Index. L Lamin A/C architecture, Laminopathies, 115

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1 A Activities of daily living (ADLs), 131 AGG interruption analysis, 269 Alzheimer s disease, 92 Amyotrophic lateral sclerosis (ALS), 111 Amyotrophic lateral sclerosis and frontotemporal dementia (ALS- FTD), Antisense transcript of the FMR1 gene ( ASFMR1 ), Anxiety and depression, 248 Anxiety Disorders Interview Schedule for DSM-IV (ADIS), 247 Autism spectrum disorder (ASD), 105, 245 B Behavioral Dyscontrol Scale (BDS), 49, 184 Benzodiazepines, 185 Blastomere biopsy, 275 Brain abnormalities, fmri, 80 Brain pathology gross, 92 microscopic, neuronal and inclusion counts, 94, 95 white matter, 95 C CATSYS system, 134 Cerebellar and Parkinsonian motor deficits, 45 Cerebral atrophy gray matter loss, 75 individuals with, 75 premutation carriers, 76 radiological features, 76 ventricle size, 75 vermis lobules, 76 Cognition, 44, 45, 56 male carriers 98 CGG repeats, 45 case studies, 44 heterogeneity, 44 Mattis Dementia Rating Scale, 44 MMSE, 44, 45 neuropsychological examination, 45 Stroop test, 44 symptomatology, 45 Cognitive dysfunction and behavioral changes, 7 Cognitive-behavioral therapy, 187 Compound muscle action potential (CMAP), 136 CVS, 273 D Deep brain stimulation (DBS), 184 Dementia, 55 56, Depression, 279 Diffusion tensor imaging (DTI), 245 Dizygotic twinning (DZ), 208 Donepezil, 189 Down syndrome, 116 Drosophila model, 234 development, 170 human neurodegenerative diseases, 170 molecular pathogenesis, 170 Dysexecutive syndrome, 41, 42, 48 DZ. See Dizygotic twinning (DZ) Springer International Publishing 2016 F. Tassone, D.A. Hall (eds.),, FXPOI, and Other Premutation Disorders, DOI /

2 288 E Embryo transfer, 274 End-of-life planning and care, 280 Epidemiology, in Women, 34 men, 28 premutation alleles, 31 premutation, movement disorder Populations, premutation, population, 26 prevalence, 25 women, 26 Estrogen deficiency, 200 Event related potential (ERP), 184 Executive dysfunction, 146 Executive functioning (EF), 41 F Fibromyalgia, 251, 252 FMR1-associated disorder, diagnostic testing AGG interruption analysis, 269 FMR1 DNA test, 267 PCR, 268 Southern blot analysis, 268 FMR1 DNA test, 267 Follicle stimulating hormone (FSH), 200 Fragile X (FMR1 ) gene, 265, 266 AGG interruptions, 107 brain atrophy, 106 clinical involvement, 103 clinical neurological signs, 136 dysexecutive and psychiatric symptoms, 155 FMRP isoforms, 106 and FXPOI, 104 genetic measures, 146 larger premutation alleles, 105 leukocytes, 153 lymphocytes and neuronal cells, 107 molecular aspects FXPOI, 266 immune- mediated diseases, 266 methylation mosaicism, 265 premutation, 265 molecular attributes, 156 molecular characterization, 264 molecular measures and psychiatric consequences, premutation, 154 neurodegenerative syndrome, 104 numerous phenotypic problems, 105 polyadenylation signals, 107 premutation, 148, 155 premutation alleles, 108 RT-PCR analysis, 106 splice variants, 106 transcript level, 151 transcript levels and protein levels, 136 translational efficiency, 107 X-chromosome and consequent random X-chromosome inactivation, 152 X-inactivation effects, 105 Fragile X mental retardation. See Fragile X (FMR1) gene Fragile X premutation, 76 Fragile X syndrome (FXS), 102 Fragile X-associated primary ovarian insufficiency (FXPOI), aneuploidy, 208 clinical characteristics menopause, 226 mouse models, 228 oligo/amenorrhea, 226 risk factor, 227 XCI, 227 clinical disorders, 201 diagnosis, diagnosis and experience, POI, 202 disorders, FMR1 premutation, 201, follicular atresia, 201 hormonal fluctuations and changes, 208 hypoestrogenism, 201 infertility and subfertility, 209 mechanisms, 203 menopause, 202, menstrual cycles, menstrual traits, 207 onset of symptoms, 215, 216 oocytes/follicles, 202 pregnancy outcomes, 207 premature ovarian failure (POF), 200 premutation experience POI, 201 primary ovarian insufficiency, reproductive health, 200 risk factors, RNA gain-of-function disorder, 228 state of early estrogen deficiency, 200 symptoms, 209 twinning, 208 Fragile X-associated tremor/ataxia syndrome (), 3 10, 13 17, 40, 42 49, 92 96, 201 AGG interruptions, 102 brain (see Brain pathology ) Brain MR images, 3 cardinal features, 41

