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https://read.qxmd.com/read/38117686/leber-hereditary-optic-neuropathy-gene-therapy
#21
JOURNAL ARTICLE
Byron L Lam
PURPOSE OF REVIEW: To discuss relevant clinical outcomes, challenges, and future opportunities of gene therapy in Leber hereditary optic neuropathy (LHON). RECENT FINDINGS: Results of G11778A LHON Phase 3 randomized clinical trials with unilateral intravitreal rAAV2/2-ND4 allotopic gene therapy show good safety and unexpected bilateral partial improvements of BCVA (best-corrected visual acuity) with mean logMAR BCVA improvements of up to near ∼0.3 logMAR (3 lines) in the treated eyes and ∼0...
December 21, 2023: Current Opinion in Ophthalmology
https://read.qxmd.com/read/38107630/case-report-mutations-in-dnajc30-causing-autosomal-recessive-leber-hereditary-optic-neuropathy-are-common-amongst-eastern-european-individuals
#22
Toby Charles Major, Eszter Sara Arany, Katherine Schon, Magdolna Simo, Veronika Karcagi, Jelle van den Ameele, Patrick Yu Wai Man, Patrick F Chinnery, Catarina Olimpio, Rita Horvath
BACKGROUND: Leber Hereditary Optic Neuropathy (LHON) is the most common inherited mitochondrial disease characterized by bilateral, painless, subacute visual loss with a peak age of onset in the second to third decade. Historically, LHON was thought to be exclusively maternally inherited due to mutations in mitochondrial DNA (mtDNA); however, recent studies have identified an autosomal recessive form of LHON (arLHON) caused by point mutations in the nuclear gene, DNAJC30 . CASE PRESENTATIONS: In this study, we report the cases of three Eastern European individuals presenting with bilateral painless visual loss, one of whom was also exhibiting motor symptoms...
2023: Frontiers in Neurology
https://read.qxmd.com/read/38071962/correlation-between-residual-sensitivity-in-the-central-inferior-nasal-visual-field-and-visual-function-in-chronic-leber-hereditary-optic-neuropathy-patients
#23
JOURNAL ARTICLE
Maya Kishi, Kaori Ueda, Takuji Kurimoto, Makoto Nakamura
INTRODUCTION: Leber hereditary optic neuropathy (LHON) is a maternally inherited, acute or subacute, optic neuropathy. The typical symptoms include reduced visual acuity and central scotoma. Despite the presence of deep central scotoma, some patients with LHON are able to perform daily activities. This study aimed to investigate the correlation between the residual visual field and visual acuity, critical flicker frequency, and fixation ellipse in patients with chronic LHON. METHODS: Residual visual function (defined as sensitivity points where patients sensed the size V stimulus) of both eyes was evaluated in 10 patients with LHON carrying the m...
December 9, 2023: Ophthalmic Research
https://read.qxmd.com/read/38069388/mitochondrially-targeted-gene-therapy-rescues-visual-loss-in-a-mouse-model-of-leber-s-hereditary-optic-neuropathy
#24
JOURNAL ARTICLE
Tsung-Han Chou, Zixuan Hao, Diego Alba, Angelina Lazo, Gabriele Gallo Afflitto, Jeremy D Eastwood, Vittorio Porciatti, John Guy, Hong Yu
Leber's hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4 ) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups ( p < 0.001), with significant differences among groups ( p = 0...
December 2, 2023: International Journal of Molecular Sciences
https://read.qxmd.com/read/38054206/exploring-mito-nuclear-genetic-factors-in-leber-s-hereditary-optic-neuropathy-insights-from-comprehensive-profiling-of-unique-cases
#25
JOURNAL ARTICLE
Prakash Chermakani, Poigaialwar Gowri, Shanmugam Mahesh Kumar, Periasamy Sundaresan
Leber's hereditary optic neuropathy (LHON) is a mitochondrial complex I disorder and causes inexorable painless vision loss. Recent studies from India reported that a significant proportion of LHON patients lack primary mitochondrial DNA mutations, suggesting that alternative genetic factors contribute to disease development. Therefore, this study investigated the genetic profile of LHON-affected individuals in order to understand the role of mito-nuclear genetic factors in LHON. A total of thirty probands displaying symptoms consistent with LHON have undergone whole mitochondrial and whole exome sequencing...
