Genetic Basis for Respiratory Control Disorders (eBook)

Introduction 6
Preface 7
Contributors 9
Contents 16
Abbreviations 21
1. Respiratory control disorders: from genes to patients and back 28
1.1 Introduction 28
1.2 Effect of sleep on breathing 29
1.3 Diagnostic approaches to the patient with suspected abnormalities in respiratory control 30
1.4 Potential consequences of delayed diagnosis and treatment 31
1.5 Where do we go from here? 31
1.6 Conclusion 32
Acknowledgements 32
References 33
2. Hereditary aspects of respiratory control in health and disease in humans 36
2.1 Introduction 36
2.2 Inter-individual variation in human ventilatory control 36
2.3 Population and species differences 38
2.4 Familial clusters 39
2.5 Genetics vs. environment 43
2.6 Locus of hereditary effects 43
2.7 Conclusion 47
References 47
3. Phox2b and the homeostatic brain 51
3.1 Introduction 51
3.2 Expression pattern of Phox2 genes 51
3.3 Gross phenotype of mouse mutants for Phox2 genes 56
3.4 Cellular functions of Phox2 genes 59
3.5 Ancestry of the homeostatic brain 64
Conclusion 64
References 64
4. Congenital central hypoventilation syndrome: from patients to gene discovery 71
4.1 Introduction 71
4.2 Clinical presentation of CCHS 72
4.3 Genetic mutations in CCHS 76
4.4 Phenotype-genotype correlations 77
4.5 Conclusion 78
References 78
5. Structural and functional brain abnormalities in Congenital Central Hypoventilation Syndrome 82
5.1 Introduction 82
5.2 Structural injury and functional deficits in CCHS 83
5.3 Imaging findings 84
5.4 Cardiovascular control deficits 89
5.5 Potential mechanisms in injury 90
5.6 Conclusion 91
Acknowledgements 92
References 92
6. In vitro studies of PHOX2B gene mutations in congenital central hypoventilation syndrome 96
6.1 Introduction 96
6.2 PHOX2B polyalanine expansions 98
6.3 PHOX2B frameshift mutations 102
6.4 Conclusion 104
References 106
7. Sudden infant death syndrome: study of genes pertinent to cardiorespiratory and autonomic regulation 109
7.1 Introduction 109
7.2 Cardiac channelopathy genes in SIDS 110
7.3 Serotonergic system genes in SIDS 112
7.4 Autonomic Nervous System (ANS) genes in SIDS 115
7.5 Nicotine metabolizing genes in SIDS 119
7.6 Clinical significance 121
7.7 Conclusion and directions for future research on genetic factors in SIDS 125
References 125
8. The genetic basis for obstructive sleep apnea: what role for variation in respiratory control? 134
8.1 Introduction 134
8.2 OSA: Definition and health impact 134
8.3 OSA: Evidence for a familial basis 136
8.4 Genetic etiology-risk factors and their use as intermediate phenotypes 138
8.5 Ventilatory control as an intermediate OSA risk factor 139
8.6 Evidence for genetically determined ventilatory control abnormalities in familial OSA 145
8.7 Candidate genes for OSA that may operate through ventilatory control 146
8.8 Inferences from other conditions which involve ventilatory control deficits 148
8.9 Studies from animals 149
8.10 Pleiotropy 149
8.11 Conclusion 149
Acknowledgements 150
References 150
9. Apnea and irregular breathing in animal models: a physiogenomic approach 159
9.1 Introduction 159
9.2 Measuring ventilatory behavior 160
9.3 Defining apnea and ventilatory irregularity 162
9.4 Models of apnea 167
9.5 Model of recurrent apneas 168
9.6 Conclusion 170
References 170
10. Genetic determinants of respiratory phenotypes in mice 174
10.1 Introduction 174
10.2 Experimental methods and design 177
10.3 Observations and results 179
10.4 Significance of genetic determinants 184
10.5 Conclusion 185
References 186
11. Genes and development of respiratory rhythm generation 190
11.1 Introduction 190
11.2 Primordial embryonic rhythm in the neural tube 192
11.3 Parafacial rhythm generators : induction requires Krox20 in r3 and Hoxa1 in r4 194
11.4 Onset of the respiratory rhythm generation 196
11.5 Neurotrophic control of breathing 199
11.6 Brainstem modulatory controls of breathing 201
11.7 Conclusion 202
Acknowledgements 203
References 203
12. Transcription factor control of central respiratory neuron development 211
12.1 Introduction 211
12.2 Brainstem populations of neurons participating in central breathing control 212
12.3 Mouse mutants of transcription factors governing development of respiratory neurons and breathing control 215
12.4. Conclusion 232
References 233
13. Lessons from mutant newborn mice with respiratory control deficits 242
13.1 Introduction 242
13.2 Developmental respiratory control disorders 243
13.3 The newborn mouse 244
13.4 Mutant newborn mice as models of abnormal respiratory rhythm 245
13.5 Mutant newborn mice with abnormal chemosensitivity 248
13.6 Clinical relevance of mutant newborn mice models 252
13.7 Conclusion 253
References 254
14. Tentative mouse model for the congenital central hypoventilation syndrome: heterozygous phox2b mutant newborn mice 261
14.1 Introduction 261
14.2 Neonatal phenotype determination 262
14.3 Non-invasive ventilatory phenotyping in newborn mice 262
14.4 Sleep-disordered breathing in Phox2b+/- newborn mice 264
14.5 Sensitivity to CO 264
14.6 Sensitivity to hypoxia 266
14.7 Arousal response to hypoxia 267
14.8 Sensitivity to hyperoxia 268
14.9 Effects of ambient temperature 268
14.10 Cognitive evaluation of Phox2b 269
mutant mice 269
14.11 Comparison between Phox2b 269
and CCHS 269
phenotypes 269
14.12 Conclusion 271
References 272
15. Respiratory control abnormalities in necdin-null mice: implications for the pathogenesis of Prader- Willi syndrome 276
15.1 Introduction 276
15.2 Transgenic mouse models 276
15.3 Central Respiratory Deficit 277
15.4 General anatomical abnormalities within the CNS 281
15.5 Respiratory dysfunction in PWS 282
15.6 Conclusion 283
References 284
16. Possible role of bioaminergic systems in the respiratory disorders of Rett syndrome 287
16.1 Introduction 287
16.2 Clinical manifestations of respiratory disorders in RTT 288
16.3 Mouse models of RTT 289
16.4 Respiratory studies in mouse models of RTT 291
16.5 Bioaminergic systems, RTT and Mecp2-/ 294
mice 294
16.6 Possible link between bioaminergic and respiratory alterations in mice and RTT patients 296
16.7 Conclusions: bioamines, respiration and RTT 298
Acknowledgements 299
References 299
17. Respiratory plasticity following intermittent hypoxia: a guide for novel therapeutic approaches to ventilatory control disorders? 306
17.1 Introduction 306
17.2 Deficiencies in respiratory motor neuron activity underlie some ventilatory control disorders 307
17.3 Intermittent hypoxia induced respiratory plasticity and metaplasticity 309
17.4 Compensatory plasticity during ventilatory control disorders 313
17.5 Possible therapeutic approaches for ventilatory control disorders: lessons from LTF? 316
17.6 Conclusion 320
Acknowledgements 320
References 321
Index 327