In recent years, there has been enormous scientific interest in the area of lysosomal storage disorders, especially the mucopolysaccharidoses. Advanced diagnostics, particularly in the field of molecular genetics, have become more widely available, and at the same time numerous new therapies have been developed for these so-called 'orphan diseases'. The current 4th edition of this book no longer only focuses on mucopolysaccharidoses, but also a number of similar diseases. Therefore, the new revised guide is intended to provide essential information not only for health professionals, but also the affected individuals themselves and their families. This book introduces the pathophysiology of these rare metabolic diseases and provides an overview of current treatment and management options such as bone marrow (stem cell) transplantation and enzyme replacement therapy. It will be a helpful companion for patients and their carers, and will also serve doctors and allied healthcare practitioners as a comprehensive reference work for the diagnosis and therapy of lysosomal storage diseases.

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1. Introduction 12 2. The history of mucopolysaccharidoses and similar disorders 15 2.1. Conspicuous features as a first indication 15 2.2. Early possible traces of mucopolysaccharidosis and similar disorders 16 2.3. First confirmed evidence of mucopolysaccharidoses and similar disorders 16 2.4. The mucopolysaccharidoses and similar lysosomal storage disorders through the ages 23 2.5. Outlook 23 3. Physiology, biochemistry and pathophysiology in mucopolysaccharidoses and similar lysosomal storage disorders 27 3.1. Physiology of lysosomes 27 3.2. Formation (synthesis) of lysosomal enzymes 27 3.3. Pathophysiology of lysosomal enzymes 28 3.4. Measuring the activity of lysosomal enzymes 29 3.5. Biochemistry 29 3.6. Biochemical detection and diagnostics 31 3.7. Further biomarkers in lysosomal storage disorders 31 4. General aspects of mucopolysaccharidoses and similar lysosomal storage disorders 34 4.1. Nomenclature and synonyms 34 4.2. Frequency of lysosomal storage disorders 35 4.3. Multisystemic diseases 35 4.4. Genotype-phenotype correlation, special types 36 4.5. Lysosomal storage disorders and co-morbidities 36 4.6. Early symptoms of MPS and similar lysosomal storage disorders 36 4.7. Clinical suspicions for lysosomal storage disorders 37 4.8. The diagnostic odyssey 40 4.9. Newborn screening 40 4.10. Patient registries 41 5. Clinical presentation of mucopolysaccharidoses 43 5.1. General clinical aspects 43 5.1.1. Dysostosis multiplex and typical radiological findings 45 5.1.2. Imaging findings in the brain and spinal cord 49 5.1.3. Heart and vessels 50 5.1.4. Airway and anesthesia problems 50 5.2. The clinical presentation of mucopolysaccharidosis 50 5.2.1. Mucopolysaccharidosis type I iduronidase deficiency 50 5.2.2. Mucopolysaccharidosis type II Hunter 54 5.2.3. Mucopolysaccharidosis type III Sanfilippo 57 5.2.4. Mucopolysaccharidosis type IV Morquio 61 5.2.5. Mucopolysaccharidosis type VI Maroteaux-Lamy 67 5.2.6. Mucopolysaccharidosis type VII Sly 69 5.2.7. Mucopolysaccharidosis type IX hyaluronidase deficiency 71 5.2.8. Mucopolysaccharidosis type X arylsulfatase K deficiency 72 5.2.9. Mucopolysaccharidosis plus syndrome 73 6. Selected similar lysosomal storage disorders and differential diagnoses 77 6.1. Selected similar lysosomal storage disorders 77 6.1.1. Oligosaccharidoses / glycoproteinoses 78 6.1.1.1. Alpha-mannosidosis (a-mannosidosis) 78 6.1.1.2. Alpha-N-acetylgalactosaminidase deficiency Schindler disease 79 6.1.1.3. Aspartylglucosaminuria 80 6.1.1.4. Beta-mannosidosis (b-mannosidosis) 80 6.1.1.5. Fucosidosis 81 6.1.1.6. Galactosialidosis (Goldberg syndrome) 82 6.1.1.7. Sialidosis neuraminidase deficiency 83 