3 289 cause of death, 12 cellular dysfunctions, 98 CGG repeat, 102 clinical features, 2 clinical signs autonomic symptoms, 8, 9 characteristics, 3 cognitive and psychiatric, 7 Eye movement abnormalities, 10 mood disorders, 6, 7 movement disorders, 4 7 peripheral Nervous System, 8 premutation carriers, 9 cognition, 41 cognitive dysfunction, 2 diagnosis, 264 criteria, 15 differential diagnosis, 13 FMR1 gene testing, 14 FMR1 premutation carriers, 16 heterogeneity, 13 MR imaging, 14 neurodegenerative disorder, 14 predominant dementia, 13 spasticity, legs, 13 testing guidelines, tremor and ataxia, 13 differential diagnosis, 14 dysexecutive syndrome, 41, 42 EF, 41, 42 executive function, 146 ferroportin and ceruloplasmin, 98 FMR1 gene analysis, 3 FMR1-related signs, 17 full mutation, 103 FXPOI, 43 FXS (see Fragile X syndrome (FXS) ) general intelligence, 145 Glu signaling, 98 hypertension and hyperlipidemia, 3 inclusion formation, intranuclear inclusions, 2, iron accumulation, 98 logistic regression, 102 MCP, 88 MCP sign, 18 motor signs, severity, nerve conduction variables, 136 neuroendocrine, 97 neuropathy rating scale, 133, 134 neuropsychological phenotype (see Neuropsychological phenotype ) peripheral nervous (see Peripheral nervous system ) POI, 43 premutation cognition, male carriers, 44, 45 gender differences, 42, 43 premutation alleles, 102, 103 premutation carrier women, premutation phenotype, 40 progression, tremor and ataxia, 12 progressive neurodegenerative disorder, 88 quantifying early motor symptoms, reduction of proteins, 98 research, 18 research subjects, 40 retrospective chart review study, 12 testing guidelines, 17 toxic RNA, 88 tremor and ataxia, 17 tremor, ataxia and cognitive, 98 FSIQ. See Full scale IQ (FSIQ) Full scale IQ (FSIQ), 146 FXPOI. See Fragile X-associated Primary Ovarian Insufficiency (FXPOI) neuropsychological findings, and model systems CGG-RNA expression, 230, 231 CTCAAG, 232 FMRpolyG protein, 232 FMRpolyG-negative mice, FMRpolyG-positive, 231 hnrnp A2/B1, 231 RAN translation, 231 rating scale, G Gastroesophageal reflux, 252 Genetic counseling, 193, definition, 269 depression, 279 end-of-life planning and care, 280 fragile X mutation testing, 270 FXD, 270 body language and wording monitor, 277 caregiver, 276, 277 clinical symptomatology, 278 female, 278, 279 male, 278 psychosocial issues, 276 medical and psychosocial history, 269, 270 molecular and hereditary aspects, 264 patient s families, 265 psychosocial issues, treatment issues, 281

