Multimodal Approach to Endophenotype Discovery in Disorders with Genetic Liability

“Multimodal Approach to Endophenotype Discovery. in Disorders with Genetic Liability”. by. Niamh Mc Devitt, B.Sc., M.Sc.. A dissertation submitted to the. University of Dublin, Trinity College Dublin,. for the degree of. Doctor of Philosophy. in the. Department of Neuropsychiatric Genetics and. Biomedical Engineering. Trinity College Dublin. Supervised by:. Professor Louise Gallagher & Professor Richard B.. Reilly. November 2019. . i. Declaration. I, Niamh Mc Devitt, confirm that this thesis has not been submitted as an exercise for a. degree at this or any other university and is entirely my own work. . I agree to deposit this thesis in the University's open access institutional repository or. allow the Library to do so on my behalf, subject to Irish Copyright Legislation and. Trinity College Library conditions of use and acknowledgement. . Signed,. . . ii. Summary . Neurodevelopmental and Neurodegenerative disorders constitute a huge weight on. society in terms of human suffering and economic cost. In recent years an increasing. amount of emphasis has been placed on investigating the existence of endophenotypes. of these disorders. An endophenotype is a measureable trait that lies between disease. and underlying causes and can inform on the mechanistic understanding of behaviour,. aid in the development of disease biomarkers and inform on the relationship between. genes and behaviour. Investigating endophenotypes in monogenic disorders, which. occur due to alterations in one gene such as the FMR1 gene and NRXN1 gene may help. researchers to develop specific drug targets for these disorders. Moreover, some. monogenic mutations can exhibit significant behavioural overlap with multifactorial. disorders, such as in the case of FXS and ASDs or can be a contributing factor to a. number of disorders such as NRXN1 deletions. . The aims of this thesis was to utilise a multimodal approach to investigate the existence. of cognitive, postural and electrophysiological endophenotypes in monogenic disorders. in order to 1) Further characterise the phenotypic presentations of these disorders and 2). To utilise the knowledge gained to inform on overlapping disorders that are genetically. more complex. . Firstly, neurocognitive deficits specifically in executive function and attention were. investigated in FMR1 PM carriers using a well validated neurocognitive test battery.. Analyses revealed that female PM carriers exhibited deficits in planning and cognitive. flexibility compared to controls and parents of children with ASDs, supporting previous. research identifying EF deficits in PM carriers. A novel aspect of this study was to. investigate the relationship between cognitive deficits and psychiatric symptoms and. stress. In contrast to other studies, female PM carriers did not exhibit higher symptoms. of depression or anxiety compared to controls. No relationship was observed between. cognitive function and psychiatric symptoms or stress levels indicating that the. cognitive deficits observed may be more related to PM carrier status. . Secondly, social cognition deficits were investigated as endophenotypes in female PM. carriers, first degree relatives of individuals with ASDs, using a task of emotion. recognition and the broad autism phenotype (BAP) questionnaire. BAP has previously. been reported in FXS and in PM carriers and in first degree relatives of individuals with. . iii. ASD. Analyses revealed the novel finding of deficits in social cognition in female PM. carriers and replicated the finding of these deficits in first-degree relatives of. individuals with ASDs. However no relationship was identified between emotion. recognition deficits and level of self-reported autistic traits. This study adds to the. literature on social cognition deficits in PM carriers however does not explain the. relationship with the BAP.. Thirdly, centre of pressure (COP) deviations as an endophenotype of postural. disturbances in female PM carriers was investigated. PM carriers were found to be more. unstable when visual information was removed. Additionally, female PM carriers. exhibited dual task-interference causing increased deviations in sway compared to. typical controls during a task of sustained attention. These results support the use of. COP measures as an endophenotype of motor deficits in PM carriers that may inform. our understanding of underlying neural mechanisms of the FMR1 premutation. . Additionally, the endophenotype approach was applied then to the characterisation of. cognitive deficits in a novel cohort of patients with a monogenetic deletion conferring. increased risk for ASD, NRXN1 deletion. Furthermore, an exploratory. electrophysiological study was undertaken. This is the first in depth study of. neurocognition and in this cohort. Cognitive deficits were noted in individuals with. NRXN1 deletions in the domains of executive function, emotion recognition and. attention. Differences observed in electrophysiological data may suggest some. underlying mechanistic differences in attention, however further investigation with. larger samples sizes are required to corroborate these results. . Finally, utilised Public and Patient Involvement (PPI), to understand research. participation and motivations and barriers for research participation in the ASD. community. Results corroborated results presented in previous research that observed a. disconnect between scientific research and public need and emphasised the importance. of PPI for study design moving forward. Results also emphasised that barriers such as. time constraints, lack of intervention based research and the possibility of causing stress. or harm to their children contribute significantly to poor engagement with research in. Neurodevelopmental disorders. . The results of this work add to the extant literature in relation to endophenotypes. associated with PM carriers. Novel data showed that deficits in emotion recognition. . iv. may be part of the phenotype associated with PM carrier status and COP deviations. may be an endophenotype for motor dysfunction in PM carriers. The endophenotype. approach was applied successfully to characterise a new monogenetic syndrome caused. by NRXN1 deletions that predisposes towards ASD. The approaches used highlight the. utility of the endophenotype approach to help explain these disorders aetiologically and. to aid the identification of new biomarkers. However careful consideration of the. methodological approaches is required to plan and implement this research in. Neurodevelopmental disorders.. . . v. Acknowledgements. This thesis would not have been possible without the invaluable support I received from. a variety of people. . Special thanks to: . Prof. Louise Gallagher and Prof. Richard Reilly for their incredible support and. guidance throughout the past four years. . Miss Clodagh O’Keefe and Laura Taboada Pascual for their invaluable help in both. data collection and analysis, and for their huge contribution to the overall PM carriers. project. . To Dr Jacqueline Fitzgerald for all the help with data collection and all the constructive. advice over the past four years. . To all the people who have participated in my research, particularly all the children. . To the Irish Fragile X Society, particularly Chairperson Maria Panza and Mrs June. O’Reilly who were integral to recruitment and information sharing. . To my friends and family, particularly my fiancé Lorcan and my parents, who gave me. continued support throughout this journey.. A special mention to all my colleagues in my both my Neural Engineering lab and the. Autism and Neurodevelopmental Research group, especially Terence, Brendan and. Giovanni who were with me every step of the way. . This research was kindly supported by Trinity College Dublin. . . Niamh Mc Devitt . Trinity College Dublin. August 2017. . . vi. Publications arising from thesis . Journal Articles .  Devitt, N.M.; Gallagher, L.; Reilly, R.B. Autism spectrum disorder (asd) and. Fragile x syndrome (fxs): Two overlapping disorders reviewed through. electroencephalography-what can be interpreted from the available information?. Brain sciences 2015, 5, 92-117 (Appendix A). Conference Presentations.  Delineating Cognitive-Motor Interference in Postural Stability of Premutation. carriers using a Dual-Task Paradigm – 3 rd. International Conference on FMR1. Premutation, Jerusalem, Israel. September 5-7 th. 2017. .  Is stress and anxiety in FMR1 premutation carriers, in part, related to parenting a. child with a developmental disability? - 3 rd. International Conference on FMR1. Premutation, Jerusalem, Israel. September 5-7 th. 2017. . Poster Presentations . - L. Taboda, N. Mc Devitt, C. O’Keefe, R. B. Reilly, Centre of pressure. regularity as a marker for Fragile X Syndrome Premutation carriers.. Bioengineering in Ireland Conference 2017. . - N. Mc Devitt, L. Gallagher, R.B Reilly. Investigation of Face Processing in. Autistic Spectrum Disorder (ASD) for the Development of Clinically Useful. Biomarkers: An Electroencephalographic Approach. International Meeting for. Autism research (IMFAR), Baltimore, May 2016,. - N. Mc Devitt, R. B. Reilly, L. Gallagher. Investigation of Parental Priorities for. Research in Children with Neurodevelopmental and Genetic Disorders: A. National Irish Study. IMFAR, Baltimore, May 2016. - C. O’Keefe, N. Mc Devitt, R.B. Reilly, Young Neuroscientists symposium. 2016, Characterisation of the Cognitive and Postural Impact of the Fragile X. Premutation.. Articles in Preparation for Submission.  Motivation and Barriers to Research Participation, how scientists and parents. can work together to create a better future for children with. . vii. Neurodevelopmental Disorders: Lessons learned from an Irish Population –. submission to the European Journal of Child and Adolescent Psychiatry. .  