Elstein / Altarescu / Beck Fabry Disease

1. Auflage 2010
ISBN: 978-90-481-9033-1
Verlag: Springer Netherlands
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 512 Seiten

Reihe: Medicine (R0)

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.

Autoren/Hrsg.

Elstein, Deborah

Altarescu, Gheona

Beck, Michael

Inhaltsverzeichnis

1;Contents;7
2;Contributors;10
3;Fabry Disease – An Overview;15
3.1; Major Signs and Symptoms;15
3.2;Pathological Biochemistry;15
3.3;Pathophysiology;17
3.4;Therapy;18
3.4.1;Enzyme Replacement;18
3.4.2;Molecular Chaperone Therapy;20
3.4.3;Substrate Reduction Therapy;20
3.4.4;Gene Therapy;20
3.4.5;The Future;21
3.5;References;21
4;Fabry Disease A Patient Perspective;24
5;Part I Preclinical;33
5.1;1 Molecular Genetics of Fabry Disease andGenotype--Phenotype Correlation;34
5.1.1;1.1 The GLA Gene Encodes -Galactosidase A ;35
5.1.1.1;1.1.1 General Classification and Nomenclature of Mutations;35
5.1.1.2;1.1.2 GLA Mutations in Fabry Disease ;36
5.1.1.3;1.1.3 De Novo Mutations;39
5.1.1.4;1.1.4 Molecular Genetic Bases of Fabry Disease in Females;41
5.1.2;1.2 Genotype--Phenotype Correlation;42
5.1.2.1;1.2.1 Classic Phenotype and GLA Mutations ;42
5.1.2.2;1.2.2 Residual Enzyme Activity and Genotype--Phenotype Correlation;44
5.1.2.3;1.2.3 Molecular Genetics of the Variant Fabry Phenotypes;45
5.2;2 The Structure of Human -Galactosidase A and Implications for Fabry Disease;51
5.2.1;2.1 Overview of the Structure;51
5.2.2;2.2 Active Site and Ligand Binding;53
5.2.3;2.3 Catalytic Mechanism;55
5.2.4;2.4 Fabry Disease Mutations;56
5.2.5;References;21
5.3;3 Subcellular, Cellular and Organ Pathology of Fabry Disease;69
5.3.1;3.1 Biological Introduction to Structural Findings (Biological Background of the Storage);69
5.3.2;3.2 Storage Lysosome and Storage Cell in a-Gal Deficiency;70
5.3.2.1;3.2.1 Storage Lysosome;70
5.3.2.1.1;3.2.1.1 Histochemistry and Biochemistry of Stored Lipids;70
5.3.2.1.2;3.2.1.2 Ultrastructure;71
5.3.2.1.3;3.2.1.3 Autofluorescent Residual Bodies;73
5.3.2.1.4;3.2.1.4 Biology of the Storage Lysosome;75
5.3.2.1.5;3.2.1.5 Integrity of the Limiting Membrane of the Storage Lysosome;75
5.3.2.1.6;3.2.1.6 Shape of the Storage Lysosome;75
5.3.2.2;3.2.2 Storage Cell--Cell with Altered Biology (Not Only in Fabry Disease);76
5.3.3;3.3 Cell Types Expressing Storage in a-Gal Deficiency;77
5.3.4;3.4 Organ Pathology;82
5.3.4.1;3.4.1 Pathology of Blood and Lymphatic Vessels;82
5.3.4.1.1;3.4.1.1 Pathology of Blood Vessels;82
5.3.4.1.2;3.4.1.2 Pathology of Lymphatic Vessels and Lymph Nodes;84
5.3.4.2;3.4.2 Pathology of the Skin;85
5.3.4.3;3.4.3 Pathology of the Heart;88
5.3.4.4;3.4.4 Pathology of the Kidney;92
5.3.4.5;3.4.5 Neuropathology;94
5.3.4.6;3.4.6 Pathology of the Lung;96
5.3.4.7;3.4.7 Pathology of the Gastrointestinal System;98
5.3.4.8;3.4.8 Pathology of the Senses;100
5.3.4.8.1;3.4.8.1 Cochleovestibular Apparatus;100
5.3.4.8.2;3.4.8.2 Ocular Pathology;100
5.3.5;References;101
5.4;4 Biochemistry of Fabry Disease;110
