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Kearns LS, Staffieri SE, Mackey DA. Leber Hereditary Optic Neuropathy: Support, Genetic Prediction and Accurate Genetic Counselling Enhance Family Planning Choices. Clin Exp Ophthalmol 2025; 53:292-301. [PMID: 39895156 PMCID: PMC11962693 DOI: 10.1111/ceo.14493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/05/2024] [Accepted: 12/12/2024] [Indexed: 02/04/2025]
Abstract
With the increased availability of genetic testing and the addition of mitochondrial genetic variants on disease panels, accurate genetic counselling for individuals and families affected by, or at risk of, Leber hereditary optic neuropathy (LHON) is becoming increasingly relevant. Challenges in providing genetic counselling for LHON include its mitochondrial inheritance pattern, different haplogroups, incomplete penetrance and that it predominantly affects males. Accurate genetic counselling aims to avoid incorrect disease-risk assessment and delays in either diagnosis or implementation of psychosocial support. Families are also empowered to make autonomous health decisions regarding potential trigger factors for LHON vision loss and informed reproductive choices. Using clinical vignettes, this review demonstrates that an increased awareness of LHON amongst eye care, general and genetic health professionals can address challenges and misconceptions.
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Affiliation(s)
- Lisa S. Kearns
- Centre for Eye Research AustraliaRoyal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
| | - Sandra E. Staffieri
- Centre for Eye Research AustraliaRoyal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
- Ophthalmology, Department of SurgeryUniversity of MelbourneParkvilleVictoriaAustralia
| | - David A. Mackey
- Centre for Eye Research AustraliaRoyal Victorian Eye and Ear HospitalEast MelbourneVictoriaAustralia
- Ophthalmology, Department of SurgeryUniversity of MelbourneParkvilleVictoriaAustralia
- Centre for Ophthalmology and Visual Science, Lions Eye InstituteUniversity of Western AustraliaNedlandsWestern AustraliaAustralia
- School of Medicine, Menzies Institute for Medical ResearchUniversity of TasmaniaHobartTasmaniaAustralia
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2
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Mackey DA, Staffieri SE, Lopez Sanchez MIG, Kearns LS. Family and genetic counseling in Leber hereditary optic neuropathy. Ophthalmic Genet 2025; 46:101-109. [PMID: 39833125 DOI: 10.1080/13816810.2025.2451175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 11/25/2024] [Accepted: 01/05/2025] [Indexed: 01/22/2025]
Abstract
AIM Leber hereditary optic neuropathy (LHON) predominantly manifests during adolescence or young adulthood, resulting in sudden and profound vision loss in individuals who previously had normal vision. This abrupt change significantly impacts daily life, necessitating emotional support, counseling and low-vision rehabilitative services to help affected individuals cope with the shock and adapt to their residual vision. The psychosocial burden of dealing with vision loss extends beyond the individuals directly affected by LHON, affecting matrilineal relatives who face the dual challenges of grieving for their loved one's vision loss and managing their own uncertainty about potential vision loss and its familial implications. METHOD We reviewed key information that needs to be obtained prior to genetic counseling for LHON. We reviewed key counseling issues within LHON-affected families and the issues pending several subgroups of family members with distinct and varying genetic counseling needs. RESULTS Family subgroups requiring specific counseling issues include the individuals affected by LHON, their mother, siblings, father, partner, and children. Genetic counseling plays an integral part of clinical care in families affected by LHON, providing tailored support and information to each subgroup. CONCLUSION To provide accurate information to families and guide them toward potential supports, treatments and preventive measures, health professionals need to be aware of the factors influencing visual recovery and individual risk of vision loss.
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Affiliation(s)
- David A Mackey
- Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Nedlands, Western Australia, Australia
- School of Medicine, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
| | - Sandra E Staffieri
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
- Department of Surgery, Ophthalmology, University of Melbourne, Parkville, Victoria, Australia
| | - M Isabel G Lopez Sanchez
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
| | - Lisa S Kearns
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia
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Hua LH, Solomon AJ, Tenembaum S, Scalfari A, Rovira À, Rostasy K, Newsome SD, Marrie RA, Magyari M, Kantarci O, Hemmer B, Hemingway C, Harnegie MP, Graves JS, Cohen JA, Bove R, Banwell B, Corboy JR, Waubant E. Differential Diagnosis of Suspected Multiple Sclerosis in Pediatric and Late-Onset Populations: A Review. JAMA Neurol 2024; 81:2823593. [PMID: 39283621 DOI: 10.1001/jamaneurol.2024.3062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
IMPORTANCE While the typical onset of multiple sclerosis (MS) occurs in early adulthood, 2% to 10% of cases initially present prior to age 18 years, and approximately 5% after age 50 years. Guidance on approaches to differential diagnosis in suspected MS specific to these 2 age groups is needed. OBSERVATIONS There are unique biological factors in children younger than 18 years and in adults older than age 50 years compared to typical adult-onset MS. These biological differences, particularly immunological and hormonal, may influence the clinical presentation of MS, resilience to neuronal injury, and differential diagnosis. While mimics of MS at the typical age at onset have been described, a comprehensive approach focused on the younger and older ends of the age spectrum has not been previously published. CONCLUSIONS AND RELEVANCE An international committee of MS experts in pediatric and adult MS was formed to provide consensus guidance on diagnostic approaches and key clinical and paraclinical red flags for non-MS diagnosis in children and older adults.
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Affiliation(s)
- Le H Hua
- Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, Nevada
| | - Andrew J Solomon
- Larner College of Medicine at the University of Vermont, Burlington
| | - Silvia Tenembaum
- Department of Neurology, National Pediatric Hospital Dr J. P. Garrahan, Buenos Aires, Argentina
| | - Antonio Scalfari
- Centre for Neuroscience, Department of Medicine, Charing Cross Hospital, Imperial College London, London, United Kingdom
| | - Àlex Rovira
- Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Kevin Rostasy
- Children's Hospital Datteln, University Witten/Herdecke, Witten, Germany
| | - Scott D Newsome
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ruth Ann Marrie
- Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Melinda Magyari
- Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Orhun Kantarci
- Department of Neurology, Mayo Clinic, Rochester, Minnesota
| | - Bernhard Hemmer
- Department of Neurology, Technical University of Munich, Munich, Germany
- Munich Cluster for Systems Neurology, Munich, Germany
| | - Cheryl Hemingway
- Paediatric Neurology, Great Ormond Street Children's Hospital, London, United Kingdom
- Institute of Neurology, University College London, London, United Kingdom
| | | | | | - Jeffrey A Cohen
- Mellen Center for MS Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio
| | - Riley Bove
- UCSF Weill Institute for Neurosciences, University of California, San Francisco
| | - Brenda Banwell
- Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia
| | - John R Corboy
- Department of Neurology, University of Colorado, School of Medicine, Aurora
| | - Emmanuelle Waubant
- UCSF Weill Institute for Neurosciences, University of California, San Francisco
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Pasqualotto BA, Nelson A, Deheshi S, Sheldon CA, Vogl AW, Rintoul GL. Impaired mitochondrial morphological plasticity and failure of mitophagy associated with the G11778A mutation of LHON. Biochem Biophys Res Commun 2024; 721:150119. [PMID: 38768545 DOI: 10.1016/j.bbrc.2024.150119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 05/07/2024] [Accepted: 05/13/2024] [Indexed: 05/22/2024]
Abstract
Mitochondrial dynamics were examined in human dermal fibroblasts biopsied from a confirmed Leber's Hereditary Optic Neuropathy (LHON) patient with a homoplasmic G11778A mutation of the mitochondrial genome. Expression of the G11778A mutation did not impart any discernible difference in mitochondrial network morphology using widefield fluorescence microscopy. However, at the ultrastructural level, cells expressing this mutation exhibited an impairment of mitochondrial morphological plasticity when forced to utilize oxidative phosphorylation (OXPHOS) by transition to glucose-free, galactose-containing media. LHON fibroblasts also displayed a transient increase in mitophagy upon transition to galactose media. These results provide new insights into the consequences of the G11778A mutation of LHON and the pathological mechanisms underlying this disease.
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Affiliation(s)
- Bryce A Pasqualotto
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Alexa Nelson
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Samineh Deheshi
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada
| | - Claire A Sheldon
- Department of Ophthalmology and Visual Sciences, University of British Columbia, Canada
| | - A Wayne Vogl
- Life Sciences Institute and the Department of Cellular & Physiological Sciences, University of British Columbia, Canada
| | - Gordon L Rintoul
- Centre for Cell Biology, Development, and Disease, and the Department of Biological Sciences, Simon Fraser University, Canada.
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Yang TH, Kang EYC, Lin PH, Yu BBC, Wang JHH, Chen V, Wang NK. Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress. Int J Mol Sci 2024; 25:8626. [PMID: 39201313 PMCID: PMC11354650 DOI: 10.3390/ijms25168626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/29/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.
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Affiliation(s)
- Tsai-Hsuan Yang
- Department of Education, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan;
- College of Medicine, National Yang Ming Chiao Tung University, Taipei 11217, Taiwan
| | - Eugene Yu-Chuan Kang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; (P.-H.L.); (J.H.-H.W.); (V.C.)
| | - Pei-Hsuan Lin
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; (P.-H.L.); (J.H.-H.W.); (V.C.)
- National Taiwan University Hospital, Yunlin 640203, Taiwan
| | - Benjamin Ben-Chi Yu
- Fu Foundation School of Engineering & Applied Science, Columbia University, New York, NY 10027, USA;
| | - Jason Hung-Hsuan Wang
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; (P.-H.L.); (J.H.-H.W.); (V.C.)
- Columbian College of Arts and Sciences, George Washington University, Washington, DC 20052, USA
| | - Vincent Chen
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA; (P.-H.L.); (J.H.-H.W.); (V.C.)
- Faculty of Health Sciences, Queen’s University, Kingston, ON K7L 3N9, Canada
| | - Nan-Kai Wang
- Department of Ophthalmology, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan 33305, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Ophthalmology, Edward S. Harkness Eye Institute, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, Columbia University, New York, NY 10032, USA
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Borrelli E, Bandello F, Boon CJF, Carelli V, Lenaers G, Reibaldi M, Sadda SR, Sadun AA, Sarraf D, Yu-Wai-Man P, Barboni P. Mitochondrial retinopathies and optic neuropathies: The impact of retinal imaging on modern understanding of pathogenesis, diagnosis, and management. Prog Retin Eye Res 2024; 101:101264. [PMID: 38703886 DOI: 10.1016/j.preteyeres.2024.101264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 03/18/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
Advancements in ocular imaging have significantly broadened our comprehension of mitochondrial retinopathies and optic neuropathies by examining the structural and pathological aspects of the retina and optic nerve in these conditions. This article aims to review the prominent imaging characteristics associated with mitochondrial retinopathies and optic neuropathies, aiming to deepen our insight into their pathogenesis and clinical features. Preceding this exploration, the article provides a detailed overview of the crucial genetic and clinical features, which is essential for the proper interpretation of in vivo imaging. More importantly, we will provide a critical analysis on how these imaging modalities could serve as biomarkers for characterization and monitoring, as well as in guiding treatment decisions. However, these imaging methods have limitations, which will be discussed along with potential strategies to mitigate them. Lastly, the article will emphasize the potential advantages and future integration of imaging techniques in evaluating patients with mitochondrial eye disorders, considering the prospects of emerging gene therapies.
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Affiliation(s)
- Enrico Borrelli
- Department of Surgical Sciences, University of Turin, Turin, Italy; Department of Ophthalmology, "City of Health and Science" Hospital, Turin, Italy.
| | - Francesco Bandello
- Vita-Salute San Raffaele University, Milan, Italy; IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Camiel J F Boon
- Department of Ophthalmology, Amsterdam University Medical Centers, Amsterdam, the Netherlands; Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands
| | - Valerio Carelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy
| | - Guy Lenaers
- Equipe MitoLab, Unité MitoVasc, INSERM U1083, Université d'Angers, 49933, Angers, France; Service de Neurologie, CHU d'Angers, 49100, Angers, France
| | - Michele Reibaldi
- Department of Surgical Sciences, University of Turin, Turin, Italy; Department of Ophthalmology, "City of Health and Science" Hospital, Turin, Italy
| | - Srinivas R Sadda
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Doheny Eye Institute, Los Angeles, CA, USA
| | - Alfredo A Sadun
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Doheny Eye Institute, Los Angeles, CA, USA
| | - David Sarraf
- Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Retinal Disorders and Ophthalmic Genetics Division, Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Patrick Yu-Wai-Man
- John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK; Institute of Ophthalmology, University College London, London, UK
| | - Piero Barboni
- IRCCS San Raffaele Scientific Institute, Milan, Italy; Studio Oculistico d'Azeglio, Bologna, Italy.