6.1.2. Sialic acid metabolic disorders 84 6.1.2.1. Sialuria 84 6.1.2.2. Free sialic acid storage disorders ISSD and Salla disease 84 6.1.3. Sphingolipidoses / neurolipidoses 85 6.1.3.1. Fabry disease 85 6.1.3.2. Farber disease and SMA-PME (ASAH1-Related Disorders) 87 6.1.3.3. GM1 and GM2 gangliosidoses 88 6.1.3.3.1. GM1 gangliosidosis (GLB1-associated disorder) 88 6.1.3.3.2. GM2 gangliosidoses (Tay-Sachs and Sandhoff) 89 6.1.3.4. Gaucher disease 91 6.1.3.5. Krabbe disease (globoid cell leukodystrophy) 93 6.1.3.6. Metachromatic leukodystrophy (arylsulfatase A deficiency) 94 6.1.3.7. Acid sphingomyelinase deficiency and Niemann-Pick type C 94 6.1.3.7.1. Acid sphingomyelinase deficiency (ASMD) 95 6.1.3.7.2. Niemann-Pick disease type C 96 6.1.4. Others 96 6.1.4.1. CDG syndromes diseases with disorders of glycosylation 96 6.1.4.2. Lysosomal acid lipase deficiency (Wolman disease and cholesteryl ester storage disease) 97 6.1.4.3. Multiple sulfatase deficiency 98 6.1.4.4. Neuronal ceroid lipofuscinoses 99 6.1.4.5. Pompe disease 99 6.1.4.6. Pycnodysostosis 100 6.2. Differential diagnoses 103 6.2.1. Williams-Beuren syndrome 103 6.2.2. Coffin-Lowry syndrome 104 6.2.3. Smith-Magenis syndrome 105 6.2.4. Beckwith-Wiedemann syndrome 107 6.2.5. Congenital hypothyroidism 108 6.2.6. Type II collagen disorders collagenopathies type II 109 6.2.7. Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia type 1 110 6.2.8. Cornelia de Lange syndrome 112 6.2.9. Costello syndrome 113 6.2.10. 3M syndrome 114 7. Mucolipidoses 117 7.1. Underlying pathomechanisms 117 7.2. Clinical presentation of mucolipidosis 118 7.2.1. Mucolipidosis I 118 7.2.2. Mucolipidosis II alpha/beta (ML II a/b) I-cell disease 119 7.2.3. Mucolipidosis III alpha/beta (ML III a/b) 121 7.2.4. Mucolipidosis III gamma (ML III g) 123 7.2.5. Mucolipidosis IV 123 8. Treatment 125 8.1. Symptomatic treatment 125 8.1.1. Musculoskeletal system 125 8.1.2. Neurological problems 126 8.1.2.1. Central and local nerve damage 126 8.1.2.2. Developmental delay, loss of mental abilities, behavioral abnormalities and epileptic seizures 127 8.1.2.3. Hydrocephalus 128 8.1.3. Sensory organs 128 8.1.4. Airways and lungs 129 8.1.5. Cardiovascular system 129 8.1.6. Anesthesia problems 129 8.2. Causal therapies 131 8.2.1. Hematopoietic stem cell transplantation (HSCT) 131 8.2.2. Systemic enzyme replacement therapy (ERT) 132 8.2.3. Substrate reduction therapy (SRT): genistein 133 8.2.4. Pharmacological chaperones (PC) 134 8.2.5. CNS-sensitive enzyme replacement therapy 134 8.2.6. Gene therapy 134 9. Emergency situations 136 9.1. Perioperative risks 136 9.2. Risk of infusion reactions 137 9.3. Other risks 137 10. Genetics and genetic counseling 139 10.1. Medical basics 139 10.2. Genetic counseling 143 10.2.1. Prenatal diagnosis 143 10.2.2. Preimplantation genetic diagnosis 143 10.2.3. Heterozygote tests 144 10.2.4. Considerations regarding genetics in a family 145 11. Puberty and transition 147 11.1. Puberty 147 11.2. Transition 149 12. Fertility and the desire to have children 152 12.1. Fertility 152 12.2. Planning the desire to have children 152 13. Living with mucopolysaccharidosis 155 13.1. Making everyday life easier for those affected 155 13.1.1. Medical aids 155 13.1.2. Wheelchairs 155 13.1.3. Electronic aids 156 13.2. Leisure, hobbies and social contacts 156 13.2.1. Sport and exercise 156 13.2.2. Exercise in the fresh air 157 13.2.3. Playing games 157 13.3. School and education 157 13.4. Siblings shadow children 160 13.5. Parents not flawless, but always striving for perfection 162 14. Self-help and self-help organizations 163 15. Important contact addresses 168 15.1. Hospitals and departments 168 15.2. Self-help associations for mucopolysaccharidosis and rehabilitation centers 170 16. Glossary Explanation of important terms 180 Index 193