Tay-Sachs Disease
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Table of contents
- Copyright Pageiv
- Contentsvii
- Contributorsxv
- Prefacexix
- Chapter 1. Tay-Sachs Disease: From Clinical Description to Molecular Defect1
- I. Introduction1
- II. 1880–1960: Clinical, Pathologic, and Genetic Advances2
- III. 1960–1980: Lysosomes, Biochemical Defect, Prospective Prevention3
- IV. 1980–present: The Molecular Era and Therapeutic Horizons5
- V. Conclusion6
- References7
- Chapter 2. Barney Sachs and The History of the Neuropathologic Description of Tay-Sachs Disease11
- Chapter 3. Early Epidemiologic Studies of Tay-Sachs Disease25
- Chapter 4. Identification of the Accumulated Ganglioside33
- I. Substance X and Ganglioside33
- II. N-Acetylgalactosamine is a Ganglioside Component34
- III. Strandin35
- IV. Chromatographic Separation of Gangliosides36
- V. Thin-Layer Chromatography„The Method of Choice for Studies of Ganglioside Structure37
- VI. Tay-Sachs Ganglioside38
- References40
- Chapter 5. Discovery of the Hexosaminidase Isoenzymes43
- I. Introduction43
- II. Fluorigenic Substrates44
- III. Mammalian Glycosidases45
- IV. Hexosaminidases46
- V. Differential Assay for Hexosaminidases A and B47
- VI. Structural Relationship Between Hexosaminidases A and B48
- References48
- Chapter 6. Tay-Sachs Disease: The Search for the Enzymatic Defect51
- I. Historical Overview51
- II. Applications58
- References59
- Chapter 7. Discovery of b -Hexosaminidase A Deficiency in Tay-Sachs Disease61
- I. Introduction61
- II. John S. O'Brien's Recollection62
- III. Shintaro Okada's Recollection62
- References66
- Chapter 8. The GM2-Gangliosidoses and the Elucidation of the b -Hexosaminidase System67
- I. Amaurotic Idiocy67
- II. Glycolipid Analysis of Brains with Amaurotic Idiocy68
- III. Tay-Sachs Disease with Visceral Involvement (Variant 0)70
- IV. Search for the Defect in Tay-Sachs Disease71
- V. Variant AB and the GM2-Activator Protein76
- VI. Variant B180
- VII. Clinical and Biochemical Heterogeneity of GM2 Gangliosidosis-Degree of Enzyme Deficiency and De83
- VIII. Addendum85
- References86
- Chapter 9. Subunit Structure of the Hexosaminidase Isozymes93
- I. Introduction93
- II. Antibodies Against Hexosaminidase95
- III. Unravelling the Subunit Structure Immunologically96
- IV. Converting Hexosaminidase A to Hexosaminidase B97
- V. Epilogue99
- References99
- Chapter 10. Molecular Genetics of the b -Hexosaminidase Isoenzymes: An Introduction101
- I. Personal Recollections102
- II. Biochemical Genetics of the Hexosaminidases104
- III. Evolution of Molecular Biology104
- IV. Analysis of DNA107
- V. Classification of Mutations108
- VI. Detection of known Mutations110
- VII. Screening for new Mutations111
- VIII. From Enzyme to Gene Structure112
- IX. Mutations in the GM2 gangliosidoses117
- X. Genetically Engineered Animal Models120
- XI. Conclusions121
- References121
- Chapter 11. Cloning the b-Hexosaminidase Genes127
- Chapter 12. The Search for the Genetic Lesion in Ashkenazi Jews with Classic Tay-Sachs Disease137
- Chapter 13. The b-Hexosaminidase Story in Toronto: From Enzyme Structure to Gene Mutation145
- I. Introduction146
- II. Structures of Hexosaminidase A and Hexosaminidase B146
- III. Isolation of cDNA Clones Coding for the A and B Chains148
- IV. Extensive Homology Between the Deduced a and b Primary Structures149
- V. Posttranslational Processing of the Pre-Pro- A and Pre-Pro- B Chains149
- VI. Structure–function Relationships154
- VII. Molecular Heterogeneity in Tay-Sachs and Sandhoff Diseases157
- References160
- Chapter 14. Biosynthesis of Normal and Mutant b -Hexosaminidases165
- I. The Normal Biosynthetic Pathway165
- II. Biosynthesis of Mutant b -Hexosaminidases169
- References170
- Chapter 15. Recognition and Delineation of b -Hexosaminidase a -Chain Variants: A Historical and Per173
- I. At the Beginning173
- II. Increasing Complexity174
- III. Era of Molecular Genetics175
- IV. Evolution of B1 Variant176
- V. Genotype–phenotype Correlation180
- References182
- Chapter 16. Late-Onset Gm2 Gangliosidosis and Other Hexosaminidase Mutations among Jews185
- I. Adult Gm2 Gangliosidosis185
- II. Tay-Sachs Disease Among Moroccan Jews192
- III. Heat-Labile b -Hexosaminidase B and the Genotyping of Tay-Sachs Disease194
- References196
- Chapter 17. Naturally Occurring Mutations in GM2 Gangliosidosis: A Compendium199
- I. Introduction199
- II. b -Hexosaminidase A Mutations201
- III. b -Hexosaminidase B Mutations210
- IV. GM2A Mutations215
- V. Structure/Function Relationships of b -Hexosaminidase215
- References216
- Chapter 18. Targeting the Hexosaminidase Genes: Mouse Models of the GM2 Gangliosidoses225
- Chapter 19. Molecular Epidemiology of Tay-Sachs Disease233
- I. Introduction233
- II. Mutations and their Frequencies236
- III. The Demographic History of the Ashkenazim244
