The Pupil Light Reflex in Leber's Hereditary Optic Neuropathy: Evidence for Preservation of Melanopsin-Expressing Retinal Ganglion Cells

Purpose. To assess the retinal ganglion cells function in patients with Leber's hereditary optic neuropathy (LHON) by registering the photopic negative response (PhNR) while the photopic electroretinography is performed. Material and methods. 14 patients with different LHON mutations and 9 healthy individuals were examined. A standard ophtalmological examination was performed, including visual fields, spectral optical coherence tomography, photopic electroretinography and PhNR tests. Results. Significant differences in the PhNR latency (68.4±4.01/64.28±5.37, p<0,01) and the PhNR amplitude (21.5±9.34/32.72±12.73, p<0,003) were revealed in patients with LHON and the control group. The study revealed significant differences between the PhNR latency (р<0.01) and the PhNR amplitude (р<0.008) in patients with visual acuity (VA) ≤ 0.1 and the control group, and between the PhNR amplitude in patients with VA≥0.13 and the control group (р<0.05). There were found significant correlations between the PhNR parameters and visual acuity, mean sensitivity, RNFL and GCC thickness. A strong positive correlation was found between the PhNR amplitude and the GCC thickness in patients with VA≥0.3. Conclusion. The PhNR parameters reflect the retinal ganglion cells function in patients with LHON and correlate with RNFL and GCC structural changes. Key words: Leber hereditary optic neuropathy, mitochondrial optical neuropathies, retinal ganglion cell, photopic negative response, PhNR.

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Leber Hereditary Optic Neuropathy: Review of Treatment and Management

Frontiers in Neurology ◽

10.3389/fneur.2021.651639 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rabih Hage ◽

Catherine Vignal-Clermont

Keyword(s):

Retinal Ganglion Cells ◽

Optic Neuropathy ◽

Visual Loss ◽

Ganglion Cells ◽

Management Strategies ◽

Retinal Ganglion ◽

Leber Hereditary Optic Neuropathy ◽

Efficient Treatment ◽

Loss Of Vision ◽

Hereditary Optic Neuropathy

Leber hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disease that specifically targets the retinal ganglion cells by reducing their ability to produce enough energy to sustain. The mutations of the mitochondrial DNA that cause LHON are silent until an unknown trigger causes bilateral central visual scotoma. After the onset of loss of vision, most patients experience progressive worsening within the following months. Few of them regain some vision after a period of ~1 year. Management of LHON patients has been focused on understanding the triggers of the disease and its pathophysiology to prevent the onset of visual loss in a carrier. Medical treatment is recommended once visual loss has started in at least one eye. Research evaluated drugs that are thought to be able to restore the mitochondrial electron transport chain of the retinal ganglion cells. Significant advances were made in evaluating free radical cell scavengers and gene therapy as potential treatments for LHON. Although encouraging the results of clinical trial have been mixed in stopping the worsening of visual loss. In patients with chronic disease of over 1 year, efficient treatment that restores vision is yet to be discovered. In this review, we summarize the management strategies for patients with LHON before, during, and after the loss of vision, explain the rationale and effectiveness of previous and current treatments, and report findings about emerging treatments.

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Exploiting hiPSCs in Leber's Hereditary Optic Neuropathy (LHON): Present Achievements and Future Perspectives

Frontiers in Neurology ◽

10.3389/fneur.2021.648916 ◽

2021 ◽

Vol 12 ◽

Author(s):

Camille Peron ◽

Alessandra Maresca ◽

Andrea Cavaliere ◽

Angelo Iannielli ◽

Vania Broccoli ◽

...