2023: EXCLI Journal
https://read.qxmd.com/read/38016117/leber-s-hereditary-optic-neuropathy-update-on-the-novel-genes-and-therapeutic-options
#26
JOURNAL ARTICLE
Jui-Lin Hu, Chih-Chien Hsu, Yu-Jer Hsiao, Yi-Ying Lin, Wei-Yi Lai, Yu-Hao Liu, Chia-Lin Wang, Yu-Ling Ko, Ming-Long Tsai, Huan-Chin Tseng, Yueh Chien, Yi-Ping Yang
A maternal inheritance disorder called Leber's hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA disorder. In most studies, there are more male patients than female patients, which contradicts the usual pattern in mitochondrial hereditary diseases. This suggests that nuclear DNA (nDNA) may influence the degeneration of retinal ganglion cells (RGCs) in LHON. The primary cause of this is dysfunction in complex I of the electron transport chain, leading to ineffective ATP production...
November 28, 2023: Journal of the Chinese Medical Association: JCMA
https://read.qxmd.com/read/37998352/hla-homozygous-ipsc-derived-mesenchymal-stem-cells-rescue-rotenone-induced-experimental-leber-s-hereditary-optic-neuropathy-like-models-in-vitro-and-in-vivo
#27
JOURNAL ARTICLE
En-Tung Tsai, Shih-Yuan Peng, You-Ren Wu, Tai-Chi Lin, Chih-Ying Chen, Yu-Hao Liu, Yu-Hsin Tseng, Yu-Jer Hsiao, Huan-Chin Tseng, Wei-Yi Lai, Yi-Ying Lin, Yi-Ping Yang, Shih-Hwa Chiou, Shih-Pin Chen, Yueh Chien
BACKGROUND: Mesenchymal stem cells (MSCs) hold promise for cell-based therapy, yet the sourcing, quality, and invasive methods of MSCs impede their mass production and quality control. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be infinitely expanded, providing advantages over conventional MSCs in terms of meeting unmet clinical demands. METHODS: The potential of MSC therapy for Leber's hereditary optic neuropathy (LHON) remains uncertain. In this study, we used HLA-homozygous induced pluripotent stem cells to generate iMSCs using a defined protocol, and we examined their therapeutic potential in rotenone-induced LHON-like models in vitro and in vivo...
November 13, 2023: Cells
https://read.qxmd.com/read/37989876/mutation-at-the-entrance-of-the-quinone-cavity-severely-disrupts-quinone-binding-in-respiratory-complex-i
#28
JOURNAL ARTICLE
Jason Tae Yi, Panyue Wang, Alexei A Stuchebrukhov
In all resolved structures of complex I, there exists a tunnel-like Q-chamber for ubiquinone binding and reduction. The entrance to the Q-chamber in ND1 subunit forms a narrow bottleneck, which is rather tight and requires thermal conformational changes for ubiquinone to get in and out of the binding chamber. The substitution of alanine with threonine at the bottleneck (AlaThr MUT), associated with 3460/ND1 mtDNA mutation in human complex I, is implicated in Leber's Hereditary Optic Neuropathy (LHON). Here, we show the AlaThr MUT further narrows the Q-chamber entrance cross-section area by almost 30%, increasing the activation free energy barrier of quinone passage by approximately 5 kJ mol-1 ...
November 21, 2023: Scientific Reports
https://read.qxmd.com/read/37983892/choriocapillaris-and-choroidal-thickness-in-all-leber-hereditary-optic-neuropathy-stages-using-swept-source-technology
#29
JOURNAL ARTICLE
Lorena Castillo, Clara Berrozpe-Villabona, Sergio Miserachs-García, Hanan Haulani, Cecilia Gómez-Gutiérrez, Alba González-Martínez, Antonio Morilla-Grasa, Luis Arias, José M Caminal, Ricardo Casaroli-Marano
PURPOSE: The role of the choroid in Leber hereditary optic neuropathy (LHON) remains unclear. The literature is scarce, with conflicting results and lacks axial length measurements. Therefore, we aimed to analyse the choriocapillaris (CC) vessel density (VD) and choroidal thickness (ChT) in all stages of LHON using swept source (SS) technology and considering the possible influence of axial length on choroidal parameters. METHODS: This was a prospective cross-sectional observational study...
