Solutions to a Radical Problem: Overview of Current and Future Treatment Strategies in Leber’s Hereditary Opic Neuropathy

Spiegel, Samuel J.; Sadun, Alfredo A.

doi:10.3390/ijms232113205

Cited by 6 publications

(5 citation statements)

References 81 publications

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“…There is a growing consensus that in LHON, the cause of RGC death comes from an excess of ROS production, not lower bioenergetics. ATP depletion would impair axon function long before leading to a wave of apoptosis as is seen clinically in LHON ( 4 ). Furthermore, ATP depletion is relatively minor compared with increased ROS production as noted in cybrid and animal models of LHON ( 5 , 7 , 8 ).…”

Section: Resultsmentioning

confidence: 99%

“…Symptoms include rapid loss of visual acuity, dyschromatopsia, dense central scotoma, and optic atrophy ( 1 , 2 ). This is known to be caused by one of several different mutations in the electron transport chain of mitochondria ( 3 , 4 ). The mitochondrial DNA (mtDNA) mutation is necessary but not sufficient to cause vision loss through this optic neuropathy.…”

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confidence: 99%

“…CoQ10 reduction occurs where the electron and proton transfer assemblies of complex 1 are most critical. This juxtaposition creates a crux for disease-causing mutations to interfere with electron transfer in a manner that promotes electron leakage, creating superoxide and other reactive oxygen species (ROS) ( 4 ).…”

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confidence: 99%

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Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

Fuller,

Barnes,

Sadun

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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How does a single amino acid mutation occurring in the blinding disease, Leber’s hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation’s replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

Fuller,

Barnes,

Sadun

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…Another predictive factor was the type of mutation found. All of our patients had the 11778 G>A mutation, which was the most common mutation and was considered to offer the worst visual outcomes [32,33].…”

Section: Discussionmentioning

confidence: 99%

Leber’s Hereditary Optic Neuropathy (LHON): Clinical Experience and Outcomes after Long-Term Idebenone Treatment

Baltă,

Cristache,

Barac

et al. 2023

Life

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Background: Leber’s hereditary optic neuropathy (LHON) is a rare disease. Large studies are difficult to conduct; therefore, case reports provide valuable data. Since 2015, patients have been treated with Idebenone. The aim of this paper is to share our experience with diagnosing and managing patients in different stages of LHON. Methods: We designed a case series study, including four patients undergoing genetic testing and ophthalmologic examination. Criteria for Idebenone administration and follow-up were presented. Results: All patients had mutation 11778G>A in MT-ND4. The first patient, an 82-year-old man, with long history of vision loss, had no indication for Idebenone. Two additional cases emerged within the same family: a 40-year-old brother and a 31-year-old sister. Both received Idebenone, with good outcomes only for the female. After a one-year regimen, they were lost to follow-up. The fourth patient, a 46-year-old man, was diagnosed in the subacute stage. Idebenone administration was deferred, allowing progression of visual field defects. After 17 months of treatment, visual improvement appeared. The treatment was continued for 36 months, with short interruptions, resulting in good outcomes. Conclusions: Our study demonstrated positive results with long-term Idebenone use. Contrary to medical literature, our female patient had a favorable evolution, despite the delayed diagnosis.

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“…Historically, treatment options have been quite limited, but ongoing clinical trials show promise, with significant advances being made in the testing of free radical scavengers and gene therapy. Spiegel and Sadun [ 11 ] summarize the management strategies and rationale of treatments based on current insights from molecular research. Their review includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics.…”

Section: Reviewsmentioning

confidence: 99%

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

Miller

Tsai

2023

IJMS

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Solutions to a Radical Problem: Overview of Current and Future Treatment Strategies in Leber’s Hereditary Opic Neuropathy

Cited by 6 publications

References 81 publications

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

Coenzyme Q10 trapping in mitochondrial complex I underlies Leber’s hereditary optic neuropathy

Leber’s Hereditary Optic Neuropathy (LHON): Clinical Experience and Outcomes after Long-Term Idebenone Treatment

Optic Neuropathies: Current and Future Strategies for Optic Nerve Protection and Repair

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