Visual Recovery in Leber Hereditary Optic Neuropathy From a Rare mt.14568 Mutation on ND6 Gene

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Visual Recovery in Leber Hereditary Optic Neuropathy From a Rare mt.14568 Mutation on ND6 Gene Nooran O. Badeeb, MBBS, Rustum Karanjia, MD, PhD L eber hereditary optic neuropathy (LHON) is the mitochondria’s most common maternal inherited disease. Over 90% of cases are associated with one of 3 primary mutations: mt.3460G.A (ND1), mt.11778G.A (ND4), and mt.14484T.C (ND6). LHON has a poor visual prognosis because of the involvement of the papillo-macular bundle and the resulting loss of central vision, which makes most patients legally blind (1). However, spontaneous vision recovery has been reported in some cases, especially if conversion to the affected state occurred at a younger age or involved the mt.14484T.C on the ND6 gene (1). We report the pedigree of a family who carries the rare mt.14568C.T LHON mutation and the first reported presentation of this mutation in a female patient with good visual recovery. Our patient is a 17-year-old woman who experienced subacute painless central vision loss that started initially in the right eye (right eye) in May 2019, followed by the left eye (left eye) in October 2019. She had no chronic medical conditions but had an upper respiratory tract infection for approximately 3 weeks before her visual symptoms that subsided after taking an oral antibiotic (amoxicillin). She had also started taking levonorgestrel and ethinyl estradiol tablets for birth control 1 month prior. Her medical history was unremarkable except for delayed menarche that occurred at 16 years that was believed to be due to her involvement in intense athletic activities. Our patient had a family history strongly suggestive of LHON with a maternal uncle affected 30 years ago at 24 years. He was a professional musician at a nightclub. There was a strong history of heavy alcohol consumption and smoking at the time of vision loss. Subsequently, he had poor visual recovery and is considered legally blind. At the patient’s first visit at our clinic, 6 weeks after the vision loss in the first eye (right eye), her visual acuity was 20/70 + 2 (0.25 decimal) in the right eye and 20/20 (1.0 decimal) in the left eye. She was able to see 14/16 in the right eye and 16/16 Department of Ophthalmology (NB, RK), University of Ottawa, Ottawa, Canada; Department of Ophthalmology (NB), University of Jeddah, Jeddah, Saudi Arabia; Department of Ophthalmology (RK), Doheny Eye Centers, David Geffen School of Medicine at UCLA, Los Angeles, California; Ottawa Hospital Research Institute (RK), The Ottawa Hospital, Ottawa, Canada; and Doheny Eye Institute (RK), Los Angeles, California. The authors report no conflicts of interest. Address correspondence to Nooran Badeeb, MBBS, 501 Smyth Road, Ottawa; E-mail: [e-mail] e134 Ishihara color plates in the left eye. The visual field testing 30-2 showed a right cecocentral scotoma (Fig. 1A). She was investigated for other etiologies of bilateral vision loss, including antimyelin oligodendrocyte and neuromyelitis optica antibodies, and MRI of the brain and orbit with contrast were all normal. As expected with LHON, the full-field electroretinogram (ERG) from both eyes showed normal electroretinal function of the outer retina but reduced photopic negative response (PhNR) in both eyes (Fig. 2A, “6 weeks”). Her pattern ERG (PERG) showed a reduced amplitude of the P50-N95 component, associated with ganglion cell function, in the right eye and normal amplitude in the left eye (Fig. 2B “6 weeks”). Given the family history and presentation, the patient was investigated for an LHON mutation and idebenone was FIG. 1. Automated visual field test. (A) Visual fields at presentation: right cecocentral scotoma and left normal VF. B. At 1 year, “Nadir”: diffuse VF loss in both eyes. C. At the 2-year follow-up: right and left cecocentral scotoma with the areas of fenestrations of clear VF. Badeeb and Karanjia: J Neuro-Ophthalmol 2023; 43: e134-e135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. A. Photopic negative response studies of both eyes. Six weeks from the onset: responses from both eyes demonstrate reduced amplitude of the N95 component, 1 year from the onset “at Nadir: both eyes had reduced amplitude and normal peak implicit time, 2 years from the onset: both eyes have nearnormal amplitude and normal peak implicit time. B. Pattern electroretinogram of both eyes. At 6 weeks: the right eye shows the reduced amplitude of the P50-N95 component and the left eye is normal, at 1 year: appeared to have reduced waveform morphology of the P50 and N95 components, at 2 years: normal waveform morphology of the P50 and N95 components. started. Mitochondrial genome analysis was completed using long-range polymerase chain reaction followed by the next generation sequencing from a blood sample. The