Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics

Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics......Page 5
Contents......Page 7
Preface......Page 19
List of Contributors......Page 21
Part I: Basics......Page 25
1.1 Definition......Page 27
1.2 The History of Tuberous Sclerosis Complex......Page 28
1.3 Hereditary Nature of TSC......Page 30
1.5 The Future of TSC......Page 31
References......Page 32
2 Natural History of Tuberous Sclerosis Complex and Overview of Manifestations......Page 35
2.1.1 TSC and the Brain......Page 37
2.1.2 TSC and the Skin......Page 39
2.1.4 TSC and the Kidney......Page 40
2.1.6 TSC and the Eye......Page 41
2.2 TSC: A Spectrum Across the Life Span......Page 42
2.3 TSC: A "Model" System......Page 43
References......Page 44
Introduction......Page 45
References......Page 48
Part II: Genetics......Page 51
4.2.1 Initial Linkage Studies......Page 53
4.2.2 Positional Cloning of TSC2 (1993)......Page 54
4.3.1 Genomic Structure and Location of TSC1 and TSC2......Page 55
4.3.2 Alternative Splicing of TSC1 and TSC2......Page 56
4.3.3 Interspecies Comparisons of TSC1 and TSC2......Page 57
4.4.1 Introduction......Page 58
4.4.3 Distribution of Mutations Along the Length of TSC1 and TSC2......Page 61
4.4.4 Single-Base Substitutions in TSC1 and TSC2......Page 64
4.4.6 Large Genomic Deletions/Rearrangements in TSC1 and TSC2......Page 66
4.4.8 Perspectives on Mutational Variation at the TSC Loci......Page 67
4.5 Frequency and Significance of Mosaicism in TSC......Page 69
4.6 Considerations in Patients in Whom No Mutation Can Be Identified......Page 70
4.7.1 The Role of TSC1 and TSC2 in Hamartoma Development in TSC Patients......Page 71
4.7.2 The Role of TSC1 and TSC2 Genes in Cancer Development in Non-TSC Patients......Page 72
4.8 The Future of Molecular Diagnostics in TSC......Page 74
References......Page 77
5.1 Introduction......Page 85
5.2 Comprehensive Genotype–Phenotype Reports......Page 86
5.3.1 TSC2 Versus TSC1 Gene Mutations......Page 91
5.3.1.1 NMI Patients......Page 92
5.3.1.2 Familial Versus Sporadic Cases......Page 93
5.3.2 Protein Truncation Versus Missense Mutations......Page 94
5.3.3.1 TSC1 Large Deletions......Page 95
5.3.4.1 TSC2 GAP Domain Mutations......Page 96
5.3.4.2 TSC2 Gene Amino-Termini Mutants Versus Carboxy-Termini Mutants......Page 97
5.3.6 Male Versus Female Sex......Page 98
5.4 Molecular Diagnostic Methods......Page 99
5.5 Conclusion......Page 101
References......Page 103
Part III: Basic Science......Page 109
6.1.1 Rapamycin and the Discovery of TOR Proteins......Page 111
6.1.2 Molecular Characteristics of mTOR and Its Complexes......Page 112
6.1.3 Downstream of mTOR......Page 113
6.1.4 Upstream of mTOR......Page 115
6.2.2 Biochemical Studies Fill in the Gaps......Page 116
6.2.3 Rheb: A Direct Target of the TSC1–TSC2 Complex That Regulates mTORC1......Page 117
6.2.4 The TSC–Rheb–mTORC1 Circuit: Important Remaining Questions......Page 118
6.3 The TSC1–TSC2 Complex as a Critical Sensor of Cellular Growth Conditions......Page 119
6.3.2 Energy and Nutrients......Page 120
6.4.1 Constitutive and Elevated mTORC1 Signaling......Page 122
6.4.2 mTORC1-Dependent Feedback Inhibition of PI3K Signaling......Page 124
6.5 Pathological Consequences of mTOR Dysregulation in TSC......Page 125
6.5.2 Benign Tumors......Page 126
6.5.3 Specific Clinical Features......Page 127
6.6 Therapeutic Opportunities: Rapamycin and Beyond......Page 128
References......Page 130
7.1 Introduction......Page 141
7.2.2 The Eker Rat Tsc2 Model......Page 142