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7
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Pasqualotto BA, Tegeman C, Frame AK, McPhedrain R, Halangoda K, Sheldon CA, Rintoul GL. Galactose-replacement unmasks the biochemical consequences of the G11778A mitochondrial DNA mutation of LHON in patient-derived fibroblasts. Exp Cell Res 2024; 439:114075. [PMID: 38710404 DOI: 10.1016/j.yexcr.2024.114075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/08/2024]
Abstract
Leber's hereditary optic neuropathy (LHON) is a visual impairment associated with mutations of mitochondrial genes encoding elements of the electron transport chain. While much is known about the genetics of LHON, the cellular pathophysiology leading to retinal ganglion cell degeneration and subsequent vision loss is poorly understood. The impacts of the G11778A mutation of LHON on bioenergetics, redox balance and cell proliferation were examined in patient-derived fibroblasts. Replacement of glucose with galactose in the culture media reveals a deficit in the proliferation of G11778A fibroblasts, imparts a reduction in ATP biosynthesis, and a reduction in capacity to accommodate exogenous oxidative stress. While steady-state ROS levels were unaffected by the LHON mutation, cell survival was diminished in response to exogenous H2O2.
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Affiliation(s)
- Bryce A Pasqualotto
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
| | - Carina Tegeman
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
| | - Ariel K Frame
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
| | - Ryan McPhedrain
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
| | - Kolitha Halangoda
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada
| | - Claire A Sheldon
- Dept. of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Gordon L Rintoul
- Department of Biological Sciences and Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, BC, Canada.
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Esteban-Vasallo MD, Domínguez-Berjón MF, Chalco-Orrego JP, González Martín-Moro J. Prevalence of Leber hereditary optic neuropathy in the Community of Madrid (Spain), estimation with a capture-recapture method. Orphanet J Rare Dis 2024; 19:220. [PMID: 38811977 PMCID: PMC11137926 DOI: 10.1186/s13023-024-03225-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 05/19/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Leber hereditary optic neuropathy (LHON) typically presents in young adults as bilateral painless subacute visual loss. Prevalence data are scarce. The aim of this study was to examine the validity of different ascertainment sources used in population-based rare diseases registries to detect cases, and to explore the impact of a capture-recapture method in the estimation of the prevalence of LHON in the Autonomous Community of Madrid (ACM) in 2022. METHODS Descriptive cross-sectional population-based study. Potential LHON cases were detected by automatic capture from the healthcare information sources usually explored for the Regional Registry for Rare Diseases (SIERMA). Ophthalmologists provided data from their clinical registry. Positive predictive values (PPV) and sensitivity with 95% confidence intervals (CI) were estimated. Global and by sex prevalences were calculated with confimed cases and with those estimated by the capture-recapture method. RESULTS A total of 102 potential LHON cases were captured from healthcare information sources, 25 of them (24.5%) finally were confirmed after revision, with an overall PPV of 24.5% (95%CI 17.2-33.7). By source, the electronic clinical records of primary care had the highest PPV (51.2, 95%CI 36.7-65.4). The ophthalmologists clinical registry provided 22 cases, 12 of them not detected in the automatic capture sources. The clinical registry reached a sensitivity of 59.5% (95%CI 43.5-73.6) and the combination of automatic capture sources reached a 67.6% (95%CI: 51.5-80.4). The total confirmed cases were 37, with a mean age of 48.9 years, and a men: women ratio of 2.4:1. Genetic information was recovered in 27 cases, with the m.3460 mutation being the most frequent (12 cases). The global prevalence was 0.55 cases/100,000 inhabitants (95%CI 0.40-0.75), and with the capture-recapture method reached 0.79 cases/100,000 (95%CI 0.60-1.03), a 43.6% higher, 1.15 cases/100,000 (95%CI 0.83-1.58) in men and 0.43 cases/100,000 (95%CI 0.26-0.70) in women. CONCLUSIONS The prevalence of LHON estimated in the ACM was lower than in other European countries. Population-based registries of rare diseases require the incorporation of confirmed cases provided by clinicians to asure the best completeness of data. The use of more specific coding for rare diseases in healthcare information systems would facilitate the detection of cases. Further epidemiologic studies are needed to assess potential factors that may influence the penetrance of LHON.
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Affiliation(s)
| | | | | | - Julio González Martín-Moro
- Department of Ophthalmology, University Hospital of Henares. Coslada, Madrid, Spain
- Faculty of Medicine, Universidad Francisco de Vitoria, Pozuelo de Alarcón, Madrid, Spain
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Duseikaite M, Gedvilaite G, Mikuzis P, Andrulionyte J, Kriauciuniene L, Liutkeviciene R. Investigating the Relationship between Telomere-Related Gene Variants and Leukocyte Telomere Length in Optic Neuritis Patients. J Clin Med 2024; 13:2694. [PMID: 38731223 PMCID: PMC11084964 DOI: 10.3390/jcm13092694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Revised: 04/26/2024] [Accepted: 04/30/2024] [Indexed: 05/13/2024] Open
Abstract
Optic neuritis (ON) is a condition marked by optic nerve inflammation due to various potential triggers. Research indicates a link between telomeres and inflammation, as studies demonstrate that inflammation can lead to increased telomere shortening. Aim: We aimed to determine the associations of telomere-related telomeric repeat binding factor 1 (TERF1) rs1545827, rs10107605, and telomeric repeat binding factor 2 (TERF2) rs251796 polymorphisms and relative leukocyte telomere length (LTL) with the occurrence of ON. Methods: In this research, a total of 73 individuals diagnosed with optic neuritis (ON) were studied and the control group included 170 individuals without any health issues. The DNA samples were obtained from peripheral blood leukocytes, which were purified using the DNA salting-out technique. Real-time polymerase chain reaction (RT-PCR) assessed single-nucleotide polymorphisms (SNPs) and relative leukocyte telomere lengths (LTL). The data obtained were processed and analyzed using the "IBM SPSS Statistics 29.0" program. Results: Our study revealed the following results: in the male group, TERF2 rs251796 (AA, AG, and TT) statistically significantly differed between the long and short telomere group, with frequencies of 65.7%, 22.9%, and 2.0% in long telomeres, compared to 35.1%, 56.8%, and 8.1% in the short telomere group (p = 0.013). The TERF2 rs251796 CT genotype, compared to CC, under the codominant genetic model, was associated with 4.7-fold decreased odds of telomere shortening (p = 0.005). Meanwhile, CT+TT genotypes, compared to CC under the dominant genetic model, were associated with 3.5-fold decreased odds of telomere shortening (p = 0.011). Also, the CT genotype, compared to CC+TT, under the overdominant genetic model, was associated with 4.4-fold decreased odds of telomere shortening (p = 0.004). Conclusions: The current evidence may suggest a protective role of TERF2 rs251796 in the occurrence of ON in men.
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Affiliation(s)
- Monika Duseikaite
- Laboratory of Ophthalmology, Institute of Neuroscience, Lithuanian University of Health Sciences, Eivenių Street 2, LT-50161 Kaunas, Lithuania; (G.G.); (L.K.); (R.L.)
- Faculty of Pharmacy, Lithuanian University of Health Sciences, Sukilėlių Pr. 13, LT-50166 Kaunas, Lithuania
| | - Greta Gedvilaite
- Laboratory of Ophthalmology, Institute of Neuroscience, Lithuanian University of Health Sciences, Eivenių Street 2, LT-50161 Kaunas, Lithuania; (G.G.); (L.K.); (R.L.)
- Medical Faculty, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (P.M.); (J.A.)
| | - Paulius Mikuzis
- Medical Faculty, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (P.M.); (J.A.)
| | - Juste Andrulionyte
- Medical Faculty, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (P.M.); (J.A.)
| | - Loresa Kriauciuniene
- Laboratory of Ophthalmology, Institute of Neuroscience, Lithuanian University of Health Sciences, Eivenių Street 2, LT-50161 Kaunas, Lithuania; (G.G.); (L.K.); (R.L.)
| | - Rasa Liutkeviciene
- Laboratory of Ophthalmology, Institute of Neuroscience, Lithuanian University of Health Sciences, Eivenių Street 2, LT-50161 Kaunas, Lithuania; (G.G.); (L.K.); (R.L.)
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10
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Karanjia R, Sadun AA. Elamipretide Topical Ophthalmic Solution for the Treatment of Subjects with Leber Hereditary Optic Neuropathy: A Randomized Trial. Ophthalmology 2024; 131:422-433. [PMID: 37923251 DOI: 10.1016/j.ophtha.2023.10.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 10/03/2023] [Accepted: 10/17/2023] [Indexed: 11/07/2023] Open
Abstract
PURPOSE This study aimed to assess the safety, tolerability, and potential efficacy of topical elamipretide in patients affected with Leber hereditary optic neuropathy (LHON). DESIGN This phase II, prospective, randomized, vehicle-controlled, single-center clinical trial involved administration of elamipretide 1% topical ophthalmic solution to patients with LHON over a 52-week double-masked treatment period, followed by an open-label extension (OLE) for up to 108 additional weeks of treatment. PARTICIPANTS Twelve patients with LHON were included in this study. Patients aged 18 to 50 years with decreased vision for at least ≥ 1 year and ≤ 10 years, and a genetically confirmed diagnosis of m.11778G>A LHON were eligible for this trial. METHODS For the first 52 weeks of the study, patients were randomized to 1 of 3 groups: elamipretide in both eyes or elamipretide in 1 eye (left eye and right eye were considered separate groups) and vehicle in the other eye, followed by an OLE in which both eyes were treated with elamipretide. MAIN OUTCOME MEASURES The primary outcome measure was assessment of adverse events (AEs) from the administration of topical elamipretide, and the primary efficacy end point was change in best-corrected visual acuity (BCVA). Secondary outcome measures included changes in color vision, visual field mean deviation, and electrophysiological outcomes. RESULTS Elamipretide was well tolerated with the majority of AEs being mild to moderate and resolving spontaneously. The change from baseline in BCVA in elamipretide-treated eyes was not significantly different from the vehicle eyes at any time point. Six of 12 subjects met the criteria for clinically relevant benefit (CRB). In the post hoc analysis, change from baseline in mean deviation in the central visual field was significantly greater in elamipretide-treated eyes versus the vehicle eyes. Compared with baseline, both treatment groups showed improvement in color discrimination and contrast sensitivity in the OLE. CONCLUSIONS Elamipretide treatment was generally well tolerated, with no serious AEs reported. Although this study did not meet its primary BCVA efficacy end point, improvements across assessments on visual function during the OLE and the post hoc findings of the Humphrey automated visual field central region were encouraging and require further exploration. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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Affiliation(s)
- Rustum Karanjia
- Doheny Eye Centers UCLA, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California; Doheny Eye Institute, Los Angeles, California; Department of Ophthalmology, Universtiy of Ottawa, Ottawa, Canada; Ottawa Eye Institute, The Otawa Hospital, Ottawa, Canada.
| | - Alfredo A Sadun
- Doheny Eye Centers UCLA, Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California; Doheny Eye Institute, Los Angeles, California
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11
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Yu-Wai-Man P, Carelli V, Newman NJ, Silva MJ, Linden A, Van Stavern G, Szaflik JP, Banik R, Lubiński W, Pemp B, Liao YJ, Subramanian PS, Misiuk-Hojło M, Newman S, Castillo L, Kocięcki J, Levin MH, Muñoz-Negrete FJ, Yagan A, Cherninkova S, Katz D, Meunier A, Votruba M, Korwin M, Dziedziak J, Jurkutė N, Harvey JP, La Morgia C, Priglinger C, Llòria X, Tomasso L, Klopstock T. Therapeutic benefit of idebenone in patients with Leber hereditary optic neuropathy: The LEROS nonrandomized controlled trial. Cell Rep Med 2024; 5:101437. [PMID: 38428428 PMCID: PMC10982982 DOI: 10.1016/j.xcrm.2024.101437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 10/24/2023] [Accepted: 01/30/2024] [Indexed: 03/03/2024]
Abstract
Leber hereditary optic neuropathy (LHON) is a mitochondrial disease leading to rapid and severe bilateral vision loss. Idebenone has been shown to be effective in stabilizing and restoring vision in patients treated within 1 year of onset of vision loss. The open-label, international, multicenter, natural history-controlled LEROS study (ClinicalTrials.gov NCT02774005) assesses the efficacy and safety of idebenone treatment (900 mg/day) in patients with LHON up to 5 years after symptom onset (N = 199) and over a treatment period of 24 months, compared to an external natural history control cohort (N = 372), matched by time since symptom onset. LEROS meets its primary endpoint and confirms the long-term efficacy of idebenone in the subacute/dynamic and chronic phases; the treatment effect varies depending on disease phase and the causative mtDNA mutation. The findings of the LEROS study will help guide the clinical management of patients with LHON.
