Progress in Heritable Soft Connective Tissue Diseases (Advances in Experimental Medicine and Biology Book 802)

This volume is a reference handbook focusing on diseases like Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome and other heritable soft connective tissue diseases. The book presents detailed information for both basic scientists and for clinicians seeing patients. It is also a stepping stone for new investigations and studies that goes beyond the facts about the composition and biochemistry of the connective tissue and extracellular matrix, as the authors connect individual components to specific aspects of various soft tissue disorders and to the actual or potential treatment of them. __Progress in Heritable Soft Connective Tissue Diseases__ features very prominent physicians and scientists as contributors who bring their most recent discoveries to the benefit of readers. Their expertise will help clinicians with proper diagnosis of sometimes elusive and uncommon heritable diseases of soft connective tissues. This book also offers an update on the pathophysiology of these diseases, including an emphasis on unifying aspects such as connections between embryonic development of the different types of connective tissues and systems, and the role of TGF-beta in development and physiology of soft tissues. This new set of data explains, at least in part, why many of these disorders are interconnected, though the primary pathophysiological events, such as gene mutations, may be different for each disorder. Contents 6 Contributors 8 1: Introduction 10 References 12 2: Structure, Physiology, and Biochemistry of Collagens 13 2.1 Introduction 14 2.2 Collagens 14 2.3 Fibril-Forming Collagens 16 2.4 Fibril-Associated Collagens with Interrupted Triple Helices (FACIT) 17 2.5 Basement Membrane Collagen 18 2.6 Beaded Filament-Forming Collagen 18 2.7 Network-Forming Collagens 21 2.8 Transmembrane Collagens 21 2.9 Procollagen Synthesis, Collagen Fibril Assembly, Growth and Maturation 21 2.10 Triple Helix Assembly and the Impact of Primary Structure on Secondary, Tertiary, and Quaternary Structures 21 2.11 Collagen Fibril Assembly 23 2.12 Assembly and Growth of Mature Tendon Collagen Fibrils 24 2.13 Regulation of Collagen Fibril Assembly and Growth 24 2.14 Effects of Composition and Structure on Function for Tendons and Ligaments 28 2.15 Effect of Anatomical Location on Tendons and Ligaments 30 2.16 Roles of Collagens in Transition from Midsubstance to Enthesis in Tendons and Ligaments 30 2.17 Summary 32 References 32 3: Basic Components of Connective Tissues and Extracellular Matrix: Elastin, Fibrillin, Fibulins, Fibrinogen, Fibronectin, Laminin, Tenascins and Thrombospondins 38 3.1 Fibronectin 40 3.2 Laminin 40 3.3 Fibrinogen 42 3.4 Elastin 42 3.5 Fibrillins 44 3.6 Fibulins 45 3.7 Tenascins 45 3.8 Thrombospondins 47 3.9 Cartilage Oligomeric Matrix Protein (COMP) or Thrombospondin-5 48 References 49 4: Proteoglycans and Diseases of Soft Tissues 55 References 61 5: Advances in the Use of Growth Factors for Treatment of Disorders of Soft Tissues 65 5.1 Basics of Tendon Repair 66 5.2 Transforming Growth Factor β (TGFβ) Family 67 5.3 Fibroblast Growth Factors 70 5.4 Role of IGF-I in Tendon Healing 71 5.5 PDGF 72 5.6 VEGF 73 5.7 Other Modalities 74 5.8 Epilogue 76 References 76 6: Clinical, Diagnostic, and Therapeutic Aspects of the Marfan Syndrome 83 6.1 Introduction 83 6.2 Clinical Phenotype 84 6.2.1 Cardiovascular System 84 6.2.2 Skeletal System 85 6.2.3 Ocular System 86 6.2.4 Other Organ Systems 86 6.3 Diagnostic