A Rare Mutation Associated With Probable Late-Onset Leber's Hereditary Optic Neuropathy

Clinical Correspondence A Rare Mutation Associated With Probable Late-Onset Leber's Hereditary Optic Neuropathy Jacob J. Fondriest, BA, BS, Karl C. Golnik, MD, MEd L eber's hereditary optic neuropathy (LHON) is a mitochondrially inherited disease with a low penetrance that causes progressive central vision loss. Ninety-five percent of cases are due to one of 3 mutations in the mitochondrial genes encoding Complex I of the electron transport chain (m.3460G.A, m.11778G.A, and m.14484T.C in the MT-ND1, MT-ND4, and MT-ND6 genes, respectively (1,2)). The mutations believed to be responsible for the remaining minority of cases are numerous, rare, and often poorly documented (2). In this clinical correspondence, we report a patient with a clinical presentation consistent with LHON who has an m.3461C.T mutation. We evaluated a 44-year-old man with no significant medical history who takes only a daily multivitamin, referred in May 2018 for progressive central vision loss in both eyes. He first noticed blurry vision 6 months earlier, in November 2017, which was not correctable with glasses. He felt that his left eye vision was worse but did not notice a delay in onset between the 2 eyes. By February 2018, his poor vision made him unable to drive. By May 2018, he had lost red vs green color discrimination. A review of systems was otherwise negative. He has no siblings, and his mother's family history is negative for any visual issues. Over the prior 2 decades, he regularly consumed 5-10 alcoholic drinks 1-2 times a week and marijuana 1-3 times a week. He denied tobacco or other substance use. Previous evaluation in January 2018 included Western blot for Lyme disease, rapid plasma reagin test, and vitamin B12, folate, as well as lead, mercury, and arsenic levels; there were no abnormalities. Brain MRI with gadolinium was also normal. On our evaluation in May 2018, the best-corrected distance visual acuity was 20/300 in the right eye and counting fingers 1 ft in the left eye. Trace afferent Department of Ophthalmology (JJF, KCG), University of Cincinnati College of Medicine, Cincinnati, Ohio; and Cincinnati Eye Institute (KCG), Cincinnati, Ohio. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Jacob J. Fondriest, BA, BS, University of Cincinnati College of Medicine, 2376 Dana Avenue, Cincinnati, Ohio 45208; E-mail: [e-mail] Fondriest and Golnik: J Neuro-Ophthalmol 2020; 40: 411-413 pupillary defect was noted in the left eye. No Ishihara plates were correctly identified. Initial visual field testing revealed cecocentral defect of the left eye greater than the right eye (Fig. 1A). In May 2019, fundus imaging and repeat visual fields were performed (Figs. 1B and 2). Vision loss in these repeat visual fields may be underestimated because of a lack of fixation tracking and, thus, inability to identify a potential eccentric view strategy. At this time, visual acuities were 20/200 in the right eye and 20/400 in the left eye. Optical coherence tomography (OCT) showed moderate thinning of the superior and inferior retinal nerve fiber layer (RNFL) in both eyes, although in the left eye interpretation of RNFL thickness was limited by artifacts (See Supplemental Digital Content, Figure E1, http://links.lww.com/WNO/A397). Analysis of the patient's leukocytes was performed at the John and Marcia Carver Nonprofit Genetic Testing Laboratory through a polymerase chain reaction-based test using the amplification-refractory mutation system (ARMS). It analyzed the mitochondrial DNA (mtDNA) in the loci corresponding to the common m.3460 G.A, m.11778G.A, and 14484T.C LHON mutations. These mutations were not present. Instead, it revealed that 40% of the patient's mtDNA contained an m.3461C.T mutation, corresponding to an A52V substitution in the protein primary structure. This ARMS result was subsequently confirmed by bidirectional DNA sequencing. This nucleotide substitution has only been reported in association with presumed LHON once before in an abstract by Llòria et al (3) presented at the 2017 European Association for Vision and Eye Research Conference. Nuclear genes were not analyzed, and confirmatory testing for the patient's heteroplasmy levels was not performed. A clinical diagnosis of LHON was made, and the patient was started on idebenone. LHON classically presents with sequential spontaneous loss of central vision. Onset between the 2 eyes is separated by 6-8 weeks, and the visual acuity reaches a nadir over the course of 6 weeks. Visual fields demonstrate cecocentral scotoma, and patients complain of deteriorating color vision. Pupillary reflexes are retained (1). Alcohol and tobacco are suggested triggers for the onset of the disease and may partially explain the male predominance: LHON has a 50% penetrance in men but only 10% in women (1). Funduscopy within 6 months of onset may show tortuosity 411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Humphrey visual field (HVF) performed 6 months after the onset of symptoms shows cecocentral scotoma of the left eye greater than the right eye. Foveal sensitivities of 7 and 8 dB correlate with visual acuities of 20/300 and counting fingers 1 ft in the right eye and the left