Leber Hereditary Optic Neuropathy: Visual Recovery in a Patient With the Rare m.3890G>A Point Mutation

Clinical Observation Leber Hereditary Optic Neuropathy: Visual Recovery in a Patient With the Rare m.3890G.A Point Mutation Jared J. Murray, BA, Kaitlyn W. Nolan, MD, Collin McClelland, MD, Michael S. Lee, MD Abstract: A 15-year-old boy experienced painless vision loss in the left eye of unknown duration. Leber hereditary optic neuropathy (LHON) was suspected, despite negative testing for the 3 most common pathogenic gene mutations and idebenone 300 mg 3 times daily was prescribed. Nine months later, the patient developed right eye involvement. Complete mitochondrial genome analysis revealed 2 rare variants-m.3890G.A of the MT-ND1 gene and m.8417C.A of the MT-ATP8 gene. The former has been described in severe infantile Leigh syndrome and LHON; the latter is of unknown significance. The patient experienced progressive visual deterioration through 12 months, but improved to 20/20, right eye and 20/25, left eye, at 21 months. Visual recovery can occur in a patient with bilateral optic neuropathy secondary to the rare m.3890G.A point mutation. other mutations can lead to LHON phenotypic expression (5). The visual prognosis for recovery is generally poor. Ubiquinone is a mitochondrial electron carrier for Complexes I, II, and III. Idebenone is a short-chain ubiquinone analog that maintains mitochondrial electron flux through bypass of Complex I (8,9). In doing so, idebenone affords antioxidant and antilipid peroxidation benefits (8,9). Idebenone was approved in September 2015 for treatment of LHON in Europe, based on a randomized clinical trial with a follow-up study and reported clinical practice data (10). We report a patient with a rare mitochondrial point mutation who experienced bilateral visual loss followed by recovery while taking idebenone. Journal of Neuro-Ophthalmology 2017;37:166-171 doi: 10.1097/WNO.0000000000000462 © 2016 by North American Neuro-Ophthalmology Society CASE REPORT L eber hereditary optic neuropathy (LHON) is a mitochondrial disease that typically presents as painless, subacute, central vision loss. Usually, 1 eye is impaired at onset with subsequent fellow eye involvement 6-8 weeks later (1,2). LHON prevalence is estimated to be 2-3 per 100,000 (3,4) and, although not an X-linked disorder, 80%-90% of patients are males (5). Most commonly, symptoms begin in the second or third decade, but reports of LHON range from age 2-87 years (1,3,6,7). Although 3 mitochondrial DNA (mtDNA) point mutations, which encode different subunits of Complex I of the mitochondrial respiratory chain, account for 90% of LHON cases, Department of Ophthalmology and Visual Neurosciences (JJM, KWN, CM, MSL), University of Minnesota, Minneapolis, Minnesota. The authors report no conflicts of interest. Address correspondence to Michael S. Lee, MD, Department of Ophthalmology and Visual Neurosciences, University of Minnesota, 420 Delaware Street SE, MMC 493, Minneapolis, MN 55455; E-mail: [e-mail] 166 A 15-year-old boy with no ocular history was evaluated for painless left eye central vision loss of unknown duration. He had an unremarkable birth history and had met all of his developmental milestones. He was in good health, took no medications, and reported no tobacco or alcohol use. Family ocular history was notable for Fuch corneal dystrophy in a maternal aunt and grandmother. He denied family history of unexplained visual loss or optic nerve disease. Visual acuity (VA) was 20/20 in both eyes 1 year previously. At the time of our initial examination, VA was 20/15 in the right eye and 6/200 in the left eye. A left relative afferent pupillary defect was present. He correctly identified all of the Ishihara color plates with his right eye, and none with his left eye. Fundus examination showed optic disc hyperemia bilaterally with temporal pallor in the left eye (Fig. 1). Visual field testing revealed scattered defects, right eye, and a cecocentral scotoma, left eye. Optical coherence tomography (OCT) studies showed normal retinal nerve fiber layer (RNFL) thickness in the right eye and temporal thinning in the left eye (Fig. 2). Normal test results included brain and orbit MRI with and without contrast, neuromyelitis optica IgG antibody, Lyme