Inherited mitochondrial optic neuropathies

Abstract

Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common inherited optic neuropathies and they result in significant visual morbidity among young adults. Both disorders are the result of mitochondrial dysfunction: LHON from primary mitochondrial DNA (mtDNA) mutations affecting the respiratory chain complexes; and the majority of DOA families have mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein critical for mtDNA maintenance and oxidative phosphorylation. Additional genetic and environmental factors modulate the penetrance of LHON, and the same is likely to be the case for DOA which has a markedly variable clinical phenotype. The selective vulnerability of retinal ganglion cells (RGCs) is a key pathological feature and understanding the fundamental mechanisms that underlie RGC loss in these disorders is a prerequisite for the development of effective therapeutic strategies which are currently limited.

Recent Advances in the Molecular Pathogenesis of Dystonia-Plus Syndromes and Heredodegenerative Dystonias

“…Mutations in mitochondrial respiratory chain complexes I, III or IV may lead to Leber’s hereditary optic neuropathy, a disorder characterized by rapid, often sequential, visual loss beginning between ages 18 and 23 [69]. There is bilateral painless optic atrophy due to death of retinal ganglion cells.…”

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“…1 Approximately 50% demonstrate some form of ocular pathology. 2 Mitochondria provide energy in the form of ATP generated by oxidative phosphorylation; therefore, mitochondrial mutations primarily affect tissues with the greatest energy requirements, such as the retina, the inner ear, central and peripheral nervous systems and cardiac and skeletal muscle.…”

“…The prevalence of at-risk carriers is much higher, estimated at 1 in 8 500 in the UK; furthermore, primary LHON mutations were found in 1 out of 350 neonatal umbilical cord samples. 1,4 LHON is maternally inherited, often results from homoplasmy of the causative mitochondrial mutation, and is incompletely penetrant; visual loss occurs in 50% of males and 10% of females. Symptoms result from retinal ganglion cell (RGC) pathology, which leads to RGC death via apoptosis, resulting in optic nerve degeneration and subsequent blindness.…”

“…Nonocular symptoms of mitochondrial dysfunction may also be present. 1,4 Although many mutations implicated in LHON have been described, 90-95% of the cases result from one of the three common mutations in mitochondrial genes including MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain (MTND1*LHON3460A, OMIM 516000.0001, MTND4*LHON 11778A, OMIM 516003.0001, MTND6*LHON14484C, OMIM 516006.0001). The mitochondrial respiratory NADH-ubiquinone oxidoreductase complex, (Complex I), is composed of 44-45 subunits, seven of which are mitochondrially encoded, and is involved in transfer of electrons from NADH to ubiquinone (coenzyme Q).…”

“…Nonocular symptoms of mitochondrial dysfunction may also be present. 1,4 Although many mutations implicated in LHON have been described, 90-95% of the cases result from one of the three common mutations in mitochondrial genes including MTND1, MTND4 and MTND6, which encode elements of the complex I respiratory chain …”