Mitochondrial optic neuropathies: our travels from bench to bedside and back again

Abstract

The standard scientific method requires that you make an interesting observation, generate a hypothesis and then design an experiment to test the hypothesis. In ophthalmology, as in most fields of medicine, the observations and hypotheses tend to have more degrees of freedom, and the interpretation of experiments is also more complicated and often indeterminate. But sometimes it works out, going back and forth from bench to bedside to bench, in reiterative cycles. A successful example of alternating bench and bedside studies was presented (AAS) at the 2012 Alper Memorial given at the Washington Hospital Medical Center, illustrating a series of questions and investigations that pertain to mitochondrial optic neuropathies, beginning two decades ago, before the concept of mitochondrial optic neuropathies had much meaning. Basic science questions are often best answered by that extraordinary experiment of nature that we call clinical disease, and clinical questions are often best tested in the laboratory.

Macular nerve fibre and ganglion cell layer changes in acute Leber's hereditary optic neuropathy

“…The present study provides key corroboration of previous investigations2 21–22 that reveal an important feature in the pathobiology of LHON. This diseases spreads as a wave, beginning with the involvement of the smallest calibre fibres found in the inferior portion of the papillomacular bundle.…”

“…Leber's hereditary optic neuropathy (LHON) is a subacute neurodegenerative blinding disorder characterised by selective loss of retinal ganglion cells (RGCs), in particular those originating from small axons from the macula 1 2. The primary cause of neurodegeneration is mitochondrial dysfunction due to maternally inherited mitochondrial DNA (mtDNA) point mutations affecting complex I subunit genes 3.…”

Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration

“…We think that a possible explanation could be found in the intraretinal unmyelinated axons, because they have been proposed to be responsible for the vulnerability of RGCs to mitochondrial dysfunction. 87,[91][92][93] In rodents, intraocular axons contain fewer mitochondria than in the human eye, because axons are shorter in the rodent eye, and thus they are less likely to be affected by light, 87 even under taurine depletion. In addition, it has been proposed that melanopsin may not only provide m þ RGCs the capacity to respond to light, but also to protect them from the damaging effects of light.…”

Leber’s hereditary optic neuropathy - Case report

“…Other, still poorly defined, genetic, or environmental factors may be implicated. About 40% of the individuals affected with LHON do not have a clear family history of this condition [5].…”