titer, angiotensin-converting enzyme, antinuclear antibody, and LHON panel for the 3 most common point mutations (3460, Murray et al: J Neuro-Ophthalmol 2017; 37: 166-171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. At presentation, there is bilateral optic disc hyperemia with temporal pallor of the left disc. 11778, and 14484). Based on continued clinical suspicion for LHON and the safety profile of idebenone, the patient was started on this compound orally at 300 mg 3 times daily. The patient remained stable until 4 months follow-up at which time the cecocentral scotoma in the left eye was slightly worse and repeat OCT showed right eye RNFL thickening inferiorly, superiorly, and temporally (Fig. 3). He returned 3 months later complaining of blurred vision in the right eye. VA was 20/20 in the right eye and 20/1000 in the left eye. OCT showed further RNFL thickening in FIG. 2. Initial optical coherence tomography study shows thinning of the temporal retinal nerve fiber layer in the left eye. Murray et al: J Neuro-Ophthalmol 2017; 37: 166-171 167 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. At 4 months follow-up, there is thickening of the retinal nerve fiber layer in the right eye (OD) inferiorly, superiorly, and temporally. OS, left eye. the right eye and visual fields revealed bilateral cecocentral scotomas. With apparent right eye involvement, the patient's entire mitochondrial genome was analyzed. Two rare variants were discovered - m.3890G.A (p.R195Q) in the MT-ND1 gene (codes for mitochondrial NADH dehydrogenase 1) and m.8417C.A (p.L181), a variant in the MT -ATP8 gene (codes for mitochondrial ATP synthase 8). Idebenone therapy 900 mg daily was continued. One year after his initial presentation to our clinic, the patient's VA was 20/250 in each eye. OCT showed reduced mean RNFL thicknesses of 91 mm in the right eye and 75 mm in the left eye (Fig. 4), and visual field testing revealed bilateral cecocentral scotomatas (Fig. 5). At 18 months after initial visual loss, VA improved to 20/150 in the right eye and 20/100 in the left. Acuity 3 months later was 20/20 in the right eye and 20/25 in the left. Visual field testing revealed marked improvement bilaterally. DISCUSSION Of the most common mitochondrial mutations occurring in LHON (3460, 11778, and 14484), 11778 occurs most frequently in approximately 70% of patients (1,5) whereas 168 about 14484 and 3460 point mutations account for 14% and 13% of cases, respectively (1,3). Numerous rare mutations also have been identified (1,4,11). Our patient possessed 2 rare mitochondrial variants-m.3890G.A (p.R195Q) in the MT-ND1 gene and m.8417C.A (p. L181) in the MT -ATP8 gene. The m.3890G.A mutation has been found in individuals with clinical presentations of mitochondrial disease ranging from severe infantile Leigh syndrome to LHON (12,13). The m.8417C.A variant is of unknown significance in the general population and not previously reported to cause disease. Caporali et al (13) described a 31-year-old man with LHON-like optic atrophy and bilateral brainstem lesions with the m.3890G.A point mutation. The patient experienced sudden painless sequential vision loss with typical features of LHON-optic disc telangiectasia and pallor and bilateral cecocentral scotomas. His vision loss was preceded by 3 months of persistent vertigo. The patient was treated with corticosteroids and cyclosporine without improvement. LHON testing for the 3 most common mitochondrial mutations was Murray et al: J Neuro-Ophthalmol 2017; 37: 166-171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 4. At 1 year follow-up, mean retinal nerve fiber layer thickness is 92 mm, right eye, and 75 mm, left eye. negative and subsequent whole mitochondrial genome analysis revealed the m.3890G.A/MT-ND1 mutation. Idebenone 405-540 mg/day was started approximately 1 year after initial visual loss. The patient did not experience visual improvement over 4 years of follow-up (13). No evidence-based therapy for LHON currently exists. Among all LHON patients, those with 14484 mutations are most likely to experience partial spontaneous recovery; rates range from 37% to 71%, while those with 11778 recover at only a 4% rate (14). Patients with 3460 have been shown to recover at a rate of 20% (15). Gene therapy and stem cell