Leber hereditary optic neuropathy: bad habits, bad vision?

Abstract

The puzzle that Leber hereditary optic neuropathy (LHON) represents has not been completely solved for over 250 years, despite 20 recent years of rapid advances in mitochondrial genetics (Newman, 2005; Yu-Wai-Man et al ., 2009). Although the majority of the underlying causative point mutations in mitochondrial DNA (mtDNA) have been identified, we still cannot answer the most fundamental questions about this disease (Newman, 2002). Why does not everyone who carries a LHON mitochondrial DNA point mutation have visual loss in their lifetime? Why are males affected more often than females? Why does visual loss occur so preferentially during the second and third decades of life, and so infrequently past the age of 50? What accounts for such an abrupt and catastrophic loss of vision, either simultaneously or sequentially, within weeks to months? And, finally, what is so special about the optic nerve, and presumably the retinal ganglion cells, that makes these structures so exclusively sensitive to an abnormality in mitochondrial DNA, when this is present in every cell of the body? Researchers have proposed multiple theories to account for these unusual features of LHON, only very few of which have been proven. Regarding possible genetic/epigenetic factors, the presence of a primary mitochondrial DNA mutation, primarily those at nucleotide positions 11 778, 14 484 or 3460, is necessary but not sufficient for the phenotypic expression of the disorder (Yu-Wai-Man et al ., 2009). Heteroplasmy, presumably in the retinal ganglion cells, may diminish the chances of visual loss, but even homoplasmy cannot of itself account for most cases of LHON (Chinnery et al ., 2001). Certain mtDNA background haplotypes may influence expression (Hudson et al ., 2007), in particular haplotype J for the 11 778 and 14 484 mutations and haplotype K for the 3460 mutation; yet still, the majority of …