Criteria 87 6.4 Management and Treatment 87 6.5 Molecular Genetics 90 6.6 Pathophysiology 91 6.7 Future Perspectives 94 References 94 7: Loeys-Dietz Syndrome 101 7.1 Introduction 101 7.2 Inheritance and Mutational Spectrum 102 7.3 Signs and Symptoms 102 7.3.1 Cardiovascular Manifestations 102 7.3.2 Skeletal Manifestations 103 7.3.3 (Cranio)facial manifestations 103 7.3.4 Cutaneous Manifestations 104 7.3.5 Other Findings 104 7.4 Clinical Presentation of LDS-Related Diseases 104 7.5 Diagnostic Criteria for LDS 105 7.6 Differential Diagnosis 106 7.6.1 Syndromic Differential Diagnosis 106 7.6.1.1 Ehlers-Danlos Syndrome 106 7.6.1.2 Arterial Tortuosity Syndrome and Autosomal Recessive Cutis Laxa Type 1 106 7.6.2 Non-syndromic Differential Diagnosis 107 7.7 Pathology 107 7.8 Biochemical Defects and Pathogenesis 107 7.9 Treatment and Management 108 7.9.1 Natural History 108 7.9.2 Medical Treatment 108 7.9.3 Surgical Treatment 109 7.10 Genetic Counseling 109 References 110 8: Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling 112 8.1 Introduction 113 8.2 TGF-β, Signaling Pathways, and Physiological Effects 114 8.2.1 “Canonical” TGF-β Signaling Pathway 114 8.2.2 Alternate “Noncanonical” TGF-β Signaling Pathways 116 8.3 TGF-β Receptor Related Connective Tissue Disorders 117 8.3.1 Familial Thoracic Aortic Aneurysm and Dissection Syndrome (FTAAD) 117 8.3.1.1 Paradoxical Signaling by Mutated TGFBRs in FTAAD 119 8.3.2 Shprintzen-Goldberg Syndrome (SGS) 120 8.3.3 Hereditary Hemorrhagic Telangiectasia (HHT) 121 8.3.4 Other Connective Tissue Disorders with TGF-β Involvement 123 8.4 Current Standard of Care for TAAs and Genetic Testing 124 8.4.1 Current Standard of Care for TAAs 124 8.4.2 Genetic Testing 125 8.4.2.1 Genetic Testing for FTAAD 125 8.4.2.2 Genetic Testing for SGS 125 8.4.2.3 Treatment and Genetic Testing for HHT 126 8.5 Summary 126 References 127 9: The Ehlers-Danlos Syndrome 133 9.1 Classification 134 9.2 General Clinical Manifestations of EDS 135 9.3 EDS-Subtypes 135 9.3.1 Ehlers-Danlos Syndrome, Classic Type 135 9.3.2 Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT) 136 9.3.3 Ehlers-Danlos Syndrome, Vascular Type 137 9.3.4 Ehlers-Danlos Syndrome, Kyphoscoliotic Type and Related Phenotypes 139 9.3.5 Ehlers-Danlos Syndrome Subtypes That Result from Aberrant Processing of the Procollagen Type I-N-Propeptide 141 9.3.6 Other EDS-Variants Caused by Mutations in the Type I Collagen-Encoding Genes 141 9.4 Diagnosis 142 9.4.1 Ultrastructural Examination of the Skin 142 9.4.2 Skin Biopsy for Fibroblast Culture and Biochemical Analysis 142 9.4.3 Urine Analysis 143 9.4.4 Molecular Genetic Testing 143 9.5 Management 143 References 145 10: Ehlers–Danlos Syndrome Associated with Glycosaminoglycan Abnormalities 148 10.1 Introduction 149 10.2 Background 149 10.3 The Progeroid Type of EDS (type 1: MIM#130070, type2: MIM#615349) 151 10.3.1 Clinical Manifestations 151 10.3.2 Genetic Information 152 10.3.2.1 B4GALT7 152 10.3.2.2 B3GALT6 153 10.3.3 Biochemical Characteristics 153 10.3.3.1 B4GALT7 153 10.3.3.2 B3GALT6 154 10.4 D4ST1-Deficient EDS (MIM#601776) 154 10.4.1 Clinical Manifestations 154 10.4.1.1 Craniofacial Features 155 10.4.1.2 Skeletal Features 155 10.4.1.3 Cutaneous Features 156 10.4.1.4 Cardiovascular Features 157 10.4.1.5 Respiratory Features 157 10.4.1.6 Gastrointestinal Features 157 10.4.1.7 Genitourinary Features 157 10.4.1.8 Ophthalmologic Features 157 10.4.1.9 Hearing Impairment 157 10.4.1.10 Growth 157 10.4.1.11 Development and Neuromuscular Features 157 10.4.2 Genetic Information 158 10.4.3 Biochemical