studies are underway and may yield better future treatments (2). Current data support the use of idebenone for potential prevention of further vision loss and promotion of visual recovery in adolescents and adults with LHON (10). Its proposed mechanism of action includes reactivation of retinal ganglion cells through antioxidant and mitochondrial electron transport stimulation (10). To our knowledge, our patient is the first with the m.3890G.A mutation to recover vision. We considered the role idebeMurray et al: J Neuro-Ophthalmol 2017; 37: 166-171 none may have played and the possibility of spontaneous recovery. Santhera Pharmaceutical's recently released Expanded Access Program reports that 80% of LHON cases of clinically relevant recovery occurred by 12 months (16). Furthermore, idebenone did not prevent fellow eye involvement in our patient. It is also important to note that disease onset at a young age (15 years in our case) is more frequently associated with spontaneous recovery (17). The timing of recovery, fellow eye involvement after initiating idebenone treatment, and young age suggest that our patient's recovery was more likely spontaneous than due to idebenone treatment. Additionally, the mean RNFL measurements of 91 mm and 75 mm may have predicted his recovery. Still, it is conceivable that his improvement in vision was, in part, aided by idebenone. It also is possible that the patient reported by Caporali et al (13) may have benefitted from earlier initiation of idebenone and/or higher dosing. LHON should be a part of the differential diagnosis for all patients with painless simultaneous or sequential optic neuropathy. Testing for the 3 most common mutations may yield negative results, but whole mitochondrial genome 169 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 5. At 1 year follow-up, cecocentral scotomas are present bilaterally. testing may identify a causative mutation. Early initiation of idebenone when LHON is suspected should be considered given its low side effect profile and potential to promote vision recovery and prevent further vision loss. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: Lee, Nolan; b. Acquisition of data: Lee, Nolan, McClelland, Murray; c. Analysis and interpretation of data: Nolan, Murray. Category 2: a. Drafting the manuscript: Murray, Nolan; b. Revising it for intellectual content: Lee, McClelland. Category 3: a. Final approval of the completed manuscript: Lee, McClelland, Murray, Nolan. REFERENCES 1. Yu-Wai-Man P, Griffiths PG, Hudson G, Chinnery PF. Inherited mitochondrial optic neuropathies. J Med Genet. 2009;46:145-158. 2. Meyerson C, Van Stavern G, McClelland C. Leber hereditary optic neuropathy: current perspectives. Clin Ophthalmol. 2015;9:1165-1176. 3. Fraser JA, Biousse V, Newman NJ. The neuro-ophthalmology of mitochondrial disease. Surv Ophthalmol. 2010;55:299-334. 4. Yu-Mai-Wan P, Votruba M, Moore AT, Chinnery PF. Treatment strategies for inherited optic neuropathies: past, present and future. Eye (Lond). 2014;28:521-537. 5. Newman NJ. Hereditary optic neuropathies: from the mitochondria to the optic nerve. Am J Ophthalmol. 2005;140:517-523. 6. Riordan-Eva P, Sanders MD, Govan GG, Sweeney MG, Da Costa J, Harding AE. 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Images in Neuro-Ophthalmology Longitudinally extensive spinal cord lesion in Leber's hereditary optic neuropathy due to the m.3460A mitochondrial DNA mutation. Leber hereditary optic neuropathy with longitudinally extensive spinal cord lesion. A 43 year-old woman developed lower limb spasms 2 years after onset of vision loss. A. At initial presentation, there was bilateral optic disc hyperemia with vessel telangiectasia in the right eye. B. Axial T2 magnetic resonance imaging (MRI) reveals a hyperintense lesion (arrow) in the right pons. C. Axial FLAIR image shows 2 periventricular white matter lesions (arrows). Sagittal T2 MRI demonstrates a hyperintense lesion extending from C1 to T3 (D), mainly involving the posterior cord (E). The patients had the m.3460A mitochondrial DNA mutation, but tested negative for AQP4-IgG antibody. (Courtesy of Althekair FY, Pruitt AA, O'Keefe L, Tamhankar MA). Althekair et al: J Neuro-Ophthalmol 2017; 37: 166-171 171 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.