7.2.5 Brain and Neurologic Features of the Eker Rat......Page 145
7.3.1 Tsc2 Knockout Mice......Page 146
7.3.3 Tsc1 Knockout Mice......Page 149
7.3.4 Mouse Studies: Interbreeding with Other Alleles......Page 151
7.3.5 Mouse Models: Results from Tissue-Restricted Knockout of Tsc1 or Tsc2......Page 152
7.3.6 Mouse Models of TSC Brain Disease......Page 154
7.3.7 Neurocognitive Studies in Tsc1+/–  and Tsc2+/– Mice......Page 157
7.4 Concluding Remarks......Page 161
References......Page 163
8.1 Introduction......Page 169
8.2 Connecting TSC1–TSC2 to the Insulin/PI3K Signaling Pathway......Page 170
8.4 Identification of the Small GTPase Rheb as a Direct Target of the Tsc1–Tsc2 Complex......Page 173
8.5 Control of Autophagy by the Tsc–Rheb–TORC1 Pathway......Page 174
8.6 Cross Talk Between the Tsc–Rheb–TORC1 Pathway and the Insulin Pathway......Page 175
8.8 Upstream of the Tsc1–Tsc2 Complex......Page 176
References......Page 178
Part IV: Brain Involvement......Page 183
9.2 Tubers......Page 185
9.3 SENs and SEGAs......Page 192
9.4 Cell Lineage......Page 195
9.5 mTOR Activation and Biallelic TSC Gene Inactivation......Page 200
9.6 Alternative Signaling Cascades in TSC Brain Lesions......Page 202
9.7 Structural Alterations in Nontuber Brain Areas......Page 203
9.8 Conclusions and Future Directions......Page 205
References......Page 206
10.2 Role of Electroencephalography......Page 211
10.3.1 Pharmacologic Treatment......Page 215
10.3.2 Nonpharmacologic Treatment......Page 216
10.3.3 Epilepsy Surgery in TSC......Page 217
10.4 Infantile Spasms......Page 221
10.4.1 Clinical Features of IS......Page 222
10.4.2 EEG Features of Infantile Spasms......Page 223
10.4.3 Treatment of Infantile Spasms in TSC......Page 226
10.5 Lennox–Gastaut Syndrome......Page 227
10.6 Pathogenesis of Epilepsy in TSC......Page 228
10.7 The Natural History of Epilepsy in TSC......Page 229
References......Page 230
11.1 Introduction......Page 235
11.2 Pathology and Pathogenesis of SEGA......Page 236
11.4 Diagnosis of SEGA Versus SEN......Page 239
11.5 Current Management of SEGASs......Page 242
11.6 Medical Management of SEGAs......Page 244
References......Page 249
12.2 Different Levels of Investigation......Page 253
12.2.1 The Behavioral Level......Page 254
12.2.2 The Psychiatric Level......Page 255
12.2.2.1 Developmental Disorders......Page 256
12.2.2.2 Mood and Anxiety Disorders......Page 258
12.2.2.3 Other Psychiatric Disorders......Page 259
12.2.2.5 Psychiatric Level: Summary......Page 260
12.2.3 The Intellectual Level......Page 261
12.2.3.1 Two Intellectual Subgroups or Phenotypes in TSC......Page 262
12.2.4 The Academic or Scholastic Level......Page 263
12.2.5.1 Overall Neuropsychological Profiles in TSC......Page 265
12.2.5.3 Memory Skills......Page 266
12.2.5.6 Executive Control Processes......Page 267
12.2.6 The Psychosocial Level......Page 268
12.2.7 The Biological Level......Page 269
12.3.1.2 Assessment is Likely to Require Multi-agency, Multi-disciplinary Involvement......Page 270
12.3.1.4 Draw Information Together into a "Formulation of Needs"......Page 274
12.3.2.2 Behavioral Interventions......Page 275
12.3.2.4 Coaching Techniques......Page 276
12.3.2.7 Other Non-pharmacological Approaches......Page 277
12.3.2.8 Pharmacological Approaches......Page 278
12.3.2.9 Educational Interventions......Page 279
12.4.1 Tuber Models......Page 280
12.4.2 Seizure Models......Page 281
12.4.3 Genotype–Phenotype Models......Page 282
12.4.4 Molecular Models......Page 283