An Investigation of Centre of Pressure Measures of Postural Stability in Carriers. of the Fragile X Premutation – submission to the Journal of gait and Posture. . . viii. Table of Contents . Declaration .............................................................................................................................. i. Summary ................................................................................................................................ ii. Acknowledgements ................................................................................................................ v. Publications arising from thesis ............................................................................................ vi. Journal Articles .................................................................................................................. vi. Conference Presentations .................................................................................................. vi. Poster Presentations ........................................................................................................... vi. Articles in Preparation for Submission .............................................................................. vi. Table of Contents ............................................................................................................... viii. Table of Figures .................................................................................................................. xvi. List of Tables ....................................................................................................................... xxi. Glossary of Acronyms ....................................................................................................... xxiv. Chapter 1 General Introduction ................................................................................................. 1. 1.1. Background ..................................................................................................................... 1. 1.2 Relationships between genes and behaviour .................................................................... 2. 1.2.1 Genetic Variation ....................................................................................................... 2. 1.2.2 Alterations in a single gene - FMR1 .......................................................................... 2. 1.2.3 Multifactorial Disorder - Autism Spectrum Disorder .............................................. 18. 1.2.4 Copy Number Variations ......................................................................................... 20. 1.3 Biomarkers and Endophenotypes ................................................................................... 22. 1.3.1 Biomarkers............................................................................................................... 22. 1.3.2 Endophenotypes and their role in research in brain disorders ................................. 23. 1.3.3 EEG in Endophenotype Discovery .......................................................................... 26. 1.4 Thesis Rationale ............................................................................................................. 28. . ix. 1.5 Aims ............................................................................................................................... 30. Chapter 2 Investigation of Executive dysfunction and attentional control as possible. cognitive endophenotypes of the FMR1 premutation. ............................................................. 31. 2.1 Introduction .................................................................................................................... 31. 2.1.1 Executive function and attentional control in parents of children with. Developmental Delays (DDs) ........................................................................................... 32. 2.1.2 Psychiatric symptoms in parents of children with Developmental Delays. (DDs) ................................................................................................................................ 35. 2.1.3 Parenting stress in parents of children with neurodevelopmental disorders ........... 36. 2.1.4 Current Study ........................................................................................................... 38. 2.1.5 Hypothesis ............................................................................................................... 39. 2.1.6 Aims ........................................................................................................................ 39. 2.2 Methods .......................................................................................................................... 39. 2.2.1 Ethical Approval ...................................................................................................... 39. 2.2.2 Participants .............................................................................................................. 40. 2.2.3 Recruitment ............................................................................................................. 40. 2.2.4 Protocol .................................................................................................................... 41. 2.2.5 Cognitive Tasks ....................................................................................................... 46. 2.2.6 Molecular Analysis .................................................................................................. 53. 2.2.7 Data Analysis ........................................................................................................... 53. 2.3 Results ............................................................................................................................ 54. 2.3.1 Descriptive statistics ................................................................................................ 54. 2.3.2 Cognitive Tests ........................................................................................................ 54. 2.3.3 Analysis of Depression, Anxiety and Stress ............................................................ 62. 2.3.4 Correlation Analysis ................................................................................................ 66. . x. 2.4 Discussion ...................................................................................................................... 70. 2.4.1 Overview of Findings .............................................................................................. 70. 2.4.2 Executive Function .................................................................................................. 70. 2.4.3 Attentional Control .................................................................................................. 72. 2.4.4 Psychological differences ........................................................................................ 73. 2.4.5 Relationship between cognitive deficits and stress ................................................. 74. 2.4.6 Limitations ............................................................................................................... 75. 2.4.7 Conclusions ............................................................................................................. 75. Chapter 3 Investigation of social communication deficits as endophenotypes for the. FMR1 premutation. .................................................................................................................. 74. 3.1 Introduction .................................................................................................................... 74. 3.1.1 Emotion processing ................................................................................................. 74. 3.1.2 The Broad Autism Phenotype .................................................................................. 78. 3.1.3 Current Study ........................................................................................................... 79. 3.1.4 Hypothesis ............................................................................................................... 80. 3.1.5 Aims......................................................................................................................... 80. 3.2 Methods .......................................................................................................................... 80. 3.2.1 Ethical Approval ...................................................................................................... 80. 3.2.2 Participants .............................................................................................................. 80. 3.2.3 Recruitment of Participants ..................................................................................... 80. 3.2.4 Protocol .................................................................................................................... 81. 3.2.5 Cognitive Tasks ....................................................................................................... 82. 3.2.6 Molecular Analysis .................................................................................................. 84. 3.2.7 Data Analysis ........................................................................................................... 84. 3.3 Results ............................................................................................................................ 85. . xi. 3.3.1 Demographics .......................................................................................................... 85. 3.3.2 Emotion Recognition Task (ERT) ........................................................................... 86. 