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Affiliation(s)
- Patrick Yu-Wai-Man
- John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, UK; MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0XY, UK; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK; Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK
| | - Valerio Carelli
- IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, 40127 Bologna, Italy
| | - Nancy J Newman
- Departments of Ophthalmology, Neurology, and Neurological Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA
| | | | | | | | - Jacek P Szaflik
- Department of Ophthalmology, Medical University of Warsaw, 02-091 Warsaw, Poland; SPKSO Ophthalmic University Hospital, 00-576 Warsaw, Poland
| | - Rudrani Banik
- New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003, USA
| | - Wojciech Lubiński
- Samodzielny Publiczny Szpital Kliniczny Nr 2 PUM w Szczecinie, 70-111 Szczecin, Poland
| | - Berthold Pemp
- Department of Ophthalmology, Medical University of Vienna, 1090 Vienna, Austria
| | | | - Prem S Subramanian
- Sue Anschutz-Rodgers University of Colorado Eye Center, Aurora, CO 80045, USA
| | | | - Steven Newman
- University of Virginia, Charlottesville, VA 22903, USA
| | | | - Jarosław Kocięcki
- Department of Ophthalmology, University of Medical Sciences, 60-806 Poznan, Poland
| | - Marc H Levin
- Department of Ophthalmology, Palo Alto Medical Foundation, Palo Alto, CA 94303, USA
| | | | - Ali Yagan
- Manchester Royal Eye Hospital, Manchester M13 9WL, UK
| | | | - David Katz
- Bethesda Neurology LLC, Bethesda, MD 20852, USA
| | - Audrey Meunier
- Department of Ophthalmology, CHU Saint-Pierre, 1000 Brussels, Belgium
| | - Marcela Votruba
- Cardiff Eye Unit, University Hospital of Wales, Cardiff CF14 4XW, UK
| | - Magdalena Korwin
- Department of Ophthalmology, Medical University of Warsaw, 02-091 Warsaw, Poland; SPKSO Ophthalmic University Hospital, 00-576 Warsaw, Poland
| | - Jacek Dziedziak
- Department of Ophthalmology, Medical University of Warsaw, 02-091 Warsaw, Poland; SPKSO Ophthalmic University Hospital, 00-576 Warsaw, Poland; Department of Experimental and Clinical Physiology, Center for Preclinical Research, Medical University of Warsaw, 02-097 Warsaw, Poland
| | - Neringa Jurkutė
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK; The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London WC1N 3BG, UK
| | - Joshua P Harvey
- Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK; Institute of Ophthalmology, University College London, London EC1V 9EL, UK
| | - Chiara La Morgia
- IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, 40127 Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy
| | - Claudia Priglinger
- Department of Ophthalmology, University Hospital of the Ludwig-Maximilians-University (LMU), 80336 Munich, Germany
| | | | | | - Thomas Klopstock
- German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377 Munich, Germany; Friedrich Baur Institute at the Department of Neurology, LMU University Hospital, LMU Munich, 80336 Munich, Germany.
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12
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Major TC, Arany ES, Schon K, Simo M, Karcagi V, van den Ameele J, Yu Wai Man P, Chinnery PF, Olimpio C, Horvath R. Case report: Mutations in DNAJC30 causing autosomal recessive Leber hereditary optic neuropathy are common amongst Eastern European individuals. Front Neurol 2023; 14:1292320. [PMID: 38107630 PMCID: PMC10722306 DOI: 10.3389/fneur.2023.1292320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 11/03/2023] [Indexed: 12/19/2023] Open
Abstract
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. After a several-year-long diagnostic journey, all three patients were found to carry the homozygous c.152A>G (p.Tyr51Cys) mutation in DNAJC30. This has been identified as the most common arLHON pathogenic variant and has been shown to exhibit a significant founder effect amongst Eastern European individuals. Conclusion This finding adds to the growing cohort of patients with arLHON and demonstrates the importance of DNAJC30 screening in patients with molecularly undiagnosed LHON, particularly in Eastern European individuals. It is of heightened translational significance as patients diagnosed with arLHON exhibit a better prognosis and response to therapeutic treatment with the co-enzyme Q10 analog idebenone.
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Affiliation(s)
- Toby Charles Major
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Eszter Sara Arany
- School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Katherine Schon
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Department of Clinical Genetics, East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Magdolna Simo
- University Clinic of Neurology, Semmelweis University, Budapest, Hungary
| | | | - Jelle van den Ameele
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Patrick Yu Wai Man
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- NIHR Biomedical Research Centre, Moorfields Eye Hospital & UCL Institute of Ophthalmology, London, United Kingdom
- Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom
| | - Patrick F. Chinnery
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Catarina Olimpio
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
- Department of Clinical Genetics, East Anglian Medical Genetics Service, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Rita Horvath
- Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
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13
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Itoh N, Itoh Y, Stiles L, Voskuhl R. Sex differences in the neuronal transcriptome and synaptic mitochondrial function in the cerebral cortex of a multiple sclerosis model. Front Neurol 2023; 14:1268411. [PMID: 38020654 PMCID: PMC10654219 DOI: 10.3389/fneur.2023.1268411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023] Open
Abstract
Introduction Multiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, sex differences in neurodegenerative mechanisms are determined in the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE). Methods Neurons from cerebral cortex tissues of chronic EAE, as well as age-matched healthy control, male and female mice underwent RNA sequencing and gene expression analyses using RiboTag technology. The morphology of mitochondria in neurons of cerebral cortex was assessed using Thy1-CFP-MitoS mice. Oxygen consumption rates were determined using mitochondrial respirometry assays from intact as well as permeabilized synaptosomes. Results RNA sequencing of neurons in cerebral cortex during chronic EAE in C57BL/6 mice showed robust differential gene expression in male EAE compared to male healthy controls. In contrast, there were few differences in female EAE compared to female healthy controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology in neurons showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male, but not female, EAE mice demonstrated significantly decreased oxygen consumption rates during respirometry assays. Discussion Cortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men.
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Affiliation(s)
- Noriko Itoh
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Yuichiro Itoh
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Linsey Stiles
- Department of Endocrinology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Rhonda Voskuhl
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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14
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Shamsnajafabadi H, MacLaren RE, Cehajic-Kapetanovic J. Current and Future Landscape in Genetic Therapies for Leber Hereditary Optic Neuropathy. Cells 2023; 12:2013. [PMID: 37566092 PMCID: PMC10416882 DOI: 10.3390/cells12152013] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 07/27/2023] [Accepted: 07/31/2023] [Indexed: 08/12/2023] Open
Abstract
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial genetic disease that causes blindness in young adults. Over 50 inherited mitochondrial DNA (mtDNA) variations are associated with LHON; however, more than 95% of cases are caused by one of three missense variations (m.11778 G > A, m.3460 G > A, and m.14484 T > C) encoding for subunits ND4, ND1, and ND6 of the respiration complex I, respectively. These variants remain silent until further and currently poorly understood genetic and environmental factors precipitate the visual loss. The clinical course that ensues is variable, and a convincing treatment for LHON has yet to emerge. In 2015, an antioxidant idebenone (Raxone) received European marketing authorisation to treat visual impairment in patients with LHON, and since then it was introduced into clinical practice in several European countries. Alternative therapeutic strategies, including gene therapy and gene editing, antioxidant and neurotrophic agents, mitochondrial biogenesis, mitochondrial replacement, and stem cell therapies are being investigated in how effective they might be in altering the course of the disease. Allotopic gene therapies are in the most advanced stage of development (phase III clinical trials) whilst most other agents are in phase I or II trials or at pre-clinical stages. This manuscript discusses the phenotype and genotype of the LHON disease with complexities and peculiarities such as incomplete penetrance and gender bias, which have challenged the therapies in development emphasising the most recent use of gene therapy. Furthermore, we review the latest results of the three clinical trials based on adeno-associated viral (AAV) vector-mediated delivery of NADH dehydrogenase subunit 4 (ND4) with mitochondrial targeting sequence, highlighting the differences in the vector design and the rationale behind their use in the allotopic transfer.
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Affiliation(s)
- Hoda Shamsnajafabadi
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
| | - Robert E. MacLaren
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
- Oxford Eye Hospital, Oxford University NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
| | - Jasmina Cehajic-Kapetanovic
- Nuffield Laboratory of Ophthalmology, Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK
- Oxford Eye Hospital, Oxford University NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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15
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Castellanos-Perilla N, Garcia-Cifuentes E, Pineda-Ortega J, Lema S, Gelvis G, Cano-Gutierrez CA, Mejia-Vergara AJ. Self-reported glaucoma prevalence and related factors, contribution to reported visual impairment, and functional burden in a cross-sectional study in Colombia. Int Ophthalmol 2023. [PMID: 36864123 DOI: 10.1007/s10792-023-02643-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
PURPOSE Describe the self-reported prevalence of glaucoma in Colombian older adults, emphasizing the most important risk factors and associated daily-life functional alterations. METHODS This a secondary analysis of the Health, Wellness, and Aging survey conducted in the year 2015. Diagnosis of glaucoma was obtained from self-report. Functional variables were assessed through activities of daily living questionnaires. A descriptive analysis followed by bivariate and multivariate regression models adjusting for confounding variables was conducted. RESULTS Self-reported prevalence of glaucoma was 5.67%, with higher rate in women, OR 1.22 (1.13-1.40) p = .003, older age OR 1.02 (1.01-1.02) p < .001, and with higher education OR 1.38 (1.28-1.50) p < .001. Glaucoma was independently associated with diabetes OR 1.37 (1.18-1.61) p < .001 and hypertension 1.26 (1.08-1.46) p = .003. It also showed statistically significant correlations with poor SRH OR 1.15 (1.02-1.32) p < .001, self-reported visual impairment 1.73 (1.50-2.01) p < .001, and impairment in money management OR 1.59 (1.16-2.08) p = .002, grocery shopping OR 1.57 (1.26-1.96) p < .001 and preparing meals OR 1.31 (1.06-1.63) p = .013 and having had falls during the last year OR 1.14 (1.01-1.31) p = 0.041. CONCLUSION Our findings suggest the self-reported prevalence of glaucoma in older adults in Colombia to be higher than reported data. Glaucoma and visual impairment in older adults represent a public health concern, since glaucoma was associated with adverse outcomes like functional loss and risk of falling, affecting the quality of life and their participation in society.
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Affiliation(s)
- Nicolás Castellanos-Perilla
- Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway. .,Department of Clinical Medicine, University of Bergen, Bergen, Norway. .,Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontificia Universidad Javeriana, Bogotá, Colombia.
| | - Elkin Garcia-Cifuentes
- Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontificia Universidad Javeriana, Bogotá, Colombia.,Neurology Department, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Juliana Pineda-Ortega
- Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Sofia Lema
- Centre for Age-Related Medicine (SESAM), Stavanger University Hospital, Stavanger, Norway
| | - Geronimo Gelvis
- Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Carlos Alberto Cano-Gutierrez
- Semillero de Neurociencias y Envejecimiento, Ageing Institute, Medical School, Pontificia Universidad Javeriana, Bogotá, Colombia.,Geriatrics Unit, Hospital Universitario San Ignacio, Bogotá, Colombia
| | - Alvaro J Mejia-Vergara
- Department of Ophthalmology, Stein and Doheny Eye Institutes, University of California, Pasadena, Los Angeles, CA, USA.,Ophthalmology Department, San Ignacio University Hospital, Pontificia Universidad Javeriana School of Medicine, Bogotá, Colombia.,School of Medicine, Ophthalmology Program, Fundación Universitaria Sanitas, Bogotá, Colombia.,Oftalmosanitas Eye Institute, Fundación Universitaria Sanitas, Bogotá, Colombia
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16
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Buonfiglio PI, Menazzi S, Francipane L, Lotersztein V, Ferreiro V, Elgoyhen AB, Dalamón V. Mitochondrial DNA variants in a cohort from Argentina with suspected Leber's hereditary optic neuropathy (LHON). PLoS One 2023; 18:e0275703. [PMID: 36827238 PMCID: PMC9956067 DOI: 10.1371/journal.pone.0275703] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 01/31/2023] [Indexed: 02/25/2023] Open
Abstract
The present study investigates the spectrum and analysis of mitochondrial DNA (mtDNA) variants associated with Leber hereditary optic neuropathy (LHON) in an Argentinean cohort, analyzing 3 LHON-associated mitochondrial genes. In 32% of the cases, molecular confirmation of the diagnosis could be established, due to the identification of disease-causing variants. A total of 54 variants were observed in a cohort of 100 patients tested with direct sequencing analysis. The frequent causative mutations m.11778G>A in MT-ND4, m.3460G>A in MT-ND1, and m.14484T>C in MT-ND6 were identified in 28% of the cases of our cohort. Secondary mutations in this Argentinean LHON cohort were m.11253T>C p.Ile165Thr in MT-ND4, identified in three patients (3/100, 3%) and m.3395A>G p.Tyr30Cys in MT-ND1, in one of the patients studied (1%). This study shows, for the first time, the analysis of mtDNA variants in patients with a probable diagnosis of LHON in Argentina. Standard molecular methods are an effective first approach in order to achieve genetic diagnosis of the disease, leaving NGS tests for those patients with negative results.
