2020–2021 BCSC Basic and Clinical Science Course™
2 Fundamentals and Principles of Ophthalmology
Part III: Genetics
Chapter 5: Molecular Genetics
Leber Hereditary Optic Neuropathy
The most important ophthalmic disease of mitochondria is Leber hereditary optic neuropathy (LHON), which is more prevalent in males than in females but does not fit a classic X-linked pattern of transmission. The trait is not transmitted to the offspring of affected males, but virtually every daughter and son of a female patient with LHON inherits the trait. In approximately 50% of cases, LHON development is correlated with a single base change (G to A at nucleotide position 11778 in the ND-4 gene) in human mtDNA involved in the synthesis of NADH dehydrogenase. In addition to optic atrophy, patients can exhibit peripapillary microangiopathy. LHON can also occur from other so-called primary mutations at nucleotide positions 3460 of ND-1 and 14484 of ND-6, as well as several other rare mutations. At least 12 secondary mutations have been associated with LHON, often when multiple mutations are present in an individual’s mitochondria. Some authors think that these secondary mutations cause disease by additive detrimental effects on the electron transport system of oxidative phosphorylation. Most of these secondary mutations appear in the general population, and debate persists on whether each mutation alone is truly pathogenic.
The likelihood of improvement of visual acuity over time appears to differ among patients with the separate mutations associated with LHON. Mutation at nucleotide position 11778 is associated with the least likelihood of recovery, and mutation at nucleotide position 14484 is associated with the greatest likelihood.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.