4 290 Genetic discrimination, Genetic Information Nondiscrimination Act of 2008 (GINA), 281 Genetic testing, 29 Genotype/Phenotype correlations, 136, 137, clinical neurological measures CATSYS system, 144 cognitive phenotype, 145 FMR1 genotype, 136 rating scale, 137 motor symptoms, 136 neuropathy screening scale, 144 olfactory dysfunction, 145 clinical neurological phenotype, men, clinical neurological phenotype, women, cognitive measures central executive function, 147 CGG repeat length and neuropsychological measures, 146 FMR1 genetic measures, 146 FSIQ, Pearson correlation, 147 MDRS, 147 psychiatric phenotype, 148 symptoms, FMR1 CGG repeat length and mrna levels, pathology outcomes, premutation carriers without, 155 psychiatric outcomes FMR1 premutation, 148 symptoms, 149 MCP, 149 MRI signs, 150 radiological phenotype, SCL-90-R except phobic anxiety, 148 psychiatric phenotype, 154 radiological outcomes, radiological phenotype, H Heterochromatin protein 1 (HP1), 110 Homologous recombination technique, 162 Hormonal dysfunction, 192 Hormone replacement therapy (HRT), 216 HRT. See Hormone replacement therapy (HRT) Hypertension (HTN), 192, 250 Hypoestrogenism, 201 Hypothalamic pituitary adrenal (HPA), 168 Hypothalamic pituitary ovarian (HPO), 201 I IMDs. See Immune-mediated disorders (IMDs) Immune-mediated disorders (IMDs), 210 case studies, 252, 253 Gastroesophageal reflux, 252 mirna maturation, 251 pain symptoms, 252 Sleep disturbances, 252 In vitro fertilization (IVF), 275 Inducible model system, 169 Infertility, 226, 233 Inheritance, Intellectual disability (ID), 244 Intranuclear inclusions, fl ow-based isolation and purification, 89 FMR1 premutation, 91, 92 FMRpolyG, 90 FRMRP protein, 90 hippocampus, 89 human brain tissues, 89 knock-in mouse model, 89 neuronal and astrocytic, 93 neuronal intranuclear inclusion disorder, 89 percentage of neurons and astrocytes, 94 proteosomal degradation product, 89 RNA gain of function, 90 time course, 90 L Lamin A/C architecture, Laminopathies, 115 M Major depressive disorder (MDD), 149 Martin Bell syndrome, 40 Mattis Dementia Rating Scale (MDRS), 44, 147 MCP. See Middle cerebellar peduncles (MCP) MCP sign radiological features, 72 Menopause, Middle cerebellar peduncle (MCP) sings, 44, 88, 92, 95, 96, 149 Midodrine, 188 Migraine headaches, 193 Migraines, 252 Mini Mental State Exam (MMSE), 44 Mitochondrial biogenesis, 115, 116 MMSE, 51

5 291 Mouse models, behavioral phenotype, 167 Drosophila, 170 FMRP levels, 164 fragile X premutation rcgg, 170, 171 human genetic disease, 162 immunological findings, 166 intranuclear neuronal inclusions, 165 mean corticosterone levels, excgg and WT mice, 168 molecular findings, , neuropathology, psychopathology, repeat instability, RNAi pathway and RAN translation, therapy, 169 Movement disorders, 7, Multiple system atrophy (MSA), 31 N National Society of Genetic Counselors (NSGC), 269 Neurodegenerative diseases, 111 Neurodevelopmental problems DTI, 245 premutation on children, 244 transcranial magnetic stimulation, 245 visual processing deficits, 244 Neuroimaging,, autopsy, 72 brain behavior relationships altered neural activity, 81 cognitive disorders, 81 IQ scores, 81 microstructural integrity, 81 mood and anxiety disorders, 82 morphometric analyses, 81 motoric features, 81 progressive intention tremor and cerebellar ataxia, 80 white matter hyperintensities, 81 differences, features, 72 fmri, 80 MRI, 82 MRI lesions, 72 radiological abnormal cortical white matter signal, 74 cerebellar and cerebral atrophy, 75, 76 MCP sign, white matter structural integrity, reconstructed fiber tracts, 79 segmentation, subcortical gray matter, 77 T2-weighted axial image, brain, 75 Neuropathic pain, 187 Neuropathy, 251 Neuropathy rating scale, Neuropsychiatric Inventory (NPI), 148 Neuropsychological phenotype, female carriers dual-task protocol, 53, 54 language dysfluencies, 53 motor reaction, 54 standardized achievement test, 53 age-related systematic bias, 47 Behavioral Dyscontrol Scale, 49 case subjects comparison, 46 cognitive impairment, 46 dysexecutive syndrome, 48 EF, 46 MMSE, VIQ, and PIQ, 47 nonparametric bootstrapping mediation analyses, 49 regression analyses, 48 men carriers age-related declines, 49 EF deficits, 49 Stroop test, 50 women Alzheimer s disease, 52 cognition, 50 cognitive deficits, 51, 52 FXPOI, 51 and dementia, 52 memory and concentration, 51 MMSE, 51 Non-penetrant transmitting males (NTM) or carriers, 242 Normal pressure hydrocephalus (NPH, 190 North American Menopause Society, 216 O Olfactory dysfunction, 145 Orthostatic hypotension, 188 P Parkinson disease (PD), 30, 92 Parkinsonism, 2, 6, 13, 14, 186 Peripheral blood monocular cells (PBMC), 166