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Affiliation(s)
- Paula I. Buonfiglio
- Laboratorio de Fisiología y Genética de la Audición, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres”, Consejo Nacional de Investigaciones Científicas y Técnicas - INGEBI / CONICET, Ciudad Autónoma de Buenos Aires, Argentina
| | - Sebastián Menazzi
- División Genética, Hospital de Clínicas “José de San Martín”, Ciudad Autónoma de Buenos Aires, Argentina
| | - Liliana Francipane
- División Genética, Hospital de Clínicas “José de San Martín”, Ciudad Autónoma de Buenos Aires, Argentina
| | - Vanesa Lotersztein
- Servicio de Genética, Hospital Militar Central “Dr. Cosme Argerich”, Ciudad Autónoma de Buenos Aires, Argentina
| | | | - Ana Belén Elgoyhen
- Laboratorio de Fisiología y Genética de la Audición, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres”, Consejo Nacional de Investigaciones Científicas y Técnicas - INGEBI / CONICET, Ciudad Autónoma de Buenos Aires, Argentina
- División Genética, Hospital de Clínicas “José de San Martín”, Ciudad Autónoma de Buenos Aires, Argentina
- Servicio de Genética, Hospital Militar Central “Dr. Cosme Argerich”, Ciudad Autónoma de Buenos Aires, Argentina
- Laboratorio Genos, Ciudad Autónoma de Buenos Aires, Argentina
- Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, C1121ABG, Ciudad Autónoma de Buenos Aires, Argentina
| | - Viviana Dalamón
- Laboratorio de Fisiología y Genética de la Audición, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular “Dr. Héctor N. Torres”, Consejo Nacional de Investigaciones Científicas y Técnicas - INGEBI / CONICET, Ciudad Autónoma de Buenos Aires, Argentina
- * E-mail:
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Esmaeil A, Ali A, Behbehani R. Leber's hereditary optic neuropathy: Update on current diagnosis and treatment. FRONTIERS IN OPHTHALMOLOGY 2023; 2:1077395. [PMID: 38983564 PMCID: PMC11182214 DOI: 10.3389/fopht.2022.1077395] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 12/20/2022] [Indexed: 07/11/2024]
Abstract
Leber's hereditary optic neuropathy (LHON) is a fairly prevalent mitochondrial disorder (1:50,000) arising from the dysfunction of the mitochondrial respiratory chain, which eventually leads to apoptosis of retinal ganglion cells. The usual presentation is that of a young male with a sequential reduction in visual acuity. OCT has been used to study the pattern of optic nerve involvement in LHON, showing early thickening of the inferior and superior retinal nerve fibre layer and ganglion cell layer thinning corresponding with the onset of symptoms. Of the three primary mutations for LHON, the m.14484T>C mutation has the best visual prognosis. Recent emerging therapeutic options for LHON include idebenone and the introduction of genetic vector therapy, which is currently in phase III clinical trials. Screening of family members and adequate advice to avoid environmental triggers, such as smoking and alcohol consumption, are also cornerstones in the management of LHON.
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Affiliation(s)
- Ali Esmaeil
- Neuro-Ophthalmology Service, Department of Ophthalmology, Ibn Sina Hospital, Kuwait City, Kuwait
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18
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Quigley C, Stephenson KAJ, Kenna P, Cassidy L. Optic Nerve Structural and Functional Changes in LHON-Affected and Asymptomatic Maternal Relatives: Association with H and HV Mitochondrial Haplogroups. Int J Mol Sci 2023; 24:ijms24021068. [PMID: 36674591 PMCID: PMC9864201 DOI: 10.3390/ijms24021068] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/22/2022] [Accepted: 12/21/2022] [Indexed: 01/09/2023] Open
Abstract
Leber Hereditary Optic Neuropathy (LHON) affects a minority of carriers of causative mitochondrial DNA mutations. We investigated a cohort of patients with LHON, including m.11778G>A, m.3460G>A, m.14484T>C and DNAJC30 c.152A>G variants, and their asymptomatic maternal carrier relatives for additional potential associations with vision loss. We assessed visual acuity, optical coherence tomography (OCT) of the peripapillary retinal nerve fibre layer (RNFL), visually evoked potential including P-100 latency, and full mitochondrial genome sequencing. Comparison was made with a reference standard for OCT; European Descent, Heidelberg Engineering ©; and electrophysiology measurements with in-house normative ranges. RNFL was thinned overall in LHON patients (n = 12); median global RNFL −54 μm in the right eye (RE) and −50 μm in the left eye (LE) versus normal, and was found to be normal overall in asymptomatic carriers at +1 μm RE and −2 μm LE (n = 16). In four asymptomatic carriers there was RNFL thinning found either unilaterally or bilaterally; these cases were associated with isolated delay in P-100 latency (25%), delay and reduced visual acuity (50%), or reduced visual acuity without P-100 latency delay (25%). Optic nerve dysfunction was associated with mitochondrial haplogroup H and HV, versus non-H haplogroups, in the asymptomatic carriers (Fisher’s exact test, p = 0.05). Our findings suggest that optic nerve abnormalities may be identified in asymptomatic LHON mitochondrial mutation carriers, which may be associated with optic nerve dysfunction. For asymptomatic carriers these findings were associated with mitochondrial haplogroup H and HV.
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19
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Abstract
Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
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Affiliation(s)
- Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
| | - Robert McFarland
- NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
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20
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Abstract
Mitochondrial optic neuropathies have a leading role in the field of mitochondrial medicine ever since 1988, when the first mutation in mitochondrial DNA was associated with Leber's hereditary optic neuropathy (LHON). Autosomal dominant optic atrophy (DOA) was subsequently associated in 2000 with mutations in the nuclear DNA affecting the OPA1 gene. LHON and DOA are both characterized by selective neurodegeneration of retinal ganglion cells (RGCs) triggered by mitochondrial dysfunction. This is centered on respiratory complex I impairment in LHON and defective mitochondrial dynamics in OPA1-related DOA, leading to distinct clinical phenotypes. LHON is a subacute, rapid, severe loss of central vision involving both eyes within weeks or months, with age of onset between 15 and 35 years old. DOA is a more slowly progressive optic neuropathy, usually apparent in early childhood. LHON is characterized by marked incomplete penetrance and a clear male predilection. The introduction of next-generation sequencing has greatly expanded the genetic causes for other rare forms of mitochondrial optic neuropathies, including recessive and X-linked, further emphasizing the exquisite sensitivity of RGCs to compromised mitochondrial function. All forms of mitochondrial optic neuropathies, including LHON and DOA, can manifest either as pure optic atrophy or as a more severe multisystemic syndrome. Mitochondrial optic neuropathies are currently at the forefront of a number of therapeutic programs, including gene therapy, with idebenone being the only approved drug for a mitochondrial disorder.
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Affiliation(s)
- Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy.
| | - Chiara La Morgia
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy; IRCCS Istituto di Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy
| | - Patrick Yu-Wai-Man
- John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom; Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom; Institute of Ophthalmology, University College London, London, United Kingdom
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21
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Zhao E, Crimmins EM. Mortality and morbidity in ageing men: Biology, Lifestyle and Environment. Rev Endocr Metab Disord 2022; 23:1285-1304. [PMID: 35697963 PMCID: PMC9748037 DOI: 10.1007/s11154-022-09737-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/15/2022] [Indexed: 01/11/2023]
Abstract
Males live shorter lives than women in all countries. The universality of shorter male life expectancy is a 21st Century phenomena. It occurs with the decline in infectious diseases and the rise in cardiovascular diseases accounting for mortality. Male/female differences in morbidity are not as succinctly characterized. Men have a higher prevalence of lethal diseases, which is linked to their lower life expectancy. Women have more non-lethal conditions such as depression and arthritis; which may also be linked in part to longer survival. Men have better physical functioning and less disability which is partly explained by gender differences in diseases and also by their greater strength, size, and stamina. Gender differences in risk factors for disease have changed over time with the prevalence and treatment of risk as well as differential behavior by gender. Examination of what are seen as basic molecular and cellular measures related to aging indicates men age faster than women; however, even these basic biological measures result from a combination of biology, behavior, and social factors.
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Affiliation(s)
- Erfei Zhao
- Davis School of Gerontology, University of Southern California, 90089-0191 Los Angeles, CA United States
| | - Eileen M. Crimmins
- Davis School of Gerontology, University of Southern California, 90089-0191 Los Angeles, CA United States
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22
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Abstract
The analogy of mitochondria as powerhouses has expired. Mitochondria are living, dynamic, maternally inherited, energy-transforming, biosynthetic, and signaling organelles that actively transduce biological information. We argue that mitochondria are the processor of the cell, and together with the nucleus and other organelles they constitute the mitochondrial information processing system (MIPS). In a three-step process, mitochondria (1) sense and respond to both endogenous and environmental inputs through morphological and functional remodeling; (2) integrate information through dynamic, network-based physical interactions and diffusion mechanisms; and (3) produce output signals that tune the functions of other organelles and systemically regulate physiology. This input-to-output transformation allows mitochondria to transduce metabolic, biochemical, neuroendocrine, and other local or systemic signals that enhance organismal adaptation. An explicit focus on mitochondrial signal transduction emphasizes the role of communication in mitochondrial biology. This framework also opens new avenues to understand how mitochondria mediate inter-organ processes underlying human health.
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Affiliation(s)
- Martin Picard
- Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA; New York State Psychiatric Institute, New York, NY 10032, USA.
| | - Orian S Shirihai
- Department of Medicine, Endocrinology, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
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23
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Spiegel SJ, Sadun AA. Solutions to a Radical Problem: Overview of Current and Future Treatment Strategies in Leber's Hereditary Opic Neuropathy. Int J Mol Sci 2022; 23:13205. [PMID: 36361994 PMCID: PMC9656544 DOI: 10.3390/ijms232113205] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 09/23/2023] Open
Abstract
Leber's Hereditary Optic Neuropathy (LHON) is the most common primary mitochondrial DNA disorder. It is characterized by bilateral severe central subacute vision loss due to specific loss of Retinal Ganglion Cells and their axons. 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. In this review, we summarize management strategies and rational of treatment based on current insights from molecular research. This includes preventative recommendations for unaffected genetic carriers, current medical and supportive treatments for those affected, and emerging evidence for future potential therapeutics.
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Affiliation(s)
- Samuel J. Spiegel
- Gavin Herbert Eye Institute, University of California, Irvine, CA 92617, USA
| | - Alfredo A. Sadun
- Jules Stein and Doheny Eye Institute, University of California, Los Angeles, CA 90095, USA
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24
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Kieninger S, Xiao T, Weisschuh N, Kohl S, Rüther K, Kroisel PM, Brockmann T, Knappe S, Kellner U, Lagrèze W, Mazzola P, Haack TB, Wissinger B, Tonagel F. DNAJC30 disease-causing gene variants in a large Central European cohort of patients with suspected Leber's hereditary optic neuropathy and optic atrophy. J Med Genet 2022; 59:1027-1034. [PMID: 35091433 PMCID: PMC9554085 DOI: 10.1136/jmedgenet-2021-108235] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 01/07/2022] [Indexed: 01/18/2023]
Abstract
BACKGROUND Leber's hereditary optic neuropathy (LHON) has been considered a prototypical mitochondriopathy and a textbook example for maternal inheritance linked to certain disease-causing variants in the mitochondrial genome. Recently, an autosomal recessive form of LHON (arLHON) has been described, caused by disease-causing variants in the nuclear encoded gene DNAJC30. METHODS AND RESULTS In this study, we screened the DNAJC30 gene in a large Central European cohort of patients with a clinical diagnosis of LHON or other autosomal inherited optic atrophies (OA). We identified likely pathogenic variants in 35/1202 patients, corresponding to a detection rate of 2.9%. The previously described missense variant c.152A>G;p.(Tyr51Cys) accounts for 90% of disease-associated alleles in our cohort and we confirmed a strong founder effect. Furthermore, we identified two novel pathogenic variants in DNAJC30: the nonsense variant c.610G>T;p.(Glu204*) and the in-frame deletion c.230_232del;p.(His77del). Clinical investigation of the patients with arLHON revealed a younger age of onset, a more frequent bilateral onset and an increased clinically relevant recovery compared with LHON associated with disease-causing variants in the mitochondrial DNA. CONCLUSION This study expands previous findings on arLHON and emphasises the importance of DNAJC30 in the genetic diagnostics of LHON and OA in European patients.
