Leber´s Hereditary Optic Neuropathy

1.History of Leber’s Hereditary Optic Neuropathy (LHON)11
1.1.First descriptions and definition of the disorder11
1.2.Subsequent reports12
1.3.Genetics12
1.4.Environment13
1.5.Treatment14
1.6.A glimpse into the future14
2.Genetics of LHON18
2.1.Maternally inherited LHON and the role of mitochondrial DNA (mtDNA) pathogenic
variants and haplotypes18
2.2.The new landscape of autosomal recessive LHON (arLHON)20
2.3.Interacting genetic variants in both mtDNA and nuclear genomes: the digenic model20
2.4.Questions that remain to be conclusively resolved21
3.Epidemiology28
3.1.Dependence on age and gender28
3.2.Penetrance and prevalence28
3.3.Genetic variation30
3.4.Association with other diseases30
4.Molecular background and pathophysiology of LHON33
4.1.From mtDNA mutations to complex I dysfunction33
4.2.Complex I dysfunction impacts cell physiology of retinal ganglion cells34
4.3.The specific vulnerability of RGCs and their axons35
5.Phenotypes of LHON39
5.1.Clinical course of adult-onset LHON39
5.1.1.Asymptomatic LHON40
5.1.2.Subacute stage of LHON41
5.1.3.Dynamic stage of LHON41
5.1.4.Chronic stage of LHON41
5.2.Atypical LHON42
5.2.1.Childhood onset LHON42
5.2.2.Late-onset LHON43
5.2.3.LHON plus and LHON-overlap syndromes43
5.2.4.Atypical clinical course43
6.Natural history of LHON45
6.1.Conversion45
6.2.Natural history of chronic LHON45
6.3.Spontaneous visual recovery49
6.4.Longterm sequelae54
6.5.Challenges54
7.Diagnostic pathway and differential diagnosis in LHON56
7.1.Symptoms and signs56
7.1.1.Visual acuity loss56
7.1.2.Visual field defect56
7.1.3.Fundus exam findings: optic disc hyperemia, microangiopathy and pseudoedema56
7.2.Diagnostic pathway: psychophysical findings, electrophysiological testing and retinal
imaging58
7.2.1.Background58
7.2.2.Dyschromatopsia58
7.2.3.Pupillary light reflex and pupillometry59
7.2.4.Electrophysiological findings59
7.2.4.1.Pattern visual evoked potentials59
7.2.4.2.Pattern electroretinogram60
7.2.4.3.PhNR60
7.2.5.Retinal imaging60
7.2.5.1.Optical coherence tomography60
7.2.6.Optic disc perfusion – laser speckle flowgraphy (LSFG)62
7.3.Differential diagnosis of LHON62
7.3.1.Optic neuritis (ON) and other inflammatory disorders of the optic nerve62
7.3.2.Toxic and nutritional optic neuropathies62
7.3.3.Ischemic optic neuropathies63
7.3.4.Compressive optic neuropathies64
8.Special topic: autosomal recessive LHON (arLHON)67
8.1.DNAJC30-associated LHON67
8.1.1.Genetics67
8.1.2.Clinical phenotype68
8.2.NDUFS2-associated LHON70
8.2.1.Genetics70
8.2.2.Clinical phenotype70
9.Treatment rationale and approaches71
9.1.Natural history and disease staging71
9.2.Treatment rationale and therapeutic approaches72
9.3.Therapeutic window and current treatments72
10.Idebenone treatment in LHON76
10.1.What is idebenone?76
10.2.Why idebenone is predestined to work in LHON76
10.3.Preclinical studies76
10.4.Clinical studies77
10.5.Safety and efficacy of idebenone in LHON patients78
10.6.Treatment effects in chronic LHON78
11.Gene therapy80
11.1.Overview of gene therapy80
11.2.Development of gene therapy in LHON – Allotopic expression80
11.3.Clinical trials of gene therapy in LHON82
11.4.Gene therapy – Looking to the future84
Index87