12.5 Animal Models for Behavioral, Psychiatric, Intellectual, Learning, and Neuropsychological Deficits in TSC......Page 284
12.6 Future Directions for the Understanding of Behavioral, Psychiatric, Intellectual, Academic, and Neuropsychological Deficits in TSC......Page 285
12.7 How to Live a Positive Life with TSC......Page 287
References......Page 288
Part V: Other Organ Systems......Page 293
13.3.1 Hamartomas......Page 295
13.3.1.1 Noncalcified Hamartomas......Page 298
13.3.2 Complications and Treatment of Retinal Hamartomas......Page 299
13.3.3 Chorioretinal Hypopigmented Lesions......Page 301
13.3.4 Differential Diagnosis......Page 302
13.5 Visual Field Defects......Page 303
13.6 Cerebral Visual Impairment......Page 304
13.8 Summary and Recommendations......Page 305
References......Page 306
14.2.1 Hypomelanotic Macules......Page 309
14.2.2 Facial Angiofibromas......Page 311
14.2.4 Shagreen Patch......Page 313
14.2.5 Ungual Fibromas......Page 315
14.2.7 Significance of Skin Lesions for Diagnosis of TSC......Page 316
14.4.1 Patient Evaluation......Page 317
14.4.3 Patient, Family, and Caregiver Education......Page 319
14.4.4 Insurance Issues......Page 320
14.5.2 Timing of Treatment......Page 321
14.5.3 Patient Preparation......Page 322
14.6.1 CO2 Laser......Page 323
14.6.3 Complications and Risks of CO2 Laser Treatment......Page 324
14.6.4 Limitations of CO2 Laser Treatment......Page 325
14.6.7 Complications and Risks of Vascular Laser Treatment......Page 326
14.7.2 Ungual Fibromas......Page 327
References......Page 329
15.2 Angiomyolipomata......Page 335
15.4 Renal Cystic Disease......Page 338
15.6 Renal Cell Carcinoma......Page 340
15.8 Treatment......Page 341
References......Page 345
16.2.1 Prevalence of Cardiac Rhabdomyomas......Page 351
16.2.3 Natural History of Cardiac Rhabdomyomas in TSC Patients......Page 352
16.3 Clinical Manifestations......Page 354
16.4 Pathology and Molecular Biology of Cardiac Tumors......Page 356
16.5 Diagnosis......Page 358
16.6 Fetal Cardiac Rhabdomyomas and Diagnosis of TSC......Page 359
16.7 Treatment......Page 361
16.9 Vascular Abnormalities in TSC......Page 362
References......Page 364
17.1 Introduction......Page 369
17.3 Epidemiology......Page 370
17.4.1 Physical Examination......Page 372
17.6 Pathology and Laboratory Studies......Page 373
17.7 Physiology......Page 374
17.8 Radiology......Page 375
17.9.2 Pleural Complications......Page 376
17.9.4 Medical Treatment......Page 377
17.9.5 Transplantation......Page 378
17.10.1 Tuberous Sclerosis Complex-Associated LAM......Page 379
17.10.3 LAM Cells Have Evidence of mTOR Activation......Page 380
17.10.5 Estrogen May Promote LAM Pathogenesis......Page 382
17.10.6 Cystic Lung Disease in LAM......Page 383
17.11 Challenges and Future Directions......Page 384
References......Page 386
18.1 Introduction and Summary......Page 393
18.2.2 Pituitary......Page 394
18.2.3 Parathyroid......Page 395
18.2.5 Pancreas......Page 396
18.2.6 Adrenal......Page 397
18.2.7 Gonads......Page 398
18.3.1 Mouth......Page 400
18.3.2 Esophagus and Stomach......Page 402
18.3.4 Large Bowel and Rectum......Page 403
18.4 Hepatic Manifestations of TSC......Page 404
18.6 Lymphatic Manifestations of TSC......Page 405
References......Page 406
Part VI: Family Impact......Page 411
19.2 Impact on the Family......Page 413
19.4 Tuberous Sclerosis Complex Organizations and Support Groups......Page 415
19.5.1 Adults with TSC......Page 416
19.5.3 Siblings of an Individual with TSC......Page 417
19.5.5 Reproductive Options and Decision Making......Page 418
References......Page 419
Index......Page 421