November 20, 2023: Acta Ophthalmologica
https://read.qxmd.com/read/37982904/progress-in-diagnosis-and-treatment-of-leber-s-hereditary-optic-neuropathy
#30
REVIEW
Qingyue Ma, Ying Sun, Ke Lei, Wenjuan Luo
Leber's hereditary optic neuropathy (LHON) is a mitochondrial genetic disease with central vision loss as the main symptom. It is one of the diseases that cause vision loss and optic atrophy in young and middle-aged people. The mutations of these three primary mitochondrial mutations, m.11778G>A, m.14484T>C, and m.3460G>A, are the main molecular basis, but their pathogenesis is also affected by nuclear genes, mitochondrial genetic background, and environmental factors. This article summarizes the research progress on molecular pathogenesis, clinical symptoms, and treatment of LHON in recent years, aiming to summarize the genetic pathogenesis and clinical treatment points of LHON...
November 20, 2023: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
https://read.qxmd.com/read/37982768/safety-and-efficacy-of-adeno-associated-viral-gene-therapy-in-patients-with-retinal-degeneration-a-systematic-review-and-meta-analysis
#31
JOURNAL ARTICLE
Mohamad Sobh, Pamela S Lagali, Maryam Ghiasi, Joshua Montroy, Michael Dollin, Bernard Hurley, Brian C Leonard, Ioannis Dimopoulos, Mackenzie Lafreniere, Dean A Fergusson, Manoj M Lalu, Catherine Tsilfidis
PURPOSE: This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). METHODS: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs)...
November 1, 2023: Translational Vision Science & Technology
https://read.qxmd.com/read/37976148/covid-19-disease-a-trigger-for-leber-hereditary-optic-neuropathy-lhon
#32
JOURNAL ARTICLE
Sol Benbunan-Ferreiro, María Calabuig Goena, Hortesia Sánchez-Tocino
No abstract text is available yet for this article.
November 17, 2023: Journal of Neuro-ophthalmology: the Official Journal of the North American Neuro-Ophthalmology Society
https://read.qxmd.com/read/37923251/elamipretide-topical-ophthalmic-solution-for-the-treatment-of-subjects-with-leber-s-hereditary-optic-neuropathy-a-randomized-trial
#33
JOURNAL ARTICLE
Rustum Karanjia, Alfredo A Sadun
PURPOSE: The purpose of this study was to assess the safety, tolerability, and potential efficacy of topical elamipretide in patients affected with Leber's Hereditary Optic Neuropathy (LHON). DESIGN: This Phase 2, prospective, randomized, vehicle controlled, single-center clinical trial involved administration of elamipretide (MTP-131) topical ophthalmic solution to LHON patients over a 52-week double-masked treatment period (DMTP), followed by an open extension label (OLE) for up to 108 additional weeks of treatment...
November 1, 2023: Ophthalmology
https://read.qxmd.com/read/37895381/leber-s-hereditary-optic-neuropathy-lhon-clinical-experience-and-outcomes-after-long-term-idebenone-treatment
#34
JOURNAL ARTICLE
George Baltă, Georgiana Cristache, Andreea Diana Barac, Nicoleta Anton, Ileana Ramona Barac
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...
September 30, 2023: Life
https://read.qxmd.com/read/37892808/leber-hereditary-optic-neuropathy-lhon-in-patients-with-presumed-childhood-monocular-amblyopia
#35
Sanja Petrovic Pajic, Ana Fakin, Maja Sustar Habjan, Martina Jarc-Vidmar, Marko Hawlina
BACKGROUND: Most Leber hereditary optic neuropathy (LHON) cases are bilateral and sequential; however, there are rare unilateral examples, or those in which the delay of onset of vision loss between one and the other eye is longer. In the case of presumed childhood amblyopia in one eye, vision loss in the good eye may be the only symptom of bilateral disease, which was unnoticed in the previously amblyopic eye, or a preexisting episode of LHON in the "amblyopic" eye. The clinical decision in such cases may be difficult and suggestive of other forms of atypical optic neuropathy until confirmed by genetic testing...