5.4.1;4.1 Introduction;110
5.4.2;4.2 Sphingolipids and Their Physiological Importance;111
5.4.3;4.3 Pathobiochemistry of Glycosphingolipid Substrates of -Galactosidase A;113
5.4.4;4.4 Biosynthesis, Degradation and Trafficking of Sphingolipids Involved in Pathology of Fabry Disease;117
5.4.5;4.5 Human -Galactosidases: -Galactosidase A and B;119
5.4.6;4.6 a-Galactosidase A (GLA);120
5.4.7;4.7 Mutant a-Galactosidases A;122
5.4.8;4.8 Saposin B;123
5.4.9;4.9 a-N-Acetylgalactosaminidase (NAGA);124
5.4.10;4.10 Other Findings;125
5.4.11;4.11 Conclusion;126
5.4.12;References;126
5.5;5 Clinically Relevant Examplesof Genotype--Phenotype Correlation;134
5.5.1;5.1 Introduction: Genotyping;134
5.5.2;5.2 Genetic Misdiagnosis and Phenotypic Presentation;135
5.5.3;5.3 Modifier Genes: Cerebral Lesions;136
5.5.4;5.4 Modifier Genes: Vasculopathy;136
5.5.5;5.5 Modifier Genes: Cardiac Left Ventricular Hypertrophy;137
5.5.6;5.6 Summary: Epigenetic Genotype--Phenotype Correlations;137
5.5.7;References;137
5.6;6 Laboratory Diagnosis of Fabry Disease;139
5.6.1;6.1 Introduction;139
5.6.2;6.2 Enzymatic Diagnosis Using Plasma/Serum or Leukocytes;140
5.6.2.1;6.2.1 Practical Aspects;140
5.6.2.2;6.2.2 a-Galactosidase A Activity in Plasma/Serum and Leukocytes ;141
5.6.3;6.3 The Role of DNA Analysis in the Diagnosis of Fabry Disease;142
5.6.3.1;6.3.1 Identification of Mutations;142
5.6.3.2;6.3.2 Effect of Genetic Variation on the Diagnosis of Fabry Disease;144
5.6.3.3;6.3.3 Confirmation of Diagnosis, Detection of Carriers and Genetic Counselling;144
5.6.4;6.4 The Role of Measurement of Storage Products in Diagnosis;145
5.6.4.1;6.4.1 Methodology;145
5.6.4.2;6.4.2 Gb3 in Plasma;146
5.6.4.3;6.4.3 LysoGb3 in Plasma;147
5.6.4.4;6.4.4 Gb3 and Ga2 in Urine ;148
5.6.5;6.5 Prenatal Diagnosis;149
5.6.6;6.6 Mass and High-Risk Screening for Fabry Disease;150
5.6.6.1;6.6.1 Measurement of a-Galactosidase A Activity in Dried Blood Spots;150
5.6.6.2;6.6.2 Screening for Fabry Disease by Measuring the Storage Products in Urine Collected on Filter Paper;152
5.6.6.3;6.6.3 Protein Profiling;152
5.6.6.4;6.6.4 DNA from Bloodspots;153
5.6.7;6.7 Conclusions;153
5.6.8;References;154
5.7;7 Biomarkers for Fabry Disease;161
5.7.1;7.1 Introduction;161
5.7.1.1;7.1.1 Molecular Basis of Fabry Disease;161
5.7.1.2;7.1.2 Enzyme Replacement Therapy of Fabry Disease;162
5.7.1.3;7.1.3 Heterogeneous Manifestation and Early Detection of Fabry Disease;163
5.7.2;7.2 Biomarkers;164
5.7.2.1;7.2.1 Definition;164
5.7.2.2;7.2.2 Nature and Application of Biomarkers;164
5.7.3;7.3 Nature, Discovery and Application of Biomarkers: Lessons from Gaucher Disease;164
5.7.3.1;7.3.1 Biomarkers of Gaucher Disease;164
5.7.3.2;7.3.2 Metabolite Biomarkers;165
5.7.3.3;7.3.3 Protein Biomarkers;165
5.7.3.3.1;7.3.3.1 Chitotriosidase;166
5.7.3.3.2;7.3.3.2 PARC/CCL18 and MIP-1Beta;166
5.7.3.4;7.3.4 Proteomics Search for Novel Biomarkers;167
5.7.3.5;7.3.5 Application of Biomarkers;168
5.7.4;7.4 Biomarkers for Fabry Disease;169
