Leber’s hereditary optic neuropathy (LHON) was the first clinically described mitochondrial disorder (1871). This article reviews the pathophysiology and clinical features of LHON with a focus on translational research. G11778A is currently the most common mutation worldwide and is associated with LHON. Other mutations at T14484C and G3460A were later identified. LHON mutations affect Complex 1 activity, resulting in malfunction of oxidative phosphorylation. This, in turn, results in inadequate production of adenosine triphosphate (ATP) and an increase in reactive oxygen species, leading to apoptosis of retinal ganglion cells (RGCs). LHON has an incomplete penetrance, since not all individuals with the affected genotype will develop visual dysfunction, but is definitely greater in men than women.
There is some evidence to support the protective role of oestrogen in vitro. Being a mitochondrial disease, LHON is unique in that it tends to affect only the optic nerve and not multiple metabolically active organs. The target tissue in LHON is the RGC and, more specifically, the papillomacular bundle, which is most sensitive to damage. A typical case of LHON is presented, followed by description of the classic clinical features of LHON, including decreased visual acuity, dyschromatopsia, central or ceco-central scotomata, and rapid progression within weeks with sequential involvement of the contralateral eye. Pathognomonic acute funduscopic abnormalities consist of swelling of the peri-papillary region (disc pseudo-oedema), hyperaemia of the optic nerve head, circumpapillary telangiectasia and tortuous, engorged retinal vessels with progressive of optic nerve pallor and late resolution of the disc pseudo-oedema. Only 4% of patients with G11778A mutation report spontaneous recovery, whereas those with T14484C mutation have the best prognosis, with up to 65% reporting spontaneous recovery. LHON plus disease, refers to patients that suffer from co-existing, extraocular manifestations, such as pre-excitation cardiac conduction arrhythmias, dystonia, encephalopathies and brainstem syndromes.
The development of an animal model for LHON has been critical to the understanding of the disease process and has been essential to evaluate the efficacy of potential treatments. Rotenone, a Complex-1 inhibitor, has been readily used as a substrate to induce selective loss of the retinal ganglion cell layer via increased reactive oxygen species and apoptosis. Gene therapy has been utilised to create defective Complex-1 subunits in vivo. Specifically, with the use of adenovirus vectors (AVV), LHON mutations have been inserted into the nuclear genome with ultimate expression of the protein in the mitochondria of mice and rat models. To date, there are no curative treatments available for LHON or other mitochondrial diseases. Corticosteroids, cyanide antagonists, vitamins, minerals, brimonidine purite 0.15%, immunosuppressants, such as Cyclosporine-A, and more recently Ubiquinone analogues, such as Co-enzyme Q10, Idebenone (RHODOS study), EPI-743, have all been tried to reverse the natural history of LHON with no proven success. In 2012, the currently available therapies for mitochondrial diseases were evaluated in a Cochrane review.
Despite an analysis of 1335 articles and 12 randomised controlled trials, there was no significant evidence that any intervention, including surgical interruption of arachnoid adhesions in the optic chiasm for LHON, changed the outcome of these disorders. Gene therapy is an attractive potential treatment for LHON. Allotopic and zenotopic gene therapy have demonstrated some benefit in preliminary pilot studies using AVV-mediated delivery systems in mice after rotenone induction. Although gene therapy has significant potential in LHON, there are many obstacles that need to be overcome prior to the implementation of such a treatment, including the analysis of the safety and efficacy of AVV, timing for initiation of therapy and determination of long-term effects and side-effects of such interventions.