What is Leber's optic neuropathy
The Leber's optic neuropathy (LHON or Leber's optic atrophy) is a mitochondrial neurodegenerative disease of the optic nerve that causes sudden bilateral vision loss. The disease manifests itself between between 15 and 30 years of age age and affects males much more frequently than females, with a ratio of 4:1 and an estimated incidence of between 1/15,000-1/50,000.
LHON is characterised by three clinical phases: pre-symptomatic, acute and atrophic.
In the phase pre-symptomaticpatients have no real visual loss, but may have a reduced contrast sensitivity and impaired red-green vision. Fundus examination may reveal peripapillary telangiectasic vessels and/or pseudo-oedema of the retinal nerve fibre layer (RNFL), particularly in the papillo-macular bundle, electroretinogram may also indicate retinal malfunction.
The acute phase of the disease is typically characterised by a painless, unilateral loss of central visual acuity. The visual field test generally reveals central or centrocecal scotoma, probably due to involvement of the papillo-macular bundle. In 75% of cases, the other eye is affected in the same way 6-8 weeks after the initial event. Defects in the central or centrocecal visual field may progressively widen over time. Eventually, it occurs an optic atrophyand the visual loss is usually permanent.
More than 95% of LHON patients show point mutations in mitochondrial DNA (mtDNA) at one of three positions: 11778 (associated with worse long-term visual prognosis), 14484 (associated with better prognosis) and 3460 (associated with intermediate prognosis). These mutations are believed to involve dysfunction of Complex I of the electron transport chain and overproduction of reactive oxygen species (ROS).
The causes of the disease
The triggering factors responsible for the progression from the pre-symptomatic to the acute phase are not yet known. An involvement of the tobacco smoke and alcohol consumption, vitamin B12 deficiency, head injury and increased intraocular pressure.
A recent study, conducted by researchers at McGill University (Montréal, Canada) and published in the journal Scientific Reports, opens the door to understanding the causes of LHON. Researchers had previously shown that the axons connecting the eye to the brain are sensitive to a certain free radical known as 'superoxide', and hypothesised that the presence of high amounts of the latter was behind the onset of LHON.
The authors pointed out that Leber's optic neuropathy preferentially involves the axons smaller than the temporal optic nerve, and then performed a simulationusing the Monte Carlo method of damage propagation in LHON-affected axons to understand why this predilection occurs. The researchers also simulated the propagation of damage from a localised concentration of superoxide by passive diffusion from one axon to adjacent axons, with basal production and scavenger rate proportional to axon area and volume, respectively.
The study shows that axonal degeneration occurred when the intra-axonal concentrations of superoxide reached a toxic threshold. The simulations showed that almost all small and medium-sized axons became degenerated by the time steady state was reached, but about 50% of the large axons were preserved. The axonal degeneration pattern of the simulations reflected both the visual fields and the histology of the optic nerve of the LHON patient.
The model provided by this study and its validation with visual fields and pathology in the patient, provides a explanation of the pathophysiological mechanism of the onset and progression of LHON consistent with the anatomical and clinical characteristics of the disease; thus unravelling part of the mystery behind it.
Source
Propagation and Selectivity of Axonal Loss in Leber Hereditary Optic Neuropathy. Razek Georges Coussa, Pooya Merat, Leonard A. Levin. Scientific Reports, 2019; 9 (1).
Dr. Carmelo Chines
Direttore responsabile
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