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Affiliation(s)
- Sinja Kieninger
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Ting Xiao
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Nicole Weisschuh
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Susanne Kohl
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Klaus Rüther
- Facharztpraxis für Augenheilkunde, Berlin-Mitte, Germany
| | - Peter Michael Kroisel
- Diagnostic & Research Institute of Human Genetics, Diagnostic & Research Centre for Molecular BioMedicine, Medical University of Graz, Graz, Austria
| | - Tobias Brockmann
- Department of Ophthalmology, Universitätsmedizin Rostock, University of Rostock, Rostock, Germany
| | - Steffi Knappe
- Department of Ophthalmology, Universitätsmedizin Rostock, University of Rostock, Rostock, Germany
| | - Ulrich Kellner
- Zentrum für Seltene Netzhauterkrankungen, AugenZentrum Siegburg, MVZ Augenärztliches Diagnostik- und Therapiecentrum Siegburg GmbH, Siegburg, Germany
- RetinaScience, Bonn, Germany
| | - Wolf Lagrèze
- Eye Centre, Medical Centre - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Pascale Mazzola
- Institute of Human Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Tobias B Haack
- Institute of Human Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
| | - Bernd Wissinger
- Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
| | - Felix Tonagel
- Centre for Ophthalmology, University of Tübingen, Tübingen, Germany
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25
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Surgical Menopause Impairs Retinal Conductivity and Worsens Prognosis in an Acute Model of Rat Optic Neuropathy. Cells 2022; 11:cells11193062. [PMID: 36231022 PMCID: PMC9564175 DOI: 10.3390/cells11193062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/24/2022] [Accepted: 09/27/2022] [Indexed: 12/03/2022] Open
Abstract
Deficiency of estradiol during the menopausal period is an important risk factor for neurodegenerative diseases, including various optic neuropathies. The aim of this study was to evaluate the impact of surgical menopause on the function and survival ratio of RGCs in the rat model of ONC (optic nerve crush). We used eight-week-old female Long Evans rats, divided into two main groups depending on the time between ovariectomy procedure (OVA) and euthanasia (two weeks vs. seven weeks), and subgroups—OVA, OVA + ONC, or ONC. Retinal function was assessed with electroretinography (ERG). RGC loss ratio was evaluated using immunolabelling and counting of RGCs. Seven weeks after OVA, the menopause morphologically affected interneurons but not RGC; however, when the ONC procedure was applied, RGCs appeared to be more susceptible to damage in case of deprivation of estrogens. In our analysis, PhNR (photopic negative responses) were severely diminished in the OVA + ONC group. A deprivation of estrogens in menopause results in accelerated retinal neurodegeneration that firstly involves retinal interneurons. The lack of estrogens increases the susceptibility of RGCs to insults.
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26
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Takano F, Ueda K, Godefrooij DA, Yamagami A, Ishikawa H, Chuman H, Ishikawa H, Ikeda Y, Sakamoto T, Nakamura M. Incidence of Leber hereditary optic neuropathy in 2019 in Japan: a second nationwide questionnaire survey. Orphanet J Rare Dis 2022; 17:319. [PMID: 35987635 PMCID: PMC9392235 DOI: 10.1186/s13023-022-02478-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 08/13/2022] [Indexed: 11/10/2022] Open
Abstract
Background Leber hereditary optic neuropathy (LHON) is an acute or subacute optic neuropathy that mainly affects young males. The first nationwide epidemiological survey of LHON was conducted in 2014 in Japan, and LHON was officially designated as a rare intractable disease by the Japanese government in 2015. We conducted a second survey of the annual incidence of LHON in 2019, and estimated the total number of patients with LHON in Japan. Results A questionnaire was sent to 997 facilities accredited by the Japanese Ophthalmological Society and/or affiliated with the councilors of the Japanese Neuro-Ophthalmology Society. Responses were received from 791 facilities, with a response rate of 79%. Fifty-five newly diagnosed cases (49 males and 6 females) of LHON were reported from 35 institutions in 2019, with a median age of 28.5 for males and 49.5 years for females. The total number of newly diagnosed cases was calculated as 69 (62 were males and 7 were females, 95% confidence interval 55–83), and the total number of patients was estimated to be 2491 (95% confidence interval: 1996–2986), suggesting a prevalence of LHON in Japan of 1:50,000. Conclusion The incidence of LHON in 2019 was lower than the estimate in 2014, whereas its prevalence may be similar to that reported in other countries. The accurate estimation of the incidence and prevalence of patients with LHON requires prospective registration.
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27
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Zhou Q, Yao S, Yang M, Guo Q, Li Y, Li L, Lei B. Superoxide dismutase 2 ameliorates mitochondrial dysfunction in skin fibroblasts of Leber’s hereditary optic neuropathy patients. Front Neurosci 2022; 16:917348. [PMID: 36017189 PMCID: PMC9398213 DOI: 10.3389/fnins.2022.917348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 07/22/2022] [Indexed: 11/20/2022] Open
Abstract
Background In Leber’s hereditary optic neuropathy (LHON), mtDNA mutations mediate mitochondrial dysfunction and apoptosis of retinal ganglion cells. Mitochondrial superoxide dismutase 2 (SOD2) is a crucial antioxidase against reactive oxygen species (ROS). This study aims to investigate whether SOD2 could ameliorate mtDNA mutation mediated mitochondrial dysfunction in skin fibroblasts of LHON patients and explore the underlying mechanisms. Methods The skin of normal healthy subjects and severe LHON patients harboring m.11778G > A mutation was taken to prepare immortalized skin fibroblast cell lines (control-iFB and LHON-iFB). LHON-iFB cells were transfected with SOD2 plasmid or negative control plasmid, respectively. In addition, human neuroblastoma SH-SY5Y cells and human primary retinal pigmental epithelium (hRPE) cells were stimulated by H2O2 after gene transfection. The oxygen consumption rate (OCR) was measured with a Seahorse extracellular flux analyzer. The level of ATP production, mitochondrial membrane potential, ROS and malondialdehyde (MDA) were measured separately with the corresponding assay kits. The expression level of SOD2, inflammatory cytokines and p-IκBα/IκBα was evaluated by western-blot. Assessment of apoptosis was performed by TUNEL assay. Results LHON-iFB exhibited lower OCR, ATP production, mitochondrial membrane potential but higher level of ROS and MDA than control-iFB. Western-blot revealed a significantly increased expression of IL-6 and p-IκBα/IκBα in LHON-iFB. Compared with the negative control, SOD2 overexpression increased OCR, ATP production and elevated mitochondrial membrane potential, but impaired ROS and MDA production. Besides, western-blot demonstrated exogenous SOD2 reduced the protein level of IL-6 and p-IκBα/IκBα. TUNEL assays suggested SOD2 inhibited cells apoptosis. Analogously, in SH-SY5Y and hRPE cells, SOD2 overexpression increased ATP production and mitochondrial membrane potential, but decreased ROS, MDA levels and suppressed apoptosis. Conclusion SOD2 upregulation inhibited cells apoptosis through ameliorating mitochondrial dysfunction and reducing NF-κB associated inflammatory response. This study further support exogenous SOD2 may be a promising therapy for the treatment of LHON.
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Affiliation(s)
- Qingru Zhou
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
| | - Shun Yao
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Eye Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, China
| | - Mingzhu Yang
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Eye Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, China
| | - Qingge Guo
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Eye Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, China
| | - Ya Li
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Eye Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, China
| | - Lei Li
- Xinxiang Medical University, Xinxiang, China
| | - Bo Lei
- Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China
- Henan Eye Hospital, Henan Provincial People’s Hospital, Henan Eye Institute, Zhengzhou, China
- *Correspondence: Bo Lei,
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28
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Pathological mitophagy disrupts mitochondrial homeostasis in Leber's hereditary optic neuropathy. Cell Rep 2022; 40:111124. [PMID: 35858578 PMCID: PMC9314546 DOI: 10.1016/j.celrep.2022.111124] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 03/27/2022] [Accepted: 06/29/2022] [Indexed: 01/18/2023] Open
Abstract
Leber’s hereditary optic neuropathy (LHON), a disease associated with a mitochondrial DNA mutation, is characterized by blindness due to degeneration of retinal ganglion cells (RGCs) and their axons, which form the optic nerve. We show that a sustained pathological autophagy and compartment-specific mitophagy activity affects LHON patient-derived cells and cybrids, as well as induced pluripotent-stem-cell-derived neurons. This is variably counterbalanced by compensatory mitobiogenesis. The aberrant quality control disrupts mitochondrial homeostasis as reflected by defective bioenergetics and excessive reactive oxygen species production, a stress phenotype that ultimately challenges cell viability by increasing the rate of apoptosis. We counteract this pathological mechanism by using autophagy regulators (clozapine and chloroquine) and redox modulators (idebenone), as well as genetically activating mitochondrial biogenesis (PGC1-α overexpression). This study substantially advances our understanding of LHON pathophysiology, providing an integrated paradigm for pathogenesis of mitochondrial diseases and druggable targets for therapy.
Autophagy and mitophagy are abnormally activated in samples carrying LHON mutations Autophagy and mitophagy affect LHON cells’ viability Therapeutic approaches targeting autophagy reverts LHON cells’ apoptotic death
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29
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Wang Y, Guo X, Hong X, Wang G, Pearson C, Zuckerman B, Clark AG, O'Brien KO, Wang X, Gu Z. Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism. Nat Commun 2022; 13:3790. [PMID: 35778412 PMCID: PMC9249801 DOI: 10.1038/s41467-022-30805-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 05/19/2022] [Indexed: 12/30/2022] Open
Abstract
Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study (n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort (n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors (P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD.
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Affiliation(s)
- Yiqin Wang
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Xiaoxian Guo
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA
| | - Xiumei Hong
- Center on Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Guoying Wang
- Center on Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Colleen Pearson
- Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Barry Zuckerman
- Department of Pediatrics, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
| | - Andrew G Clark
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA
- Department of Computational Biology, Cornell University, Ithaca, NY, USA
| | | | - Xiaobin Wang
- Center on Early Life Origins of Disease, Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Zhenglong Gu
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, USA.
- Center for Mitochondrial Genetics and Medicine, Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China.
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30
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Stephenson KAJ, McAndrew J, Kenna PF, Cassidy L. The Natural History of Leber's Hereditary Optic Neuropathy in an Irish Population and Assessment for Prognostic Biomarkers. Neuroophthalmology 2022; 46:159-170. [PMID: 35574161 PMCID: PMC9103396 DOI: 10.1080/01658107.2022.2032761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
Abstract
In this study we have assessed the clinical and genetic characteristics of an Irish Leber's hereditary optic neuropathy (LHON) cohort and assessed for useful biomarkers of visual prognosis. We carried out a retrospective review of clinical data of patients with genetically confirmed LHON presenting to an Irish tertiary referral ophthalmic hospital. LHON diagnosis was made on classic clinical signs with genetic confirmation. Alternate diagnoses were excluded with serological investigations and neuro-imaging. Serial logarithm of the minimum angle of resolution (logMAR) visual acuity (VA) was stratified into 'on-chart' for logMAR 1.0 or better and 'off-chart' if worse than logMAR 1.0. Serial optical coherence tomography scans of the retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) monitored structure. Idebenone-treated and untreated patients were contrasted. Statistical analyses were performed to assess correlations of presenting characteristics with final VA. Forty-four patients from 34 pedigrees were recruited, of which 87% were male and 75% harboured the 11778 mutation. Legal blindness status was reached in 56.8% of patients by final review (mean 74 months). Preservation of initial nasal RNFL was the best predictor of on-chart final VA. Females had worse final VA than males and patients presenting at < 20 years of age had superior final VA. Idebenone therapy (50% of cohort) yielded no statistically significant benefit to final VA, although study design precludes definitive comment on efficacy. The reported cases represent the calculated majority of LHON pedigrees in Ireland. Visual outcomes were universally poor; however, VA may not be the most appropriate outcome measure and certain patient-reported outcome measures may be of more use when assessing future LHON interventions.
