Isolated Asymmetric Progressive Optic Neuropathy as a First Presentation of Charcot-Marie-Tooth Disease Type 2A

The differential diagnosis of optic neuropathy is broad and includes inflammatory, ischemic, nutritional, and hereditary etiologies. The most common hereditary optic neuropathies are autosomal dominant optic atrophy and mitochondrially inherited Leber optic neuropathy.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Isolated Asymmetric Progressive Optic Neuropathy as a First Presentation of Charcot–Marie–Tooth Disease Type 2A Maya Gabel, BS, Jamie Mitchell, MD, Bidyut Pramanik, MD, Anthony Geraci, MD, Asaff Harel, MD, MSc T he differential diagnosis of optic neuropathy is broad and includes inflammatory, ischemic, nutritional, and hereditary etiologies. The most common hereditary optic neuropathies are autosomal dominant optic atrophy and mitochondrially inherited Leber optic neuropathy (1). A less prevalent hereditary etiology of optic neuropathy is Charcot–Marie–Tooth disease (CMT), which encompasses a varied group of familial conditions, the hallmark of which is progressive sensorimotor polyneuropathy (2). In this article, we describe a case of CMT presenting as gradually progressive sequential bilateral optic neuropathy in the absence of symptomatic peripheral neuropathy. A 39-year-old woman with a past history of migraines presented to the ophthalmology clinic complaining of worsening vision in the right eye over 2 weeks. Family history included gradual visual loss in multiple family members as follows: glaucoma in her father and sister and cataracts in her father, paternal uncle, and paternal aunt. Visual impairments in family members reportedly improved with appropriate therapy for glaucoma and cataracts, but further information was not available. There was no family history of neuropathy. Visual acuity (VA) of the patient measured 20/40 in the right eye and 20/20 in the left eye. Intraocular pressure was 15 in the right eye and 16 in the left eye, and the cup-to-disc ratio was 0.3 in both eyes. There was no notching or optic nerve hemorrhage. The angle seemed open (although gonioscopy was not performed), and the anterior chamber was deep. Visual field testing was somewhat unreliable due to high fixation losses, but did not show characteristic glaucomatous defects. There Medical School for International Health (MG), Faculty of Health Sciences, Ben-Gurion University of the Negev, Be’er Sheva, Israel; Department of Ophthalmology (JM) Manhattan Eye and Ear Hospital, Northwell Health, New York, New York; Zucker School of Medicine at Hofstra/Northwell (JM, BP, AG, AH), Hempstead, New York; Department of Radiology (BP), Lenox Hill Hospital, New York, New York; Department of Neurology (AG, AH), North Shore University Hospital, Manhasset, New York; and Department of Neurology (AH), Lenox Hill Hospital, New York, New York. The authors report no conflicts of interest. Address correspondence to Asaff Harel, MD, MSc, Lenox Hill Hospital, 130 East 77th Street, 8th Floor, Black Hall, New York, NY 10075; E-mail: [e-mail] Gabel et al: J Neuro-Ophthalmol 2021; 41: e699-e702 was no afferent pupillary defect noted. There was a small central scotoma in the right eye (Fig. 1). The rest of the anterior segment and dilated fundus examination were normal. Color vision was decreased in the right eye (the right eye 11/15 Ishihara plates vs 15/15 in the left eye). Optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) and macula was normal in both eyes. Because of her headache history, there was a concern for pseudotumor cerebri. However, initial noncontrast brain MRI was unrevealing, and a lumbar puncture demonstrated normal opening pressure (9 cm of water in the left lateral decubitus position). Three months later, she returned to the ophthalmology clinic with progressive worsening of vision in the right eye. VA was 20/80 in the right eye and 20/20 in the left eye. Subsequent visual field testing showed a larger central scotoma in the right eye, but fundus examination and OCT of the RNFL and macula were still normal (Fig. 1). She underwent MRI of brain and orbits with and without contrast (Fig. 2) and MR Venogram of head these were unremarkable. Over the next 4 months, the vision in her right eye continued to deteriorate, and she gradually developed temporal optic nerve pallor and temporal RNFL thinning in the right eye (Fig. 1). Neurological examination on presentation to our center 7 months after onset of symptoms revealed VA of 20/400 in the right eye and 20/25 