Mitochondrial diseases are often hard to diagnose. From the time they were first researched without animal models, patients of mitochondrial diseases were of equal interest to both clinical and basic scientists. With the new research done, this book includes updates on the normal structure, function, and molecular biology of the mitochondrial respiratory chain, information on traditional diagnostical methodologies, and an overview of the diagnostic promise of new technologies. The hypermetabolism of Luft disease, although only seen twice, is also studied. There are critical reviews of symptoms and signs associated with syndromes, as well as updates on the genetic defects of either the mitochondrial or the nuclear genome responsible for many disorders.

Foreword

xiii

1. The Human OXPHOS System: Structure, Function and Physiology

1

(27)

Immo E. Scheffler

Complexes of the Electron Transport Chain

2

(13)

The ATP Synthase

15

(4)

Regulation of Oxidative Phosphorylation

19

(1)

Assembly of Electron Transport Complexes

20

(8)

2. Molecular Biology of the OXPHOS System

28

(15)

Richard C. Scarpulla

mtDNA

28

(2)

Mitochondrial Inheritance

30

(1)

Replication, Transcription, RNA Processing

30

(5)

Recombination and Repair

35

(1)

Mitochondrial Translation System

35

(1)

Bi-Genomic Expression of the Respiratory Chain

36

(7)

3. Clinical Diagnosis of Oxidative Phosphorylation Disorders

43

(10)

Robert McFarland, Patrick F. Chinnery, Robert W. Taylor, Andrew M. Schaefer and Douglass M. Turnbull

Epidemiology of Defects of Mitochondrial Oxidation

44

(2)

Clinical Features of Patients with Defects of Mitochondrial Oxidation

46

(3)

Investigation of Suspected Mitochondrial Disease

49

(4)

4. Contribution of Histopathological Examination to the Diagnosis of OXPHOS Disorders

53

(26)

Martin Lammens and Henk ter Laak

Muscle Biopsy Diagnosis

53

(6)

Morphological Hallmarks for Diagnosis of OXPHOS Disorders

59

(6)

Mitochondrial Changes in Muscle Biopsies without OXPHOS Disorder

65

(1)

Muscle Biopsy in OXPHOS Disorders

65

(7)

Pathological Findings in Other Organs

72

(7)

5. Biochemical Diagnosis of OXPHOS Disorders

79

(16)

J.M. Frans Trijbels, Antoon J.M Janssen, Lambert P. van den Heuvel, Rob C.A. Sengers and Jan A.M. Smeitink

Examination of Body Fluids

80

(1)

Examination of Tissues

81

(1)

Biochemical Diagnostic Investigations

82

(8)

Frozen Muscle Samples

90

(1)

Complex IV (Cytochrome c Oxidase)

91

(1)

Complex V

91

(1)

Practical Guidelines for Biochemical Examinations of Muscle

92

(1)

Investigation of Fibroblasts

93

(1)

Residual Enzyme Activity

93

(2)

6. Mitochondrial DNA and OXPHOS Disorders

95

(22)

Massimo Zeviani and Valerio Carelli

General Background

95

(1)

Mitochondrial Genetics

96

(1)

Sequence and Gene Organization of mtDNA

97

(3)

Mitochondrial Disorders Due to Mutations of mtDNA

100

(2)

Mutations of mtDNA

102

(1)

Large-Scale Rearrangements

103

(4)

Point Mutations

107

(1)

Heteroplasmic Point Mutations

107

(2)

Other Syndromes

109

(1)

Homoplasmic mtDNA Mutations

109

(1)

Other Homoplasmic Mutations

110

(1)

Genetic Counseling

111

(6)

7. Nuclear DNA and Oxidative Phosphorylation

117

(13)

Lambert P. van den Heuvel and Jan A.M. Smeitink

Biochemistry and Molecular Biology of the OXPHOS System

118

(1)

Nuclear DNA Mutations

119

(11)

8. Cell Biological Consequences of OXPHOS Disorders

130

(19)

Werner J. H. Koopman, Henk-Jan Visch, Sjoerd Verkaart and Peter H.G.M. Willems

Mitochondrial Function in the Living Cell

130

(2)

Cellular Calcium Signalling

132

(7)

Cellular Consequences of OXPHOS Deficiency

139

(10)

9. Animal Models of OXPHOS Disorders

149

(21)

Nicole Hance and Nils-Göran Larsson

A Drosophila Model of Mitochondrial Deafness

150

(1)

Mouse Models of Nuclear DNA Mutations

150

(7)

Manipulation of Mitochondrial Transcription Factor A Expression in Mice

157

(5)

Transmitochondrial Mouse Models

162

(4)

Defective Nuclear-Mitochondrial DNA Interactions Resulting in Hearing Loss

166

(4)

10. Therapeutic Options in OXPHOS Disorders

170

(6)

Rob C.A. Sengers, J.M. Frans Trijbels, Carolien C.A. Boelen, Eva Morava and Jan A.M. Smeitink

Therapeutic Approaches

171

(1)

Practical Approaches

172

(1)

Future Therapies

173

(1)

Evaluation of Treatment

174

(2)

11. Prenatal Diagnostics in Oxidative Phosphorylation Disorders

176

(11)

Antoon J.M. Janssen, Letitia E.M. Niers, Lambert P. van den Heuvel, Jan A.M. Smeitink, Rob C.A. Sengers and J.M. Frans Trijbels

Prerequisites for Offering Prenatal Diagnosis in OXPHOS Disorders

177

(3)

Tissues to Be Used for Prenatal Diagnosis in OXPHOS Disorders

180

(1)

Methods for Prenatal Diagnosis in OXPHOS Disorders

181

(1)

Results of Prenatal Diagnosis for OXPHOS Disorders in Our Center

182

(2)

General Considerations

184

(3)

12. Future Developments in the Laboratory Diagnosis of OXPHOS Disorders

187

(14)

David R. Thorburn

In Vivo Assessment of OXPHOS Function

188

(1)

Minimally Invasive Tissue Samples

188

(2)

OXPHOS Function

190

(2)

OXPHOS Constituents

192

(2)

OXPHOS Genetics

194

(1)

Prenatal Diagnosis & Prevention

195

(6)

Index

201

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Oxidative Phosphorylation In Health And Disease

9780306482328

0306482320

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