Mitochondrial optic neuropathies (MON)
Authors: Sadun Alfredo A. 
Published: December 2022

When we first proposed the term, Mitochondrial Optic Neuropathies (MON) (Sadun AA. Mitochondrial optic neuropathies. J Neurol Neurosurg Psychiatry. 2002 Apr;72(4):423–5.), it may have seemed odd. The paradigm before then was that many things could injure the optic nerves, and genetic, nutritional and many toxic causes made the list alongside tumours, infections, inflammations, etc. Our experiences in Cuba changed this mode of thinking. There, an epidemic of optic neuropathy (CEON) was found to exist among those consuming small amounts of methanol in the presence of folic acid deficiency. This demonstrated the convergence of toxic and nutritional causes that affected the same (oxidative‐phosphorylation) systems. Several publications have demonstrated that certain metabolic optic neuropathies are more likely in the setting of genetic predispositions. In short, asymptomatic carriers of well characterized genetic disorders such as Leber's Hereditary Optic Neuropathy (LHON), may lose vision when additionally stressed by exposures to certain drugs like ethambutol or to nutritional deficiencies. Several studies have revisited the original diagnosis of tobacco‐alcohol amblyopia (their term) and found about 20% harboured LHON mtDNA mutations (Cullom, et al., Arch Ophthalmol. 1993 Nov;111(11):1482–5).

We hereby present a framework for seeing many forms of metabolic (hereditary, nutritional and toxic) optic neuropathies as related. One unifier is the stereotypic clinical presentation. These patients have, after a while, very symmetric visual losses. The loss of visual acuity, colour vision, and high spatial frequency contrast sensitivity, reflects a pair of symmetrical central or cecocentral scotomas. These aforementioned functional defects are to be expected by the equally characteristic anatomical loss of the small fibres of the papillo‐macular bundle (PMB) which also explains the temporal optic disc pallor. The other unifier is that the molecular injuries cause impairments of mitochondria, and specifically oxidative phosphorylation (Ox‐Phos). We and others have further demonstrated that this especially entails the accumulation of reactive oxygen species (ROS) more than a problem with bioenergetics. This also explains the particular predilection for injury of the smallest and unmyelinated fibres of the PMB.

Several drugs are causes or additional risk factors in MON. Remarkably, most drugs that are best demonstrated to injure the optic nerve are also understood to impair mitochondria and Ox‐Phos. These include ethambutol and linezolid, chloramphenicol, streptomycin, and some antivirals (Wang and Sadun, J Neuroophthalmol. 2013 Jun;33(2):172–8). These drugs can also be regarded, in addition to heavy smoking and binge drinking of alcohol, as exogenous sources of ROS that are likely to bring out Type II LHON (vs Type I LHON which is apt to be genetic/genetic, and occurs at an early age more acutely).

In general, MON represent the unique susceptibility of the optic nerve, and most specifically, the small fibres of the PMB, to the ROS that are generated when mitochondrial Ox‐Phos is defective. When the ROS threshold is exceeded, these fibres are the first to decompensate and this leads to a remarkably consistent phenotype.