The Natural History of Leber Hereditary Optic Neuropathy in the Subacute/Dynamic Phase: Visual Acuity Outcomes from the Historical Case Record Survey-2 (CRS-2)

Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder resulting in severe bilateral vision loss. The natural history of LHON is influenced by the age of onset and the causative mitochondrial DNA (mtDNA) mutations, among other factors. The Case Record Survey-2 (CRS-2; ClinicalTrials.gov NCT02796274) was conducted to establish the clinical course in patients with a genetically confirmed diagnosis of LHON.

306 The natural history of Leber hereditary optic neuropathy in the subacute/dynamic phase: Visual acuity outcomes from the historical Case Record Survey-2 (CRS-2) Patrick Yu-Wai-Man 1, Maciej Krawczynski 2, Judith van Everdingen 3, Costanza Lamperti 4, Valerio Carelli 5, Xavier Llòria 6, Thomas Klopstock 7 1 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, 2 Department of Medical Genetics, Poznan University of Medical Sciences, Poland; GENESIS - Centers for Medical Genetics, Poznan, Poland, 3 Department of Neuro-ophthalmology The Rotterdam Eye Hospital (OZR), Rotterdam, The Netherlands; The Rotterdam Ophthalmologic Institute (ROI), Rotterdam, The Netherlands, 4 Department of Medical Genetic and Neurogenetic Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy, 5 IRCCS Istituto di Scienze Neurologiche di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy, 6 Chiesi Farmaceutici S.p.A, Parma, Emilia-Romagna, Italy, 7 Department of Neurology, Friedrich-Baur-Institute, University Hospital of the Ludwig-Maximilians-Universität München, Munich, Germany Introduction: Leber hereditary optic neuropathy (LHON) is a rare mitochondrial disorder resulting in severe bilateral vision loss. The natural history of LHON is influenced by the age of onset and the causative mitochondrial DNA (mtDNA) mutations, among other factors. The Case Record Survey-2 (CRS-2; ClinicalTrials.gov NCT02796274) was conducted to establish the clinical course in patients with a genetically confirmed diagnosis of LHON. Methods: Retrospective clinical data was extracted from case records between May 2016-March 2018 from 20 sites in 7 European countries. Patients carrying one of the three common LHON mtDNA mutations (m.11778G>A, m.3460G>A, or m.14484T>C) aged ≥12 years, with onset of symptoms after 1999, and with at least two visual acuity (VA) assessments within 5 years of symptom onset and prior to any potential idebenone use, were eligible for enrolment. Outcome measures were: (i) clinically relevant recovery (CRR): improvement from 'off-chart' VA to ≤1.6 logMAR, or an improvement of ≥0.2 logMAR if on-chart; (ii) clinically relevant stabilization (CRS): maintenance of VA < 1.0 logMAR; (iii) clinically relevant benefit (CRB): reaching a CRR, a CRS, or both; and (iv) clinically relevant worsening (CRW): worsening to 'off-chart' or a VA loss of ≥0.2 logMAR if on-chart. The baseline was defined as the first VA assessment after symptom onset. Results: CRS-2 included data from 219 patients. In eyes with symptom onset ≤1 year prior to baseline, the following outcome rates were observed at 12 months from baseline: CRB: 20.8% (20/96 eyes; primary endpoint); CRR: 12.5% (12/96 eyes); CRS: 26.2% (11/42 eyes); CRW: 52.1% (50/96 eyes). The following outcome rates were observed at 24 months from baseline: CRB: 43.2% (19/44 eyes); CRR: 27.3% (12/44 eyes); CRS: 45.5% (10/22 eyes); CRW: 36.4% (16/44 eyes). Conclusions: CRS-2 provides important insight into the natural history of LHON, which is essential for the interpretation of clinical trials for this rare disease. References: None provided. Keywords: Optic neuropathy, Genetic disease, Retina Financial Disclosures: Patrick Yu-Wai-Man: Received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics.; Maciej Krawczynski: Consultant for and research support from Chiesi Farmaceutici SpA; Judith van Everdingen: Consultant for and research support from Chiesi Farmaceutici SpA; Costanza Lamperti: Consultant for and research support from Chiesi Farmaceutici SpA; Valerio Carelli: Received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics; Xavier Llòria: Employee of Chiesi Farmaceutici S.p.A; Thomas Klopstock: Received research support and/or personal compensation from Santhera Pharmaceuticals, Chiesi, and GenSight Biologics Grant Support: None. Contact Information: Patrick Yu-Wai-Man, [e-mail] 464 | North American Neuro-Ophthalmology Society