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Affiliation(s)
- Kirk A. J. Stephenson
- Department of Neuro-ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland,CONTACT Kirk A. J. Stephenson Department of Neuro-ophthalmology, Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin2 D02 XK51, Ireland
| | - Joseph McAndrew
- Department of Neuro-ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
| | - Paul F. Kenna
- Department of Neuro-ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
| | - Lorraine Cassidy
- Department of Neuro-ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin, Ireland
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31
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Tian Q, Wang L, Zhang Y, Fan K, Liang M, Shi D, Qin W, Ding H. Brain Gray Matter Atrophy and Functional Connectivity Remodeling in Patients With Chronic LHON. Front Neurosci 2022; 16:885770. [PMID: 35645726 PMCID: PMC9135140 DOI: 10.3389/fnins.2022.885770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/19/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose The aim of this study was to investigate the brain gray matter volume (GMV) and spontaneous functional connectivity (FC) changes in patients with chronic Leber's hereditary optic neuropathy (LHON), and their relations with clinical measures. Methods A total of 32 patients with chronic LHON and matched sighted healthy controls (HC) underwent neuro-ophthalmologic examinations and multimodel magnetic resonance imaging (MRI) scans. Voxel-based morphometry (VBM) was used to detect the GMV differences between the LHON and HC. Furthermore, resting-state FC analysis using the VBM-identified clusters as seeds was carried out to detect potential functional reorganization in the LHON. Finally, the associations between the neuroimaging and clinical measures were performed. Results The average peripapillary retinal nerve fiber layer (RNFL) thickness of the chronic LHON was significantly thinner (T = −16.421, p < 0.001), and the mean defect of the visual field was significantly higher (T = 11.28, p < 0.001) than the HC. VBM analysis demonstrated a significantly lower GMV of bilateral calcarine gyri (CGs) in the LHON than in the HC (p < 0.05). Moreover, in comparison with the HC, the LHON had significantly lower FC between the centroid of the identified left CG and ipsilateral superior occipital gyrus (SOG) and higher FC between this cluster and the ipsilateral posterior cingulate gyrus (p < 0.05, corrected). Finally, the GMV of the left CG was negatively correlated with the LHON duration (r = −0.535, p = 0.002), and the FC between the left CG and the ipsilateral posterior cingulate gyrus of the LHON was negatively correlated with the average peripapillary RNFL thickness (r = −0.522, p = 0.003). Conclusion The atrophied primary visual cortex of the chronic LHON may be caused by transneuronal degeneration following the retinal damage. Moreover, our findings suggest that the functional organization of the atrophied primary visual cortex has been reshaped in the chronic LHON.
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Affiliation(s)
- Qin Tian
- Department of Medical Imaging, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Ling Wang
- Department of Medical Imaging, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
| | - Yu Zhang
- Department of Radiology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
| | - Ke Fan
- Henan Eye Institute, Henan Eye Hospital, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China
| | - Meng Liang
- Department of Radiology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
- School of Medical Imaging, Tianjin Medical University, Tianjin, China
| | - Dapeng Shi
- Department of Medical Imaging, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, China
- *Correspondence: Dapeng Shi
| | - Wen Qin
- Department of Radiology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
- Wen Qin
| | - Hao Ding
- Department of Radiology, Tianjin Medical University, Tianjin, China
- Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin, China
- School of Medical Imaging, Tianjin Medical University, Tianjin, China
- Hao Ding
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32
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Kuan SW, Chua KH, Tan EW, Tan LK, Loch A, Kee BP. Whole mitochondrial genome sequencing of Malaysian patients with cardiomyopathy. PeerJ 2022; 10:e13265. [PMID: 35441061 PMCID: PMC9013480 DOI: 10.7717/peerj.13265] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 03/23/2022] [Indexed: 01/13/2023] Open
Abstract
Cardiomyopathy (CMP) constitutes a diverse group of myocardium diseases affecting the pumping ability of the heart. Genetic predisposition is among the major factors affecting the development of CMP. Globally, there are over 100 genes in autosomal and mitochondrial DNA (mtDNA) that have been reported to be associated with the pathogenesis of CMP. However, most of the genetic studies have been conducted in Western countries, with limited data being available for the Asian population. Therefore, this study aims to investigate the mutation spectrum in the mitochondrial genome of 145 CMP patients in Malaysia. Long-range PCR was employed to amplify the entire mtDNA, and whole mitochondrial genome sequencing was conducted on the MiSeq platform. Raw data was quality checked, mapped, and aligned to the revised Cambridge Reference Sequence (rCRS). Variants were named, annotated, and filtered. The sequencing revealed 1,077 variants, including 18 novel and 17 CMP and/or mitochondrial disease-associated variants after filtering. In-silico predictions suggested that three of the novel variants (m.8573G>C, m.11916T>A and m.11918T>G) in this study are potentially pathogenic. Two confirmed pathogenic variants (m.1555A>G and m.11778G>A) were also found in the CMP patients. The findings of this study shed light on the distribution of mitochondrial mutations in Malaysian CMP patients. Further functional studies are required to elucidate the role of these variants in the development of CMP.
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Affiliation(s)
- Sheh Wen Kuan
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kek Heng Chua
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - E-Wei Tan
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Lay Koon Tan
- National Heart Institute, Kuala Lumpur, Malaysia
| | - Alexander Loch
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Boon Pin Kee
- Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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33
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Sex Hormones and Their Effects on Ocular Disorders and Pathophysiology: Current Aspects and Our Experience. Int J Mol Sci 2022; 23:ijms23063269. [PMID: 35328690 PMCID: PMC8949880 DOI: 10.3390/ijms23063269] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/15/2022] [Accepted: 03/16/2022] [Indexed: 12/27/2022] Open
Abstract
Sex hormones are molecules produced by the gonads and to a small extent by the adrenal gland, which not only determine the primary and secondary sexual characteristics of an individual, differentiating man from woman, but also participate in the functioning of the various systems of the body. The evidence that many eye diseases differ in terms of prevalence between men and women has allowed us, in recent years, to carry out several studies that have investigated the association between sex hormones and the pathophysiology of eye tissues. Specific receptors for sex hormones have been found on the lacrimal and meibomian glands, conjunctiva, cornea, lens, retina, and choroid. This work summarizes the current knowledge on the role that sex hormones play in the pathogenesis of the most common ocular disorders and indicates our clinical experience in these situations. The aim is to stimulate an interdisciplinary approach between endocrinology, neurology, molecular biology, and ophthalmology to improve the management of these diseases and to lay the foundations for new therapeutic strategies.
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Mahmud S, Biswas S, Afrose S, Mita MA, Hasan MR, Shimu MSS, Paul GK, Chung S, Saleh MA, Alshehri S, Ghoneim MM, Alruwaily M, Kim B. Use of Next-Generation Sequencing for Identifying Mitochondrial Disorders. Curr Issues Mol Biol 2022; 44:1127-1148. [PMID: 35723297 PMCID: PMC8947152 DOI: 10.3390/cimb44030074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/18/2022] [Accepted: 02/24/2022] [Indexed: 12/06/2022] Open
Abstract
Mitochondria are major contributors to ATP synthesis, generating more than 90% of the total cellular energy production through oxidative phosphorylation (OXPHOS): metabolite oxidation, such as the β-oxidation of fatty acids, and the Krebs's cycle. OXPHOS inadequacy due to large genetic lesions in mitochondrial as well as nuclear genes and homo- or heteroplasmic point mutations in mitochondrially encoded genes is a characteristic of heterogeneous, maternally inherited genetic disorders known as mitochondrial disorders that affect multisystemic tissues and organs with high energy requirements, resulting in various signs and symptoms. Several traditional diagnostic approaches, including magnetic resonance imaging of the brain, cardiac testing, biochemical screening, variable heteroplasmy genetic testing, identifying clinical features, and skeletal muscle biopsies, are associated with increased risks, high costs, a high degree of false-positive or false-negative results, or a lack of precision, which limits their diagnostic abilities for mitochondrial disorders. Variable heteroplasmy levels, mtDNA depletion, and the identification of pathogenic variants can be detected through genetic sequencing, including the gold standard Sanger sequencing. However, sequencing can be time consuming, and Sanger sequencing can result in the missed recognition of larger structural variations such as CNVs or copy-number variations. Although each sequencing method has its own limitations, genetic sequencing can be an alternative to traditional diagnostic methods. The ever-growing roster of possible mutations has led to the development of next-generation sequencing (NGS). The enhancement of NGS methods can offer a precise diagnosis of the mitochondrial disorder within a short period at a reasonable expense for both research and clinical applications.
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Affiliation(s)
- Shafi Mahmud
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Suvro Biswas
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Shamima Afrose
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Mohasana Akter Mita
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Md. Robiul Hasan
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Mst. Sharmin Sultana Shimu
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Gobindo Kumar Paul
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Sanghyun Chung
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea;
| | - Md. Abu Saleh
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh; (S.B.); (S.A.); (M.A.M.); (M.R.H.); (M.S.S.S.); (G.K.P.); (M.A.S.)
| | - Sultan Alshehri
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Momammed M. Ghoneim
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia; (M.M.G.); (M.A.)
| | - Maha Alruwaily
- Department of Pharmacy Practice, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Saudi Arabia; (M.M.G.); (M.A.)
| | - Bonglee Kim
- Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea;
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Siedlecki J, Koenig S, Catarino C, Schaumberger MM, Schworm B, Priglinger SG, Rudolph G, von Livonius B, Klopstock T, Priglinger CS. Childhood versus early-teenage onset Leber's hereditary optic neuropathy: visual prognosis and capacity for recovery. Br J Ophthalmol 2022:bjophthalmol-2021-320580. [PMID: 35190400 DOI: 10.1136/bjophthalmol-2021-320580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 01/22/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE In Leber's hereditary optic neuropathy (LHON) in children and teenagers, the influence of age on visual prognosis has not yet been investigated. METHODS Patients from the mitoNET registry with LHON onset at age 4-16 years with at least 4 years of follow-up without treatment were included. Visual acuity (VA) at baseline, lowest VA ever recorded (nadir) and VA at end of follow-up were compared between childhood onset (ChO, ≤12 years of age) and early-teenage onset (eTO; 13-16 years). RESULTS Out of 231 patients with LHON, 19 met the inclusion criteria (8.2%). There were 11 patients in the ChO and 8 patients in the eTO group. Mean age at onset was 8.6 (SD 2.1) years (ChO) and 15.4 (SD 0.7) years (eTO) (p<0.00001). Follow-up was mean 184 (SD 129) months (ChO) and 119 (SD 78) months (eTO) (p=0.22). Baseline VA was similar between both groups in better (p=0.96) and worse eyes (p=0.54). In worse eyes, both groups deteriorated similarly (p=0.79) until nadir and showed similar recovery until end of follow-up (p=0.38). In better eyes, both groups deteriorated similarly (p=0.16) until nadir. From nadir until end of follow-up, better eyes in the ChO group showed a significantly better recovery (-0.35 (SD 0.36) vs -0.01 (SD 0.06) logMAR; p=0.02) than eTO eyes. CONCLUSION Visual prognosis of LHON in children is much more favourable in cases of childhood onset (≤12 years of age) as compared with teenage onset (13-16 years), mostly due to better recovery from nadir in childhood onset.
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Affiliation(s)
- Jakob Siedlecki
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Susanna Koenig
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Claudia Catarino
- Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Markus M Schaumberger
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Benedikt Schworm
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | | | - Guenther Rudolph
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Bettina von Livonius
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Thomas Klopstock
- Friedrich-Baur-Institut, Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
| | - Claudia S Priglinger
- Department of Ophthalmology, Ludwig-Maximilians-Universität München, Munchen, Bayern, Germany
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36
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Beikoghli Kalkhoran S, Kararigas G. Oestrogenic Regulation of Mitochondrial Dynamics. Int J Mol Sci 2022; 23:ijms23031118. [PMID: 35163044 PMCID: PMC8834780 DOI: 10.3390/ijms23031118] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/15/2022] [Accepted: 01/16/2022] [Indexed: 02/04/2023] Open
Abstract
Biological sex influences disease development and progression. The steroid hormone 17β-oestradiol (E2), along with its receptors, is expected to play a major role in the manifestation of sex differences. E2 exerts pleiotropic effects in a system-specific manner. Mitochondria are one of the central targets of E2, and their biogenesis and respiration are known to be modulated by E2. More recently, it has become apparent that E2 also regulates mitochondrial fusion–fission dynamics, thereby affecting cellular metabolism. The aim of this article is to discuss the regulatory pathways by which E2 orchestrates the activity of several components of mitochondrial dynamics in the cardiovascular and nervous systems in health and disease. We conclude that E2 regulates mitochondrial dynamics to maintain the mitochondrial network promoting mitochondrial fusion and attenuating mitochondrial fission in both the cardiovascular and nervous systems.
