Fabry Disease (eBook)

Deborah Elstein, Gheona Altarescu, Michael Beck (Herausgeber)

eBook Download: PDF

2010 | 2010
XXXVII, 512 Seiten
Springer Netherland (Verlag)
978-90-481-9033-1 (ISBN)

Infos

Fabry disease is an X-linked inborn error of metabolism wherein deficiency of a lysosomal enzyme results in systemic deposition of glycosphingolipids. Storage deposition, and hence pathological disease, occurs preferentially in renal glomerular and tubular epithelial cells, myocardial cells, heart valve fibrocytes, neurons of dorsal root ganglia, and in endothelial smooth muscle cells of blood vessels. Thus, Fabry disease is a multi-system disorder, albeit with considerable phenotypic heterogeneity in onset and in severity; however, it is progressive, exhibits extensive morbidity, and is life-threatening. Within the past two decades, there has been a radical change in the natural course Fabry disease by virtue of the availability of specific enzyme replacement therapy. Moreover, there has been a concerted effort to better understand the underlying pathology and equally to identify patients prior to the onset of irreversible end-organ damage. It is to be hoped that the future for patients with Fabry disease can be viewed with greater, albeit guarded, optimism. This state-of-the-art textbook attempts to bridge the span of pre-clinical studies, clinical finding, and management options in a readable but comprehensive manner for the medical practitioner as well as the interested non-medical reader.

Inhalt

Contents 7
Contributors 10
Fabry Disease – An Overview 15
Major Signs and Symptoms 15
Pathological Biochemistry 15
Pathophysiology 17
Therapy 18
Enzyme Replacement 18
Molecular Chaperone Therapy 20
Substrate Reduction Therapy 20
Gene Therapy 20
The Future 21
References 21
Fabry Disease A Patient Perspective 24
Part I Preclinical 33
1 Molecular Genetics of Fabry Disease andGenotype--Phenotype Correlation 34
1.1 The GLA Gene Encodes -Galactosidase A 35
1.1.1 General Classification and Nomenclature of Mutations 35
1.1.2 GLA Mutations in Fabry Disease 36
1.1.3 De Novo Mutations 39
1.1.4 Molecular Genetic Bases of Fabry Disease in Females 41
1.2 Genotype--Phenotype Correlation 42
1.2.1 Classic Phenotype and GLA Mutations 42
1.2.2 Residual Enzyme Activity and Genotype--Phenotype Correlation 44
1.2.3 Molecular Genetics of the Variant Fabry Phenotypes 45
2 The Structure of Human -Galactosidase A and Implications for Fabry Disease 51
2.1 Overview of the Structure 51
2.2 Active Site and Ligand Binding 53
2.3 Catalytic Mechanism 55
2.4 Fabry Disease Mutations 56
References 21
3 Subcellular, Cellular and Organ Pathology of Fabry Disease 69
3.1 Biological Introduction to Structural Findings (Biological Background of the Storage) 69
3.2 Storage Lysosome and Storage Cell in a-Gal Deficiency 70
3.2.1 Storage Lysosome 70
3.2.1.1 Histochemistry and Biochemistry of Stored Lipids 70
3.2.1.2 Ultrastructure 71
3.2.1.3 Autofluorescent Residual Bodies 73
3.2.1.4 Biology of the Storage Lysosome 75
3.2.1.5 Integrity of the Limiting Membrane of the Storage Lysosome 75
3.2.1.6 Shape of the Storage Lysosome 75
3.2.2 Storage Cell--Cell with Altered Biology (Not Only in Fabry Disease) 76
3.3 Cell Types Expressing Storage in a-Gal Deficiency 77
