Leber´s Hereditary Optic Neuropathy

1. History of Leber's Hereditary Optic Neuropathy (LHON) 11
1.1. First descriptions and definition of the disorder 11
1.2. Subsequent reports 12
1.3. Genetics 12
1.4. Environment 13
1.5. Treatment 14
1.6. A glimpse into the future 14
2. Genetics of LHON 18
2.1. Maternally inherited LHON and the role of mitochondrial DNA (mtDNA) pathogenic
variants and haplotypes 18
2.2. The new landscape of autosomal recessive LHON (arLHON) 20
2.3. Interacting genetic variants in both mtDNA and nuclear genomes: the digenic model 20
2.4. Questions that remain to be conclusively resolved 21
3. Epidemiology 28
3.1. Dependence on age and gender 28
3.2. Penetrance and prevalence 28
3.3. Genetic variation 30
3.4. Association with other diseases 30
4. Molecular background and pathophysiology of LHON 33
4.1. From mtDNA mutations to complex I dysfunction 33
4.2. Complex I dysfunction impacts cell physiology of retinal ganglion cells 34
4.3. The specific vulnerability of RGCs and their axons 35
5. Phenotypes of LHON 39
5.1. Clinical course of adult-onset LHON 39
5.1.1. Asymptomatic LHON 40
5.1.2. Subacute stage of LHON 41
5.1.3. Dynamic stage of LHON 41
5.1.4. Chronic stage of LHON 41
5.2. Atypical LHON 42
5.2.1. Childhood onset LHON 42
5.2.2. Late-onset LHON 43
5.2.3. LHON plus and LHON-overlap syndromes 43
5.2.4. Atypical clinical course 43
6. Natural history of LHON 45
6.1. Conversion 45
6.2. Natural history of chronic LHON 45
6.3. Spontaneous visual recovery 49
6.4. Longterm sequelae 54
6.5. Challenges 54
7. Diagnostic pathway and differential diagnosis in LHON 56
7.1. Symptoms and signs 56
7.1.1. Visual acuity loss 56
7.1.2. Visual field defect 56
7.1.3. Fundus exam findings: optic disc hyperemia, microangiopathy and pseudoedema 56
7.2. Diagnostic pathway: psychophysical findings, electrophysiological testing and retinal
imaging 58
7.2.1. Background 58
7.2.2. Dyschromatopsia 58
7.2.3. Pupillary light reflex and pupillometry 59
7.2.4. Electrophysiological findings 59
7.2.4.1. Pattern visual evoked potentials 59
7.2.4.2. Pattern electroretinogram 60
7.2.4.3. PhNR 60
7.2.5. Retinal imaging 60
7.2.5.1. Optical coherence tomography 60
7.2.6. Optic disc perfusion - laser speckle flowgraphy (LSFG) 62
7.3. Differential diagnosis of LHON 62
7.3.1. Optic neuritis (ON) and other inflammatory disorders of the optic nerve 62
7.3.2. Toxic and nutritional optic neuropathies 62
7.3.3. Ischemic optic neuropathies 63
7.3.4. Compressive optic neuropathies 64
8. Special topic: autosomal recessive LHON (arLHON) 67
8.1. DNAJC30-associated LHON 67
8.1.1. Genetics 67
8.1.2. Clinical phenotype 68
8.2. NDUFS2-associated LHON 70
8.2.1. Genetics 70
8.2.2. Clinical phenotype 70
9. Treatment rationale and approaches 71
9.1. Natural history and disease staging 71
9.2. Treatment rationale and therapeutic approaches 72
9.3. Therapeutic window and current treatments 72
10. Idebenone treatment in LHON 76
10.1. What is idebenone? 76
10.2. Why idebenone is predestined to work in LHON 76
10.3. Preclinical studies 76
10.4. Clinical studies 77
10.5. Safety and efficacy of idebenone in LHON patients 78
10.6. Treatment effects in chronic LHON 78
11. Gene therapy 80
11.1. Overview of gene therapy 80
11.2. Development of gene therapy in LHON - Allotopic expression 80
11.3. Clinical trials of gene therapy in LHON 82
11.4. Gene therapy - Looking to the future 84
Index 87