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37
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Qiu Y, Yu J, Tang L, Ren J, Shao M, Li S, Song Y, Cao W, Sun X. Association Between Sex Hormones and Visual Field Progression in Women With Primary Open Angle Glaucoma: A Cross-Sectional and Prospective Cohort Study. Front Aging Neurosci 2022; 13:756186. [PMID: 35002675 PMCID: PMC8741302 DOI: 10.3389/fnagi.2021.756186] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/02/2021] [Indexed: 11/15/2022] Open
Abstract
Purpose: We evaluated the level of sex hormones in female patients with primary open angle glaucoma (POAG) to determine whether they are associated with the onset and/or progression of POAG. Methods: The cross-sectional study enrolled 63 women with POAG and 56 healthy women as normal control subjects. Furthermore, 57 women with POAG were included and followed-up for at least 2 years in the cohort study. All subjects were evaluated for serum concentration of sex hormones [prolactin (PRL), luteinizing hormone (LH), testosterone (TESTO), follicle-stimulating hormone (FSH), progesterone (PROG), and estrogen (E2)] and underwent visual field (VF) examination. In the cross-sectional study, Spearman analysis, linear regression analysis, and logistic regression analysis were performed to assess risk factors for POAG in women. In the cohort study, Cox regression analyses and Kaplan–Meier survival analysis were performed to identify factors associated with VF progression in women with POAG. Results: In the cross-sectional study, the level of E2 was significantly lower in the POAG group than in the normal group (p < 0.05). Multiple logistic regression showed that the decreased level of E2 was a risk factor of POAG (OR = 0.27, 95% CI = 0.09–0.78, p < 0.05), especially in premenopausal subjects. In the cohort study, there were 29 non-progression subjects and 28 progression subjects. Patients in the progression group had significantly lower levels of E2 than those in the no progression group (p < 0.01). The decreased level of E2 at baseline was associated with POAG progression (HR = 0.08, 95% CI = 0.02–0.46, p < 0.05), especially in premenopausal subjects. Patients with POAG and with lower baseline E2 levels had significantly lower VF non-progression rates than patients with higher E2 levels (log-rank test p < 0.001), especially premenopausal subjects (log-rank test p < 0.05). Additionally, logistic regression analyses, Cox regression analyses, and Kaplan–Meier survival analysis showed that PROG, LH, FSH, and TESTO were risk factors of POAG and/or significantly associated with POAG progression. Conclusion: A decreased E2 level is a POAG risk factor and is associated with VF progression in women with POAG, especially in premenopausal subjects. Additionally, other sex hormones (PROG, LH, FSH, and TESTO) might also play a role in POAG pathogenesis.
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Affiliation(s)
- Yichao Qiu
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Jian Yu
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Li Tang
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Jun Ren
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Mingxi Shao
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Shengjie Li
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China.,Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China
| | - Yunxiao Song
- Department of Clinical Laboratory, Shanghai Xuhui Central Hospital, Shanghai, China
| | - Wenjun Cao
- Clinical Laboratory, Eye & ENT Hospital, Fudan University, Shanghai, China.,Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Myopia, Fudan University - Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
| | - Xinghuai Sun
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, China.,NHC Key Laboratory of Myopia, Fudan University - Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China.,Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China
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38
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Fotesko K, Thomsen BSV, Kolko M, Vohra R. Girl Power in Glaucoma: The Role of Estrogen in Primary Open Angle Glaucoma. Cell Mol Neurobiol 2022; 42:41-57. [PMID: 33040237 PMCID: PMC11441221 DOI: 10.1007/s10571-020-00965-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022]
Abstract
Estrogen is essential in maintaining various physiological features in women, and a decline in estrogen levels are known to give rise to numerous unfortunate symptoms associated with menopause. To alleviate these symptoms hormone replacement therapy with estrogen is often used, and has been shown to be fruitful in improving quality of life in women suffering from postmenopausal discomforts. An often forgotten condition associated with menopause is the optic nerve disorder, glaucoma. Thus, estrogen may also have an impact in maintaining the retinal ganglion cells (RGCs), which make up the optic nerve, thereby preventing glaucomatous neurodegeneration. This review aims to provide an overview of possible associations of estrogen and the glaucoma subtype, primary open-angle glaucoma (POAG), by evaluating the current literature through a PubMed-based literature search. Multiple in vitro and in vivo studies of RGC protection, as well as clinical and epidemiological data concerning the well-defined retinal neurodegenerative disorder POAG have been reviewed. Over all, deficiencies in retinal estrogen may potentially instigate RGC loss, visual disability, and eventual blindness. Estrogen replacement therapy may therefore be a beneficial future treatment. However, more studies are needed to confirm the relevance of estrogen in glaucoma prevention.
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Affiliation(s)
- Kyrylo Fotesko
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | | | - Miriam Kolko
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
- Department of Ophthalmology, Rigshospitalet-Glostrup, Glostrup, Denmark.
| | - Rupali Vohra
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
- Department of Veterinary and Animal Sciences, University of Copenhagen, Copenhagen, Denmark.
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Zeviani M, Carelli V. Mitochondrial Retinopathies. Int J Mol Sci 2021; 23:210. [PMID: 35008635 PMCID: PMC8745158 DOI: 10.3390/ijms23010210] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/13/2022] Open
Abstract
The retina is an exquisite target for defects of oxidative phosphorylation (OXPHOS) associated with mitochondrial impairment. Retinal involvement occurs in two ways, retinal dystrophy (retinitis pigmentosa) and subacute or chronic optic atrophy, which are the most common clinical entities. Both can present as isolated or virtually exclusive conditions, or as part of more complex, frequently multisystem syndromes. In most cases, mutations of mtDNA have been found in association with mitochondrial retinopathy. The main genetic abnormalities of mtDNA include mutations associated with neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) sometimes with earlier onset and increased severity (maternally inherited Leigh syndrome, MILS), single large-scale deletions determining Kearns-Sayre syndrome (KSS, of which retinal dystrophy is a cardinal symptom), and mutations, particularly in mtDNA-encoded ND genes, associated with Leber hereditary optic neuropathy (LHON). However, mutations in nuclear genes can also cause mitochondrial retinopathy, including autosomal recessive phenocopies of LHON, and slowly progressive optic atrophy caused by dominant or, more rarely, recessive, mutations in the fusion/mitochondrial shaping protein OPA1, encoded by a nuclear gene on chromosome 3q29.
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Affiliation(s)
- Massimo Zeviani
- Department of Neurosciences, The Clinical School, University of Padova, 35128 Padova, Italy
- Veneto Institute of Molecular Medicine, Via Orus 2, 35128 Padova, Italy
| | - Valerio Carelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139 Bologna, Italy
- Programma di Neurogenetica, IRCCS Istituto delle Scienze Neurologiche di Bologna, Via Altura 6, 40139 Bologna, Italy
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40
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Zaslavsky K, Margolin EA. Leber's Hereditary Optic Neuropathy in Older Individuals Because of Increased Alcohol Consumption During the COVID-19 Pandemic. J Neuroophthalmol 2021; 41:316-320. [PMID: 34415266 DOI: 10.1097/wno.0000000000001333] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Leber's hereditary optic neuropathy (LHON) is a disorder affecting oxidative phosphorylation in mitochondria. A majority of affected patients are men of 15 to 35 years of age. Phenotypic penetrance of this condition is only 50% in man and 10% in women and increases if the cellular energy demands go up, with the most common risk factors being smoking and alcohol use. METHODS Review of clinical features of 3 patients who were diagnosed with LHON in their sixth decade of life after doubling their alcohol intake during the recent COVID-19 pandemic. RESULTS All 3 patients were older than the age of 50 when they developed severe sequential visual loss. All have at least doubled their alcohol intake for at least 4 weeks preceding visual loss, and 2 who were smokers increased the number of cigarettes consumed daily because of the stress and boredom during the lockdowns triggered by the pandemic. CONCLUSIONS Significant increase in substance abuse in the general population during the recent lockdowns to combat the COVID-19 pandemic is well documented. We report 3 patients older than the age of 50, one of them a woman, who developed severe bilateral visual loss due to LHON after doubling their alcohol consumption and increasing number of cigarettes smoked daily during the pandemic. Clinicians are reminded to consider LHON in the differential diagnosis when encountering older patients with bilateral sequential visual loss and to specifically inquire about alcohol use and cigarette smoking in these patients.
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Affiliation(s)
- Kirill Zaslavsky
- Departments of Ophthalmology and Vision Sciences (KZ, EM), University of Toronto, Toronto, Canada ; and Department of Medicine (EM), Division of Neurology, University of Toronto, Toronto, Canada
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41
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Sundaramurthy S, SelvaKumar A, Ching J, Dharani V, Sarangapani S, Yu-Wai-Man P. Leber hereditary optic neuropathy-new insights and old challenges. Graefes Arch Clin Exp Ophthalmol 2021; 259:2461-2472. [PMID: 33185731 DOI: 10.1007/s00417-020-04993-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/16/2020] [Accepted: 10/23/2020] [Indexed: 12/20/2022] Open
Abstract
Leber hereditary optic neuropathy (LHON) is the most common primary mitochondrial DNA (mtDNA) disorder with the majority of patients harboring one of three primary mtDNA point mutations, namely, m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6). LHON is characterized by bilateral subacute loss of vision due to the preferential loss of retinal ganglion cells (RGCs) within the inner retina, resulting in optic nerve degeneration. This review describes the clinical features associated with mtDNA LHON mutations and recent insights gained into the disease mechanisms contributing to RGC loss in this mitochondrial disorder. Although treatment options remain limited, LHON research has now entered an active translational phase with ongoing clinical trials, including gene therapy to correct the underlying pathogenic mtDNA mutation.
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Affiliation(s)
- Srilekha Sundaramurthy
- 1SN Oil and Natural Gas Corporation (ONGC) Department of Genetics & Molecular Biology, Vision Research Foundation, Chennai, India.
| | - Ambika SelvaKumar
- Department of Neuro-Ophthalmology, Medical Research Foundation, Chennai, India
| | - Jared Ching
- Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
- John Van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
| | - Vidhya Dharani
- Department of Neuro-Ophthalmology, Medical Research Foundation, Chennai, India
| | - Sripriya Sarangapani
- 1SN Oil and Natural Gas Corporation (ONGC) Department of Genetics & Molecular Biology, Vision Research Foundation, Chennai, India
| | - Patrick Yu-Wai-Man
- Cambridge Eye Unit, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
- John Van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
- NIHR Biomedical Research Centre, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK
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Yang TC, Yarmishyn AA, Yang YP, Lu PC, Chou SJ, Wang ML, Lin TC, Hwang DK, Chou YB, Chen SJ, Yu WK, Wang AG, Hsu CC, Chiou SH. Mitochondrial transport mediates survival of retinal ganglion cells in affected LHON patients. Hum Mol Genet 2021; 29:1454-1464. [PMID: 32277753 DOI: 10.1093/hmg/ddaa063] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 03/02/2020] [Accepted: 03/30/2020] [Indexed: 01/17/2023] Open
Abstract
The mutations in the genes encoding the subunits of complex I of the mitochondrial electron transport chain are the most common cause of Leber's hereditary optic neuropathy (LHON), a maternal hereditary disease characterized by retinal ganglion cell (RGC) degeneration. The characteristics of incomplete penetrance indicate that nuclear genetic and environmental factors also determine phenotypic expression of LHON. Therefore, further understanding of the role of mutant mitochondrial nicotinamide adenine dinucleotide dehydrogenase subunit proteins and nuclear genetic factors/environmental effects in the etiology of LHON is needed. In this study, we generated human-induced pluripotent stem cells (hiPSCs) from healthy control, unaffected LHON mutation carrier, and affected LHON patient. hiPSC-derived RGCs were used to study the differences between affected and unaffected carriers of mitochondrial DNA point mutation m.11778G > A in the MT-ND4 gene. We found that both mutated cell lines were characterized by increase in reactive oxygen species production, however, only affected cell line had increased levels of apoptotic cells. We found a significant increase in retrograde mitochondria and a decrease in stationary mitochondria in the affected RGC axons. In addition, the messenger RNA and protein levels of KIF5A in the LHON-affected RGCs were significantly reduced. Antioxidant N-acetyl-L-cysteine could restore the expression of KIF5A and the normal pattern of mitochondrial movement in the affected RGCs. To conclude, we found essential differences in the mutually dependent processes of oxidative stress, mitochondrial transport and apoptosis between two LHON-specific mutation carrier RGC cell lines, asymptomatic carrier and disease-affected, and identified KIF5A as a central modulator of these differences.
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Affiliation(s)
- Tien-Chun Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | | | - Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.,School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.,School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan
| | - Pin-Chen Lu
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Shih-Jie Chou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.,Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Mong-Lien Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.,School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.,School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Institute of Pharmacology, National Yang-Ming University, Taipei 11221, Taiwan
| | - Tai-Chi Lin
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - De-Kuang Hwang
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Yu-Bai Chou
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Shih-Jen Chen
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Wei-Kuang Yu
- Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - An-Guor Wang
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Chih-Chien Hsu
- School of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Shih-Hwa Chiou
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.,School of Pharmaceutical Sciences, National Yang-Ming University, Taipei 11221, Taiwan.,Department of Ophthalmology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
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43
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Bernardino Gomes TM, Ng YS, Pickett SJ, Turnbull DM, Vincent AE. Mitochondrial DNA disorders: From pathogenic variants to preventing transmission. Hum Mol Genet 2021; 30:R245-R253. [PMID: 34169319 PMCID: PMC8490015 DOI: 10.1093/hmg/ddab156] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/28/2021] [Accepted: 06/01/2021] [Indexed: 11/27/2022] Open
Abstract
Mitochondrial DNA (mtDNA) disorders are recognized as one of the most common causes of inherited metabolic disorders. The mitochondrial genome occurs in multiple copies resulting in both homoplasmic and heteroplasmic pathogenic mtDNA variants. A biochemical defect arises when the pathogenic variant level reaches a threshold, which differs between variants. Moreover, variants can segregate, clonally expand, or be lost from cellular populations resulting in a dynamic and tissue-specific mosaic pattern of oxidative deficiency. MtDNA is maternally inherited but transmission patterns of heteroplasmic pathogenic variants are complex. During oogenesis, a mitochondrial bottleneck results in offspring with widely differing variant levels to their mother, whilst highly deleterious variants, such as deletions, are not transmitted. Complemented by a complex interplay between mitochondrial and nuclear genomes, these peculiar genetics produce marked phenotypic variation, posing challenges to the diagnosis and clinical management of patients. Novel therapeutic compounds and several genetic therapies are currently under investigation, but proven disease-modifying therapies remain elusive. Women who carry pathogenic mtDNA variants require bespoke genetic counselling to determine their reproductive options. Recent advances in in vitro fertilization techniques, have greatly improved reproductive choices, but are not without their challenges. Since the first pathogenic mtDNA variants were identified over 30 years ago, there has been remarkable progress in our understanding of these diseases. However, many questions remain unanswered and future studies are required to investigate the mechanisms of disease progression and to identify new disease-specific therapeutic targets.