5.7.4.1;7.4.1 Lipid Abnormalities as Potential Biomarkers;169
5.7.4.1.1;7.4.1.1 Gb3 as Biomarker;169
5.7.4.1.2;7.4.1.2 Globotriaosylsphingosine (LysoGb3);170
5.7.4.2;7.4.2 Protein Abnormalities as Potential Biomarkers;171
5.7.4.2.1;7.4.2.1 Markers of Endothelial Activation;172
5.7.4.2.2;7.4.2.2 Proteomics Investigations;172
5.7.4.3;7.4.3 Urinary Protein Abnormalities;173
5.7.4.4;7.4.4 Antibodies Towards Therapeutic Enzyme;174
5.7.5;7.5 Discussion and Conclusions;174
5.7.6;References;175
5.8;8 Fabry Disease Case Finding Studies in High-Risk Populations;181
5.8.1;8.1 Introduction;181
5.8.2;8.2 Kidney Disease;182
5.8.3;8.3 Heart Disease;182
5.8.4;8.4 Stroke;184
5.8.5;8.5 Summary;187
5.8.6;References;187
5.9;9 Small Molecule Drug Discovery for Fabry Disease;191
5.9.1;9.1 Introduction;191
5.9.2;9.2 Strategies for Drug Discovery and Drug Targets;192
5.9.3;9.3 The Process of Small Molecule Drug Discovery;194
5.9.4;9.4 Assay Development and HTS to Identify New GLA Inhibitors/Activators;195
5.9.5;9.5 Assay Validation;199
5.9.5.1;9.5.1 Test Screen;199
5.9.6;9.6 Full-Scale Compound Screen (HTS);200
5.9.7;9.7 Confirmation and Secondary Screens;200
5.9.8;9.8 Tertiary Screens;201
5.9.9;9.9 Western Blot and Immunofluorescence Analysis of GLA in Cells;202
5.9.10;9.10 Probe Identification and Optimization;202
5.9.11;9.11 Further Testing in Animal Models;202
5.9.12;9.12 Conclusions;203
5.9.13;References;203
6;Part II Clinical;206
6.1;10 Clinical Manifestations of Fabry Disease: An Overview;207
6.1.1;10.1 Introduction;207
6.1.2;10.2 Prevalence;208
6.1.3;10.3 Registry Studies;209
6.1.4;10.4 Rarer Manifestations;210
6.1.5;10.5 Is the Natural History Changing?;210
6.1.6;10.6 GenotypePhenotype Correlations;211
6.1.7;References;211
6.2;11 The Heart in Fabry Disease from Pathogenesis to Enzyme Replacement Therapy;214
6.2.1;11.1 Introduction;214
6.2.2;11.2 Pathogenesis of the Cardiac Involvement;215
6.2.2.1;11.2.1 Cardiac Hypertrophy -- Hypertrophic Cardiomyopathy;218
6.2.2.2;11.2.2 Cardiac Systolic and Diastolic Function;220
6.2.2.3;11.2.3 Ischemia, Coronary Artery Disease and Coronary Flow Reserve;220
6.2.2.4;11.2.4 Arrhythmias and Electrophysiological Abnormalities;221
6.2.2.5;11.2.5 Autonomic Cardiac Control and Cardio Neuropathy;222
6.2.2.6;11.2.6 Valvular Involvement in Fabry Disease;222
6.2.2.7;11.2.7 Fabry Disease with the Main Manifestation in the Heart;223
6.2.2.8;11.2.8 Cardiac Involvement in Children;224
6.2.2.9;11.2.9 Clinical Signs and Symptoms;225
6.2.3;11.3 Treatment Options;226
6.2.3.1;11.3.1 Adjuvant Therapeutic Interventions;226
6.2.3.2;11.3.2 Enhancement of Enzyme Activity and Enzyme Replacement Therapy;227
6.2.3.2.1;11.3.2.1 Agalsidase Alfa;228
6.2.3.2.2;11.3.2.2 Agalsidase Beta;229
6.2.4;References;230
6.3;12 Renal Manifestations of Fabry Disease;236
6.3.1;12.1 Fabry Nephropathy;237
6.3.2;12.2 Diagnosis of Fabry Nephropathy;237
6.3.3;12.3 Clinical and Laboratory Manifestations of Fabry Nephropathy;238
6.3.4;12.4 The Epidemiology of Fabry Disease and Nephropathy;244
