Neill and Dr Hugh Gurling. For the section on Single Photon Emission Tomography, the author herself carried out the direct clinical examination and collated the data. Dr J Moriarty performed the SPET scanning and Dr DC Costa provided the blind rating. Dr Mary M Robertson helped in the diagnostic process by providing consensus diagnosis on the GTS probands and First Degree Relatives. The data analyses for the section on phenomenology and the segregation analysis were carried out by the author under the supervision of Dr David Pauls. TABLE OF CONTENTS Page ABSTRACT 3 ACKNOWLEDGEMENTS 5 STATEMENT 6 TABLE OF CONTENTS 7 LIST OF TABLES 11 LIST OF FIGURES 14 LIST OF APPENDICES 15 GLOSSARY OF ABBREVIATIONS 16 BIBLIOGRAPHY 18 6 SECTION 1 - INTRODUCTION 19 SECTION 11 - REVIEW OF THE LITERATURE CHAPTER 1 GILLES DE LA TOURETTE SYNDROME (GTS) 1.1 History 23 1.2 Definition & Clinical phenomenology 24 1.2i GTS and tics 28 1.2Ü GTS and Attention Deficit 31 Hyperactivity Disorder (ADHD) 1.3 Epidemiology 37 1.4 Neuroimaging 39 1.5 Genetics 43 CHAPTER 2 OBSESSIVE COMPULSIVE DISORDER (OCD) 2.1 Definition and Clinical phenomenology 50 2.2 Epidemiology 52 2.3 Genetics 53 CHAPTER 3 GTS AND OCD 3.1 Phenomenology 59 3.2 Neurochemistry and Neuropathology 64 3.3 Neuroimaging 65 3.4 Genetics 66 SECTION 111 THE INVESTIGATION CHAPTER 4 SUBJECTS AND METHODS 4.1 Genetic transmission in GTS and OCD 70 4.1i GTS subjects 70 4.1Ü OCD subjects 79 4.1iii Segregation analyses 80 4.1iv Genomic imprinting 85 4.2 Clinical phenotypes in GTS: Tics, 8 6 Obsessive Compulsive Behaviours (OCB) & ADHD 4.2.i Subjects 8 6 4.2Ü Goodness of fit test 88 4.3 Single Photon Emission Tomography 90 4.3i Subjects 90 4.3Ü The Procedure 91 4.4 The phenomenology of OCB in GTS & OCD 93 4.4i Subjects 93 4.4Ü Psychological data 94 4.4iii Statistical Analysis 95 RESULTS 5.1 Genetic transmission in GTS 97 5.1i Segregation analyses 97 5.1Ü Genomic imprinting 100 5.2 Genetic transmission in OCD 101 5.3 Clinical Phenotypes in GTS 102 5.3i Tics and OCB in GTS 102 5.3Ü ADHD and GTS 103 5.4 Single Photon Emission Tomography 105 5.5 The phenomenology of OCB in GTS & OCD 106 SECTION IV DISCUSSION, SUMMARY AND CONCLUSIONS CHAPTER 6 DISCUSSION 6.1 Genetic transmission in GTS 113 6.1i Segregation analyses 113 6.1Ü Genomic imprinting 116 6.2 Genetic transmission in OCD 119 6.3 Clinical phenotypes in GTS 122 6.31 Tics and OCB in GTS 122 6.3Ü ADHD and GTS 125 6.4 Single Photon Emission Tomography 130 6.5 The phenomenology of OCB in GTS & OCD 135 CHAPTER 7 SUMMARY OF MAIN FINDINGS AND IMPLICATIONS FOR FUTURE RESEARCH 7.1 Summary of main findings 140 7.2 Conclusions and implications for 143 future research 10 LIST OF TABLES Table No page Table 1 Age & Sex distribution of the GTS probands 150 Table 11 Age & Sex distribution of GTS family members 151 Table 111 Diagnostic status of GTS family members 152 Table IV Diagnostic schemes as used in the analyses 153 of GTS family data Table V Age liability classes for 'POINTER' (GTS data) 154 Table VI Age liability classes for 'POINTER' (OCD data) 155 Table VI1 Recurrence rate of GTS/CMT/OCB in GTS families 156 Table Vlll Genetic model estimates on segregation 157 analyses of GTS families(GTS only scheme) Table IX Summary of complex segregation analyses 158 findings for all the diagnostic schemes 11 Table X Genetic model estimates for male and female 159 GTS subjects according to the diagnostic schemes Table XI Comparison of age at onset in offsprings of 160 affected males Vs offsprings of affected females Table Xll Rates of GTS, GMT and OCB in offsprings of 161 transmitting males and females Table XI11 Recurrence risk of OCD and or tics in FDRs of 162 OCD probands Table XIV Genetic model estimates on segregation 163 analyses of OCD families Table XV Observed and Expected rates of GTS, Tics and 164 OCB in the First Degree Relatives (FDRs) of GTS probands Table XVI Results of goodness of fit test analyses in 165 GTS families Table XVI1 Rates of Tics and ADHD among relatives of 166 GTS probands with and without ADHD 12 Table XVI11 Frequency of GTS, Chronic Motor Tics (GMT) 167 and ADHD among FDRs of GTS probands Table XIX Frequency of GTS, GMT and ADHD among 168 relatives of GTS+ADHD & GTS-ADHD probands Table XX Expected and observed rates of GTS, GMT 169 and ADHD in FDRs of GTS+ADHD probands Table XXI SPET Perfusion findings in GTS families 170 Table XXI1 Number of GTS and OGD probands with 171 specific obsessions Table XXll 1 Number of GTS and OGD probands with 172 specific compulsions Table XXIV Anxiety and obsessional scores in GTS 173 and OGD probands Table XXV Obsessive compulsive symptom profile 174 significantly contributing to GTS & OGD clusters Table XXVI Rates of OGD in relatives of GTS & OGD clusters 175 13 LIST OF FIGURES Page Pedigree showing decomposition into 17 6 nuclear families 1.2 The mixed model for liability to affection 177 in a dichotomous trait determined by a major locus with a polygenic background 2.01 - Multigenerational