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Affiliation(s)
- Tiago M Bernardino Gomes
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH, UK
| | - Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE2 4HH, UK
| | - Sarah J Pickett
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Doug M Turnbull
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Amy E Vincent
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
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44
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Hage R, Vignal-Clermont C. Leber Hereditary Optic Neuropathy: Review of Treatment and Management. Front Neurol 2021; 12:651639. [PMID: 34122299 PMCID: PMC8187781 DOI: 10.3389/fneur.2021.651639] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 04/06/2021] [Indexed: 01/16/2023] Open
Abstract
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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Affiliation(s)
- Rabih Hage
- Neuro-ophthalmology Department, Hôpital Fondation Rothschild, Paris, France
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45
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Jodeiri Farshbaf M, Alviña K. Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin. Front Aging Neurosci 2021; 13:649929. [PMID: 33935687 PMCID: PMC8086837 DOI: 10.3389/fnagi.2021.649929] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 03/15/2021] [Indexed: 12/11/2022] Open
Abstract
Exercise has multiple beneficial effects on health including decreasing the risk of neurodegenerative diseases. Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle synthesizes and secretes a wide range of myokines which contribute to different functions in different organs, including the brain. One such myokine is the recently discovered protein Irisin, which is secreted into circulation from skeletal muscle during exercise from its membrane bound precursor Fibronectin type III domain-containing protein 5 (FNDC5). Irisin contributes to metabolic processes such as glucose homeostasis and browning of white adipose tissue. Irisin also crosses the blood brain barrier and initiates a neuroprotective genetic program in the hippocampus that culminates with increased expression of brain derived neurotrophic factor (BDNF). Furthermore, exercise and FNDC5/Irisin have been shown to have several neuroprotective effects against injuries in ischemia and neurodegenerative disease models, including Alzheimer's disease. In addition, Irisin has anxiolytic and antidepressant effects. In this review we present and summarize recent findings on the multiple effects of Irisin on neural function, including signaling pathways and mechanisms involved. We also discuss how exercise can positively influence brain function and mental health via the "skeletal muscle-brain axis." While there are still many unanswered questions, we put forward the idea that Irisin is a potentially essential mediator of the skeletal muscle-brain crosstalk.
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Affiliation(s)
| | - Karina Alviña
- Department of Biological Sciences, Texas Tech University, Lubbock, TX, United States.,Department of Neuroscience, University of Florida, Gainesville, FL, United States
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46
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Maldonado R, Jalil S, Wartiovaara K. Curative gene therapies for rare diseases. J Community Genet 2021; 12:267-276. [PMID: 32803721 PMCID: PMC8141081 DOI: 10.1007/s12687-020-00480-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 07/29/2020] [Indexed: 02/06/2023] Open
Abstract
Diseases caused by alterations in the DNA can be overcome by providing the cells or tissues with a functional copy of the mutated gene. The most common form of gene therapy implies adding an extra genetic unit into the cell. However, new genome engineering techniques also allow the modification or correction of the existing allele, providing new possibilities, especially for dominant diseases. Gene therapies have been tested for 30 years in thousands of clinical trials, but presently, we have only three authorised gene therapy products for the treatment of inherited diseases in European Union. Here, we describe the gene therapy alternatives already on the market in the European Union and expand the scope to some clinical trials. Additionally, we discuss the ethical and regulatory issues raised by the development of these new kinds of therapies.
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Affiliation(s)
- Rocio Maldonado
- Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland
| | - Sami Jalil
- Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland
| | - Kirmo Wartiovaara
- Stem Cells and Metabolism Research Program, University of Helsinki, Helsinki, Finland.
- Clinical Genetics, Helsinki University Hospital, Helsinki, Finland.
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47
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Maresca A, Carelli V. Molecular Mechanisms behind Inherited Neurodegeneration of the Optic Nerve. Biomolecules 2021; 11:496. [PMID: 33806088 PMCID: PMC8064499 DOI: 10.3390/biom11040496] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 01/01/2023] Open
Abstract
Inherited neurodegeneration of the optic nerve is a paradigm in neurology, as many forms of isolated or syndromic optic atrophy are encountered in clinical practice. The retinal ganglion cells originate the axons that form the optic nerve. They are particularly vulnerable to mitochondrial dysfunction, as they present a peculiar cellular architecture, with axons that are not myelinated for a long intra-retinal segment, thus, very energy dependent. The genetic landscape of causative mutations and genes greatly enlarged in the last decade, pointing to common pathways. These mostly imply mitochondrial dysfunction, which leads to a similar outcome in terms of neurodegeneration. We here critically review these pathways, which include (1) complex I-related oxidative phosphorylation (OXPHOS) dysfunction, (2) mitochondrial dynamics, and (3) endoplasmic reticulum-mitochondrial inter-organellar crosstalk. These major pathogenic mechanisms are in turn interconnected and represent the target for therapeutic strategies. Thus, their deep understanding is the basis to set and test new effective therapies, an urgent unmet need for these patients. New tools are now available to capture all interlinked mechanistic intricacies for the pathogenesis of optic nerve neurodegeneration, casting hope for innovative therapies to be rapidly transferred into the clinic and effectively cure inherited optic neuropathies.
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Affiliation(s)
- Alessandra Maresca
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy;
| | - Valerio Carelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, 40139 Bologna, Italy;
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40139 Bologna, Italy
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48
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Amore G, Romagnoli M, Carbonelli M, Barboni P, Carelli V, La Morgia C. Therapeutic Options in Hereditary Optic Neuropathies. Drugs 2021; 81:57-86. [PMID: 33159657 PMCID: PMC7843467 DOI: 10.1007/s40265-020-01428-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Options for the effective treatment of hereditary optic neuropathies have been a long time coming. The successful launch of the antioxidant idebenone for Leber's Hereditary Optic Neuropathy (LHON), followed by its introduction into clinical practice across Europe, was an important step forward. Nevertheless, other options, especially for a variety of mitochondrial optic neuropathies such as dominant optic atrophy (DOA), are needed, and a number of pharmaceutical agents, acting on different molecular pathways, are currently under development. These include gene therapy, which has reached Phase III development for LHON, but is expected to be developed also for DOA, whilst most of the other agents (other antioxidants, anti-apoptotic drugs, activators of mitobiogenesis, etc.) are almost all at Phase II or at preclinical stage of research. Here, we review proposed target mechanisms, preclinical evidence, available clinical trials with primary endpoints and results, of a wide range of tested molecules, to give an overview of the field, also providing the landscape of future scenarios, including gene therapy, gene editing, and reproductive options to prevent transmission of mitochondrial DNA mutations.
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Affiliation(s)
- Giulia Amore
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
| | - Martina Romagnoli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Michele Carbonelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | | | - Valerio Carelli
- Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy
| | - Chiara La Morgia
- IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Bologna, Via Altura 3, 40139, Bologna, Italy.
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Ng WSV, Trigano M, Freeman T, Varrichio C, Kandaswamy DK, Newland B, Brancale A, Rozanowska M, Votruba M. New avenues for therapy in mitochondrial optic neuropathies. THERAPEUTIC ADVANCES IN RARE DISEASE 2021; 2:26330040211029037. [PMID: 37181108 PMCID: PMC10032437 DOI: 10.1177/26330040211029037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/10/2021] [Indexed: 05/16/2023]
Abstract
Mitochondrial optic neuropathies are a group of optic nerve atrophies exemplified by the two commonest conditions in this group, autosomal dominant optic atrophy (ADOA) and Leber's hereditary optic neuropathy (LHON). Their clinical features comprise reduced visual acuity, colour vision deficits, centro-caecal scotomas and optic disc pallor with thinning of the retinal nerve fibre layer. The primary aetiology is genetic, with underlying nuclear or mitochondrial gene mutations. The primary pathology is owing to retinal ganglion cell dysfunction and degeneration. There is currently only one approved treatment and no curative therapy is available. In this review we summarise the genetic and clinical features of ADOA and LHON and then examine what new avenues there may be for therapeutic intervention. The therapeutic strategies to manage LHON and ADOA can be split into four categories: prevention, compensation, replacement and repair. Prevention is technically an option by modifying risk factors such as smoking cessation, or by utilising pre-implantation genetic diagnosis, although this is unlikely to be applied in mitochondrial optic neuropathies due to the non-life threatening and variable nature of these conditions. Compensation involves pharmacological interventions that ameliorate the mitochondrial dysfunction at a cellular and tissue level. Replacement and repair are exciting new emerging areas. Clinical trials, both published and underway, in this area are likely to reveal future potential benefits, since new therapies are desperately needed. Plain language summary Optic nerve damage leading to loss of vision can be caused by a variety of insults. One group of conditions leading to optic nerve damage is caused by defects in genes that are essential for cells to make energy in small organelles called mitochondria. These conditions are known as mitochondrial optic neuropathies and two predominant examples are called autosomal dominant optic atrophy and Leber's hereditary optic neuropathy. Both conditions are caused by problems with the energy powerhouse of cells: mitochondria. The cells that are most vulnerable to this mitochondrial malfunction are called retinal ganglion cells, otherwise collectively known as the optic nerve, and they take the electrical impulse from the retina in the eye to the brain. The malfunction leads to death of some of the optic nerve cells, the degree of vision loss being linked to the number of those cells which are impacted in this way. Patients will lose visual acuity and colour vision and develop a central blind spot in their field of vision. There is currently no cure and very few treatment options. New treatments are desperately needed for patients affected by these devastating diseases. New treatments can potentially arise in four ways: prevention, compensation, replacement and repair of the defects. Here we explore how present and possible future treatments might provide hope for those suffering from these conditions.
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Affiliation(s)
| | - Matthieu Trigano
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Thomas Freeman
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Carmine Varrichio
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Dinesh Kumar Kandaswamy
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Ben Newland
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Andrea Brancale
- School of Pharmacy and Pharmaceutical Sciences,
Cardiff University, Cardiff, UK
| | - Malgorzata Rozanowska
- Mitochondria and Vision Lab, School of
Optometry and Vision Sciences, Cardiff University, Cardiff, UK
| | - Marcela Votruba
- School of Optometry and Vision Sciences,
Cardiff University, Maindy Road, Cardiff, CF24 4HQ, Wales, UK; Cardiff Eye
Unit, University Hospital of Wales, Cardiff, UK
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50
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Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum Genet 2020; 140:849-861. [PMID: 33385171 PMCID: PMC8099832 DOI: 10.1007/s00439-020-02249-w] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 12/15/2020] [Indexed: 12/13/2022]
Abstract
Mitochondrial (MT) dysfunction is a hallmark of aging and has been associated with most aging-related diseases as well as immunological processes. However, little is known about aging, lifestyle and genetic factors influencing mitochondrial DNA (mtDNA) abundance. In this study, mtDNA abundance was estimated from the weighted intensities of probes mapping to the MT genome in 295,150 participants from the UK Biobank. We found that the abundance of mtDNA was significantly elevated in women compared to men, was negatively correlated with advanced age, higher smoking exposure, greater body-mass index, higher frailty index as well as elevated red and white blood cell count and lower mortality. In addition, several biochemistry markers in blood-related to cholesterol metabolism, ion homeostasis and kidney function were found to be significantly associated with mtDNA abundance. By performing a genome-wide association study, we identified 50 independent regions genome-wide significantly associated with mtDNA abundance which harbour multiple genes involved in the immune system, cancer as well as mitochondrial function. Using mixed effects models, we estimated the SNP-heritability of mtDNA abundance to be around 8%. To investigate the consequence of altered mtDNA abundance, we performed a phenome-wide association study and found that mtDNA abundance is involved in risk for leukaemia, hematologic diseases as well as hypertension. Thus, estimating mtDNA abundance from genotyping arrays has the potential to provide novel insights into age- and disease-relevant processes, particularly those related to immunity and established mitochondrial functions.
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