6.3.5;12.5 Phenotype/Genotype Correlations and Residual Enzyme Activity;246
6.3.6;12.6 The Renal and Cardiac Variant Phenotypes;246
6.3.7;12.7 Glycosphingolipid Accumulation in Fabry Nephropathy;249
6.3.8;12.8 Pathology of Fabry Nephropathy;250
6.3.9;12.9 Dysfunction of the Microcirculation in Fabry Disease;255
6.3.10;12.10 Progressive Loss of Glomerular Filtration in Fabry Nephropathy;257
6.3.11;12.11 Proteinuria, ERT and Progression of Fabry Nephropathy;258
6.3.12;12.12 Other Considerations for Treating Fabry Nephropathy;260
6.3.13;12.13 Treatment Goal for Fabry Nephropathy;260
6.3.14;References;260
6.4;13 Neurological Manifestations in Fabry Disease;269
6.4.1;13.1 Fabry Disease and the Brain;269
6.4.1.1;13.1.1 Cerebrovascular Disease;272
6.4.1.2;13.1.2 Classification of Stroke in Fabry Disease;273
6.4.1.3;13.1.3 Cerebrovascular Events in Women;275
6.4.1.4;13.1.4 Cerebrovascular Pathology in Fabry Disease and Enzyme Replacement Treatment;276
6.4.1.5;13.1.5 Fabry Disease Mimicking Multiple Sclerosis;277
6.4.1.6;13.1.6 Fabry Disease and Hearing;277
6.4.2;13.2 Peripheral Nervous System in Fabry Disease;278
6.4.3;References;279
6.5;14 Dermatological Manifestations of Fabry Disease;282
6.5.1;14.1 Cutaneous Vascular Lesions;283
6.5.1.1;14.1.1 Angiokeratoma;283
6.5.1.2;14.1.2 Other Cutaneous Vascular Lesions;284
6.5.1.3;14.1.3 Therapy;287
6.5.1.4;14.1.4 Relationship to Disease Severity;288
6.5.2;14.2 Facial Features;289
6.5.3;14.3 Raynaud's Phenomenon;290
6.5.4;14.4 Lower Limb Oedema and Lymphoedema;292
6.5.5;14.5 Abnormalities of Sweating;294
6.5.6;14.6 Summary;294
6.5.7;References;295
6.6;15 Histopathology of Skin in Fabry Disease;298
6.6.1;15.1 Introduction;298
6.6.2;15.2 Methodology;299
6.6.2.1;15.2.1 Biopsy Procedure;299
6.6.2.2;15.2.2 Electron Microscopy;300
6.6.2.3;15.2.3 Gb3 Immunocytochemistry;300
6.6.2.4;15.2.4 Epidermal Nerve Endings;300
6.6.3;15.3 Results;301
6.6.3.1;15.3.1 Histopathology of Clinically Normal Skin in Fabry Disease;301
6.6.3.2;15.3.2 Histopathology of Skin Lesions in Fabry Disease;307
6.6.3.3;15.3.3 Epidermal Nerve Endings in Fabry Disease;309
6.6.4;15.4 Summary;312
6.6.5;References;312
6.7;16 Bone and Muscle Involvement in Fabry Disease;316
6.7.1;16.1 Introduction;316
6.7.2;16.2 Skeletal Involvement in Fabry Disease;317
6.7.3;16.3 Muscular Involvement;318
6.7.4;16.4 Pathological Hypotheses;320
6.7.5;16.5 Conclusions;321
6.7.6;References;321
6.8;17 The Eye in Fabry Disease;322
6.8.1;17.1 Ocular Manifestations in Fabry Disease (FD);322
6.8.1.1;17.1.1 Specific Ocular Abnormalities;322
6.8.1.2;17.1.2 Uncommom Ocular Findings;326
6.8.2;17.2 Clinical Interest of Ocular Abnormalities in FD;327
6.8.3;17.3 Technological Developments for the Study of Ocular Signs in FD;327
6.8.4;17.4 Summary;328
6.8.5;References;328
6.9;18 Pulmonary, Ear and Less Commonly AppreciatedManifestations;330
6.9.1;18.1 Fabry Disease and the Lung;330
6.9.1.1;18.1.1 Background;330
6.9.1.2;18.1.2 Aetiology;331