Information 158 10.4.4 Pathology and Pathophysiology 158 References 160 11: Cutis Laxa 163 11.1 Introduction 164 11.2 Autosomal Dominant Cutis Laxa Syndrome (ADCL, MIM 1301160) 168 11.3 Autosomal Recessive Cutis Laxa Type I (ARCL1) 169 11.4 Metabolic Cutis Laxa Syndromes 169 11.4.1 Menkes Disease 170 11.4.2 COG7-CDG 170 11.4.3 ATP6V0A2-CDG 171 11.4.4 P5CS 171 11.4.5 PYCR1 172 11.4.6 RIN2 173 11.4.7 Gerodermia Osteodysplastica 173 11.4.8 Metabolic Pathway Defects Described in Association with Wrinkled Skin or Cutis Laxa 174 11.5 Histological Abnormailities in Cutis Laxa Syndromes 174 11.5.1 Autosomal Dominant Cutis Laxa 174 11.5.2 X-Linked Cutis Laxa 175 11.5.3 Autosomal Recessive Cutis Laxa 175 11.5.4 Differential Diagnosis 176 11.6 Multiple Malformation Syndromes Associated with Cutis Laxa 177 11.7 Differential Diagnosis in Cutis Laxa Syndromes 179 References 181 12: Collagen Type VI Myopathies 187 12.1 Collagen VI Related: Myopathies 188 12.1.1 Clinical Presentation 188 12.1.1.1 Ullrich Congenital Muscular Dystrophy 188 12.1.1.2 Bethlem Myopathy 189 12.1.1.3 Autosomal Dominant Limb Girdle Muscular Dystrophy Phenotype 191 12.1.1.4 Autosomal Recessive Myosclerosis Myopathy 192 12.1.2 Laboratory Findings 192 12.1.3 Biochemical Defect and Pathogenesis 194 12.1.4 Treatment 196 12.1.5 Genetic Counseling 197 12.1.6 Related Disorders 197 12.1.6.1 Limb-Girdle Muscular Dystrophy 198 12.1.6.2 Congenital Muscular Dystrophy 198 12.1.6.3 Central Core Disease 198 12.1.6.4 Emery-Dreifuss Muscular Dystrophy 198 12.1.6.5 Ehlers-Danlos Syndrome 198 References 199 13: Mouse Models in Tendon and Ligament Research 202 13.1 Introduction 203 13.2 Mouse Models for Structural and Fibril-Forming Collagens and Related Molecules 203 13.3 Fibril-Forming Collagens 203 13.4 Enzymes Affecting Collagen Processing 206 13.5 Regulatory Molecules: FACITs 208 13.6 Regulatory Molecules: SLRPs 209 13.7 Beaded Filament-Forming Collagens 213 13.8 Fibrillin 214 13.9 Growth Factors 215 13.10 Transforming Growth Factor Beta 216 13.11 Growth/Differentiation Factors 216 13.12 Transcription Factors 218 13.13 Scleraxis 218 13.14 Mohawk 220 13.15 Transcription Factors Early Growth Response 1 and 2 221 13.16 Cell-Membrane Proteins Tenomodulin and CD44 221 13.17 Tenomodulin 221 13.18 Cd44 222 13.19 The Future of Mouse Models 222 13.20 Transgenic Mice 222 13.21 Conditional and Inducible Mice 223 13.22 Summary 225 References 225 14: Connective Tissue Disorders in Domestic Animals 232 References 238 Index 242 Front Matter....Pages i-viii Introduction....Pages 1-3 Structure, Physiology, and Biochemistry of Collagens....Pages 5-29 Basic Components of Connective Tissues and Extracellular Matrix: Elastin, Fibrillin, Fibulins, Fibrinogen, Fibronectin, Laminin, Tenascins and Thrombospondins....Pages 31-47 Proteoglycans and Diseases of Soft Tissues....Pages 49-58 Advances in the Use of Growth Factors for Treatment of Disorders of Soft Tissues....Pages 59-76 Clinical, Diagnostic, and Therapeutic Aspects of the Marfan Syndrome....Pages 77-94 Loeys-Dietz Syndrome....Pages 95-105 Connective Tissue Disorders and Cardiovascular Complications: The Indomitable Role of Transforming Growth Factor-Beta Signaling....Pages 107-127 The Ehlers-Danlos Syndrome....Pages 129-143 Ehlers–Danlos Syndrome Associated with Glycosaminoglycan Abnormalities....Pages 145-159 Cutis Laxa....Pages 161-184 Collagen Type VI Myopathies....Pages 185-199 Mouse Models in Tendon and Ligament Research....Pages 201-230 Connective Tissue Disorders in Domestic Animals....Pages 231-240 Back Matter....Pages 241-245