Keyword(s):

Optic Neuropathy ◽

Ganglion Cells ◽

Deep Understanding ◽

Specific Cell ◽

Leber’S Hereditary Optic Neuropathy ◽

Inherited Disease ◽

Leber's Hereditary Optic Neuropathy ◽

Mtdna Mutations ◽

Hereditary Optic Neuropathy

More than 30 years after discovering Leber's hereditary optic neuropathy (LHON) as the first maternally inherited disease associated with homoplasmic mtDNA mutations, we still struggle to achieve effective therapies. LHON is characterized by selective degeneration of retinal ganglion cells (RGCs) and is the most frequent mitochondrial disease, which leads young people to blindness, in particular males. Despite that causative mutations are present in all tissues, only a specific cell type is affected. Our deep understanding of the pathogenic mechanisms in LHON is hampered by the lack of appropriate models since investigations have been traditionally performed in non-neuronal cells. Effective in-vitro models of LHON are now emerging, casting promise to speed our understanding of pathophysiology and test therapeutic strategies to accelerate translation into clinic. We here review the potentials of these new models and their impact on the future of LHON patients.

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Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

Journal of Ophthalmology ◽

10.1155/2011/179412 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 26

Author(s):

Rajeshwari D. Koilkonda ◽

John Guy

Keyword(s):

Optic Neuropathy ◽

Ganglion Cells ◽

Phenotypic Expression ◽

Point Mutations ◽

Population Based ◽

Incomplete Penetrance ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Mtdna Mutation ◽

Hereditary Optic Neuropathy

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

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XIAP Protects Retinal Ganglion Cells in the Mutant ND4 Mouse Model of Leber Hereditary Optic Neuropathy

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.61.8.49 ◽

2020 ◽

Vol 61 (8) ◽

pp. 49

Author(s):

Sarah J. Wassmer ◽

Yves De Repentigny ◽

Derek Sheppard ◽

Pamela S. Lagali ◽

Lijun Fang ◽

...

Keyword(s):

Mouse Model ◽

Retinal Ganglion Cells ◽

Optic Neuropathy ◽

Ganglion Cells ◽

Retinal Ganglion ◽

Leber Hereditary Optic Neuropathy ◽

Hereditary Optic Neuropathy

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Three Cases of Leber’s Hereditary Optic Neuropathy with Rapid Increase in Visual Acuity After Gene Therapy

Current Gene Therapy ◽

10.2174/1566523219666190618094505 ◽

2019 ◽

Vol 19 (2) ◽

pp. 134-138 ◽

Cited By ~ 2

Author(s):

Yong Zhang ◽

Jia-jia Yuan ◽

Hong-li Liu ◽

Zhen Tian ◽

Si-wei Liu ◽

...

Keyword(s):

Gene Therapy ◽

Visual Acuity ◽

Optic Neuropathy ◽

Ganglion Cells ◽

Mitochondrial Gene ◽

Genetic Diagnosis ◽

Leber’S Hereditary Optic Neuropathy ◽

Leber's Hereditary Optic Neuropathy ◽

Spontaneous Improvement ◽

Hereditary Optic Neuropathy

Background: During the first few trials of gene therapy for Leber’s hereditary optic neuropathy performed by our group, the visual acuity of the patients increased gradually over several months, or even years. However, in the current round of gene therapy for Leber’s hereditary optic neuropathy, we noted that the visual acuity of three patients increased rapidly, within a few days after treatment. Case presentation: Three patients who were diagnosed with mitochondrial gene 11778 mutation (associated with a G-to-A transition at Mt-11778 in the ND4 subunit gene of complex I of mitochondrial DNA that changes an arginine to histidine at amino acid 340) by genetic diagnosis were followed up three times before gene therapy, which lasted for 1 year, without spontaneous improvement of vision. Visual acuity in one or both eyes of each of the three patients increased rapidly after the initial gene therapy treatment. Conclusions: We suspect that in some patients with Leber’s hereditary optic neuropathy, a portion of the retinal ganglion cells might remain in a “dormant” state for a certain period of time; these may be activated, within an optimal timeframe, during gene therapy for Leber’s hereditary optic neuropathy.

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