6.9.1.3;18.1.3 Pathophysiology;332
6.9.1.4;18.1.4 Treatment;332
6.9.2;18.2 Fabry Disease and the Ear;332
6.9.2.1;18.2.1 Epidemiology;333
6.9.2.2;18.2.2 Audiological Spectrum;334
6.9.2.3;18.2.3 Hearing Loss in Children;335
6.9.2.4;18.2.4 Pathogenesis and Disease Association;335
6.9.2.5;18.2.5 Response to Treatment;336
6.9.3;18.3 Less Commonly Appreciated Manifestations;336
6.9.3.1;18.3.1 Less Common Manifestations: Cognition;336
6.9.3.2;18.3.2 Less Common Manifestations: Dysmorphic Features;337
6.9.3.3;18.3.3 Less Common Manifestations: Gastrointestinal Disease;337
6.9.3.4;18.3.4 Less Common Manifestations: Psychosexual Disturbance;339
6.9.3.5;18.3.5 Less Common Manifestations: Spermatic Dysfunction;339
6.9.3.6;18.3.6 Less Common Manifestations: Endocrine Dysfunction;340
6.9.3.7;18.3.7 Less Common Manifestations: Bone Mineral Density;340
6.9.4;18.4 Conclusions;340
6.9.5;References;341
6.10;19 Neuropsychiatric Manifestations of AFD;344
6.10.1;19.1 Introduction;344
6.10.2;19.2 Neuro-Psychiatric Manifestations;345
6.10.3;19.3 Brain Imaging Studies;345
6.10.4;19.4 Summary;345
6.10.5;References;346
6.11;20 Genetic Counseling and Psychosocial Issues for Individuals and Their Families with Fabry Disease;348
6.11.1;20.1 Introduction;348
6.11.1.1;20.1.1 Definition of Genetic Counseling;349
6.11.1.2;20.1.2 A Multidisciplinary Approach is Best;349
6.11.2;20.2 X-Linked Inheritance Pattern;350
6.11.3;20.3 Family Health History;351
6.11.3.1;20.3.1 A Pedigree Has Multiple Functions;351
6.11.3.2;20.3.2 Standard Pedigree Symbols;353
6.11.4;20.4 Psychosocial Issues;353
6.11.5;20.5 Sexuality;353
6.11.6;20.6 Influence on Family;356
6.11.7;20.7 Trust in Health Professionals;357
6.11.8;20.8 Reproductive Options;357
6.11.8.1;20.8.1 Gamete Donation;358
6.11.8.2;20.8.2 Preimplantation Diagnosis;358
6.11.8.3;20.8.3 Prenatal Diagnosis;358
6.11.9;20.9 Potential Teratogenic Effects on Pregnancy;358
6.11.10;20.10 Summary;359
6.11.11;References;359
6.12;21 Fabry Disease in Females;361
6.12.1;21.1 Introduction;361
6.12.2;21.2 Pathology of Fabry Disease in Females;362
6.12.3;21.3 Diagnosis of Fabry Disease in Females;363
6.12.4;21.4 Prenatal Diagnosis;363
6.12.5;21.5 Clinical Manifestations of Fabry Disease in Females;364
6.12.6;21.6 Pain;364
6.12.7;21.7 Dermatological and Ophthalmological Findings;364
6.12.8;21.8 Gastrointestinal Manifestations;366
6.12.9;21.9 Cardiac Manifestations;366
6.12.10;21.10 Renal Failure;366
6.12.11;21.11 Neurovascular Complications;366
6.12.12;21.12 Quality of Life, Fatigue, and Depression;367
6.12.13;21.13 Survival;367
6.12.14;21.14 Enzyme Replacement Therapy (ERT) for Females with Fabry Disease;367
6.12.15;21.15 Clinical Trials;368
6.12.16;21.16 Observational Studies;368
6.12.17;21.17 ERT During Pregnancy and Lactation;369
6.12.18;21.18 Antibody Responses in Females;369
6.12.19;21.19 Which Females Should Receive ERT and When;370
6.12.20;21.20 Conclusions;370
6.12.21;References;371
6.13;22 Fabry Disease in Pediatric Patients;374