3.3.3 Broad Autism Phenotype Questionnaire (BAPQ) ................................................... 91. 3.3.4 Correlation of ERT task with repeat length and BAPQ scores. .............................. 92. 3.4 Discussion ...................................................................................................................... 93. 3.4.1 Recognition of Emotional Facial Expressions ........................................................ 93. 3.4.2 Broad Autism Phenotype ......................................................................................... 94. 3.4.3 Strengths and Limitations ........................................................................................ 95. 3.4.4 Conclusions ............................................................................................................. 96. Chapter 4 Centre of Pressure Disturbances in FMR1 premutation carriers as a possible. endophenotype for FXTAS ...................................................................................................... 97. 4.1 Introduction .................................................................................................................... 97. 4.1.1 FXTAS .................................................................................................................... 97. 4.1.2 Balance and postural control ................................................................................. 100. 4.1.3 Current study ......................................................................................................... 103. 4.1.4 Hypothesis ............................................................................................................. 103. 4.1.5 Aims ...................................................................................................................... 103. 4.2 Methods ........................................................................................................................ 104. 4.2.1 Ethical Approval .................................................................................................... 104. 4.2.2 Participants ............................................................................................................ 104. 4.2.3 Recruitment ........................................................................................................... 104. 4.2.4 Protocol .................................................................................................................. 104. 4.2.5 Postural Sway Assessment .................................................................................... 106. 4.2.6 Data Analysis ......................................................................................................... 111. 4.2.6 Statistical Analysis ................................................................................................ 116. . xii. 4.3 Results .......................................................................................................................... 117. 4.3.1 Descriptive statistics .............................................................................................. 117. 4.3.2 Dual Cognitive Task Scores .................................................................................. 117. 4.3.3 Postural Data.......................................................................................................... 119. 4.4 Discussion .................................................................................................................... 125. 4.4.1 Overview of Results .............................................................................................. 125. 4.4.2 Limitations ............................................................................................................. 127. 4.4.3 Conclusions ........................................................................................................... 127. Chapter 5 Endophenotype Discovery in NRXN1: A cognitive and electrophysiological. investigation. .......................................................................................................................... 129. 5.1 Introduction .................................................................................................................. 129. 5.1.1 Rare monogenetic syndromes associated with ASD ............................................. 130. 5.1.2 NRXN1 deletions and neurodevelopmental disorders ........................................... 132. 5.1.3 NRXN1 Gene.......................................................................................................... 132. 5.1.4 The Current Study. ................................................................................................ 135. 5.1.5 Hypothesis ............................................................................................................. 135. 5.1.6 Aims....................................................................................................................... 135. 5.2. Methods ....................................................................................................................... 136. 5.2.1 Ethical Approval .................................................................................................... 136. 5.2.2 Participants ............................................................................................................ 136. 5.2.3 Recruitment ........................................................................................................... 136. 5.2.4 Clinical Protocol .................................................................................................... 137. 5.2.5 Cognitive Paradigms.............................................................................................. 137. 5.2.5 EEG Acquisition .................................................................................................... 138. 5.2.6 Data Analysis ......................................................................................................... 142. . xiii. 5.3. Results ......................................................................................................................... 143. 5.3.1 Demographics ........................................................................................................ 143. 5.3.2 Cognitive Data ....................................................................................................... 144. 5.3.3 EEG Analysis ........................................................................................................ 150. 5.4 Discussion .................................................................................................................... 153. 5.4.1 Overview of Findings ............................................................................................ 153. 5.4.2 Cognitive ............................................................................................................... 153. 5.4.3 EEG ....................................................................................................................... 155. 5.4.4 Limitations ............................................................................................................. 157. 5.4.5 Conclusions ........................................................................................................... 157. Chapter 6 Motivation and Barriers to Research Participation, how scientists and parents. can work together to create a better future for children with Neurodevelopmental. Disorders: Lessons learned from an Irish Population. ........................................................... 158. 6.1. Introduction ................................................................................................................. 158. 6.1.1 Public and Patient Involvement ............................................................................. 158. 6.1.2 PPI in Autism Research ......................................................................................... 159. 6.1.3 The current study ................................................................................................... 161. 6.2. Methods ....................................................................................................................... 161. 6.2.1 Survey Study ......................................................................................................... 161. 6.2.2 Database Search ..................................................................................................... 162. 6.3. Results ......................................................................................................................... 163. 6.3.1 Survey Response Data ........................................................................................... 163. 6.3.2 Participation in Research ....................................................................................... 164. 6.3.3 Motivations and Barriers for Research .................................................................. 164. 6.3.4 Research Priorities ................................................................................................. 165. . xiv. 6.3.5 Qualitative Data ..................................................................................................... 166. 6.3.6 Database Search ..................................................................................................... 167. 6.4. Discussion ................................................................................................................... 168. 6.4.1 Research participation ........................................................................................... 168. 6.4.2 Parental Opinions on Important Research Themes for NDDs .............................. 170. 