3.4 Organ Pathology 82
3.4.1 Pathology of Blood and Lymphatic Vessels 82
3.4.1.1 Pathology of Blood Vessels 82
3.4.1.2 Pathology of Lymphatic Vessels and Lymph Nodes 84
3.4.2 Pathology of the Skin 85
3.4.3 Pathology of the Heart 88
3.4.4 Pathology of the Kidney 92
3.4.5 Neuropathology 94
3.4.6 Pathology of the Lung 96
3.4.7 Pathology of the Gastrointestinal System 98
3.4.8 Pathology of the Senses 100
3.4.8.1 Cochleovestibular Apparatus 100
3.4.8.2 Ocular Pathology 100
References 101
4 Biochemistry of Fabry Disease 110
4.1 Introduction 110
4.2 Sphingolipids and Their Physiological Importance 111
4.3 Pathobiochemistry of Glycosphingolipid Substrates of -Galactosidase A 113
4.4 Biosynthesis, Degradation and Trafficking of Sphingolipids Involved in Pathology of Fabry Disease 117
4.5 Human -Galactosidases: -Galactosidase A and B 119
4.6 a-Galactosidase A (GLA) 120
4.7 Mutant a-Galactosidases A 122
4.8 Saposin B 123
4.9 a-N-Acetylgalactosaminidase (NAGA) 124
4.10 Other Findings 125
4.11 Conclusion 126
References 126
5 Clinically Relevant Examplesof Genotype--Phenotype Correlation 134
5.1 Introduction: Genotyping 134
5.2 Genetic Misdiagnosis and Phenotypic Presentation 135
5.3 Modifier Genes: Cerebral Lesions 136
5.4 Modifier Genes: Vasculopathy 136
5.5 Modifier Genes: Cardiac Left Ventricular Hypertrophy 137
5.6 Summary: Epigenetic Genotype--Phenotype Correlations 137
References 137
6 Laboratory Diagnosis of Fabry Disease 139
6.1 Introduction 139
6.2 Enzymatic Diagnosis Using Plasma/Serum or Leukocytes 140
6.2.1 Practical Aspects 140
6.2.2 a-Galactosidase A Activity in Plasma/Serum and Leukocytes 141
6.3 The Role of DNA Analysis in the Diagnosis of Fabry Disease 142
6.3.1 Identification of Mutations 142
6.3.2 Effect of Genetic Variation on the Diagnosis of Fabry Disease 144
6.3.3 Confirmation of Diagnosis, Detection of Carriers and Genetic Counselling 144
6.4 The Role of Measurement of Storage Products in Diagnosis 145
6.4.1 Methodology 145
6.4.2 Gb3 in Plasma 146
6.4.3 LysoGb3 in Plasma 147
6.4.4 Gb3 and Ga2 in Urine 148
6.5 Prenatal Diagnosis 149
6.6 Mass and High-Risk Screening for Fabry Disease 150
6.6.1 Measurement of a-Galactosidase A Activity in Dried Blood Spots 150
6.6.2 Screening for Fabry Disease by Measuring the Storage Products in Urine Collected on Filter Paper 152
6.6.3 Protein Profiling 152
6.6.4 DNA from Bloodspots 153
6.7 Conclusions 153
References 154
7 Biomarkers for Fabry Disease 161
7.1 Introduction 161
7.1.1 Molecular Basis of Fabry Disease 161
7.1.2 Enzyme Replacement Therapy of Fabry Disease 162
7.1.3 Heterogeneous Manifestation and Early Detection of Fabry Disease 163
7.2 Biomarkers 164
7.2.1 Definition 164
7.2.2 Nature and Application of Biomarkers 164
7.3 Nature, Discovery and Application of Biomarkers: Lessons from Gaucher Disease 164
7.3.1 Biomarkers of Gaucher Disease 164
7.3.2 Metabolite Biomarkers 165
7.3.3 Protein Biomarkers 165
7.3.3.1 Chitotriosidase 166
7.3.3.2 PARC/CCL18 and MIP-1Beta 166
7.3.4 Proteomics Search for Novel Biomarkers 167
7.3.5 Application of Biomarkers 168
7.4 Biomarkers for Fabry Disease 169
7.4.1 Lipid Abnormalities as Potential Biomarkers 169
7.4.1.1 Gb3 as Biomarker 169
7.4.1.2 Globotriaosylsphingosine (LysoGb3) 170
