The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)

In __The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS)__, the editors present information on all aspects of FXTAS, including clinical features and current supportive management, radiological, psychological, and pathological findings, genotype-phenotype relationships, animal models and basic molecular mechanisms. Genetic counseling issues are also discussed. The book should serve as a resource for professionals in all fields regarding diagnosis, management, and counseling of patients with FXTAS and their families, as well as presenting the molecular basis for disease that may lead to the identification of new markers to predict disease risk and eventually lead to target treatments. Preface 6 Acknowledgements 9 Contents 10 Contributors 11 1 Clinical Neurological Phenotype of FXTAS 13 Introduction 13 Clinical Signs of FXTAS 16 Female Premutation Carriers 19 Natural History of FXTAS 21 Diagnosis of FXTAS 21 Summary and Future Perspectives 25 References 25 2 The Epidemiology of FXTAS 29 Introduction 29 Prevalence of the Premutation in the General Population 30 Females 30 Males 32 Penetrance of FXTAS Among Premutation Carriers 33 Prevalence of the Premutation in Movement Disorder Populations 33 Estimating the Prevalence of FXTAS 38 FXTAS in Female Populations 38 Summary 38 References 39 3 FXTAS: Neuropsychological/Neuropsychiatric Phenotypes 43 Introduction 44 Executive Cognitive Disorders in FXTAS 44 Phenotypic Gender Differences 45 Cognition Among Male Carriers of the FMR1 Premutation: Case Studies and Series 46 Comparison with Asymptomatic Carriers and Normal Controls 49 Neuropsychological Functioning Among Women with FXTAS 54 Similarity of Neuropsychological Findings in FXTAS to Other Disorders 55 Psychiatric Disorders in FXTAS 57 Summary 59 References 60 4 Radiological Findings in FXTAS 66 Introduction 66 Radiological Signs in FXTAS 67 The MCP Sign 67 Abnormal Cortical White Matter Signal 68 Cerebral Atrophy 68 MRI Findings in Females with FXTAS 68 BrainMolecular Relationships 69 Brain Behavior Relationships 69 Findings in Brain Connectivity 70 Functional Brain Abnormalities 73 Summary 75 References 75 5 The Pathology of FXTAS 78 Introduction 78 Intranuclear Inclusions 79 Brain Pathology 81 Gross Pathology 81 Microscopic Brain Pathology 81 Morphometric Analysis: Neuronal and Inclusion Counts 83 White Matter Pathology 84 Peripheral Nervous System 84 Autonomic System 84 Peripheral Nerve 84 Skeletal Muscle 85 Neuroendocrine 85 Summary 85 References 86 6 The Molecular Biology of FXTAS 88 Introduction 88 Clinical Involvement in FMR1 Premutation Carriers 89 FMR1 Gene Structure 92 Higher FMR1 Transcription Rate in Premutation Alleles 94 ASFMR1 : The Antisense Transcript at the FMR1 Locus 94 Inclusion Formation 95 RNA Toxic Gain-of-Function Model 97 Disruption of the Lamin Architecture 98 Summary 98 References 99 7 Genotype/Phenotype Relationships in FXTAS 105 Introduction 105 Genotype/Phenotype Correlation Among Men with the Premutation 106 Clinical Neurological Phenotype 106 Overview 106 FXTAS Rating Scale: Quantifying the Severity of Motor Signs of FXTAS 108 Neuropathy Rating Scale 108 CATSYS: Quantifying Early Motor Symptoms of FXTAS 109 Nerve Conduction Studies: Tools to Identify Additional Symptoms of FXTAS 111 Genotype/Phenotype Correlations with Clinical Neurological Measures 111 Cognitive Phenotype 120 General Intelligence 120 Executive Function 120 Genotype/Phenotype Correlations with Cognitive Measures 121 Psychiatric Phenotype 122 Genotype/Phenotype Correlations with Psychiatric Outcomes 122 Radiological Phenotype 123 Genotype/Phenotype Correlations with Radiological Outcomes 124 Pathology Phenotype 125 Genotype/Phenotype Correlations with Pathology Outcomes 125 Genotype/Phenotype Correlations Among Women with the Premutation 126 Clinical Neurological Phenotype 127 Psychiatric Phenotype 128 Radiological Phenotype 128 Summary 129 References 130 8 Animal Models for FXTAS 133 Mouse Models for FXTAS 133 Repeat Instability 134 Molecular Findings 135 Neuropathology 136 Behavioral Phenotype 137 Psychopathology 138 Therapy and Mouse Models 138 Drosophila Model of FXTAS 139 Development of FXTAS Drosophila Model 140 Molecular Findings 140 RNAi Pathway and FXTAS 142 Summary 143 References 143 9 Treatment and Management of FXTAS 147 General Approaches to Management 147 Treatment for the Movement Disorders in FXTAS 149 Treatment of Tremor 149 Treatment of Ataxia 151 Treatment of Parkinsonism 151 Physical Therapy for Motor Dysfunction in FXTAS 152 Treatment for Neuropathy and Pain in FXTAS 152 Treatment for Autonomic Symptoms in FXTAS 153 Treatment for Swallowing Difficulties 154 Treatment for Dementia in FXTAS 155 Treatment for Psychiatric Symptoms in FXTAS 156 Psychosocial Approaches to Cognitive and Psychiatric Problems in FXTAS 157 Treatment of Hormonal Dysfunction 158 Treatment of Other Comorbidities 159 Genetic Counseling 160 Future Treatments to Target the Underlying Mechanism of Disease in FXTAS 160 Summary 160 References 161 10 Genetic Counseling for FXTAS and FMR1-AssociatedDisorders 165 Introduction 165 Molecular Aspects 166 Inheritance 167 Diagnostic Testing 168 Genetic Counseling 170 Reproductive Issues 172 Adult Male Carriers 172 Prenatally Detected Male Carriers 172 Reproductive Options for Female FMR1 Carriers 173 Prenatal Diagnosis 173 Egg Donation 174 Embryo Transfer 174 Preimplantation Genetic Diagnosis 174 Special Considerations in Genetic Counseling for FXTAS 176 Psychosocial Issues 177 End-of-Life Planning 181 Genetic Discrimination 181 Treatment Issues 182 Summary 183 References 183 Subject Index 187 Front Matter....Pages i-xvi Clinical Neurological Phenotype of FXTAS....Pages 1-16 The Epidemiology of FXTAS....Pages 17-30 FXTAS: Neuropsychological/Neuropsychiatric Phenotypes....Pages 31-53 Radiological Findings in FXTAS....Pages 55-66 The Pathology of FXTAS....Pages 67-76 The Molecular Biology of FXTAS....Pages 77-93 Genotype/Phenotype Relationships in FXTAS....Pages 95-122 Animal Models for FXTAS....Pages 123-136 Treatment and Management of FXTAS....Pages 137-154 Genetic Counseling for FXTAS and FMR1-Associated Disorders....Pages 155-176 Back Matter....Pages 177-188 The Fragile X-Associated Tremor Ataxia Syndrome (FXTAS) serves as a resource for professionals in all fields regarding diagnosis, management, and counseling of patients with FXTAS and their families, as well as presenting the molecular basis for disease that may lead to the identification of new markers to predict disease risk and eventually lead to target treatments. --Book Jacket