6.4.3 Funding .................................................................................................................. 171. 6.4.4 Limitations ............................................................................................................. 171. 6.4.5 Conclusions ........................................................................................................... 172. Chapter 7 General Discussion ................................................................................................ 173. 7.1 Introduction ............................................................................................................. 173. 7.2 Contributions of Research and Overview of Findings ................................................. 173. 7.2.1 Novel endophenotypes in Female PM carriers ...................................................... 173. 7.2.2 Investigation of Cognitive and Electrophysiological endophenotypes in. NRXN1 deletion ............................................................................................................. 177. 7.2.3 Using PPI to improve future research study design .............................................. 178. 7.3 Limitations & challenges ............................................................................................. 179. 7.3.1 Limitations of Study Design .................................................................................. 179. 7.3.2 Challenges with research in neurodevelopmental disorders.................................. 180. 7.4 Future Directions .......................................................................................................... 180. 7.4.1 Precision Psychiatry .............................................................................................. 180. 7.4.2 International Collaborations .................................................................................. 181. 7.4.3 Linking biology to endophenotypes and behaviour .............................................. 182. 7.4.4 Improving Neuroimaging Approaches .................................................................. 182. 7.5 Final conclusions .......................................................................................................... 184. References .......................................................................................................................... 185. . xv. Appendices ......................................................................................................................... 215. Appendix A .................................................................................................................... 215. Appendix B1: Info Sheet ................................................................................................ 249. Appendix B2: Consent Form .......................................................................................... 252. Appendix C: Parallel Studies of Force plate Validity .................................................... 254. C.1. Calibration Study .................................................................................................... 254. C.2. Test re-test reliability of COP measures during standing balance in individuals. with EO and EC ................................................................................................................. 257. C.2.1. Methodology ........................................................................................................ 257. C.2.2. Results .................................................................................................................. 259. C.3. Force Platform Comparison ....................................................................................... 261. C.3.1. Methodology ........................................................................................................ 261. C.3.2. Results .................................................................................................................. 262. Appendix D1: Social Story for EEG experiment ............................................................... 265. Appendix D2 ...................................................................................................................... 266. Appendix E: Survey Questions .......................................................................................... 267. . xvi. Table of Figures. Figure 1-1 Schematic of the Hypothalamic Pituitary Adrenal Axis. ................................ 4. Figure 1-2 Roles of Fragile X Mental Retardation Protein (FMRP) in RNA and Channel. Binding at the Neuronal Synapse. Adapted from (J. K. Davis & Broadie, 2017).. Activity-dependent functions of FMRP in RNA-binding translation regulation and. direct channel-binding activity regulation. In the uncoupled mechanism (A), RNA- and. channel-binding roles are unrelated, representing two evolutionarily divergent. functions. In the coupled mechanism (B), channel binding (i) is an integral activity-. sensing step in the translational regulation of FMRP-bound transcripts (ii). ................... 5. Figure 1-3 Details the process of inheritance in a female premutation carrier. ................ 8. Figure 1-4 Schematic of the Hypothalamic Pituitary Adrenal Axis. .............................. 14. Figure 1-5 Details the phenotypes associated with FXS. ............................................... 17. Figure 1-6 Vesicle trafficking and CAM signalling. The binding interactions and. signalling of NRXN and NLGN can be seen here (Adapted from (Ushkaryov, Rohou, &. Sugita, 2008)). ................................................................................................................. 22. Figure 2-1 Theoretical model for PSI adapted from (Abidin, 1976). ............................. 46. Figure 2-2 Intra/Extra-Dimensional Set Shift – Protocol and Stimuli. Details the stages. and protocol of the IED task, participants are required to learn a rule through prompts. from the computer; they must then follow this rule until it changes. This figure was. adapted from http://www.cambridgecognition.com/. ..................................................... 47. Figure 2-3 Stockings of Cambridge – Protocol and Stimuli Details the set-up and. protocol of the SOC task, participants must move balls in order to match the bottom. pattern to the top pattern. This figure was adapted from. http://www.cambridgecognition.com/. ........................................................................... 48. Figure 2-4 Spatial Working Memory – Protocol and Stimuli. Details the set-up and. protocol of the SWM task, participants must search for blue tokens inside coloured. boxes. This figure was adapted from http://www.cambridgecognition.com/. ................ 49. . xvii. Figure 2-5 Rapid Visual Processing Protocol and Stimuli. Details the set-up and. protocol of the RVP task, participants must respond only after they see they see the last. number in the target series. This figure was adapted from. http://www.cambridgecognition.com/. ........................................................................... 50. Figure 2-6 Match to Sample Visual search – Protocol and Stimuli. Details the set-up. and protocol of the MTS task, participants must identify a surrounding pattern that is. identical to the middle pattern. This figure was adapted from. http://www.cambridgecognition.com. ............................................................................ 51. Figure 2-7 Reaction Time Task – Protocol and Stimuli. Details the set-up and protocol. of the RTI task, participants are required to respond as quickly and accurately as. possible when a yellow dot appears inside a white circle by touching it. This figure was. adapted from http://www.cambridgecognition.com/. ..................................................... 52. Figure 2-8 Repeat Length Distribution Details CGG repeat length distribution for PM. carriers. PM carriers lie between 55 and 200 repeats, <45 repeats = normal, 45-54. repeats =grey zone allele and >200 repeats = Full mutation (FXS). .............................. 53. Figure 2-9 Mean no. of double errors committed for all three groups (SWM)Details. mean double errors scores for three participant groups in the SWM task,*statistically. significant (p<0.05), **statistically significant (p<0.01). ............................................... 56. Figure 2-10 Mean Initial Thinking Time for all three groups – Two moves (SOC). Details Mean Initial thinking time for all three participant groups for the SOC task. *statistically significant (p<0.05), **statistically significant (p<0.01). ......................... 57. Figure 2-11 Mean Errors Stage Nine for all three groups (IED). Details errors for stage. 9 for all three participant groups for the IED task *statistically significant (p<0.05). ... 59. Figure 2-12 Mean Correct Movement Time for all groups (MTS). Details mean correct. movement time between groups for the MTS task *statistically significant (p<0.05). .. 60. Figure 2-13 Mean A’ (stimulus detectability index) values for all three groups (RVP).. Details A’ for each of the three groups for the RVP task *statistically significant. (p<0.05)........................................................................................................................... 61. file://mmuh.ie/groups/groups/DNI%20Research/Niamh's%20Research%20documents/Research/NiamhMcDevitt_Thesis_Corrected.docx%23_Toc23767834 file://mmuh.ie/groups/groups/DNI%20Research/Niamh's%20Research%20documents/Research/NiamhMcDevitt_Thesis_Corrected.docx%23_Toc23767834 file://mmuh.ie/groups/groups/DNI%20Research/Niamh's%20Research%20documents/Research/NiamhMcDevitt_Thesis_Corrected.docx%23_Toc23767834. . xviii. Figure 2-14 Mean no. of Total misses for all three groups (RVP). Details total number. of misses between groups for the RVP task *statistically significant (p<0.05). ............ 