• Written By: Alfredo A. Sadun, MD, PhD

    Leber's Hereditary Optic Neuropathy (LHON) is due to one of several mitochondrial DNA mutations and hence all offspring of a carrier or an affected mother will at least be carriers of the disease.  Some, but not all of these offspring will go on to severe and abrupt loss of vision, usually as young adults. Disease penetrance, meaningthe  frequency with which carriers convert to the disease, varies with the pedigree. Generally, about 50 percent of men and 10 percent of women will go on to develop devastating optic neuropathy. The explanation for why one brother suffers profound visual loss and the other maintains 20/20 vision all his life is the subject of much inquiry. Various genetic, epigenetic and environmental risk factors have been proposed and investigated. 

    This study provides evidence that optic nerve head (ONH) size may predispose or protect LHON carriers from going blind. Because ONH anatomy is presumably determined by nuclear genes, these findings also provide another mechanism by which nuclear-modifying genes might affect penetrance in LHON.

    Researchers took two independent samples, one from a very large pedigree of 11778 LHON from Brazil and the other from a cohort of 45 Italian pedigrees with different mutation types (11778, 3460, 14484 and 3733). All were studied using OCT to ascertain whether ONH size was associated with variations in the clinical expression of LHON.  In both the Brazilian (p < .002) and Italian (P < .001) pedigrees, ONH area was significantly larger in LHON carriers than in the control groups. In the Italian samples, the mean ONH area and vertical disc diameter were significantly higher in the LHON carriers than in LHON-affected subjects (P < .001).  Furthermore, visual recovery (infrequent in LHON and usually found only in mutation type 14484) was associated with a larger vertical disc diameter (P < .03). In Brazilian and Italian families, a large ONH was found to be protective with regard to lowering the risk of conversion or increasing the chances of recovery in LHON. 

    The large Brazilian cohort offered an opportunity to study many subjects with the same mutation within a similar environment. However, there could be co-existing nuclear genes that might segregate within this large family. For the Italian cohort there would be larger variances in both mitochondrial and nuclear genetics and also in the environment, but any co-existing family traits would be expected to dilute out. 

    Previous studies have demonstrated factors that might influence penetrance. For example, heteroplasmy (less than 100 percent of mitochondria in an LHON subject carry the mutated gene) can decrease the risk of becoming affected. On the other hand, some environmental factors - including tobacco, alcohol and pesticides -  can increase the risk of LHON carriers becoming affected. This current study suggests that the anatomical predisposition of the so-called disc at risk might apply to LHON as well as to anterior ischemic optic neuropathy.


    Financial Disclosures

    Dr. Sadun is a consultant to Allergan, Inc., and Pfizer Ophthalmics.