7.4.2 Protein Abnormalities as Potential Biomarkers 171
7.4.2.1 Markers of Endothelial Activation 172
7.4.2.2 Proteomics Investigations 172
7.4.3 Urinary Protein Abnormalities 173
7.4.4 Antibodies Towards Therapeutic Enzyme 174
7.5 Discussion and Conclusions 174
References 175
8 Fabry Disease Case Finding Studies in High-Risk Populations 181
8.1 Introduction 181
8.2 Kidney Disease 182
8.3 Heart Disease 182
8.4 Stroke 184
8.5 Summary 187
References 187
9 Small Molecule Drug Discovery for Fabry Disease 191
9.1 Introduction 191
9.2 Strategies for Drug Discovery and Drug Targets 192
9.3 The Process of Small Molecule Drug Discovery 194
9.4 Assay Development and HTS to Identify New GLA Inhibitors/Activators 195
9.5 Assay Validation 199
9.5.1 Test Screen 199
9.6 Full-Scale Compound Screen (HTS) 200
9.7 Confirmation and Secondary Screens 200
9.8 Tertiary Screens 201
9.9 Western Blot and Immunofluorescence Analysis of GLA in Cells 202
9.10 Probe Identification and Optimization 202
9.11 Further Testing in Animal Models 202
9.12 Conclusions 203
References 203
Part II Clinical 206
10 Clinical Manifestations of Fabry Disease: An Overview 207
10.1 Introduction 207
10.2 Prevalence 208
10.3 Registry Studies 209
10.4 Rarer Manifestations 210
10.5 Is the Natural History Changing? 210
10.6 GenotypePhenotype Correlations 211
References 211
11 The Heart in Fabry Disease from Pathogenesis to Enzyme Replacement Therapy 214
11.1 Introduction 214
11.2 Pathogenesis of the Cardiac Involvement 215
11.2.1 Cardiac Hypertrophy -- Hypertrophic Cardiomyopathy 218
11.2.2 Cardiac Systolic and Diastolic Function 220
11.2.3 Ischemia, Coronary Artery Disease and Coronary Flow Reserve 220
11.2.4 Arrhythmias and Electrophysiological Abnormalities 221
11.2.5 Autonomic Cardiac Control and Cardio Neuropathy 222
11.2.6 Valvular Involvement in Fabry Disease 222
11.2.7 Fabry Disease with the Main Manifestation in the Heart 223
11.2.8 Cardiac Involvement in Children 224
11.2.9 Clinical Signs and Symptoms 225
11.3 Treatment Options 226
11.3.1 Adjuvant Therapeutic Interventions 226
11.3.2 Enhancement of Enzyme Activity and Enzyme Replacement Therapy 227
11.3.2.1 Agalsidase Alfa 228
11.3.2.2 Agalsidase Beta 229
References 230
12 Renal Manifestations of Fabry Disease 236
12.1 Fabry Nephropathy 237
12.2 Diagnosis of Fabry Nephropathy 237
12.3 Clinical and Laboratory Manifestations of Fabry Nephropathy 238
12.4 The Epidemiology of Fabry Disease and Nephropathy 244
12.5 Phenotype/Genotype Correlations and Residual Enzyme Activity 246
12.6 The Renal and Cardiac Variant Phenotypes 246
12.7 Glycosphingolipid Accumulation in Fabry Nephropathy 249
12.8 Pathology of Fabry Nephropathy 250
12.9 Dysfunction of the Microcirculation in Fabry Disease 255
12.10 Progressive Loss of Glomerular Filtration in Fabry Nephropathy 257
12.11 Proteinuria, ERT and Progression of Fabry Nephropathy 258
12.12 Other Considerations for Treating Fabry Nephropathy 260
12.13 Treatment Goal for Fabry Nephropathy 260
References 260
13 Neurological Manifestations in Fabry Disease 269
13.1 Fabry Disease and the Brain 269
13.1.1 Cerebrovascular Disease 272
13.1.2 Classification of Stroke in Fabry Disease 273
13.1.3 Cerebrovascular Events in Women 275
