Analysis of Triplet Repeat Disorders is aimed at clinicians and scientists who work with these diseases or who have an interest in the field. Using the clinical picture of these diseases as a starting point, the book reviews and integrates the current understanding of their molecular pathologies, the genotype-phenotype relationships, the mutational processes of trinucleotide repeats, and the laboratory and clinical issues relating to genetic testing for these disorders.
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'This is the sort of book that can de dipped into to read about a particular subject matter. The volume of the text in this book makes this a managable reference book.' - Cambridge Journals
Contributors ix Abbreviations xii Preface xiv Foreword xv Introduction. 1(12) D.C. Rubinsztein M.R. Hayden Non-Mendelian inheritance 2(1) Trinucleotide repeat diseases -- overview 2(8) Conclusions 10(1) References 10(3) The FRAXA fragile site and fragile X syndrome. 13(38) E.E. Eichler D.L. Nelson Introduction 13(1) Clinical aspects 14(4) Historical aspects 18(5) The fragile X mutation 23(9) The FMRI gene 32(7) Summary 39(1) References 39(12) Molecular studies of the fragile sites FRAXE and FRAXF. 51(10) J.A. Skinner G.S. Foss W.J. Miller K.E. Davies Introduction 51(1) The FRAXE trinucleotide repeats 51(1) Expansion and transmission of the FRAXE trinucleotide repeat 52(1) Molecular diagnosis of FRAXE 53(1) Prevalence of FRAXE expansion 53(1) Clinical phenotype of FRAXE individuals 54(1) Patient management 55(1) Identification of the gene FMR2 associated with FRAXE 55(1) The FRAXF trinucleotide repeat 56(2) Summary 58(1) References 58(3) Myotonic dystrophy. 61(24) M. Hamshere E. Newman M. Alwazzan J.D. Brook Introduction 61(1) Epidemiology and prevelance 61(1) Clinical features 62(3) Evidence for anticipation 65(1) Identification of the gene 66(1) DMPK: normal function of the protein 67(2) The mutation genotype/phenotype relationship 69(1) Molecular phenotype of DM 70(3) Three models for the molecular mechanism of DM 73(3) Mouse models 76(2) References 78(7) Spinobulbar muscular atrophy. 85(20) L.K. Beitel M.A. Trifiro L. Pinsky Introduction 85(1) Epidemiology and prevalence 86(1) Clinical features and natural history of SBMA 86(3) Laboratory features 89(2) Expression in carriers 91(1) Genetic features 91(2) Mutation and its relation to phenotype 93(1) Pathogenetic concepts 94(4) Management 98(1) Summary 98(1) References 99(6) Polyglutamine tract vs. protein context in SCA1 pathogenesis. 105(14) H.T. Orr H.Y. Zoghbi Introduction 105(1) Cellular localization studies of wild-type and mutant ataxin-1 106(1) Ataxin-1 interacting proteins 107(2) SCA1 transgenic mice develop a progressive neurological disease 109(4) The importance of protein context in SCA1 pathogenesis 113(2) References 115(4) Spinocerebellar ataxia type 2 (SCA2). 119(10) S.-M. Pulst Epidemiology 119(1) Identification of the SCA2 gene 119(1) cDNA sequence 120(7) References 127(2) Spinocerebellar ataxia type 3/Machado-Joseph disease. 129(16) H.L. Paulson History of SCA3/MJD: two names one disease 129(2) Clinical features 131(1) Pathological features 131(4) Molecular genetics of disease 135(4) Molecular mechanism of degeneration 139(2) References 141(4) Spinocerebellar ataxia type 6 (SCA6). 145(10) Cheng Chi Lee Introduction 145(1) The human α voltage-dependent Ca2+ channel 146(1) Allelic disorders of spinocerebellar ataxia type 6 (SCA6) 147(1) Clinical and pathological findings in SCA6 patients 148(1) Ethnic frequency, age-of-onset and CAG repeat length 149(1) Clinical anticipation and transmission stability of expanded SCA6 allele 150(1) Summary 150(1) References 151(4) Spinocerebellar ataxia type 7 (SCA7). 