Variable Presentation of Leber Hereditary Optic Neuropathy in Children of a Family Harboring a Rare m.13051GA mtDNA Mutation

Leber hereditary optic neuropathy (LHON) is typically characterized by a subacute painless sequential visual loss in young or middle-aged men.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Variable Presentation of Leber Hereditary Optic Neuropathy in Children of a Family Harboring a Rare m.13051G.A mtDNA Mutation Vasily M. Smirnov, MD, Jean-Marie Cuisset, MD, Caroline Marks, MD, Philippe Debruyne, MSc, Claire-Marie Dhaenens, PharmD, PhD, Sabine DefoortDhellemmes, MD L eber hereditary optic neuropathy (LHON) is typically characterized by a subacute painless sequential visual loss in young or middle-aged men. Most cases are associated with 3 primary mitochondrial DNA (mtDNA) point mutations, that is, m.11778G.A, m.14484T.C, and m.3460G.A, involving different subunits of the mitochondrial respiratory chain complex 1. Here, we describe a family harboring the rare m.13051G.A mutation with variable clinical presentation of the mitochondrial disease among the affected subjects. PROBAND (III-3) The male patient (5 years old) was referred to our department for a subacute onset of large exotropia and bilateral ptosis. During the first evaluation, the best-corrected visual acuity (BVCA) was diminished in both eyes (right eye [RE]: 20/63, left eye [LE]: 20/125 Snellen). He presented a large X-pattern divergent squint. Elevation and adduction were limited to the same extent in both eyes. There was also a marked gaze-evoked nystagmus (see Supplemental Digital Content, Figure E1, http://links.lww.com/WNO/A437). On fundus examination, the patient showed bilateral temporal optic disc pallor (Fig. 1). Full-field electroretinogram (ERG) ERG was normal. Exploration de la Vision et Neuro-Ophtalmologie (VMS, CM, PD, SDD), CHU de Lille, Lille, France; Université de Lille (VMS), Faculté de Médecine, Lille Cedex, France; Neurologie pédiatrique (J-MC), CHU de Lille, Lille, France; and Université de Lille (C-MD), Inserm UMRS 1172, CHU Lille, Biochemistry and Molecular Biology Department UF Génopathies, Lille, France. 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). This retrospective study was approved by our Institutional Review Board (Comité de la Protection des Personnes Nord-Ouest IV) and fulfilled the tenets of the Declaration of Helsinki. Informed consent was obtained for all participants to the study. C.-M. Dhaenens and S. Defoort-Dhellemmes equally contributed to the article. Address Correspondence to Vasily M. Smirnov, MD, Exploration de la Vision et Neuro-Ophtalmologie, CHU de Lille, F-59000 Lille, France; E-mail: [e-mail] Smirnov et al: J Neuro-Ophthalmol 2020; 40: 569-571 Neurological assessment revealed an ataxic gait and a limb tremor. Brain MRI found a hyperintensity of the periaqueductal gray matter (unfortunately, images are unavailable). Based on these findings, a mitochondrial disease was suspected. However, testing for mitochondrial respiratory chain activity on deltoid muscle biopsy was normal. Blood and cerebrospinal fluid lactate levels were also normal. Furthermore, genetic testing for point mtDNA mutations commonly associated with mitochondrial cytopathies (e.g., LHON, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes MELAS, neuropathy-ataxia-retinitis pigmentosa syndrome NARP, and Leigh syndrome) was negative. During several years of follow-up, ptosis spontaneously disappeared and visual acuity gradually improved without any treatment (RE: 20/32, LE: 20/50 Snellen; age 18 years). Strabismus surgery was eventually performed with good results. However, mild gait ataxia and limb tremor persisted unchanged. SIBLINGS During the follow-up visits of the proband, his mother asked to examine one of his older brothers who complained for a “bad vision” and a difficulty of reading at school. Sibling III-2 (12 years old) surprisingly showed a bilateral amblyopia. The fundus examination revealed bilateral optic disc pallor. The BVCA was relatively good and unchanged within 8 years of follow-up (RE: 20/40, LE: 20/43 Snellen; age 19 years). During this period, no oculomotor and/or neurological abnormalities manifested. Brain MRI was also normal. The eldest brother III-1 (15 years old) was referred to our department in 2007 for a sudden visual loss in his RE. Indeed, the BCVA was limited to “light perception” in the RE, while the LE preserved 20/20 Snellen vision. Fundus examination revealed temporal optic disc pallor in the RE; while in the LE, there was a disc swelling with telangiectasias. Within a month, visual loss occurred also in the LE. At the same time, he developed a large-angle right exotropia. Since then, the patient did not show visual recovery. The mother of these 3 patients II-1 was examined at the age of 35 years. Similar to her children, she also presented bilateral optic disc pallor with good BCVA (RE 20/20, LE 569 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus findings and RNFL (Zeiss Cirrus HD-OCT, Carl Zeiss Meditec, Jena, Germany) in affected members. Pedigree is at bottom right. 