While several different mtDNA variants are known to be associated with Leber’s hereditary optic neuropathy (LHON), penetrance is not 100%, and many of the factors contributing to increased penetrance have not been solved.
One theory is that additive mitochondrial dysfunction caused by multiple LHON associated mtDNA variants could contribute to increased severity and/or penetrance of LHON. However, a recent report by Cruz-Bermudez et al (PLOSone 2016 Jan 19;11(1):e0146816.) offers some evidence against this.
In their paper, this group describes the functional and clinical consequences of an mtDNA molecule with three LHON-associated pathogenic variants (m.11778G>A, m.14484T>C, m.11253T>C) . Comparison of cell lines harboring all 3 variants versus only one of the variants revealed no differences in mitochondrial function. In addition, the ophthalmological characteristics found in the patient harboring all three variants were found to be similar to patients harboring only a single mtDNA LHON associated pathogenic variant.
-Hilary Vernon, MD PhD