most common variants associated with LHON were not detected. However, a rare familial variant mt.14568C.T was detected with near complete homoplasmy (99%). This amino acid location is highly conserved (98%) and has been described in the literature as causing LHON (2,3). Our patient’s mother was tested for this variant and was a carrier at a heteroplasmy level of 77%. The mother had a normal examination. As anticipated, her vision loss continued to progress, and she reached a nadir at 1 year; her vision in both eyes was counting fingers at 2 feet with diffuse central scotomas (Fig. 1B). Her color vision was diminished entirely in both eyes. Her PhNR amplitude and PERG are reduced in both eyes (Figs. 2A, B “1 year”). At the most recent follow-up visit, 2 years after the presentation, our patient’s vision recovered to 20/20 in the right eye and 20/20 in the left eye. Her color vision was 14/ 16 in the right eye and 16/16 in the left eye. Her fundus examination showed bilateral temporal pallor of the optic discs with mild peripapillary telangiectasia. Her visual field continued to show diffuse loss with a small fenestration accounting for the improvement in her visual acuity (Fig. 1C). In addition, both P50-N95 and PhNR have improved (Figs. 2A, B “2 years”). LHON is a mitochondrial inherited optic neuropathy transmitted only by women to their offspring (1). The mt.14568C.T mutation was first reported in 1999 by Besch et al (2). They described a case of an affected 16-year-old man with positive carriers in maternal family members. His visual acuity was 20/200 in both eyes 2.5 years after the onset of vision loss. In another case of a 42-year-old male patient with an image of LHON, he also had a positive family history of the Badeeb and Karanjia: J Neuro-Ophthalmol 2023; 43: e134-e135 same mutation. Sadly, he died 10 months after being diagnosed, and his only vision documented was 5 months after the visual loss onset in the right eye which was 20/500 and 2 months after the vision loss in the left eye which was 20/250 (3). Our patient has performed considerably better than these other case reports of patients with the mt.14568T.C mutation. Unfortunately, the percentage of heteroplasmy was not noted for the other case reports. Yet, our patient is the only female case reported and was almost homoplasmic for the mutation, suggesting that they had a high propensity for being affected, a Type I LHON case (4). Our patient’s good visual recovery could be explained by several factors, the young age of conversion to clinically manifest disease, which was a strong prognostic factor of recovery (1). In this clinical context, we speculate that early age of conversion, avoidance of reactive oxygen species (ROS) triggers such as alcohol and smoking, and the use of idebenone contributed to our patients’ excellent visual recovery. Although it is impossible to state the relative effects of these different interventions, it is important to consider idebenone and the avoidance of ROS generating activities in all patients with LHON regardless of the causative mutation (5). STATEMENT OF AUTHORSHIP Conception and design: N. O. Badeeb, R. Karanjia; Acquisition of data: N. O. Badeeb, R. Karanjia; Analysis and interpretation of data: N. O. Badeeb, R. Karanjia. Drafting the manuscript: N. O. Badeeb, R. Karanjia; Revising it for intellectual content: N. O. Badeeb, R. Karanjia. Final approval of the completed manuscript: N. O. Badeeb, R. Karanjia. ACKNOWLEDGMENTS The authors acknowledge Ms. Risa Shorr our librarian for her collaboration and help in the process of literature review. REFERENCES 1. Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet. 2002;39:162–169. 2. Besch D, Leo-Kottler B, Zrenner E, Wissinger B. Leber’s hereditary optic neuropathy: clinical and molecular genetic findings in a patient with a new mutation in the ND6 gene. Graefes Arch Clin Exp Ophthalmol. 1999;237:745–752. 3. Fauser S, Leo-Kottler B, Besch D, Lubrichs J. Confirmation of the 14568 mutation in the mitochondrial ND6 gene as causative in Leber’s hereditary optic neuropathy. Ophthalmic Genet. 2002;23:191–197. undefined. 4. Carelli V, D’Adamo P, Valentino ML, la Morgia C, Ross-Cisneros FN, Caporali L, Maresca A, Loguercio Polosa P, Barboni P, De Negri A, Sadun F, Karanjia R, Salomao SR, Berezovsky A, Chicani F, Moraes M, Moraes Filho M, Belfort R Jr, Sadun AA. Parsing the differences in affected with LHON: genetic versus environmental triggers of disease conversion. Brain. 2016;139:e17. 5. Carelli V, Carbonelli M, de Coo IF, Kawasaki A, Klopstock T, Lagrèze WA, La Morgia C, Newman NJ, Orssaud C, Pott JWR, Sadun AA, van Everdingen J, Vignal-Clermont C, Votruba M, YuWai-Man P, Barboni P. International consensus statement on the clinical and therapeutic management of leber hereditary optic neuropathy. J Neuroophthalmol. 2017;37:371–381. e135 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.