13.1.4 Cerebrovascular Pathology in Fabry Disease and Enzyme Replacement Treatment 276
13.1.5 Fabry Disease Mimicking Multiple Sclerosis 277
13.1.6 Fabry Disease and Hearing 277
13.2 Peripheral Nervous System in Fabry Disease 278
References 279
14 Dermatological Manifestations of Fabry Disease 282
14.1 Cutaneous Vascular Lesions 283
14.1.1 Angiokeratoma 283
14.1.2 Other Cutaneous Vascular Lesions 284
14.1.3 Therapy 287
14.1.4 Relationship to Disease Severity 288
14.2 Facial Features 289
14.3 Raynaud's Phenomenon 290
14.4 Lower Limb Oedema and Lymphoedema 292
14.5 Abnormalities of Sweating 294
14.6 Summary 294
References 295
15 Histopathology of Skin in Fabry Disease 298
15.1 Introduction 298
15.2 Methodology 299
15.2.1 Biopsy Procedure 299
15.2.2 Electron Microscopy 300
15.2.3 Gb3 Immunocytochemistry 300
15.2.4 Epidermal Nerve Endings 300
15.3 Results 301
15.3.1 Histopathology of Clinically Normal Skin in Fabry Disease 301
15.3.2 Histopathology of Skin Lesions in Fabry Disease 307
15.3.3 Epidermal Nerve Endings in Fabry Disease 309
15.4 Summary 312
References 312
16 Bone and Muscle Involvement in Fabry Disease 316
16.1 Introduction 316
16.2 Skeletal Involvement in Fabry Disease 317
16.3 Muscular Involvement 318
16.4 Pathological Hypotheses 320
16.5 Conclusions 321
References 321
17 The Eye in Fabry Disease 322
17.1 Ocular Manifestations in Fabry Disease (FD) 322
17.1.1 Specific Ocular Abnormalities 322
17.1.2 Uncommom Ocular Findings 326
17.2 Clinical Interest of Ocular Abnormalities in FD 327
17.3 Technological Developments for the Study of Ocular Signs in FD 327
17.4 Summary 328
References 328
18 Pulmonary, Ear and Less Commonly AppreciatedManifestations 330
18.1 Fabry Disease and the Lung 330
18.1.1 Background 330
18.1.2 Aetiology 331
18.1.3 Pathophysiology 332
18.1.4 Treatment 332
18.2 Fabry Disease and the Ear 332
18.2.1 Epidemiology 333
18.2.2 Audiological Spectrum 334
18.2.3 Hearing Loss in Children 335
18.2.4 Pathogenesis and Disease Association 335
18.2.5 Response to Treatment 336
18.3 Less Commonly Appreciated Manifestations 336
18.3.1 Less Common Manifestations: Cognition 336
18.3.2 Less Common Manifestations: Dysmorphic Features 337
18.3.3 Less Common Manifestations: Gastrointestinal Disease 337
18.3.4 Less Common Manifestations: Psychosexual Disturbance 339
18.3.5 Less Common Manifestations: Spermatic Dysfunction 339
18.3.6 Less Common Manifestations: Endocrine Dysfunction 340
18.3.7 Less Common Manifestations: Bone Mineral Density 340
18.4 Conclusions 340
References 341
19 Neuropsychiatric Manifestations of AFD 344
19.1 Introduction 344
19.2 Neuro-Psychiatric Manifestations 345
19.3 Brain Imaging Studies 345
19.4 Summary 345
References 346
20 Genetic Counseling and Psychosocial Issues for Individuals and Their Families with Fabry Disease 348
20.1 Introduction 348
20.1.1 Definition of Genetic Counseling 349
20.1.2 A Multidisciplinary Approach is Best 349
20.2 X-Linked Inheritance Pattern 350
20.3 Family Health History 351
20.3.1 A Pedigree Has Multiple Functions 351
20.3.2 Standard Pedigree Symbols 353
20.4 Psychosocial Issues 353
20.5 Sexuality 353
20.6 Influence on Family 356
20.7 Trust in Health Professionals 357
20.8 Reproductive Options 357
20.8.1 Gamete Donation 358
