Leber hereditary optic neuropathy

Abstract

Purpose of reviewLeber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) genetic disorder in the population. We address the clinical evolution of the disease, the secondary etiological factors that could contribute to visual loss, and the challenging task of developing effective treatments.Recent findingsLHON is characterized by a preclinical phase that reflects retinal ganglion cell (RGC) dysfunction before rapid visual deterioration ensues. Children can present atypically with slowly progressive visual loss or an insidious/subclinical onset that frequently results in considerable diagnostic delays. The LHON mtDNA mutation is not sufficient on its own to precipitate RGC loss and the current body of evidence supports a role for smoking and estrogen levels influencing disease conversion. Clinical trials are currently investigating the efficacy of adeno-associated viral vectors-based gene therapy approaches for patients carrying the m.11778G>A mutation. Mitochondrial replacement therapy is being developed as a reproductive option to prevent the maternal transmission of pathogenic mtDNA mutations.SummaryLHON is phenotypically more heterogeneous than previously considered and a complex interplay of genetic, environmental and hormonal factors modulates the risk of a LHON carrier losing vision. Advances in disease modelling, drug screening and genetic engineering offer promising avenues for therapeutic breakthroughs in LHON.

The Evaluation of Optic Nerves Using 7 Tesla “Silent” Zero Echo Time Imaging in Patients with Leber’s Hereditary Optic Neuropathy with or without Idebenone Treatment

“…Our results, obtained with Silent-MT imaging, show significantly larger diameter and surface area of the left nerve at the third measuring point (distal part of the optic nerve), compared to the group not receiving the treatment. Previous research papers reported the presence of hyperintense areas within the distal part of optic nerves [29,[50][51][52]. Although the duration of illness among analyzed patients is one year at minimum, (post-acute phase of the disease) there were hyperintense lesions visible within the optic nerves in acquired images, which could suggest the degeneration of the optic nerve as a late complication of the disease.…”

“…Idebenone, a short-chain analogue of ubiquinone, has an ability to shuttle electrons from complexes I and II to complex III. Clinical trials proved the visual benefit after Idebenone treatment and suggest that when used within the time window, it may prevent the retinal ganglion cell death [29][30][31][32][46][47][48][49][50][51][52]. Disease onset among LHON carriers is characterized by acute or subacute painless loss of central vision, which is unilateral at the beginning; the other eye is usually affected within six to eight weeks, which may suggest more advanced abnormalities within the single starting nerve [53].…”

Treatment strategies for Leber hereditary optic neuropathy

“…Idebenone is a synthetic, short-chain analogue of ubiquinone, which is responsible for shuttling electrons from complexes I and II directly to complex III [13]. Idebenone has greater bioavailability compared with coenzyme Q10 (CoQ10) as it possesses a less lipophilic tail that allows it to penetrate the blood-brain barrier and mitochondrial membrane more readily [14].…”

“…Both these studies support a visual benefit in a proportion of patients is provided within a critical time window. Idebenone has been approved by the European Medicine Agency (EMA) to treat LHON and post-marketing studies are currently underway to collect additional safety and efficacy data [13].…”

Pluripotent Stem Cell-Based Approaches to Explore and Treat Optic Neuropathies

“…The prevalence is variable according to the geographic zone ranging from 1 in 30 000 to 1 in 100 000 ( Milea and Verny, 2012 ; Carelli et al, 2017 ; Jurkute and Yu-Wai-Man, 2017 ). Three primary mutations, associated with a weak penetrance, have been reported in the mitochondrial genome – revealed by a maternal transmission – which account for approximately 90% of all cases, and all located in genes encoding subunits of the complex I of the respiratory chain ( Wallace et al, 1988 ; Yu-Wai-Man et al, 2011 ; Carelli et al, 2017 ; Jurkute and Yu-Wai-Man, 2017 ). The pathogenic mechanism is mainly due to a reduced energetic efficiency, an increased production of reactive oxygen species, and a disruption of anti-apoptotic pathways ( Carelli et al, 2017 ).…”