Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

Manickam, Agaath Hedina; Anto, Minu Jenifer; Ramasamy, Sivasamy

doi:10.4103/ijo.ijo_358_17

Cited by 45 publications

(20 citation statements)

References 70 publications

(73 reference statements)

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“…For non-muscle affected mitochondrial diseases, the relation with plasma GDF-15 levels is less clear. In this context, Leber Hereditary Optic Neuropathy (LHON) patients form an interesting group [ 51 , 52 ]. Similar to glaucoma, LHON patients suffer from specific loss of RGCs, which in these patients, is the result of mitochondrial dysfunction caused by mutations in mtDNA.…”

Section: Discussionmentioning

confidence: 99%

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

et al. 2021

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Aim Recently, the level of growth differentiation factor 15 (GDF-15) in blood, was proposed as biomarker to detect mitochondrial dysfunction. In the current study, we evaluate this biomarker in open-angle glaucoma (OAG), as there is increasing evidence that mitochondrial dysfunction plays a role in the pathophysiology of this disease. Methods Plasma GDF-15 concentrations were measured with ELISA in 200 OAG patients and 61 age-matched controls (cataract without glaucoma). The OAG patient group consisted of high tension glaucoma (HTG; n = 162) and normal tension glaucoma (NTG; n = 38). Groups were compared using the Kruskal-Wallis nonparametric test with Dunn’s multiple comparison post-hoc correction. GDF-15 concentration was corrected for confounders identified with forward linear regression models. Results Before correcting for confounders, median plasma GDF-15 levels was significantly lower in the combined OAG group (p = 0.04), but not when analysing HTG and NTG patients separately. Forward linear regression analysis showed that age, gender, smoking and systemic hypertension were significant confounders affecting GDF-15 levels. After correction for these confounders, GDF-15 levels in OAG patients were no longer significantly different from controls. Subgroup analysis of the glaucoma patients did not show a correlation between disease severity and plasma GDF-15, but did reveal that for NTG patients, intake of dietary supplements, which potentially improve mitochondrial function, correlated with lower plasma GDF-15. Conclusion The present study suggests that plasma GDF-15 is not suited as biomarker of mitochondrial dysfunction in OAG patients.

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Section: Discussionmentioning

confidence: 99%

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

et al. 2021

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“…Avoiding harmful environmental factors such as tobacco and alcohol exposure is highly recommended to ameliorate the condition. Translational research for DOA is entering an accelerated phase with the availability of animal models, and a variety of pharmacological and genetic therapies are being developed [42, 43]. Further functional studies are needed to provide further insights into this inherited eye disease.…”

Section: Discussionmentioning

confidence: 99%

A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

Mei

Huang

Cheng

et al. 2019

Journal of Ophthalmology

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Background To investigate the genetic causes and clinical characteristics of dominant optic atrophy (DOA) in a Chinese family. Methods A 5-generation pedigree of 35 family members including 12 individuals affected with DOA was recruited from Shenzhen Eye Hospital, China. Four affected family members and one unaffected family member were selected for whole exome sequencing. Sanger sequencing was used to confirm and screen the identified mutation in 18 members of the family. The disease-causing mutation was identified by bioinformatics analysis and confirmed by segregation analysis. The clinical characteristics of the family members were analyzed. Results A heterozygous missense mutation (c.1313A>G, p.D438G) in optic atrophy 1 (OPA1) was identified in 10 individuals affected with DOA in this family. None of the unaffected family members had the mutation. Patients in this family had vision loss since they were children or adolescence. The visual acuity decreased progressively to hand movement, except for one patient (IV-12) who had relatively good vision of 20/30 and 20/28. The fundus typically manifested as optic disc pallor. The visual fields, optical coherence tomography, and visual evoked potential suggested variable degree of abnormality in patients. Patients who had a history of cigarette smoking and alcohol drinking had more severe clinical manifestations. Conclusions Our results suggest that the p.D438G mutation in OPA1 causes optic atrophy in this family. The patients who carried the mutation demonstrated heterogeneous clinical manifestations in this family. This is the first report on the c.1313A>G (p.D438G) mutation of OPA1 in a Chinese family affected with DOA.

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“…Over 100 years later, the first genetic mutation associated with LHON was described in the mitochondrial encoded gene for NADH Dehydrogenase 4 ( MTND4 ) and subsequent mutations causing LHON have been reported in the MTND1 and MTND6 genes as well. Collectively, between 90 and 95% of all LHON cases are linked to mutations in these genes (reviewed by [ 180 , 181 , 182 ]). The MTND genes encode subunits that are part of respiratory Complex I in the electron transport chain.…”

Section: The Role Of Mitochondria In Optic Nerve and Rgc Pathologymentioning

confidence: 99%

The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

Muench

Patel

Maes

et al. 2021

Cells

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The important roles of mitochondrial function and dysfunction in the process of neurodegeneration are widely acknowledged. Retinal ganglion cells (RGCs) appear to be a highly vulnerable neuronal cell type in the central nervous system with respect to mitochondrial dysfunction but the actual reasons for this are still incompletely understood. These cells have a unique circumstance where unmyelinated axons must bend nearly 90° to exit the eye and then cross a translaminar pressure gradient before becoming myelinated in the optic nerve. This region, the optic nerve head, contains some of the highest density of mitochondria present in these cells. Glaucoma represents a perfect storm of events occurring at this location, with a combination of changes in the translaminar pressure gradient and reassignment of the metabolic support functions of supporting glia, which appears to apply increased metabolic stress to the RGC axons leading to a failure of axonal transport mechanisms. However, RGCs themselves are also extremely sensitive to genetic mutations, particularly in genes affecting mitochondrial dynamics and mitochondrial clearance. These mutations, which systemically affect the mitochondria in every cell, often lead to an optic neuropathy as the sole pathologic defect in affected patients. This review summarizes knowledge of mitochondrial structure and function, the known energy demands of neurons in general, and places these in the context of normal and pathological characteristics of mitochondria attributed to RGCs.

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Mitochondrial genetics and therapeutic overview of Leber's hereditary optic neuropathy

Cited by 45 publications

References 70 publications

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

Plasma GDF-15 concentration is not elevated in open-angle glaucoma

A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

The Influence of Mitochondrial Dynamics and Function on Retinal Ganglion Cell Susceptibility in Optic Nerve Disease

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