Nancy J Newman1, Valerio Carelli, Magali Taiel, Patrick Yu-Wai-Man. 1. Departments of Ophthalmology (NJN), Neurology and Neurological Surgery, Emory University School of Medicine, Atlanta, Georgia, IRCCS Istituto Delle Scienze Neurologiche di Bologna (VC), UOC Clinica Neurologica, Bologna, Italy, Department of Biomedical and Neuromotor Sciences (DIBINEM) (VC), Unit of Neurology, University of Bologna, Bologna, Italy, GenSight Biologics (MT), Paris, France, Cambridge Centre for Brain Repair and MRC Mitochondrial Biology Unit (PY-W-M), Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom, Cambridge Eye Unit (PY-W-M), Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, United Kingdom, Moorfields Eye Hospital (PY-W-M), London, United Kingdom, and UCL Institute of Ophthalmology (PY-W-M), University College London, London, United Kingdom.
Abstract
BACKGROUND: Leber hereditary optic neuropathy (LHON) is a maternally inherited bilaterally blinding optic neuropathy, predominantly affecting otherwise healthy young individuals, mostly men. The visual prognosis is generally poor, with most patients worsening to at least 20/200 visual acuity. The m.11778G>A (MTND4) mitochondrial DNA mutation is the most common cause of LHON and is associated with poor outcomes and limited potential for meaningful visual recovery. Treatments for LHON are limited, and clinical trials are hampered by inadequate data regarding the natural history of visual loss and recovery. In this article, we review the current literature specifically related to visual function of LHON patients with the m.11778G>A mutation. EVIDENCE ACQUISITION: Literature review was performed using MEDLINE through PubMed, Cochrane Reviews Library, and Orpha.net with search terms of "Leber hereditary optic neuropathy," "LHON," "ND4," "G11778A," "visual acuity," "nadir," "natural history," and "registry." All English-language, peer-reviewed publications with study cohorts of at least 5 LHON patients with the molecularly confirmed m.11778G>A mutation were included. RESULTS: Meta-analysis of 12 retrospective and 3 prospective studies provided visual function information on 695 LHON patients with the m.11778G>A mutation, 100 (14.4%) of whom were reported to have "recovered" some vision, although definitions of "recovery" varied among studies and idebenone use could not always be excluded. When incorporating age at onset of visual loss into the analyses, and specifically addressing those patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) patients. A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults. CONCLUSIONS: The classic presentation of LHON patients with the m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. Among patients 15 years and older, recovery of meaningful vision likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare. Adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated LHON patients stratified by age, immediately enrolled when symptomatic, followed regularly for adequate periods of time with consistent measures of visual function, and analyzed with a standard definition of visual improvement are unfortunately lacking. Future clinical trials for LHON will require more standardized reporting of the natural history of this disorder.
BACKGROUND:Leber hereditary optic neuropathy (LHON) is a maternally inherited bilaterally blinding optic neuropathy, predominantly affecting otherwise healthy young individuals, mostly men. The visual prognosis is generally poor, with most patients worsening to at least 20/200 visual acuity. The m.11778G>A (MTND4) mitochondrial DNA mutation is the most common cause of LHON and is associated with poor outcomes and limited potential for meaningful visual recovery. Treatments for LHON are limited, and clinical trials are hampered by inadequate data regarding the natural history of visual loss and recovery. In this article, we review the current literature specifically related to visual function of LHON patients with the m.11778G>A mutation. EVIDENCE ACQUISITION: Literature review was performed using MEDLINE through PubMed, Cochrane Reviews Library, and Orpha.net with search terms of "Leber hereditary optic neuropathy," "LHON," "ND4," "G11778A," "visual acuity," "nadir," "natural history," and "registry." All English-language, peer-reviewed publications with study cohorts of at least 5 LHON patients with the molecularly confirmed m.11778G>A mutation were included. RESULTS: Meta-analysis of 12 retrospective and 3 prospective studies provided visual function information on 695 LHON patients with the m.11778G>A mutation, 100 (14.4%) of whom were reported to have "recovered" some vision, although definitions of "recovery" varied among studies and idebenone use could not always be excluded. When incorporating age at onset of visual loss into the analyses, and specifically addressing those patients aged 15 years or older, meaningful visual recovery occurred in 23 of 204 (11.3%) patients. A younger age at onset, especially less than 12 years, portends a better visual prognosis and a different natural history of visual loss progression and recovery than in adults. CONCLUSIONS: The classic presentation of LHON patients with the m.11778G>A mutation of severe visual loss with rare or poor recovery from nadir still holds true for most affected individuals. Among patients 15 years and older, recovery of meaningful vision likely occurs in less than 20% of patients, irrespective of how recovery is defined, and ultimate visual acuities of better than 20/200 are rare. Adequate prospective studies with sufficient sample sizes of genotypically homogeneous untreated LHON patients stratified by age, immediately enrolled when symptomatic, followed regularly for adequate periods of time with consistent measures of visual function, and analyzed with a standard definition of visual improvement are unfortunately lacking. Future clinical trials for LHON will require more standardized reporting of the natural history of this disorder.
Authors: Nancy J Newman; Patrick Yu-Wai-Man; Valerio Carelli; Valerie Biousse; Mark L Moster; Catherine Vignal-Clermont; Robert C Sergott; Thomas Klopstock; Alfredo A Sadun; Jean-François Girmens; Chiara La Morgia; Adam A DeBusk; Neringa Jurkute; Claudia Priglinger; Rustum Karanjia; Constant Josse; Julie Salzmann; François Montestruc; Michel Roux; Magali Taiel; José-Alain Sahel Journal: Front Neurol Date: 2021-05-24 Impact factor: 4.003
Authors: Sarah L Stenton; Marketa Tesarova; Natalia L Sheremet; Claudia B Catarino; Valerio Carelli; Elżbieta Ciara; Kathryn Curry; Martin Engvall; Leah R Fleming; Peter Freisinger; Katarzyna Iwanicka-Pronicka; Elżbieta Jurkiewicz; Thomas Klopstock; Mary K Koenig; Hana Kolářová; Bohdan Kousal; Tatiana Krylova; Chiara La Morgia; Lenka Nosková; Dorota Piekutowska-Abramczuk; Sam N Russo; Viktor Stránecký; Iveta Tóthová; Frank Träisk; Holger Prokisch Journal: Brain Date: 2022-06-03 Impact factor: 15.255
Authors: Nancy J Newman; Matthew Schniederjan; Pia R Mendoza; David J Calkins; Patrick Yu-Wai-Man; Valérie Biousse; Valerio Carelli; Magali Taiel; Francois Rugiero; Pramila Singh; Alexandra Rogue; José-Alain Sahel; Philippe Ancian Journal: BMC Neurol Date: 2022-07-12 Impact factor: 2.903