20/25). She reported an episode of bilateral ophthalmoplegia and ptosis when she was 7 years old. However, she recovered without any treatment within few months. The suspicion of LHON in this family arose on the basis of its typical presentation in the brother I-1; nevertheless, only recently, we had a genetic confirmation by whole mitochondrial genome sequencing. A homoplasmic mutation m.13051G.A (c.MT-ND5:715G.A, p.ND5: Ser239Gly) affecting an ND5 subunit of respiratory chain complex 1 was found in all affected members of this family. The region coding for the ND5 subunit is characterized by a stringent evolutionary conservation (1). Therefore, even a small physicochemical difference between serine and glycine is enough to be deleterious for the protein function. In the cultured fibroblasts from affected patients, there was an evidence of fragmented mitochondrial network, increased mitochondrial volume, and elevated levels of mitophagy in the response to increased reactive oxygen species production, as it occurs in classical NOHL-associated mutations (2). 570 This secondary mtDNA mutation is extremely rare (https://mitomap.org/foswiki/bin/view/MITOMAP/ Mutations), and few patients were published to date, that is, three families and one singleton case (2,3). Indeed, this mutation was absent from a large Chinese cohort of LHON patients (4). A heterogeneous phenotype is reported in affected patients. A Dutch family (3) carrying m.13051G.A was diagnosed with LHON (2 affected siblings and their maternal aunt). Dombi et al (2) reported 2 families and one singleton case with clinical manifestations ranged from a longstanding mild optic atrophy to a prominent acute LHON and Leighlike phenotypes with systemic involvement. The authors claimed that there was no respiratory chain abnormality in the skeletal muscle. Thus, ocular motility abnormalities were likely to be central in their origin. The origin of ptosis is probably the same as in other mitochondrial cytopathies (e.g., chronic progressive external ophthalmoplegia, Kearns–Sayre, and Pearson syndrome). Primary myopathy with ragged-red fiber appearance resulting in extraocular muscle atrophy (5) coexists with evidence Smirnov et al: J Neuro-Ophthalmol 2020; 40: 569-571 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence of brain atrophy and oculomotor nucleus vacuolic degeneration in some patients (6) thus supporting a mixed—myogenic and neurogenic—involvement. We hypothesized that the ptosis in our patient III-3 was of central origin as it recovered. Wax and wane evolution is typical for mitochondrial encephalomyelopathies with some recovery after acute attacks. Oculomotor and lid position abnormalities are frequently observed in Leigh disease as the brainstem gray matter is primarily involved (7). Our family supports these data. Proband III-3 had a Leighlike disease with acute onset of neurological and oculomotor abnormalities with subsequent partial recovery. His brother III-2 had a mild chronic optic atrophy without progression, consistent with pediatric-onset LHON (8,9). The elder brother III-1 presented a typical adult-onset LHON. Finally, their mother had a Leigh-like episode in early childhood and only a mild asymptomatic optic nerve disease. Diagnosis in such cases could be challenging. Systematic examination of available relatives is very important when mitochondrial disease is suspected because the clinical manifestations could be very heterogeneous. The high clinical suspicion given by the associated ocular and neurological signs and a maternal pattern of inheritance should prompt an extensive testing for mtDNA mutations. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: V. M. Smirnov, P. Debruyne, C.-M. Dhaenens, and S. Defoort-Dhellemmes; b. Acquisition of data: V. M. Smirnov, J.-M. Cuisset, C.-M. Dhaenens, and S. DefoortDhellemmes; c. Analysis and interpretation of data: V. M. Smirnov, C.-M. Dhaenens, and S. Defoort-Dhellemmes. Category 2: a. Drafting the manuscript: V. M. Smirnov and C.-M. Dhaenens; b. Revising it for intellectual content: C.-M. Dhaenens and J.-M. Cuisset. Category 3: a. Smirnov et al: J Neuro-Ophthalmol 2020; 40: 569-571 Final approval of the completed manuscript: V. M. Smirnov, J.-M. Cuisset, C.-M. Dhaenens, and S. Defoort-Dhellemmes. REFERENCES 1. Liolitsa D, Rahman S, Benton S, Carr LJ, Hanna MG. Is the mitochondrial complex I ND5 gene a hot-spot for MELAS causing mutations? Ann Neurol. 2003;53:128–132. 2. 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