61. Figure 2-15 Mean Depression Scores for all three groups. Details depression scores. from the BDI for all three groups *statistically significant (p<0.05). ............................ 63. Figure 2-16 Mean Parenting Stress Scores for all three groups. Details PSI scores for all. three groups; A – Child Domain Score, B – Parent Domain Score, C – Total score.. *statistically significant (p<0.05), **statistically significant (p<0.01). ......................... 65. Figure 2-17 Spearman’s Rank Correlation Analysis between PSI scores and Depression.. Correlation Analysis between depression scores and PSI scores. A = Depression and. Child Domain Score, B = Depression and Parent Domain Score and C = Depression and. Total Score. ..................................................................................................................... 67. Figure 3-1 Emotion Recognition Task – Protocol and Stimuli. (A) Details four. examples of the faces presented as part of the ERT task, Sadness, Surprise, Fear and. Anger respectively. (B) Details the running order of the ERT task. ............................... 84. Figure 3-2 Mean Overall Latency Response Time to Emotions for all three groups.. Mean Overall Latency of Response time A) Fear, B) Disgust, C) Sad and D) Surprise.. *statistically significant (p<0.05), **statistically significant (p<0.01). ......................... 90. Figure 4-1 Schematic of Biosignals Plux Force Platform. ........................................... 107. Figure 4-2 Details of experimental set-up and equipment. ........................................... 108. Figure 4-3 Schedule of Postural Assessment. ............................................................... 109. Figure 4-4 SART stimuli and protocol. ........................................................................ 110. Figure 4-5 N-back protocol and stimuli ........................................................................ 111. Figure 4-6 BiosignalsPlux force platform and its corresponding schematic drawing on. how to calculate the COP measurement. ...................................................................... 113. Figure 4-7 Hardware connections of all the measurement equipment. ........................ 113. Figure 4-8 Force plate data analysis flow-chart Details the steps taken to collect and. analyse the postural data from each participant. ........................................................... 116. . xix. Figure 4-9 Mean COP area- Eyes Closed-Both groups. The PM carriers are represented. in red and the controls are represented in blue. * represents statistical significance. (p<0.05)......................................................................................................................... 121. Figure 4-10 COP Path length – N-Back task. ............................................................... 123. Figure 4-11 Stabilogram of a single PM-carrier during the EO, EC and N-back task. 124. Figure 5-1 Nrxn-α and -β isoform structures. Illustrates Nrxn-α and -β isoform. structures and location at the membrane (Reissner, Runkel, & Missler, 2013). .......... 134. Figure 5-2 Details 10-20 electrode placement system for 128 electrode density. (https://www.biosemi.com/headcap.htm). .................................................................... 139. Figure 5-3 Experimental Set-up and Equipment. A & B detail experimental set-up and. C details some of the challenges associated with EEG in children with developmental. disabilities. .................................................................................................................... 139. Figure 5-4 Details Protocol and Sitmuli for EEG experiment. The oddball paradigm. consisted of two conditions each with a different combination above schematic faces.. The standard stimulus was always the neutral face (75% occurrence), the target (Face. like object) occurred 12.5% of the time. The deviant stimulus varied and was angry for. condition A and happy for condition B this also occurred 75% of the time. ................ 141. Figure 5-5 Percent Correct (MTS) *statistically significant (p<0.05) .......................... 146. Figure 5-6 (A) Strategy Score (SWM) (B) Total Errors (SWM) *statistically significant. (p<0.05)......................................................................................................................... 146. Figure 5-7 Problems Solved in Minimum Moves (SOC). ............................................ 147. Figure 5-8 No. of Hits (ERT).. ...................................................................................... 147. Figure 5-9 Mean Response Latency (RVP). ................................................................. 148. Figure 5-10 MMN waveforms compared between condition A and condition B, the. angry MMN waveform consists of the standard waveform – the deviant (angry. waveform), the happy MMN waveform consists of the standard – the deviant (happy). waveform. Details MMNs for both the Neurexin Group and the control group. A. compares the MMN in response to the Angry and Happy stimulus in the Neurexin. . xx. group, B compares the MMN in response to the Angry and Happy face in the control. group. ............................................................................................................................ 151. Figure 5-11 A) condition A – NRXN1 group, deviant = standard – deviant (angry) and. target = standard – target (face like object) B) same as previous for Control group, C). condition B – NRXN1 group, deviant = standard – deviant (happy) and target = standard. – target (face like object), D) Same as previous for control group. .............................. 152. Figure 6-1 Division of funding into six thematic categories: Genetics, Brain and. Cognition, translational medicine, treatments, epidemiology and service and societal. issues. ............................................................................................................................ 167. Figure 7-1 Summarises the results of the studies 1, 2 and 3 which investigating the. presence of possible psychiatric, cognitive and postural endophenotypes in the both PM. carriers and Parents of children with ASD. .................................................................. 177. Figure 7-2 Bland-Altman plot representing agreement of measurements of recording in. two different days. ........................................................................................................ 260. Figure 7-3 Bland-Altman plot representing agreement of measurements of recording in. two different days. ........................................................................................................ 263. . xxi. List of Tables . Table 1-1 Details of prevalence studies of premutation carriers around the world. .................. 7. Table 1-2 Details different types of symptoms associated with FXTAS (D. A. Hall et. al., 2005). ................................................................................................................................. 10. Table 3 Age of participant’s children ...................................................................................... 40. Table 2-2 Brief Protocol of Clinical Assessment. ................................................................... 41. Table 2-3 Cambridge Neuropsychological Test automated Battery (CANTAB). ................... 42. Table 2-4 Interpretation of BDI and BAI Scores. .................................................................... 43. Table 2-5 Detailed Description of PSI Subscales. ................................................................... 45. Table 2-6 Participant descriptive variables. ............................................................................. 54. Table 2-7 Kruskal Wallis Analysis of SWM variables. ........................................................... 55. Table 2-8 Kruskal Wallis Analysis of SOC variables. ............................................................ 56. Table 2-9 Kruskal Wallis Analysis of IED variables. ............................................................. 58. Table 2-10 Kruskal Wallis Analysis of MTS variables. .......................................................... 59. Table 2-11 Kruskal Wallis Analysis of RVP variables. .......................................................... 60. Table 2-12 Kruskal Wallis Analysis of Reaction Time. .......................................................... 62. Table 2-13 Overall Anxiety and Depression Scores. ............................................................... 63. Table 2-14 Kruskal Wallis Analysis of Parenting Stress Index. .............................................. 64. Table 2-15 Correlation analysis between PSI scores and Depression Scores. ........................ 66. Table 2-16 Spearman’s Rank Correlation Analysis of Life stress levels and depression. scores. ...................................................................................................................................... 68. Table 2-17 Spearman’s Rank Correlation Analysis of Parent Domain Scores and Child. Domain Scores in the Parental Stress Index. ........................................................................... 69. Table 3-1 Brief description of Clinical Measures. ................................................................... 81. . xxii. Table 3-2 Participant descriptive variables. ............................................................................. 85. Table 3-3 Kruskal Wallis Analysis of ERT Frequency of Emotions Chosen.......................... 86. Table 3-4 Kruskal Wallis Analysis of ERT Accuracy Scores. ................................................ 87. Table 3-5 Kruskal Wallis Analysis for Median overall Latency response times to. emotions. .................................................................................................................................. 