20.8.2 Preimplantation Diagnosis 358
20.8.3 Prenatal Diagnosis 358
20.9 Potential Teratogenic Effects on Pregnancy 358
20.10 Summary 359
References 359
21 Fabry Disease in Females 361
21.1 Introduction 361
21.2 Pathology of Fabry Disease in Females 362
21.3 Diagnosis of Fabry Disease in Females 363
21.4 Prenatal Diagnosis 363
21.5 Clinical Manifestations of Fabry Disease in Females 364
21.6 Pain 364
21.7 Dermatological and Ophthalmological Findings 364
21.8 Gastrointestinal Manifestations 366
21.9 Cardiac Manifestations 366
21.10 Renal Failure 366
21.11 Neurovascular Complications 366
21.12 Quality of Life, Fatigue, and Depression 367
21.13 Survival 367
21.14 Enzyme Replacement Therapy (ERT) for Females with Fabry Disease 367
21.15 Clinical Trials 368
21.16 Observational Studies 368
21.17 ERT During Pregnancy and Lactation 369
21.18 Antibody Responses in Females 369
21.19 Which Females Should Receive ERT and When 370
21.20 Conclusions 370
References 371
22 Fabry Disease in Pediatric Patients 374
22.1 Introduction 374
22.2 Fabry Disease Clinical Manifestation 375
22.3 Fabry Pain and Acroparesthesis 375
22.4 Gastrointestinal Symptoms 377
22.5 Dermatological Findings 377
22.6 Angiokeratomas 378
22.7 Sweating Deficit 379
22.8 Eye Findings 380
22.9 Psycho-Social Issues 381
22.10 Renal Disease 382
22.11 Cardiac Disease 382
22.12 CNS/TIAs 382
22.13 Growth and Development 382
22.14 Others 383
22.15 Family History 383
22.16 Discussion 383
References 384
23 Experimental Studies in Mice on the Vasculopathyof Fabry Disease 386
23.1 Introduction 386
23.2 Vascular Disease and Dysregulation in Humans with Fabry Disease 387
23.3 Models of Vasculopathy in the Gla Knockout Mouse 388
23.3.1 Accelerated Thrombosis 388
23.3.2 Atherogenesis 389
23.3.3 Impaired Vasoreactivity 390
23.3.4 eNOS Dysregulation as the Common Link in the Three Models of Vasculopathy 391
23.4 Glycolipid Localization in Endothelial Cells 392
23.5 eNOS Activity and Regulation in Fabry Endothelia 393
23.5.1 Treatment of Gla--/0 Mice with D-Threo- Ethylenedioxyphenyl-P4 393
23.5.2 Decreased eNOS and Caveolin-1 in Gla Null Mouse Aortas 393
23.5.3 Impaired eNOS Activity 394
23.5.4 Oxidant Formation Secondary to eNOS Uncoupling 394
23.6 A Proposed Model for eNOS Uncoupling 395
23.7 Future Directions and Challenges 396
References 397
Part III Management 399
24 Overview 400
24.1 Enzyme Replacement Therapy 400
24.1.1 Clinical Trials 400
24.1.2 Limitations 402
24.2 Chaperones 402
24.3 Gene Therapy 404
24.3.1 In Vivo Gene Therapy 404
24.3.2 Ex Vivo Gene Therapy 405
References 405
25 Agalsidase Alfa in the Treatment of Anderson-Fabry Disease 408
25.1 Introduction 408
25.2 Agalsidase Alfa: Product Characteristics and Pharmacology 409
25.3 The Use of Agalsidase Alfa in Clinical Trials 410
25.4 The Use of Agalsidase Alfa in Postmarketing Studies 411
25.5 Agalsidase Alfa: Safety Considerations 413
25.6 Summary and Final Comments 414
References 416
26 Agalsidase Beta Clinical Trials and Long Term Experience 419
26.1 Introduction 419
26.2 Clinical Trials Agalsidase Beta 420
26.2.1 Cardiac Function in Response to Agalsidase Beta 423
26.2.2 Kidney Function in Response to Agalsidase Beta 424
26.2.3 Cerebrovascular Function in Response to Agalsidase Beta 425