- IV. Statistical Modeling246
- V. Conclusion249
- References250
- Chapter 20. Screening and Prevention in Tay-Sachs Disease: Origins, Update, and Impact253
- I. Program Origins: The Place253
- II. The Events and the People254
- III. The Program is Conceived256
- IV. From Baltimore to Jerusalem257
- V. Results and Update257
- VI. Impact and Conclusion259
- References260
- Appendix 1261
- Chapter 21. Not Preventing„Yet, Just Avoiding Tay-Sachs Disease267
- I. Introduction267
- II. Context268
- III. The Patient with the Disease268
- IV. Strategies to Avoid Tay-Sachs Disease270
- V. Tay-Sachs Disease Carrier Testing: an Illustration of "community Genetics’271
- VI. Conclusion272
- References273
- Chapter 22. Experiences in Molecular-Based Prenatal Screening for Ashkenazi Jewish Genetic Diseases275
- I. Introduction276
- II. Common Recessive Diseases in the Ashkenazim277
- III. Sensitivity of Enzymatic and DNA-Based Carrier Screening281
- IV. Experience with Multiple-Option Prenatal Carrier Screening282
- V. Rationale for Multiple-Option Carrier Screening283
- VI. Strategy for Multiple-Option Carrier Screening284
- VII. Enzyme and DNA Testing285
- VIII. Demographics and Test Acceptance285
- IX. Frequency of Detected Carriers286
- X. Detected Carrier Couples Choose Prenatal Diagnosis287
- XI. Importance of Educational Intervention287
- XII. Group Counseling Preferred288
- XIII. Couple Screening Reduces Anxiety288
- XIV. Acceptance and Selection of Prenatal Screening Tests289
- XV. Confidentiality Issues290
- XVI. Lessons Learned and Future Prospects290
- XVII. Type A Niemann-Pick Disease Detectability and Carrier Frequency in the Ashkenazi Population291
- XVIII. Canavan Disease Detectability and Carrier Frequency in The Ashkenazi Population291
- XIX. Multiple-Option Carrier Screening for Five Disorders292
- XX. Summary293
- References294
- Chapter 23. The Dor Yeshorim Story: Community-Based Carrier Screening for Tay-Sachs Disease297
- I. Introduction298
- II. Understanding a Community at Risk298
- III. Early Efforts at Screening301
- IV. Mechanics of the Premarital, Anonymous Screening Program302
- V. Findings and Accomplishments305
- VI. Research308
- VII. Can the Dor Yeshorim Model Be Applied to Other Communities?308
- VIII. Analytical Laboratories309
- References310
- Chapter 24. Tay-Sachs Disease and Preimplantation Genetic Diagnosis311
- I. Tay-Sachs Disease311
- II. Preimplantation Genetic Diagnosis312
- References314
- Chapter 25. Treatment of GM2 Gangliosidosis: Past Experiences, Implications, and Future Prospects317
- I. Introduction317
- II. Early Enzyme Infusion Trials318
- III. Studies In Gm2 Gangliosidosis Cats321
- IV. Cell Targeting of Hexosaminidase A322
- V. TTC-HEX A and Neuronal Storage324
- VI. Implications and Open Questions326
- VII. Bone Marrow Transplantation and Enzyme Secretion327
- VIII. Delivery of Macromolecules to the Brain Parenchyma329
- IX. CNS Gene Therapy330
- X. Conclusions332
- References333
- Chapter 26. Tay-Sachs Disease: Psychologic Care of Carriers and Affected Families341
- Chapter 27. Future Perspectives for Tay-Sachs Disease349
- I. Introduction349
- II. Substrate Deprivation350
- III. Chemical Chaperones351
- IV. Stem Cells351
- V. Oligonucleotide Recombination352
- VI. Genetic Counseling and Psychosocial Support352
- VII. Prevention353
- References354
- Index357
Tay-Sachs disease is a rare hereditary disease caused by a genetic mutation that leaves the body unable to produce an enzyme necessary for fat metabolism in nerve cells, producing central nervous system degeneration. In infants, it is characterized by progressive mental deterioration, blindness, paralysis, epileptic seizures, and death by age four. Adult-onset Tay-Sachs occurs in persons who have a genetic mutation that is similar but allows some production of the missing enzyme. There is no treatment for Tay-Sachs.
A test to determine whether an infant is carrying the Tay-Sachs disease was introduced in 1969. However, work continues to be done to help find a cure. Because there is no cure for this deadly disease, genetic research is essential.
Advances in Genetics presents an eclectic mix of articles of use to all human and molecular geneticists. They are written and edited by recognized leaders in the field and make this an essential series of books for anyone in the genetics field.
A test to determine whether an infant is carrying the Tay-Sachs disease was introduced in 1969. However, work continues to be done to help find a cure. Because there is no cure for this deadly disease, genetic research is essential.
Advances in Genetics presents an eclectic mix of articles of use to all human and molecular geneticists. They are written and edited by recognized leaders in the field and make this an essential series of books for anyone in the genetics field.