88. Table 3-6 Kruskal Wallis Analysis of BAPQ scores. .............................................................. 91. Table 3-7 Kruskal Wallis Analysis of BAPQ scores including AGP data. ............................. 92. Table 4-1 Therapeutic interventions in FXTAS patients. Based on Capelli et al. (2010). .... 100. Table 4-2 Brief Protocol of Clinical measures - Details Clinical and. Neuropsychological assessments completed by participants. ................................................ 104. Table 4-3 Posture Experiment paradigms. ............................................................................. 105. Table 4-4 Description of COP metrics derived from Force Plate data. ................................. 115. Table 4-5 Details Participant Demographics. ........................................................................ 117. Table 4-6 Mann Whitney U Analysis of SART and N-Back performance scores for both. groups. .................................................................................................................................... 118. Table 4-7 Mann Whitney U Analysis of Averaged COP variables for eyes open and. eyes closed tasks. ................................................................................................................... 120. Table 4-8 COP parameters for both groups under the N-back condition. ............................. 122. Table 4-9 COP parameters for both groups under the SART condition. ............................... 123. Table 5-1 Frequencies and Penetrance for the Schizophrenia (SCZ)-associated Copy. Number variant only, this Table was adapted from Kirov et al (2014) (Kirov et al.,. 2014) ...................................................................................................................................... 131. Table 37 Age of participants .................................................................................................. 136. Table 5-3 Details of the 7 CANTAB subtests completed by participants as part of this. research. ................................................................................................................................. 137. . xxiii. Table 5-4 Descriptive statistics for all participants. .............................................................. 144. Table 5-5 Cognitive results for both the NRXN group and the Control group. .................... 145. Table 6-1 Highlights some of the quantitative information gathered as part of the survey. including; A) comorbid diagnoses and B) age of respondents. ............................................. 164. Table 6-2 Examples of Qualitative parental responses. ......................................................... 166. Table 7-1 R2 values while applying increasing loads to each sensor. The values that. appear in bold correspond to the R2 when looking at the loads applied to the. respectively sensor1. .............................................................................................................. 255. Table 7-2 Linear regression of each of the sensors when responding to the different. loads. ...................................................................................................................................... 256. Table 7-3 Loads converted into weights. ............................................................................... 257. Table 7-4 Demographics of the test re-test reliability study population. ............................... 258. Table 7-5 Reliability and concurrent validity analysis of COP path length (mm) and. Ellipse area (mm2) measures during each of the two standing balance trials. ...................... 259. Table 7-6 Demographics of force platform comparison study population. ........................... 262. Table 7-7 Reliability and concurrent validity analysis of COP path length (mm) and. Ellipse area(mm2) measures during eyes open and eyes closed condition. .......................... 262. . xxiv. Glossary of Acronyms. 5’UTR 5’ untranslated region. AD Alzheimer’s Disease. ADHD Attention Deficit Hyperactivity Disorder. AGP Autism Genome Project. AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. ANOVA Analysis of Variance. AP Anterior/Posterior. ASDs Autistic Spectrum Disorders. BAI Beck Anxiety Inventory. BAP Broad Autism Phenotype. BAP-Q Broad Autism Phenotype Questionnaire. BDI Beck Depression Inventory. CANTAB Cambridge Neuropsychological Test Automated Battery. CGG Cytosine Guanine Guanine. CI Complexity Index. CMS Common Mode Sense. CNS Central Nervous System. CNVs Copy number variants. COM Centre of Mass. COP Centre of Pressure. CpG Cytosine Phosphate Guanine. . xxv. CSRT Choice stepping reaction time. CVD Cardiovascular Disease. DD Developmental Disabilities. DNA Deoxy-ribonucleic acid. DRL Driven Right Leg. EEG Electroencephalography. EF Executive Function. ERPs Event Related Potentials. ERT Emotion Recognition Task. FM Full mutation. FMR1 Fragile X Mental Retardation 1. FMRP Fragile X Mental Retardation Protein. FSIQ Full Scale Intelligence Quotient. FXPOI Fragile X Primary Ovarian Insufficiency. FXS Fragile X Syndrome. FXSD Fragile X Spectrum Disorder. FXTAS Fragile X Associated Tremor Ataxia Syndrome. GABA γ-aminobutyric acid. GCs Glucocorticoids. GRDO Genetic and Rare Disorders Organisation. HFA High Functioning Autism. HPA Hypothalamic-Pituatry-Adrenal axis. . xxvi. HRB Health Research Board. IDs Intellectual Disabilities. IED Intra/Extra Dimensional Set Shift. IQ Intelligence Quotient. IRC Irish Research Council. KI Knock In. MCI Mild Cognitive Impairment. MCP Middle Cerebellar Peduncles. MDD Major Depressive Disorder. mGLuR5 Metabatropic Glutamate Receptor 5. ML Mediolateral. MMN Mismatch Negativity. MOLR Mean Overall Latency Response. MRCG Medical Research Charities Group. MRI Magnetic Resonance Imaging. mRNP messenger Ribonucleic Protein. MSE Multiscale Entropy. NCRC National Children’s Research Centre. NRXN-1 Neurexin 1. OCD Obsessive Compulsive Disorder. PCR Polymerase Chain Reaction. PD Parkinson’s Disease. . xxvii. PM Premutation. PoH Probability of Hit. PPI Public & Patient Involvement. PRS Pragmatic Language Score. PSI Parenting Stress Index. PTSD Post-Traumatic Stress Disorder. RNA Ribonucleic Acid. RVP Rapid Visual Processing. SART Sustained Attention to Response Task. SFI Science Foundation Ireland. SNPs Single Nucleotide Polymorphisms. SOC Stockings of Cambridge. SPSS Statistical Package for Social Sciences. SWM Spatial Working Memory. TD Typically Developing. TMT Trail Making Test. WASI Wechsler Abbreviated Scale of Intelligence. XCI X chromosome inactivation. . 1. Chapter 1 General Introduction . 1.1. Background. Brain disorders encompassing developmental, neurodevelopmental and. neurodegenerative constitutes a huge weight in terms human suffering. The US. National Institute of mental health estimates that about 25% of adults in the US have a. diagnosable psychiatric disorder. Psychiatric disorders are also the most burdensome in. terms of economic cost, with studies reporting that mental illness accounts for. approximately $193 billion in loss of earnings in the US, and this does not include. health costs, homelessness, incarceration or substance abuse (Kessler et al., 2008).. Neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease. (AD) are rapidly increasing with the increasing age of the population particularly in. high income countries. It is estimated by 2050 that between 11-16 million people in the. US will have AD. Although the prevalence of PD is lower, numbers have also seen a. significant increase, with incidence rates of parkinsonism increasing from 38.9 per. 100,000 people a year between 1976 and 1985 to 55.9 between 1996 and 205 in men. (Savica, Grossardt, Bower, Ahlskog, & Rocca, 2016). The median worldwide. prevalence of Autism Spectrum disorder (ASD) is 0.62-0.70% (Elsabbagh et al., 2012),. with economic cost of ASD in the US has been estimated at about $35 billion per year. . Brain disorders such as the ones mentioned above are aetiologically heterogeneous. making their processes thoroughly difficult to understand. Research in monogenetic. neurodevelopmental disorders that theoretically are impacted fewer or more specific. brain pathways, will not only help researchers to understand the disorder in question but. . 2. may also aid in understanding neurobiological underpinnings of more complex related. disorders. . 1.2 Relationships between genes and behaviour . 1.2.1 Genetic Variation. Human behaviour is influenced both by the genes that are inherited through family and. by the environment in which we live. In recent years knowledge of human genetics has. advanced significantly and now some researchers are attempting to locate specific. genes or groups of genes that influence specific behavioural traits and to understand. how our environment influences our genetics. In terms of disease if these genes that. influence behavioural traits could be identified, specific drug targets could be identified. for treatment. . Human genetic variation leads to phenotypic diversity; this variation accounts for. physiological differences in individuals that may lead to increased or decreased risk for. specific disorders/diseases (https://www.genome.gov/). Based on genetic contribution,. human diseases can be classified as monogenic, chromosomal or multifactorial.. Monogenic disease such as Fragile X Syndrome (FXS) can be caused by alterations in a. single gene, chromosomal are caused by variation in a chromosome and the vast. majority of humans diseases such as ASDs are multifactorial. . More than 5 million short variations have been identified in humans and can come in. various form such as; single nucleotide polymorphisms (SNPs) somatic mutations,. insertions and deletions. Structural changes can also occur and over 9 million of these. have been described, these can be duplications, insertions, inversions translocations or. copy number variants (CNVs). . 