155(14) G. Stevanin G. David N. Abbas A. Durr M. Holmberg C. Duyckaerts P. Giunti G. Cancel M. Ruberg J.-L. Mandel A. Brice Introduction 155(1) Clinical and neuropathological features 155(2) Genetics and epidemiology 157(1) Identification of the SCA7 gene and the unstable mutation 158(1) Analysis of the CAG repeat sequence 159(2) Phenotype-genotype correlations 161(1) Intermediate alleles and new mutations to SCA7 162(2) Pathophysiology of SCA7 164(1) Summary 165(1) References 166(3) Huntingtons Disease. 169(40) C.A. Ross M.R. Hayden Clinical features of Huntingtons disease 169(2) The genetic aetiology of HD 171(1) Diagnosis of HD 172(1) The genetics of HD 173(6) Pathology of HD 179(2) Targeted gene deletions: insights into the role of the normal gene 181(1) Biochemistry and cell biology 182(1) Interacting proteins 183(1) Neurotoxicity 184(1) Polyglutamine 185(1) In vitro studies to understand the pathogenesis of HD 185(3) Transgenic animal models 188(1) Studies of human post-mortem brains 189(1) A model connecting aggregates and cell death 190(1) References 191(18) Dentatorubral-pallidoluysian atrophy (DRLPA). 209(10) S. Tsuji Introduction 209(1) Molecular genetics of DRPLA 210(1) Clinical features of DRPLA and the genotype-phenotype correlation 211(2) Molecular basis of genetic anticipation 213(1) Mechanisms of neurodegeneration caused by CAG repeat expansion 213(2) References 215(4) Friedreichs ataxia. 219(20) M. Koenig Introduction and history 219(1) Clincal aspects 219(4) Identification of the Friedriechs ataxia gene 223(3) Analysis of the GAA trinucleotide expansion 226(4) A mitochondrial function for frataxin 230(3) Conclusions 233(1) References 234(5) Anticipation, triplet repeats and psychiatric disorders. 239(18) M.G. McInnis R. L. Margolis Introduction 239(1) Psychiatric disorders and anticipation 240(4) Does anticipation in psychiatric disorders derive from trinucleotide repeat expansions? 244(4) Conclusion 248(1) References 249(8) Trinucleotide repeat mutation processes. 257(12) D.C. Rubinsztein B. Amos Introduction 257(1) General principles, features of microsatellite mutations 257(4) Mutations at triplet repeat disease loci 261(3) Conclusions 264(1) References 265(4) Diagnostic testing for trinucleotide repeat diseases. 269(36) B.W. Popovich F. Quan Introduction 269(1) Diagnostic techniques 270(2) An overview of testing strategies 272(1) Fragile X syndrome 273(4) FRAXE mental retardation 1 277(1) Myotonic dystrophy 278(2) Autosomal dominant cerebellar ataxias 280(5) Dentatorubralpallidoluysion atrophy 285(1) Huntingtons disease 286(3) Spinal bulbar muscular atrophy 289(1) Friedreichs ataxia 290(1) Summary 291(1) References 292(13) Predictive testing for trinucleotide repeat disorders. 305(20) D. Craufurd Introduction 305(1) Predictive testing by linkage analysis 306(1) Direct testing 306(1) Practical consequences 307(1) The psychological impact of predictive testing 308(2) Impact on family 310(1) Uptake of predictive testing 311(2) Guidelines for genetic counselling 313(2) Relevance of predictive test guidelines for diagnostic testing 315(1) Prenatal testing 316(2) Testing for other trinucleotide repeat disorders 318(2) References 320(5) Index 325
D. C. Rubinsztein (University of Cambridge, U.K.) (Volume editor) , M. R. Hayden (University of British Columbia, Vancouver, Canada) (Volume editor)
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