LHON is classically associated with mitochondrial base pair mutations G11778A (guanine to adenine at position 11778), T14484C (tyrosine to cytosine), and G3460A. These mutations primarily affect respiratory chain complex I genes, mitochondrial genes ND1, ND4 and ND6 among others.
The G11778A is the most common, reported to account for 70% of cases in Northern European populations, and 90% in Asian populations. It is associated with more severe disease, with less chance of significant visual recovery.
The T14484C mutation is associated with the best overall prognosis, with some visual recovery in 37-58% of cases. This typically occurs after reaching a visual ‘nadir’. The G3460A mutation usually portends a more intermediate course.
It is unknown why males are preferentially affected. Theories include the presence of a ‘susceptibility locus’ on the Y chromosome, or to estrogen protecting women.