6 292 Peripheral nervous system (PNS), 96, 97, 244 autonomic pathology, 96 axonal degeneration, 96 neuropathic features, 96 skeletal muscle, 97 Polar body analysis, 275 Polymerase chain reaction (PCR), 268 Population studies, 27 Prefrontal cortex (PFC), 41, 42 Preimplantation genetic diagnosis (PGD), 275 fragile X blastomere biopsy, 275 polar body analysis, 275 in vitro fertilization (IVF), 275 ovarian insufficiency, 275 Premutation (PM), 225 Premutation-associated disorders, 250 ADHD and ID, 242 animal data, 243 definition, 242 medical and neurological findings, 249 hypertension, 250 Sleep apnea, 250 Prenatal testing, 274 Prepulse inhibition (PPI), 167 Primary ovarian insufficiency (POI), 43, 200 Problem-solving therapy (PST, 191 Protein Sequestration model, 229 Psychiatric symptoms, 7 Psychiatric/cognitive issues ADHD and ASD, 246 alcohol abuse, 249 ASD and ID, 246 depression and anxiety, 248 executive functioning, 247 psychosocial impact, 249 women, 248 Psychosocial issues, R RAN translation, , , 230, 231 Rehabilitative Therapies, Repeat expansion diseases, 225 AUG-initiated translation, 230 CGG-RNA hairpin, 229 DM1 and DM2, 229 Protein Sequestration model, 229 RAN translation, 230 RNA-mediated repeat pathology, 229 Repeat expansion disorder, 201, 217 Reproductive issues, 274 adult male carriers, 271 female FMR1 carriers, 275 eggs donation, 274 embryo transfer, 274 PGD (see Preimplantation genetic diagnosis (PGD) ) prenatal testing, 274 FMR1 premutations in pregnancy, 272, 273 prenatally detected male carriers, 271, 272 Riluzole group, 186 RNA disease CUGBP1, 110 DROSHA-DGCR8, 111 Drosophila, 110, 109, 110 hnrnp A2/B1, 110 myotonic dystrophies, 109 P68/DDX5, 111 Purα, 111 SAM68, 110 TDP-43, 111 RNA toxicity,, 90 Rodent models Akt/mTOR pathway, 234 Fmr1 mrna, 233 FMRpolyG-negative KI mouse mode, 233 granulosa cell health, 233 LH receptor (LHR), 233 transgenic model, YAC, 233 TUNEL staining, 233 ubiquitin-positive inclusions, 234 wild-type rodents, 232 S SCA spinocerebellar ataxia, 33 Semiquantitative Western blot techniques, 164 Sensorimotor gating, 167 Sensory nerve action potential (SNAP), 136 Severe subcortical white matter degeneration, 91 Sleep apnea, 250 Southern blot analysis, 268 Stroop test, 44 T The American College of Obstetricians and Gynecologists, 214 Thyroid dysfunction, 192 Treatment and management

7 293 autonomic dysfunction, 188 beta-blockers and primidone, 185 cognitive and psychiatric problems, constipation, 188 dementia, medical records, 182 movement disorders, neurological symptoms and medical conditions, 182 neuropathy and pain, 187 psychiatric symptoms, swallowing difficulties, 189 tremor, Ttranscriptional initiation sites, 106 U Ubiquitin proteasome system (UPS), 114 Unified Parkinson s Disease Rating Scale (UPDRS), 132 V Verbal IQ (VIQ), 147 Visual spatial deficits, 243 W White matter disease abnormal cortical white matter signal, 74 axial diffusivity, 78 diffusivity measures, 78 DTI, 77 DTI measures, 79 fractional anisotropy, 78 free diffusion of hydrogen, 78 intra-voxel directionality of hydrogen diffusion, 78 MCP microstructure, 78 MRI, 76 MRI techniques, 77 T2-weighted MRI scans, 78 White matter pathology, 91, Whole-brain white matter hyperintensity (WMH), 55 X X inactivation (XCI), 227, 235 Y Yeast artificial chromosomes (YACs), 162