in the left eye, as well as mild symmetric vibratory sense loss in distal lower extremities. Repeat MRIs of the orbits at that time revealed new bilateral optic nerve atrophy and T2 hyperintensity without abnormal enhancement (Fig. 2). A full workup for nutritional and rheumatological conditions was unremarkable. Cerebrospinal fluid analysis was normal aside from a mild elevation in the Immunoglobulin G index (0.9, ref #0.7) of unclear significance. Aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were negative, and MRIs of the entire spinal cord revealed no abnormalities. A full sequence analysis and deletion testing of the mitochondrial genome plus sequence analysis and exon-level deletion/duplication testing of 202 nuclear genes revealed a heterogeneous mutation of mitofusin-2 (MFN-2) (T236M [ACG . ATG], c.707 C.T, exon 7), suggesting a diagnosis of CMT. Of note, genetic analysis did not reveal any mutations associated with e699 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Funduscopy and optical coherence tomography. Visual field testing at symptom onset (A) and 5-month follow-up (B) reveals gradual worsening of central scotoma in the right eye. OCT result at 3 months after symptom onset (C) was within normal limits in both eyes (the left eye not imaged). OCT at 7 months after symptom onset (D) revealed temporal RNFL thinning in the right eye and was normal in the left eye (the left eye not imaged). Funduscopy at 7 months (E and F) revealed temporal pallor in the right eye. OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. autosomal dominant optic atrophy or mitochondrially inherited Leber optic neuropathy. Nerve conduction studies were subsequently performed demonstrating a mild subclin- ical distal axonal neuropathy in both lower extremities. Ten months after she first developed visual symptoms in the right eye, vision in the left eye also began to deteriorate. FIG. 2. MRI of orbits. MRI of the orbits at 3 months after symptom onset (A) was unremarkable. Coronal (B) and axial (C) MRI of the orbits at 7 months after symptom onset reveals the development of right greater than left optic atrophy and diffuse abnormal T2 hyperintensity. e700 Gabel et al: J Neuro-Ophthalmol 2021; 41: e699-e702 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence CMT includes a group of heterogeneous genetic disorders with a variety of clinical presentations primarily characterized by peripheral motor and sensory neuropathies. Patterns of inheritance are varied and include autosomal dominant, autosomal recessive, X-linked dominant, and de novo mutations. The immense heterogeneity of CMT is such that mutations in different genes may share similar clinical presentations, whereas a mutation in one particular gene can lead to a wide spectrum of phenotypes. Most CMT cases can be divided into 2 major types as follows: demyelinating neuropathies or myelinopathies, categorized under CMT-1 disorders, and CMT-2 disorders, which are characterized by primary axonal defects (2). The most common type of autosomal dominant axonal CMT is CMT-2A, corresponding to hereditary motor and sensory neuropathy VI in older nomenclature, which is caused by mutations in the mitofusin 2 gene (MFN-2). This subtype accounts for approximately 30% of autosomal dominant CMT cases. Classically, it presents with progressive motor impairment mainly in the distal lower limbs accompanied by marginal sensory loss. Other common signs are foot drop, gait abnormalities, weakness, and atrophy. Non-neuropathic phenotypic descriptions include white matter alterations, hearing loss, pyramidal signs, and optic atrophy (2). The age of onset of CMT-2A is highly variable within and between families, from one to 60 years old, with most individuals developing symptoms in the first or second decade. The initial presentation normally involves motor signs, such as foot drop or weakness. However, there are some individuals with MFN-2 variants who are asymptomatic or only have mild findings (3,4). Optic atrophy has been reported in CMT-2A patients, and it is believed that up to 75% of all CMT patients have at least some afferent visual pathway dysfunction. This suggests that subclinical optic neuropathy occurs in a high percentage of CMT cases (3). More than 100 pathogenic variants of MFN-2 have been recognized as causes of CMT-2A, leading to a wide spectrum of clinical presentations (2). The MFN-2 gene encodes for the mitochondrial dynamin-like GTPase mitofusin protein in the outer mitochondrial membrane (5). Intact