eye, respectively. B. Repeat HVF taken 18 months after the onset of symptoms shows prominent centrocecal scotomas in both eyes. Corresponding visual acuities were 20/200 in the right eye and 20/400 in the left eye. of the retinal vessels, RNFL swelling, and circumpapillary telangiectatic microangiopathy but is normal in 1/5 of cases (1). After this, funduscopy may only be significant for optic atrophy (1). There is some evidence that long-term treatment with idebenone may likely result in visual improvement for patients with rare mtDNA mutations associated with LHON, including the m.3461C.T mutation (3). The 3460 mutation, which makes up w13% of LHON cases, is of interest because it affects the same alanine residue as the 3461 mutation (4,5). It progresses to clinical blindness in an average of 3 months at an average age of 29 years, and in about 80% of cases, it is associated with a positive family history (4). It is also associated with a 20% chance of spontaneous visual recovery per eye (4). Our patient progressed to clinical blindness over 3 months at the age of 44 years with a positive history of alcohol use, a negative family history of ocular disease, and no evidence of visual recovery. Funduscopy and OCT demonstrated optic nerve pallor and RNFL thinning, respectively. After 1 year of coenzyme Q therapy, he has experienced no improvements in vision. The alanine at position 52 is on the first of 7 subunits of the NADH:ubiquinone oxidoreductase protein. Although the subunit is largely hydrophobic with 5 large transmembrane domains, the residue at position 52 is in FIG. 2. Fundus photography performed 18 months after the onset of symptoms. Mild tortuosity of the retinal vessels, peripapillary atrophy, and optic nerve pallor can be seen in both eyes. 412 Fondriest and Golnik: J Neuro-Ophthalmol 2020; 40: 411-413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence a hydrophilic region of an alpha helix just outside those domains. The residue at position 52 is either an alanine or glycine in nearly all species and is adjacent to a universally invariant aspartic acid residue at position 51.5 This suggests that even small changes to the tertiary structure in this region can have profound effects. The m.3460G.A (A52T) mutation represents a change from the hydrophobic alanine to a slightly larger and polar threonine, whereas the m.3461C.T mutation represents a change to a hydrophobic valine. Because valine and threonine are similarly shaped, it is reasonable to conjecture that the m.3460G.A and m.3461C.T mutations be associated with similar symptoms, with m.3461C.T being the milder of the 2, owing to its hydrophobic substitution. The presence of this m.3461C.T mutation in the same codon as the m.3460G.A mutation, along with the absence of the 3 most common primary LHON mutations, makes it highly likely to be a novel primary LHON mutation. However, the patient's degree of heteroplasmy was not confirmed through other tissues, which remains a limitation of this hypothesis. With limited epidemiological data, it is also difficult to speculate which features of this patient's presentation may represent true differences between the phenotypes of the 2 mutations. Nevertheless, the hypothesis that the m.3461C.T mutation is a primary LHON mutation characterized by a delayed onset, and decreased penetrance relative to the m.3460G.A mutation is consistent with the molecular biology. Fondriest and Golnik: J Neuro-Ophthalmol 2020; 40: 411-413 STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. J. Fondriest and K. C. Golnik; b. Acquisition of data: J. J. Fondriest and K. C. Golnik; c. Analysis and interpretation of data: J. J. Fondriest and K. C. Golnik. Category 2: a. Drafting the manuscript: J. J. Fondriest and K. C. Golnik; b. Revising it for intellectual content: J. J. Fondriest and K. C. Golnik. Category 3: a. Final approval of the completed manuscript: J. J. Fondriest and K. C. Golnik. REFERENCES 1. Man PYW, Turnbull DM, Chinnery PF. Leber hereditary optic neuropathy. J Med Genet. 2002;39:162-169. 2. Achilli A, Lommarini L, Olivieri A, Pala M, Kashani BH, Reyneir P, La Morgia C, Valentino ML, Liguori R, Pizza F, Barboni P, Sadun F, De Negri AM, Zeviani M, Dollfus H, Moulignier A, Ducos G, Orssaud C, Bonneau D, Procaccio V, Leo-Kottler B, Fauser S, Wissinger B, Amati-Bonneau P, Torroni A, Carelli V. Rare primary mitochondrial DNA mutations and probable synergistic variants in Leber's hereditary optic neuropathy. PLoS One. 2012;7:e42242. 3. Llòria X, Catarino C, Downes S, Vincent A, Matloob S, Silva M, Klopstock T. Clinical experience with idebenone in the treatment of patients harboring rare mutations related to Leber's hereditary optic neuropathy (LHON). 2017;95. Special Issue: Abstracts from the 2017 European Association for Vision and Eye Research Conference. 4. Johns DR, Smith KH, Miller NR. Leber's hereditary optic neuropathy: clinical manifestations of the 3460 mutation. Arch Ophthalmol. 1992;110:1577-1581. 5. Howell N, Bindoff LA, McCullough DA, Kubacka I, Poulton J, Mackey D, Taylor L, Turnbull DM. Leber hereditary optic neuropathy: identification of the same mitochondrial ND1 mutation in six pedigrees. Am J Hum Genet. 1991;49:939. 413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.