1.2.2 Alterations in a single gene - FMR1. 1.2.2.1 Background & Structure. The Fragile x mental retardation 1 (FMR1) gene was first discovered 25 years ago and. was named because of its role as a causative gene in Fragile X syndrome (FXS) (Oberle. et al., 1991; Verkerk et al., 1991; Yu et al., 1991). Fragile X syndrome was uncovered. by positioning cloning and was observed to be related to a huge trinucleotide expansion. . . 3. The FMR1 gene consists of 17 exons and spans ∼38kb. A CGG trinucleotide repeat is. located at the 5’- untranslated region within the 4.4 kb of the FMR1 transcription site.. FXS is associated with a Fragile site (a specific point on a chromosome that tends to. form a gap or constriction and may break when exposed to replication stress), this is. found at the end of the long arm of the chromosome (Jin & Warren, 2000; Loomis et. al., 2013). . The number off CGG trinucleotide repeats on the 5’untranslated region (5’UTR) region. of the FMR1 gene can give rise to more than one genetically determined phenotype and. is polymorphic for the number of repeats (Figure 1-1). In normal individuals, the CGG. repeat length is highly polymorphic in length and content and is often punctuated by. AGG interruptions. The normal repeat range is between 5-45 repeats, with 30 repeats. found to be the most common allele (Jin & Warren, 2000; Snow, Tester, Kruckeberg,. Schaid, & Thibodeau, 1994; Verkerk et al., 1991). The full mutation (FM) occurs when. CGG repeat length is greater than 200 and up to over 1000 repeats. The FM is. abnormally hypermethylated and causes a loss of Fragile X Mental Retardation Protein. (FMRP). This results in Fragile X Syndrome (FXS). A repeat length of between 45-200. repeats is known as the premutation (PM), these are generally unmethylated with. normal transcript and protein level, however they are extremely unstable during. transmission to the next generation (Jin & Warren, 2000). Traditionally, when an. individual has between 6-55 CGG repeats they were considered normal and have no. phenotypes associated with this number of repeats, however in more recent years there. has been increasing interest in what is known as the grey zone allele or intermediate. allele (44-54 CGG repeats), which has reported similar phenotypes as the premutation. (between 55-200 repeats) e.g. FXTAS (Debrey et al., 2016).. . 4. Figure 1-1 Schematic of the Hypothalamic Pituitary Adrenal Axis.. 1.2.2.2 FMRP. Fragile X Mental Retardation Protein (FMRP) is the protein that FMR1 codes for. It is a. RNA (ribonucleic acid) binding protein that is important for many complex processes.. It is important in the differentiation and migration of neurons and glia cells. FMRP is. recognised as being involved in localization and translation of neuronal messenger. RNAs (Zalfa et al., 2005). It is highly expressed in neurons, where it is involved in. transport and translation of mRNP (ribonucleic protein), two processes that are required. for synaptic plasticity. It is important for embryonic development aiding in the. differentiation and migration of neurons and glia cells. It is also important in regulating. synaptic plasticity throughout life and in adult as neurogenesis. . In recent year there are two recognised roles for FMRP in neurons (Figure 1-2). Firstly,. FMRP exhibits ion channel biding that directly influences pore conductivity properties. and it has been hypothesised that this could explain some of the neurological deficits of. FXS (Myrick et al., 2015). Secondly, FMRPs role in neurons and glia is also under. . 5. consideration. FMRP deficient mouse models exhibit altered cell differentiation. mechanisms of both neurons and glia (Khalfallah et al., 2017). Furthermore, mouse. models with astrocyte specific FMRP knockout exhibited increased neuronal spine. density similar to that observed in FXS (Hodges et al., 2017). . Figure 1-2 Roles of Fragile X Mental Retardation Protein (FMRP) in RNA and Channel. Binding at the Neuronal Synapse. Adapted from (J. K. Davis & Broadie, 2017). Activity-. dependent functions of FMRP in RNA-binding translation regulation and direct channel-. binding activity regulation. In the uncoupled mechanism (A), RNA- and channel-binding. roles are unrelated, representing two evolutionarily divergent functions. In the coupled. mechanism (B), channel binding (i) is an integral activity-sensing step in the translational. regulation of FMRP-bound transcripts (ii).. Another role of FMRP is in maintaining a balance of excitatory (glutamate) and. inhibitory (γ-aminobutyric acid (GABA)) circuits in the brain. Pharmaceutical. interventions to treat excess of glutamate and insufficient GABA are currently ongoing. and have reported different levels of success (Davenport, Schaefer, Friedmann,. . 6. Fitzpatrick, & Erickson, 2016). It has been hypothesized that increased levels of. extracellular glutamate cause over stimulation of receptors and this can result in. “excitotoxicity”, leading to neuronal cell death. An excess of glutamate has been linked. to various pathologies such as stroke, trauma, seizure and age related cognitive decline. (Atlante et al., 2001; Coyle & Puttfarcken, 1993).. 1.2.2.3 Prevalence of the FMR1 Premutation. If an individual has between 55 and 200 repeats they are considered a Fragile X. premutation carrier (from now on these will be referred to as PM carriers). Two distinct. phenotypes arising in a proportion of cases with the PM are described: Fragile X. Associated Tremor/Ataxia Syndrome (FXTAS) and Fragile X Associated Primary. Ovarian Insufficiency (FXPOI) (in women). In addition several more subtle cognitive. and psychiatric phenotypes have been reported in PM carriers however, these. phenotypes are less clearly defined and rate of occurrence is less clear. Reporting of. premutation carrier prevalence varies somewhat between studies but is estimated at. around 1 in 159 females and 1 in 362 males (average of all studies available) (Table. 1.)(Fernandez-Carvajal et al., 2009; Hantash et al., 2011; Tassone, Iong, et al., 2012;. Toledano-Alhadef et al., 2001). The prevalence of the premutation translates to about 1. million carriers in the United States (Seltzer et al., 2012), implying that a significant. proportion of individuals may be at risk of developing associated phenotypes. Until. recently PM associated phenotypes were relatively understudied despite the significant. associated morbidity. . . 7. Table 1-1 Details of prevalence studies of premutation carriers around the world.. Country Authors N Prevalence . Israel (Toledano-Alhadef et. al., 2001). 14,334 females 1 in 113-157 females . Spain (Fernandez-Carvajal. et al., 2009). 5367 males 1 in 130 females, 1 in. 250 males . USA (Hantash et al., 2011) 11,759 1 in 178 females, 1-. 400 males. USA (Wisconsin) (Seltzer et al., 2012). (Maenner et al., 2013). 6,747. 11,527 females &. 8,469 males. 1 in 151 females, 1 in. 468 males. 1 in 148 females and. 1-290 males . USA (California) (Tassone, Iong, et al.,. 2012). 7312 males &. 6895 females. 1in 209 females, 1 in. 400 males. . 8. 1.2.2.4 X- inactivation . FXS and indeed the FMR1 premutation are ‘X-linked’, which means the mutation is. found on the X chromosome. Male carriers may pass the premutation or full mutation to. daughters only, whereas female carriers may pass the premutation on to offspring of. both genders.. Figure 1-3 Details the process of inheritance in a female premutation carrier.. X-chromosome inactivation (XCI) has been proposed as a factor possibly mediating. phenotypic outcomes in female PM carriers that could explain the milder clinical. phenotypes in female PM carriers. XCI is the process whereby females. transcriptionally silence one X chromosome resulting in a proportion of cells with an. active abnormal FMR1 allele and the remainder with an active normal allele. On. average this should affect 50% of cells however skewed proportions of abnormal vs. normal alleles have been reported in some female carriers (Wang, Yu, & Shete, 2014).. It is suggested that this variation in the activation ratio (AR) may lead to the widespread. phenotypic heterogeneity in female premutation carriers (D. A. Hall et al., 2016).. . 9. However, these findings should be viewed with caution as tissue specific differences in. repeat length have been observed in both male and carriers of the full mutation. (Maddalena et al., 2001). . 1.2.2.5 FXTAS . Classification and Diagnosis. Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset. neurodegenerative disorder that can affect older PM carriers. It is characterised by. cerebellar ataxia, progressive attention tremor and cognitive decline that notably. includes dysexecutive function (Brega et al., 2008). Other symptoms can include. peripheral neuropathy, dysautonomia, autoimmune dysfunction and psychiatric. symptoms such as depression and anxiety (Careaga et al., 2014; R. J. Hagerman et al.,. 2007; Louis, Moskowitz, Friez, Amaya, & Vonsattel, 2006; Seritan, Ortigas, Seritan,. Bourgeois, & Hagerman, 2013). It has been estimated that approximately 1 in 3000 men. and a smaller number of women will develop FXTAS at some time in their life (P. J.. Hagerman, 2008). The most common method for diagnosing FXS is using Southern. blot analysis, however Southern blot cannot identify smaller premutation alleles. A. definitive diagnosis of FXTAS is made when a Polymerase Chain Reaction (PCR). exhibits an FMR1 gene that is increased in length in an individual with tremor or gait. ataxia (Chaudhary et al., 2014). . . 10. There are two categories of symptoms for FXTAS; ‘major’ and ‘minor’ and three. categories for diagnosis; ‘definite’, ‘probable’ and ‘possible’ FXTAS (Table 1-2). . Table 1-2 Details different types of symptoms associated with FXTAS (D. A. Hall et al.,. 