6.13.1;22.1 Introduction;374
6.13.2;22.2 Fabry Disease Clinical Manifestation;375
6.13.3;22.3 Fabry Pain and Acroparesthesis;375
6.13.4;22.4 Gastrointestinal Symptoms;377
6.13.5;22.5 Dermatological Findings;377
6.13.6;22.6 Angiokeratomas;378
6.13.7;22.7 Sweating Deficit;379
6.13.8;22.8 Eye Findings;380
6.13.9;22.9 Psycho-Social Issues;381
6.13.10;22.10 Renal Disease;382
6.13.11;22.11 Cardiac Disease;382
6.13.12;22.12 CNS/TIAs;382
6.13.13;22.13 Growth and Development;382
6.13.14;22.14 Others;383
6.13.15;22.15 Family History;383
6.13.16;22.16 Discussion;383
6.13.17;References;384
6.14;23 Experimental Studies in Mice on the Vasculopathyof Fabry Disease;386
6.14.1;23.1 Introduction;386
6.14.2;23.2 Vascular Disease and Dysregulation in Humans with Fabry Disease;387
6.14.3;23.3 Models of Vasculopathy in the Gla Knockout Mouse;388
6.14.3.1;23.3.1 Accelerated Thrombosis;388
6.14.3.2;23.3.2 Atherogenesis;389
6.14.3.3;23.3.3 Impaired Vasoreactivity;390
6.14.3.4;23.3.4 eNOS Dysregulation as the Common Link in the Three Models of Vasculopathy;391
6.14.4;23.4 Glycolipid Localization in Endothelial Cells;392
6.14.5;23.5 eNOS Activity and Regulation in Fabry Endothelia;393
6.14.5.1;23.5.1 Treatment of Gla--/0 Mice with D-Threo- Ethylenedioxyphenyl-P4;393
6.14.5.2;23.5.2 Decreased eNOS and Caveolin-1 in Gla Null Mouse Aortas;393
6.14.5.3;23.5.3 Impaired eNOS Activity;394
6.14.5.4;23.5.4 Oxidant Formation Secondary to eNOS Uncoupling;394
6.14.6;23.6 A Proposed Model for eNOS Uncoupling;395
6.14.7;23.7 Future Directions and Challenges;396
6.14.8;References;397
7;Part III Management;399
7.1;24 Overview;400
7.1.1;24.1 Enzyme Replacement Therapy;400
7.1.1.1;24.1.1 Clinical Trials;400
7.1.1.2;24.1.2 Limitations;402
7.1.2;24.2 Chaperones;402
7.1.3;24.3 Gene Therapy;404
7.1.3.1;24.3.1 In Vivo Gene Therapy;404
7.1.3.2;24.3.2 Ex Vivo Gene Therapy;405
7.1.4;References;405
7.2;25 Agalsidase Alfa in the Treatment of Anderson-Fabry Disease;408
7.2.1;25.1 Introduction;408
7.2.2;25.2 Agalsidase Alfa: Product Characteristics and Pharmacology;409
7.2.3;25.3 The Use of Agalsidase Alfa in Clinical Trials;410
7.2.4;25.4 The Use of Agalsidase Alfa in Postmarketing Studies;411
7.2.5;25.5 Agalsidase Alfa: Safety Considerations;413
7.2.6;25.6 Summary and Final Comments;414
7.2.7;References;416
7.3;26 Agalsidase Beta Clinical Trials and Long Term Experience;419
7.3.1;26.1 Introduction;419
7.3.2;26.2 Clinical Trials Agalsidase Beta;420
7.3.2.1;26.2.1 Cardiac Function in Response to Agalsidase Beta;423
7.3.2.2;26.2.2 Kidney Function in Response to Agalsidase Beta;424
7.3.2.3;26.2.3 Cerebrovascular Function in Response to Agalsidase Beta;425
7.3.2.4;26.2.4 Gastroenterology Function in Response to Agalsidase Beta;425
7.3.2.5;26.2.5 Pain and Quality of Life After Agalsidase Beta;426
7.3.2.6;26.2.6 Pulmonary Function in Response to Agalsidase Beta;427
7.3.3;26.3 Agalsidase Beta in Pediatric Patients with Fabry Disease;427
7.3.4;26.4 Agalsidase Beta in Women with Fabry Disease;428