26.2.4 Gastroenterology Function in Response to Agalsidase Beta 425
26.2.5 Pain and Quality of Life After Agalsidase Beta 426
26.2.6 Pulmonary Function in Response to Agalsidase Beta 427
26.3 Agalsidase Beta in Pediatric Patients with Fabry Disease 427
26.4 Agalsidase Beta in Women with Fabry Disease 428
26.4.1 Immune Response to Agalsidase Beta 429
26.4.2 Comparison Between Recombinant Forms of -gal A 430
26.5 Summary 430
References 431
27 Analyses of Agalsidase Alfa and Agalsidase Beta for the Treatment of Fabry Disease 434
27.1 Biochemical/Pharmacokinetic Properties 434
27.2 Analysis of Previous Clinical Trial Designs 436
27.3 Direct Comparisons of Agalsidase Alfa and Beta 439
27.3.1 Differential Clinical Effects of Agalsidase Alfa and Beta 442
27.3.1.1 Cardiac 442
27.3.1.2 Renal 443
27.3.1.3 Gastrointestinal 444
27.3.1.4 Central Nervous System Disease 444
27.3.1.5 Pain and Quality of Life 444
27.4 Conclusions 445
References 446
28 Enzyme Replacement Therapy in Children with Fabry Disease 450
28.1 Usefulness of Disease Severity Scores in Children 456
28.2 Home Therapy 460
28.3 Dosing Studies: Agalsidase Alfa and Agalsidase Beta 462
28.4 Discussion 464
References 467
29 Pharmacological Chaperone Therapy for Fabry Disease 472
29.1 Introduction 472
29.2 Lysosomal Enzyme Biosynthesis and ERAD 473
29.3 Misfolding Conformation in Missense -Galactosidase a Mutant Enzymes 475
29.4 Development of DGJ as a Pharmacological Chaperone for Fabry Disease 477
29.5 Preclinical Efficacy and Safety of DGJ in Mice 480
29.6 Clinical Development of DGJ 482
29.7 Outlook of PCT for the Treatment of Fabry Disease 483
References 484
30 Potential Factors Influencing Treatment Outcomes 486
30.1 Introduction 486
30.2 Patient Related Factors 487
30.2.1 General Patient Related Factors 487
30.2.2 Renal Disease 488
30.2.3 Cardiac Disease 489
30.2.4 Cerebral Disease 490
30.3 Product Related Factors 491
30.3.1 Dose of Agalsidase-Alfa and Agalsidase-Beta 491
30.3.2 Antibody Formation 492
30.4 Conclusions 493
References 494
31 Symptomatic and Ancillary Therapy 497
31.1 Supportive and Ancillary Therapy in Fabry Disease 497
31.2 Pain Relief 499
31.3 Kidney Function 499
31.4 Angiokeratomas 500
31.5 Lymphadenopathy 501
31.6 Pulmonary 501
31.7 Heart 501
31.8 Cerebrovascular 502
31.9 Psychiatric Signs and Symptoms 502
References 503
32 The Price of Care Versus the Cost of Caring 504
32.1 Introduction 504
32.2 Evidence of the Effectiveness of ERT of Fabry Disease 505
32.3 Cost-Effectiveness Analysis 506
32.4 Importance of Social Values 506
32.5 The Case of Rare Diseases 508
32.6 Non-medical Costs 508
32.7 Concluding Remarks 509
References 510
Summary: Fabry Disease, a Uniquely Different Lysosomal Storage Disorder 513
Introduction 513
Diagnosis 514
Clinical Features 515
Management 518
Summary 518
Fabry Patient Associations 519
Index 524

Produkt-Details

• Erscheint lt. Verlag: 2.8.2010
• Zusatzinfo: XXXVII, 512 p.
• Verlagsort: Dordrecht
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Themenwelt: Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
• Schlagworte: Blood vessel • Bone • Cells • Endothelium • Genetics • Metabolic disease • smooth muscle
• ISBN-10: 90-481-9033-9 / 9048190339
• ISBN-13: 978-90-481-9033-1 / 9789048190331