October 22, 2023: Journal of Clinical Medicine
https://read.qxmd.com/read/37866435/approaches-to-the-epidemiology-of-nohl-in-the-region-of-madrid-survey-of-neuro-ophthalmologists
#36
JOURNAL ARTICLE
J González-Martín-Moro, J A Reche Sainz, T Gracia, B Maroto Rodríguez, L Cabrejas Martínez, C Gutiérrez Ortiz, P Rojas, J Fraile Maya, N Blanco Calvo, F Muñoz Negrete
OBJECTIVE: To estimate the epidemiology of Leber's optic neuropathy (NOHL) in the Region of Madrid. MATERIAL AND METHODS: The neuro-ophthalmologists who work at public hospitals of the CAM were interviewed by telephone. They were asked about the number of patients with NOHL that they had diagnosed during the time that they had been responsible for the neuro-ophthalmology department of that public hospital. The time worked and the population attended by the hospital were used to calculate the number of patient-years in follow-up by each center during the corresponding period...
October 20, 2023: Archivos de la Sociedad Española de Oftalmología
https://read.qxmd.com/read/37854028/a-rare-likely-pathogenic-variant-causing-leber-s-hereditary-optic-neuropathy-in-three-generation-females-of-an-african-american-family
#37
Yanjun Chen, Elizabeth R Kellom
PURPOSE: We report a rare, likely pathogenic variant gene causing Leber's hereditary optic neuropathy (LHON) in three-generation female members of an African-American family. OBSERVATIONS: The granddaughter and mother presented with a subacute, painless visual loss in both eyes at age 10 and 42 years to legal blindness. The maternal grandmother presented with a gradual onset of moderate visual loss at age 60. The mother and grandmother reported a history of bariatric surgery and subsequent vitamin deficiencies...
December 2023: American Journal of Ophthalmology Case Reports
https://read.qxmd.com/read/37808372/leber-hereditary-optic-neuropathy-presenting-as-bilateral-visual-loss-and-white-matter-disease
#38
JOURNAL ARTICLE
Hussein Algahtani, Bader Shirah, Angham Abdulrhman Abdulkareem, Fehmida Bibi, Peter Natesan Pushparaj, Muhammad Imran Naseer
Leber hereditary optic neuropathy (LHON) is a rare maternally inherited mitochondrial disorder that typically affects young male adults in their second and third decades of life. It usually manifests as painless, subacute, progressive, bilateral vision loss, with more than 90% of affected individuals losing their vision before age 50. Compared with other diseases that cause optic neuritis (multiple sclerosis or neuromyelitis optica spectrum disorders), LHON has worsening visual function in the first 6-12 months of disease progression, is predominantly male, the optic nerve is affected bilaterally from onset, there is no gadolinium enhancement on MRI, no response to disease-modifying therapy, and there is a family history of mutation in mitochondrial DNA...
2023: Bioinformation
https://read.qxmd.com/read/37734847/recessive-mecr-pathogenic-variants-cause-an-lhon-like-optic-neuropathy
#39
JOURNAL ARTICLE
Claudio Fiorini, Andrea Degiorgi, Maria Lucia Cascavilla, Concetta Valentina Tropeano, Chiara La Morgia, Marco Battista, Danara Ormanbekova, Flavia Palombo, Michele Carbonelli, Francesco Bandello, Valerio Carelli, Alessandra Maresca, Piero Barboni, Enrico Baruffini, Leonardo Caporali
BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder characterised by complex I defect leading to sudden degeneration of retinal ganglion cells. Although typically associated with pathogenic variants in mitochondrial DNA, LHON was recently described in patients carrying biallelic variants in nuclear genes DNAJC30 , NDUFS2 and MCAT . MCAT is part of mitochondrial fatty acid synthesis (mtFAS), as also MECR, the mitochondrial trans-2-enoyl-CoA reductase. MECR mutations lead to a recessive childhood-onset syndromic disorder with dystonia, optic atrophy and basal ganglia abnormalities...
September 21, 2023: Journal of Medical Genetics
https://read.qxmd.com/read/37733737/coenzyme-q10-trapping-in-mitochondrial-complex-i-underlies-leber-s-hereditary-optic-neuropathy
#40
JOURNAL ARTICLE
Jack T Fuller, Steven Barnes, Lorenzo A Sadun, Pujan Ajmera, Anastassia N Alexandrova, Alfredo A Sadun
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...
September 26, 2023: Proceedings of the National Academy of Sciences of the United States of America
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