Tay-Sachs Disease (eBook)

Cover 1
Copyright Page 5
Contents 8
Contributors 16
Preface 20
Chapter 1. Tay-Sachs Disease: From Clinical Description to Molecular Defect 22
I. Introduction 22
II. 1880–1960: Clinical, Pathologic, and Genetic Advances 23
III. 1960–1980: Lysosomes, Biochemical Defect, Prospective Prevention 24
IV. 1980–present: The Molecular Era and Therapeutic Horizons 26
V. Conclusion 27
References 28
Chapter 2. Barney Sachs and The History of the Neuropathologic Description of Tay-Sachs Disease 32
Chapter 3. Early Epidemiologic Studies of Tay-Sachs Disease 46
Chapter 4. Identification of the Accumulated Ganglioside 54
I. Substance X and Ganglioside 54
II. N-Acetylgalactosamine is a Ganglioside Component 55
III. Strandin 56
IV. Chromatographic Separation of Gangliosides 57
V. Thin-Layer Chromatography„The Method of Choice for Studies of Ganglioside Structure 58
VI. Tay-Sachs Ganglioside 59
References 61
Chapter 5. Discovery of the Hexosaminidase Isoenzymes 64
I. Introduction 64
II. Fluorigenic Substrates 65
III. Mammalian Glycosidases 66
IV. Hexosaminidases 67
V. Differential Assay for Hexosaminidases A and B 68
VI. Structural Relationship Between Hexosaminidases A and B 69
References 69
Chapter 6. Tay-Sachs Disease: The Search for the Enzymatic Defect 72
I. Historical Overview 72
II. Applications 79
References 80
Chapter 7. Discovery of b -Hexosaminidase A Deficiency in Tay-Sachs Disease 82
I. Introduction 82
II. John S. O'Brien's Recollection 83
III. Shintaro Okada's Recollection 83
References 87
Chapter 8. The GM2-Gangliosidoses and the Elucidation of the b -Hexosaminidase System 88
I. Amaurotic Idiocy 88
II. Glycolipid Analysis of Brains with Amaurotic Idiocy 89
III. Tay-Sachs Disease with Visceral Involvement (Variant 0) 91
IV. Search for the Defect in Tay-Sachs Disease 92
V. Variant AB and the GM2-Activator Protein 97
VI. Variant B1 101
VII. Clinical and Biochemical Heterogeneity of GM2 Gangliosidosis-Degree of Enzyme Deficiency and Development of Different Clinical Syndromes 104
VIII. Addendum 106
References 107
Chapter 9. Subunit Structure of the Hexosaminidase Isozymes 114
I. Introduction 114
II. Antibodies Against Hexosaminidase 116
III. Unravelling the Subunit Structure Immunologically 117
IV. Converting Hexosaminidase A to Hexosaminidase B 118
V. Epilogue 120
References 120
Chapter 10. Molecular Genetics of the b -Hexosaminidase Isoenzymes: An Introduction 122
I. Personal Recollections 123
II. Biochemical Genetics of the Hexosaminidases 125
III. Evolution of Molecular Biology 125
IV. Analysis of DNA 128
V. Classification of Mutations 129
VI. Detection of known Mutations 131
VII. Screening for new Mutations 132
VIII. From Enzyme to Gene Structure 133
IX. Mutations in the GM2 gangliosidoses 138
X. Genetically Engineered Animal Models 141
XI. Conclusions 142
References 142
Chapter 11. Cloning the b-Hexosaminidase Genes 148
Chapter 12. The Search for the Genetic Lesion in Ashkenazi Jews with Classic Tay-Sachs Disease 158
Chapter 13. The b-Hexosaminidase Story in Toronto: From Enzyme Structure to Gene Mutation 166
I. Introduction 167
II. Structures of Hexosaminidase A and Hexosaminidase B 167
III. Isolation of cDNA Clones Coding for the A and B Chains 169
IV. Extensive Homology Between the Deduced a and b Primary Structures 170
V. Posttranslational Processing of the Pre-Pro- A and Pre-Pro- B Chains 170
VI. Structure–function Relationships 175
VII. Molecular Heterogeneity in Tay-Sachs and Sandhoff Diseases 178
References 181
Chapter 14. Biosynthesis of Normal and Mutant b -Hexosaminidases 186
I. The Normal Biosynthetic Pathway 186
II. Biosynthesis of Mutant b -Hexosaminidases 190
References 191
Chapter 15. Recognition and Delineation of b -Hexosaminidase a -Chain Variants: A Historical and Personal Perspective 194
I. At the Beginning 194
II. Increasing Complexity 195
III. Era of Molecular Genetics 196
IV. Evolution of B1 Variant 197
V. Genotype–phenotype Correlation 201
References 203
Chapter 16. Late-Onset Gm2 Gangliosidosis and Other Hexosaminidase Mutations among Jews 206