7.3.4.1;26.4.1 Immune Response to Agalsidase Beta;429
7.3.4.2;26.4.2 Comparison Between Recombinant Forms of -gal A;430
7.3.5;26.5 Summary;430
7.3.6;References;431
7.4;27 Analyses of Agalsidase Alfa and Agalsidase Beta for the Treatment of Fabry Disease;434
7.4.1;27.1 Biochemical/Pharmacokinetic Properties;434
7.4.2;27.2 Analysis of Previous Clinical Trial Designs;436
7.4.3;27.3 Direct Comparisons of Agalsidase Alfa and Beta;439
7.4.3.1;27.3.1 Differential Clinical Effects of Agalsidase Alfa and Beta;442
7.4.3.1.1;27.3.1.1 Cardiac;442
7.4.3.1.2;27.3.1.2 Renal;443
7.4.3.1.3;27.3.1.3 Gastrointestinal;444
7.4.3.1.4;27.3.1.4 Central Nervous System Disease;444
7.4.3.1.5;27.3.1.5 Pain and Quality of Life;444
7.4.4;27.4 Conclusions;445
7.4.5;References;446
7.5;28 Enzyme Replacement Therapy in Children with Fabry Disease;450
7.5.1;28.1 Usefulness of Disease Severity Scores in Children;456
7.5.2;28.2 Home Therapy;460
7.5.3;28.3 Dosing Studies: Agalsidase Alfa and Agalsidase Beta;462
7.5.4;28.4 Discussion;464
7.5.5;References;467
7.6;29 Pharmacological Chaperone Therapy for Fabry Disease;472
7.6.1;29.1 Introduction;472
7.6.2;29.2 Lysosomal Enzyme Biosynthesis and ERAD;473
7.6.3;29.3 Misfolding Conformation in Missense -Galactosidase a Mutant Enzymes;475
7.6.4;29.4 Development of DGJ as a Pharmacological Chaperone for Fabry Disease;477
7.6.5;29.5 Preclinical Efficacy and Safety of DGJ in Mice;480
7.6.6;29.6 Clinical Development of DGJ;482
7.6.7;29.7 Outlook of PCT for the Treatment of Fabry Disease;483
7.6.8;References;484
7.7;30 Potential Factors Influencing Treatment Outcomes;486
7.7.1;30.1 Introduction;486
7.7.2;30.2 Patient Related Factors;487
7.7.2.1;30.2.1 General Patient Related Factors;487
7.7.2.2;30.2.2 Renal Disease;488
7.7.2.3;30.2.3 Cardiac Disease;489
7.7.2.4;30.2.4 Cerebral Disease;490
7.7.3;30.3 Product Related Factors;491
7.7.3.1;30.3.1 Dose of Agalsidase-Alfa and Agalsidase-Beta;491
7.7.3.2;30.3.2 Antibody Formation;492
7.7.4;30.4 Conclusions;493
7.7.5;References;494
7.8;31 Symptomatic and Ancillary Therapy;497
7.8.1;31.1 Supportive and Ancillary Therapy in Fabry Disease;497
7.8.2;31.2 Pain Relief;499
7.8.3;31.3 Kidney Function;499
7.8.4;31.4 Angiokeratomas;500
7.8.5;31.5 Lymphadenopathy;501
7.8.6;31.6 Pulmonary;501
7.8.7;31.7 Heart;501
7.8.8;31.8 Cerebrovascular;502
7.8.9;31.9 Psychiatric Signs and Symptoms;502
7.8.10;References;503
7.9;32 The Price of Care Versus the Cost of Caring;504
7.9.1;32.1 Introduction;504
7.9.2;32.2 Evidence of the Effectiveness of ERT of Fabry Disease;505
7.9.3;32.3 Cost-Effectiveness Analysis;506
7.9.4;32.4 Importance of Social Values;506
7.9.5;32.5 The Case of Rare Diseases;508
7.9.6;32.6 Non-medical Costs;508
7.9.7;32.7 Concluding Remarks;509
7.9.8;References;510
7.10;Summary: Fabry Disease, a Uniquely Different Lysosomal Storage Disorder;513
7.10.1; Introduction;513
7.10.2; Diagnosis;514
7.10.3; Clinical Features;515
7.10.4; Management;518
7.10.5; Summary;518
7.10.6; Fabry Patient Associations;519
8;Index;524