function of this GTPase and complementary proteins is paramount for the establishment of a uniform membrane potential at the mitochondrial double membrane and for outer mitochondrial membrane fusion. The process of mitochondrial fusion regulates essential mitochondrial functions, aiding in axonal transport, cell cycle progression, and mitochondrial–endoplasmic reticulum juxtaposition (6). Normal formation of the mitochondrial network by fusion is essential for proper functioning of the peripheral nervous system because mitochondria are essential generators of the energy required for bidirectional transport of molecules and neurotransmitters Gabel et al: J Neuro-Ophthalmol 2021; 41: e699-e702 along the vast microtubular network in the peripheral nerve (3). Mutations in MFN-2 lead to changes in GTP hydrolysis function, resulting in impaired fusion and mitochondrial anchoring function (6). Most lead to protein misfolding or truncation and can be mapped to 4 functional zones of the molecule as follows: the “nucleotidebinding site,” the “G domain,” the “hinge 2,” and the “HD1 interface” (6). Some mutations may lead to haploinsufficiency, whereas others are hypothesized to produce abnormal MFN-2 protein that competitively inhibits normal MFN-2, exerting a dominant negative effect (6). However, the precise effect of each mutation has not been described. Moreover, although our patient’s mutation (T236M [ACG . ATG], c.707 C.T, exon 7) has been previously described to cause neuropathy and CMT (7), its molecular effects have not been fully characterized nor has it ever been described to present with optic neuropathy (7). This underscores the phenotypic variability of CMT, the driver of which is not fully understood and may be related to environmental factors, and further research is warranted. Our patient was the first in her family to have been diagnosed with optic neuropathy and CMT. However, it is of interest that other members of the paternal side of her family exhibited visual disturbances. although they were diagnosed with other more common conditions, such as glaucoma and cataracts, it is certainly plausible that optic neuropathy was the actual etiology of symptoms but perhaps was not severe enough to have led to a diagnosis. The involvement of the patient’s father, paternal uncle, paternal aunt, and sister is compatible with an autosomal dominant inheritance pattern. Unfortunately, further detail regarding the patient’s family members is unavailable at this time due to practical reasons. CMT-2A typically presents with severe motor and sensory impairments of the distal lower extremities and milder impairment of the upper extremities. Our case is unique in that the patient presented with severe visual symptoms and profound progressive optic neuropathy accompanied by a relatively mild axonal neuropathy that did not reach clinical relevance at the time of diagnosis. This case report illustrates the immense clinical heterogeneity of CMT, which remains poorly understood, and contributes to previously described CMT presentations accompanied with optic neuropathy. It also demonstrates that profound asymmetry in optic neuropathy and resultant symptoms does not rule out a genetic etiology. Furthermore, this case highlights that optic neuropathy can indeed be the only clinically relevant symptom at presentation of CMT. Consequently, CMT should be considered as part of the differential diagnosis for anyone presenting with progressive optic neuropathy along with the more common hereditary optic neuropathies, such as e701 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Leber hereditary optic neuropathy and autosomal dominant optic atrophy. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M. Gabel and A. Harel; b. Acquisition of data: J. Mitchell, B. Pramanik, and A. Geraci; c. Analysis and interpretation of data: M. Gabel, J. Mitchell, B. Pramanik, and A. Harel. Category 2: a. Drafting the manuscript: M. Gabel and A. Harel; b. Revising it for intellectual content: M. Gabel, J. Mitchell, B. Pramanik, A. Geraci, and A. Harel. Category 3: a. Final approval of the completed manuscript: A. Harel. 4. 5. 6. REFERENCES 1. Newman NJ, Biousse V. Hereditary optic neuropathies. Eye (Lond). 2004;18:1144–1160. 2. Iapadre G, Morana G, Vari MS, Pinto F, Lanteri P, Tessa A, Santorelli FM, Striano P, Verrotti A. A novel homozygous MFN2 mutation associated with severe and atypical CMT2 phenotype. Eur J Paediatr Neurol. 2018;22:563–567. 3. 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