Lysosomal Storage Disorders (eBook)

Lysosomal Storage Disorders: A Practical Guide 3
Copyright 4
Contents 5
List of Contributors 7
Preface 10
Foreword 12
Part 1 General Aspects of Lysosomal Storage Diseases 13
1 The Lysosomal System: Physiology and Pathology 15
Introduction 15
The greater lysosomal system 15
Lysosomal diseases 18
References 24
2 Clinical Aspects and Clinical Diagnosis 25
Introduction 25
Clinical presentation 25
References 31
3 Laboratory Diagnosis of Lysosomal Storage Diseases 32
Referral to specialist laboratory 32
Preliminary screening tests on urine or blood 32
Diagnosis of lysosomal enzyme defects 34
LSDs due to defects in non-enzymatic proteins 37
Neuronal ceroid lipofuscinoses (NCLs) 38
Molecular genetic testing 38
Prenatal diagnosis 39
Prospects 39
Acknowledgements 39
References 39
4 Genetics of Lysosomal Storage Disorders and Counselling 41
Introduction 41
Genes, proteins, stored substrates, clinical phenotypes and diagnosis 41
Incidence and prevalence 45
Populations at a high-risk 46
Burden of illness 46
Population screening and diagnostic methods 46
Counselling issues 47
References 47
5 Classification of Lysosomal Storage Diseases 49
Basis of classification of lysosomal storage diseases 49
Acknowledgements 49
Part 2 The Individual Diseases 59
6 Gaucher Disease 61
A representative case history 61
Gaucher disease 61
Epidemiology 61
Etiology and pathogenesis:genetic basis 62
Clinical forms 62
Diagnosis 64
Biomarkers 64
Routine follow-up of patients 64
Enzyme replacement therapy (ERT) for Gaucher disease: alglucerase and imiglucerase 66
Dosing regimens 67
Malignancies 67
Global shortage of imiglucerase (June 2009) 67
Other treatment options: substrater eduction therapy (SRT) 68
Summary 68
References 68
7 Fabry Disease 70
Epidemiology 70
Genetic basis 70
Pathophysiology 71
Clinical presentation 71
Natural history 72
Laboratory diagnosis 72
Treatment 73
Treatment guidelines 73
Further reading 73
8 The Gangliosidoses 75
References 80
9 Metachromatic Leukodystrophy and Globoid Cell Leukodystrophy 82
MLD and GLD 82
Case studies 82
Epidemiology 84
Genetics 84
Pathophysiology 86
Clinical presentation 87
Diagnosis by MRI 87
Laboratory diagnosis 88
Treatment 89
Natural history studies 90
References 91
10 Types A and B Niemann–Pick Disease 92
Representative case histories 92
Epidemiology 92
Genetics 93
Pathophysiology 93
Clinical presentation 94
Natural history 95
Laboratory diagnosis 96
Treatment 96
Acknowledgements and conflicts of interest 97
References 97
11 Niemann–Pick Disease Type C 99
Case histories 99
Epidemiology 100
Genetic basis 100
Pathophysiology 100
Clinical presentation 101
Natural history 103
Laboratory diagnosis 103
Treatment 104
References 104
12 The Mucopolysaccharidoses 106
Epidemiology 106
Genetic basis 106
Pathophysiology 107
Clinical presentation 107
Natural history 108
Laboratory diagnosis 109
Treatment 111
Acknowledgements 112
References 112
13 Pompe Disease 113
Case histories 113
Confusing nomenclature 114
Epidemiology 115
Genetic basis 115
Pathophysiology 115
Clinical presentation 115
Natural history 116
Enzymatic and molecular diagnosis 116
Treatment 117
Acknowledgment 117
Selected literature 117
14 Glycoproteinoses 119
Epidemiology 119
Pathophysiology 119
Genetic basis 121
Clinical presentation 121
Laboratory diagnosis 121
Treatment 123
An example of glycoproteinosis: ? -mannosidosis 123
Genetic basis 123
Pathophysiology 124
Clinical presentation 124
Natural history 124
Treatment 125
References 125
15 Defect in Protective Protein/Cathepsin A: Galactosialidosis 127
Epidemiology and clinical presentation 127
Genetic basis 128
Biochemistry 129
Pathophysiology 129
Diagnosis 129
Mouse model 130
Treatment 131
References 131
16 Multiple Enzyme Deficiencies 133
16.1 Defects in Transport: Mucolipidosis II alpha/beta, Mucolipidosis III alpha/beta and Mucolipidosis III gamma 133
Case histories 133
Epidemiology 134
Genetic basis 134
Pathophysiology 135
Clinical presentation 135
Natural history 136
Laboratory diagnosis 137
Treatment 138
References 138
16.2 Multiple Sulfatase Deficiency 139
Clinical presentation 139
Genetic basis 139
Biochemistry 139
Pathophysiology 141
Diagnosis 141
Treatment 141
References 141
17 Lysosomal Membrane Defects 143
Introduction 143
Cystinosis 143
Conclusions 147
Acknowledgements 147
References 147
18 Neuronal Ceroid Lipofuscinoses 149
Typical case scenarios 149
Epidemiology 150
Genetic basis 150
Pathophysiology 151
Natural history 151
Laboratory diagnosis 151
Treatment 152
Treatment guidelines 153
Helpful further reading and websites 153
19 Other Lysosomal Disorders 154
Introduction 154
Farber disease: acid ceramidase deficiency ( OMIM : 228000) 154
Lysosomal acid lipase deficiency: Wolman Disease and Cholesteryl Ester Storage Disease ( OMIM : 278000) 155
Defects in equilibrative nucleoside transporter 3 – a new lysosomal transporter defect? 156
Defects in the lysosomal proteases,cathepsins 156
Disorders of biogenesis of lysosome-related organelles 157
Stuttering 160
Further reading 160
Part 3 Therapy and Patient Issues 163
20 Current Treatments 165
Introduction 165
General considerations 165
Specific strategies for treating lysosomal diseases 167
Enzyme enhancement 168
Substrate restriction therapy(“substrate reduction therapy”) 171
Pharmacological chaperone therapy (also see Chapter 22) 172
Substrate removal 173
Conclusions 175
References 176
Further reading 176
21 Central Nervous System Aspects, Neurodegeneration and the Blood–Brain Barrier 178
Introduction 178
CNS storage and neuropathology 178
Normal function of the blood–brain barrier 179
Therapeutic delivery across the blood–brain barrier 181
Development of the blood–brain barrier 183
Damage to the blood–brain barrier in lysosomal storage diseases 185
Bibliography 185
22 Emerging Treatments and Future Outcomes 186
Introduction 186
Approaches to CNS Enzyme Delivery 188
Alternative Enzyme Variants for CNS Targeting 188
Gene/Cell Based Interventions 189
Augmentation of mRNA Translation/ Natural Enzyme Function 190
Indirect therapies 191
Combination therapies 191
Conclusions 191
References 191
23 Newborn, High Risk and Carrier Screening for Lysosomal Storage Disorders 193
Introduction 193
Carrier screening 194
High risk population screening 194
Newborn screening 194
Methodological issues of screening 195
Considerations of screening 195
Conclusions 196
References 196
24 The Patient Perspective on Rare Diseases 198
Introduction 198
The scale of the problem 198
Facing the challenges 199
Access to treatment 200
A United Kingdom perspective 201
The current situation in the UK, 2012 202
A European perspective 202
Conclusion 203
References 204
Index 205