2005).. Type of Symptom Major Minor Other . Intention tremor Parkinsonism Neuropathy,. numbness, tingling. of extremities. Gait ataxias Short term memory. problems . Cognitive decline. MRI findings;. “MCP” sign. . Problems with. executive function. and decision. making . Impotence . FXTAS inclusions Lesions of cerebral. white matter . High blood. pressure, thyroid. disorders,. fibromyalgia. Moderate to severe. generalised brain. atrophy . A large proportion of individuals with FXTAS are misdiagnosed with other. neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s. Diseases (AD) or other cerebellar ataxias. Hall et al (2005) observed that 56 patients. with FXTAS were given 98 prior diagnoses and that the majority of these diagnoses. were in the categories of Parkinsonism, tremor, ataxia dementia or stroke (D. A. Hall et. al., 2005). Clinical misdiagnosis is costly in terms of time and resources and detrimental. . 11. to patient quality of life of the patient in the absence of treatment appropriate to the. diagnosis. . Molecular Understanding of FXTAS. The identification of FXTAS and the relationship with the PM suggests that there is. distinct molecular mechanisms in operation in the PM range. . There are two mechanisms for FXTAS that are widely accepted, firstly RNA toxicity. and secondly, non-AUG translation (RAN) protein toxicity (Kong, Zhao, Xu, Jin, & Jin,. 2017). There are several arguments for RNA toxicity as a molecular mechanism for. FXTAS. Firstly, FMR1 mRNA is present in intranuclear inclusions that have been. observed in the FXTAS post-mortem brain of humans (Tassone, Iwahashi, &. Hagerman, 2004). In addition animal models of FXTAS have been observed to develop. similar inclusions (Jin et al., 2003; Willemsen et al., 2003). Secondly, older adults with. the FM, do not express FMR1 mRNA and lack FMRP. Furthermore, they have not been. shown to develop FXTAS (Feng et al., 1995). Finally, individuals with FXTAS exhibit. a significant upregulation in FMR1 mRNA, which result in RNA aggregate formation.. These aggregates function by sequestering CGG-binding proteins, preventing normal. biological function (Kenneson, Zhang, Hagedorn, & Warren, 2001; Tassone et al.,. 2000). Although RNA toxicity is a contributing factor to FXTAS pathology, it is not. solely responsible for the large ubiquitin-positive inclusions observed in FXTAS.. Furthermore, these inclusions are similar to those observed in protein-mediated. neurodegenerative disorders (Greco et al., 2006; Iwahashi et al., 2006). For this reason a. protein driven mechanism for FTXAS pathogenesis was investigated. Todd et al, (2013). observed that the CGG repeat expansion induced RAN translation within the 5’UTR of. the FMR1 mRNA via an AUG-independent mechanism (Todd et al., 2013). . Neuroanatomy and Neuropathology of FXTAS . Neuropathological evidence suggests that degeneration of cerebral white matter is core. component of FXTAS, this potentially puts FXTAS in a category with white matter. dementia (Filley, 2016). In fact several studies have observed extensive cerebral and. cerebellar white matter degeneration in individuals with FXTAS. A major pathological. feature of FXTAS are the widespread presence of intranuclear neuronal and astroglial. inclusions (Greco et al., 2002). These inclusions have been observed to be dispersed. . 12. throughout the cortex, in addition to in the basal ganglia, thalamus, substantia nigra,. dentate nuclei and the inferior olivary nucleus (Greco et al., 2006). . T2 signal intensities observed on magnetic resonance imaging (MRI) in the middle. cerebellar peduncles (MCPs) are considered a major radiological sign of FXTAS. This. is also known as the MCP sign and has been demonstrated in approximately 60% of. affected men and approximately 13% of affected women (Cohen et al., 2006).. However, the MCP sign is not specific to FXTAS and therefore cannot provide a. definitive diagnosis. Moreover, the MCP sign and cerebellar atrophy is also common in. patients with FXTAS, this is important to note as the cerebellum is responsible for. control and monitoring of posture and gait which are severely affected in FXTAS. . The FXTAS mouse model, the CGG Knock-in mouse has provided insight into the. underlying molecular biological and pathophysiology of FXTAS. Similarities observed. between the mouse model and the human manifestation of the disorder include increase. in repeat length, elevated levels of FMR1 mRNA (Bontekoe et al., 2001), impaired. motor coordination (Van Dam et al., 2005) and psychiatric phenotypes such as anxiety.. In parallel with human studies, animal models form an important part of the. development of new pharmacotherapies. . Despite growing understanding of FXTAS, questions remain regarding the condition. and the relationship with the FMR1 PM. The effects of the premutation are not fully. penetrant and it is not clear why some FMR1 premutation carriers do not develop. FXTAS during their lifetime. The extent to which other genetic effects or. environmental factors contribute to the condition has not been estimated. From a. therapeutic perspective, it is not yet clear if treatment is best commenced when patients. become symptomatic or whether earlier treatment may be beneficial. The efficacy of. treatment and the effect on progression of the condition has not yet been determined. . 1.2.2.6 Other FMR1 related Disorders. Fragile X Associated Primary Ovarian Insufficiency (FXPOI). FXPOI is associated with irregular periods, menopausal symptoms, early menopause. and infertility and affects approximately 20% of female PM carriers. PM carriers with. between 59 and 99 repeats are more likely to develop FXPOI. This linear relationship. appears to breakdown when repeat size is greater than 100 in females, in fact some. . 13. individuals with intermediate alleles (44-54 repeats) have been observed to have an. increased risk of developing FXPOI (Mailick, Hong, Greenberg, Smith, & Sherman,. 2014). The underlying mechanisms are unknown and current research is focused on. potential causal factors of FXPOI, including; repeat length (Mailick et al., 2014),. skewed X-activation, smoking (Allen et al., 2007) and background genes. . Gender specific phenotypic differences in PM carriers. Females and Males with the FMRP PM demonstrate differing severities of numerous. debilitating physical, mental and emotional symptoms that are likely attributable to. levels of FMRP as a consequence of X inactivation. . Medical Phenotypes. Neuropathy scores have been shown to be significantly higher in male PM carriers. compared to age matched controls. No significant differences in female premutation. neuropathy scores compared to controls were reported although correlations were. reported between repeat length and total scores in females (Berry-Kravis et al., 2007).. Females PM carriers exhibit higher rates of thyroid conditions than age matched. controls independent of a diagnosis of FXTAS (Rodriguez-Revenga et al., 2009). Other. medical conditions that have been noted in premutation carriers are hypertension,. chronic muscle pain, fibromyalgia, seizures, and chronic muscle pain (Hamlin et al.,. 2012; Leehey, Legg, Tassone, & Hagerman, 2011; Rodriguez-Revenga et al., 2009). . Psychiatric Phenotypes. Psychiatric and neurodevelopmental symptoms are also reported in PM carriers. (Bourgeois et al., 2009). While these associations were not initially apparent, (Reiss,. Freund, Abrams, Boehm, & Kazazian, 1993), continued investigation has revealed. differences in psychiatric phenotypes of PM carriers compared with controls (Grigsby. et al., 2008). PM carriers appear to exhibit a greater propensity to develop mood and. anxiety disorders than the general population. Increased Lifetime risk for Major. Depressive Disorder has been observed in female premutation carriers (J. E. Roberts et. al., 2015). Increased levels of anxiety disorder are observed in both male and female. premutation carriers (D. B. Bailey, Jr., Raspa, Olmsted, & Holiday, 2008). On a. molecular level, anxiety and obsessive compulsive disorder (OCD) features have been. associated with atypical increase of FMR1 mRNA in male PM carriers with and without. FXTAS (Hessl et al., 2005). Furthermore, other anxiety such as agoraphobia, panic. . 14. disorder, and social phobia are also present in female PM carriers (D. B. Bailey, Jr. et. al., 2008). Increased rates of ADHD have also been observed in male carriers (Farzin et. al., 2006) and females (Hunter, Rohr, & Sherman, 2010). . Chronic stress can have a highly detrimental effect on health and cognition and can. increase vulnerability to mental illness(Goh & Agius, 2010). Glucocorticoids (GCs) are. a group of stress hormones that are released upon exposure to stressful situations, most. commonly cortisol in humans. GCs result from the activation of the Hypothalamic-. pituitary-adrenal axis (HPA). The HPA axis is regulated by three structures in the brain;. the amygdala, the hippocampus and the medial prefrontal cortex. . Figure 1-4 Schematic of the Hypothalamic Pituitary Adrenal Axis.. The hippocampus is implicated in several psychiatric disorders including; depression,. Alzheimer’s disease (AD), and post-traumatic stress disorder (PTSD). Stress exposure. has been extensively investigated in relation to cognitive decline in disorders such as. AD and Mild Cognitive Impairment (Borcel et al., 2008; Kerr, Campbell, Applegate,. Brodish, & Landfield, 1991; Sandi & Touyarot, 2006). Therefore a lifetime of increased. stress may leave individuals vulnerable to pathological aging. . . 15. Cognitive Phenotypes. Intelligence Quotient (IQ) scores in carriers without FXTAS are typically observed to. be within the normal range (Grigsby et al., 2008). A large US study reported that one. third of male PM carriers had been diagnosed or treated for developmental de

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