Dominant Optic Atrophy and Leber’s Hereditary Optic Neuropathy: Update on Clinical Features and Current Therapeutic Approaches,☆☆

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Dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON) are the two most common inherited optic neuropathies encountered in clinical practice. This review provides a summary of recent advances in the understanding of the clinical manifestations, current treatments, and ongoing clinical trials of these two optic neuropathies. Substantial progress has been made in the understanding of the clinical, genetic, and pathophysiological basis of DOA and LHON. Pathogenic OPA1 gene mutations in DOA and 3 primary mutations of mitochondrial DNA in LHON-induced mitochondrial dysfunction, which in turn leads to increased reactive oxygen species levels in mitochondria and possibly insufficient ATP production. The pathologic hallmark of these inherited optic neuropathies is primary degeneration of retinal ganglion cells, preferentially in the papillomacular bundle, which results in temporal optic disc pallor and central or cecocentral visual loss. There are no effective treatments for patients with LHON and DOA, although clinical trials are underway for the former. Translational research for these diseases is entering an accelerated phase with the availability of animal models, and a variety of pharmacological and genetic therapies are being developed.

Introduction

Inherited optic neuropathies cause irreversible, bilateral visual loss that almost always presents in young patients, with an estimated prevalence of 1 in 10,000.1, 2 Leber hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA) are the two most common disorders of the inherited optic neuropathies seen in clinical practice.2 During the past 25 years, there has been significant progress in the understanding of the clinical, genetic, and pathophysiological basis of these disorders.3 Point mutations of mitochondrial DNA (mtDNA) cause LHON, whereas mutations in the nuclear optic atrophy 1 (OPA1) gene is responsible for most cases of DOA.1, 3, 4 Despite these different genetic bases, LHON and DOA have some overlapping clinical and pathological features, such as selective vulnerability of the retinal ganglion cell (RGC) layer and progressive visual loss due to the mitochondrial dysfunction.1, 2, 3, 5 Respiratory complex I dysfunction caused by mutations of mtDNA in LHON leads to increased production of reactive oxygen species (ROS) and possibly deficient ATP production. Abnormal mitochondrial metabolism caused by OPA1 mutations in DOA makes the RGCs vulnerable to apoptotic-induced degeneration.3, 5, 6 Both disorders have a common pathophysiological outcome that is the generation of excessive ROS cause by mitochondrial dysfunction, which acts as a signal for RGC apoptosis.3, 4, 5 The following discussion provides a review of the current state of understanding about the pathogenesis of these disorders. Our focus is on how emerging insights are leading to new therapeutic approaches, with special emphasis on the ongoing clinical trials for LHON and DOA.

Section snippets

Genetics

DOA is the most commonly diagnosed inherited optic neuropathy, with a prevalence of 1:12,000 to 1:50,000.3, 7, 8 The OPA1 gene is a nuclear gene on chromosome 3q28-q29, and the protein produced by the OPA1 gene is a dynamin-related GTPase, which is essential for mitochondrial inner membrane fusion and maintenance of mitochondrial cristae network.3, 11, 12, 13 The OPA1 protein also is associated with other functions in mitochondria, including interaction with the oxidative phosphorylation

Genetics

LHON is the second most common inherited optic neuropathy and the most common primary mtDNA disorder. LHON is a maternally inherited genetic disorder with an estimated prevalence of 1 in 35,000.1, 18, 35 Up to 90% of LHON cases are owing to 1 of the 3 “major” mtDNA point mutations: m.3460G > A (MTND1); m.11778G > A (MTND4); and m.14484T > C (MTND6). These mutations occur in the ND1, ND4, and ND6 genes of the mtDNA, respectively, and they all encode protein subunits of the metabolically

Treatments

Various vitamin supplements, especially vitamins E and C, and other compounds, including alpha-lipoic acid, l-carnitine, creatine, l-arginine, and cysteine, have been used alone or in combination in an attempt to treat blindness caused by mitochondrial optic neuropathies. However, there is limited evidence of the benefit for these approaches.2, 18, 52

More recently, clinical studies have been interpreted as providing evidence in support of the use of ubiquinone analogues.2, 18, 52 Ubiquinone is

Conclusions

Blindness can result from mutations involving mitochondrial genes, either at the level of the nucleus (the OPA1 gene) or at the level of the mitochondria, although the clinical profile for each differs. In the former, insidious bilateral visual loss occurs, where in the latter, acute or subacute, typically sequential blindness ensues. Both disorders, however, share the preferential involvement of the papillomacular bundle. No definitive and widely accepted treatment exists for either disorder,

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      Nonetheless, there are reports which show non-toxic stress response due to CSE induces mitochondrial elongation and also discusses the contrast/varied observation based on different cell types used in the study [41]. Apart from lung diseases, the most common inherited and observed optic neuropathies Dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON) are linked to the mutations in the mitochondrial related genes [42]. Among them, the DOA is associated with the mutations in the OPA1 and its isoforms [43].

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    Research on DOA in Korea (BYC) was supported by Biomedical Research Institute grant, Kyungpook National University Hospital (2013).

    ☆☆

    J.F.R. is on the data safety monitoring committee for GenSight.

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