I. Adult Gm2 Gangliosidosis 206
II. Tay-Sachs Disease Among Moroccan Jews 213
III. Heat-Labile b -Hexosaminidase B and the Genotyping of Tay-Sachs Disease 215
References 217
Chapter 17. Naturally Occurring Mutations in GM2 Gangliosidosis: A Compendium 220
I. Introduction 220
II. b -Hexosaminidase A Mutations 222
III. b -Hexosaminidase B Mutations 231
IV. GM2A Mutations 236
V. Structure/Function Relationships of b -Hexosaminidase 236
References 237
Chapter 18. Targeting the Hexosaminidase Genes: Mouse Models of the GM2 Gangliosidoses 246
Chapter 19. Molecular Epidemiology of Tay-Sachs Disease 254
I. Introduction 254
II. Mutations and their Frequencies 257
III. The Demographic History of the Ashkenazim 265
IV. Statistical Modeling 267
V. Conclusion 270
References 271
Chapter 20. Screening and Prevention in Tay-Sachs Disease: Origins, Update, and Impact 274
I. Program Origins: The Place 274
II. The Events and the People 275
III. The Program is Conceived 277
IV. From Baltimore to Jerusalem 278
V. Results and Update 278
VI. Impact and Conclusion 280
References 281
Appendix 1 282
Chapter 21. Not Preventing„Yet, Just Avoiding Tay-Sachs Disease 288
I. Introduction 288
II. Context 289
III. The Patient with the Disease 289
IV. Strategies to Avoid Tay-Sachs Disease 291
V. Tay-Sachs Disease Carrier Testing: an Illustration of "community Genetics’ 292
VI. Conclusion 293
References 294
Chapter 22. Experiences in Molecular-Based Prenatal Screening for Ashkenazi Jewish Genetic Diseases 296
I. Introduction 297
II. Common Recessive Diseases in the Ashkenazim 298
III. Sensitivity of Enzymatic and DNA-Based Carrier Screening 302
IV. Experience with Multiple-Option Prenatal Carrier Screening 303
V. Rationale for Multiple-Option Carrier Screening 304
VI. Strategy for Multiple-Option Carrier Screening 305
VII. Enzyme and DNA Testing 306
VIII. Demographics and Test Acceptance 306
IX. Frequency of Detected Carriers 307
X. Detected Carrier Couples Choose Prenatal Diagnosis 308
XI. Importance of Educational Intervention 308
XII. Group Counseling Preferred 309
XIII. Couple Screening Reduces Anxiety 309
XIV. Acceptance and Selection of Prenatal Screening Tests 310
XV. Confidentiality Issues 311
XVI. Lessons Learned and Future Prospects 311
XVII. Type A Niemann-Pick Disease Detectability and Carrier Frequency in the Ashkenazi Population 312
XVIII. Canavan Disease Detectability and Carrier Frequency in The Ashkenazi Population 312
XIX. Multiple-Option Carrier Screening for Five Disorders 313
XX. Summary 314
References 315
Chapter 23. The Dor Yeshorim Story: Community-Based Carrier Screening for Tay-Sachs Disease 318
I. Introduction 319
II. Understanding a Community at Risk 319
III. Early Efforts at Screening 322
IV. Mechanics of the Premarital, Anonymous Screening Program 323
V. Findings and Accomplishments 326
VI. Research 329
VII. Can the Dor Yeshorim Model Be Applied to Other Communities? 329
VIII. Analytical Laboratories 330
References 331
Chapter 24. Tay-Sachs Disease and Preimplantation Genetic Diagnosis 332
I. Tay-Sachs Disease 332
II. Preimplantation Genetic Diagnosis 333
References 335
Chapter 25. Treatment of GM2 Gangliosidosis: Past Experiences, Implications, and Future Prospects 338
I. Introduction 338
II. Early Enzyme Infusion Trials 339
III. Studies In Gm2 Gangliosidosis Cats 342
IV. Cell Targeting of Hexosaminidase A 343
V. TTC-HEX A and Neuronal Storage 345
VI. Implications and Open Questions 347
VII. Bone Marrow Transplantation and Enzyme Secretion 348
VIII. Delivery of Macromolecules to the Brain Parenchyma 350
IX. CNS Gene Therapy 351
X. Conclusions 353
References 354
Chapter 26. Tay-Sachs Disease: Psychologic Care of Carriers and Affected Families 362
Chapter 27. Future Perspectives for Tay-Sachs Disease 370
I. Introduction 370
II. Substrate Deprivation 371
III. Chemical Chaperones 372
IV. Stem Cells 372
V. Oligonucleotide Recombination 373
VI. Genetic Counseling and Psychosocial Support 373
VII. Prevention 374
References 375
Index 378