Diagnosis of Charcot-Marie-Tooth Disease in a Patient With Decreased Vision From Optic Atrophy and No Other Neurological Symptoms

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Diagnosis of Charcot–Marie–Tooth Disease in a Patient With Decreased Vision From Optic Atrophy and No Other Neurological Symptoms Joseph A. Chacko, BS, Paul H. Phillips, MD, Raghu H. Ramakrishnaiah, MD, G. Bradley Schaefer, MD, Sami H. Uwaydat, MD H ereditary optic neuropathy normally presents with bilateral involvement and is often linked to genetic mutations causing mitochondrial dysfunction (1). Distinct causes of hereditary optic neuropathy include autosomal dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON) (1). Charcot–Marie–Tooth disease (CMT) encompasses a group of hereditary sensory and motor neuropathies with a variety of different mutations that cause distinctive phenotypes (2). It has an overall estimated prevalence of 1 in 2,500 in the general population (2). Charcot–Marie–Tooth disease axonal form Type 2A (CMT2A) is an autosomal dominant form of CMT that may occur with optic atrophy (3). Most of the patients with CMT2A and optic atrophy have other clinical manifestations of CMT, such as peripheral neuropathy, before the diagnosis of optic atrophy (4). We present a 15-year-old boy who had progressive bilateral optic neuropathy and was subsequently diagnosed with subclinical CMT2A. To the best our knowledge, this is the first description of a patient with CMT2A who presented exclusively with bilateral optic neuropathy without a family history of neurologic or ophthalmologic disease. A previously healthy 15-year-old boy first noticed a “constant black spot” in his vision. He denied any history of previous vision loss, and he reported a negative family history for ophthalmologic and neurologic disease. His local ophthalmologist recorded a visual acuity of 20/80 in the right eye and 20/150 in the left eye with central scotomas in both eyes. He continued to have progressive bilateral visual loss and was referred to our pediatric neuro-ophthalmology clinic 4 months after the onset of his visual symptoms. Neuroophthalmologic examination showed a visual acuity of 20/ 400 in the right eye and 20/600 in the left eye. On Ishihara Jones Eye Institute (JAC, PHP, SHU), University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas; Department of Ophthalmology (PHP), Arkansas Children’s Hospital, Little Rock, Arkansas; and Departments of Radiology (RHR) and Genetics (GBS), UAMS & Arkansas Children’s Hospital, Little Rock, Arkansas. The authors report no conflicts of interest. Address correspondence to Paul H. Phillips, MD, Arkansas Children’s Hospital, 1 Children’s Way, Slot 111, Little Rock, AR 72202; E-mail: [e-mail] e146 color plate testing, he identified 1/11 in both eyes. Confrontational visual fields were full in both eyes. Intraocular pressure was 18 mm Hg in the right eye and 16 mm Hg in the left eye. Pupils were equal, round, and reactive to light in both eyes. There was no relative afferent pupillary defect. External and anterior segment examination was normal. Funduscopic examination showed a cup-to-disc ratio of 0.2 in both eyes with mild temporal disc pallor in both eyes (Fig. 1). Automated visual field testing (HVF 24-2) revealed cecocentral scotomas in both eyes. Optical coherence tomography (OCT) displayed the attenuation of the papillomacular bundle in both eyes (Fig. 1). Full-field electroretinography displayed normal rod and cone responses. MRI of the brain and orbits with contrast revealed bilateral optic nerve atrophy (Fig. 2A). Mito Genome Sequencing & Deletion Testing (GeneDx, Gaithersburg, MD) was negative for mutations of LHON. Subsequently, the Inherited Retinal and Optic Nerve Disorders Panel (Invitae, San Francisco, CA) disclosed a pathogenic variant in MFN2 c.839G.A (p.Arg280His) diagnostic of CMT2A. This panel also revealed no mutations in OPA1 or OPA3. Our patient was referred to the neurology clinic. He had a normal neurological examination; however, electromyography (EMG) testing revealed a mild chronic axonal sensorimotor polyneuropathy with no evidence of a myopathy. MRI of the entire spine revealed bilateral brachial plexus and lumbar plexus thickening (Fig. 2B, C). The EMG and MRI findings were consistent with his diagnosis of CMT2A. Two months after our evaluation, vision worsened to count fingers (CF) at 4 feet in the right eye and CF at 6 feet in the left eye. He was started on a trial of a mitochondrial cocktail consisting of daily L-carnitine 1000 mg, CoQ 600 mg, thiamine suspension 20 mg/cc, riboflavin 500 mg, nicotinamide 1000 mg, biotin 20 mg, and L-creatine 5 g to hopefully improve his vision loss. Hereditary optic neuropathies typically present with symmetric, bilateral, and central vision loss due to progressive optic nerve damage (5). The optic neuropathy may be isolated or may occur with concurrent neurological or systemic dysfunction (1). The common pathogenesis of many genetic optic neuropathies may reflect the vulnerability of the retinal ganglion cells and their axons to inherited mitochondrial abnormalities (5). Chacko et al: J Neuro-Ophthalmol 2023; 43: e146-e148 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Color fundus photography showing mild temporal optic disc pallor in the right eye (A) and in the left eye (B). C. OCT RNFL analysis: mild temporal thinning in both eyes. OCT macula showing significant attenuation of the papillomacular bundle in the right eye (D) and in the left eye (E) (arrows). F. Ganglion cell analysis: The ganglion cell layers are significantly attenuated in both eyes. Charcot–Marie–Tooth disease encompasses a group of hereditary polyneuropathies characterized by progressive muscular weakness (5). Most of the patients begin to manifest symptoms aged between 2 and 15 years (5). Our patient began to have visual symptoms at 15 years. Clinically, patients present with peripheral neuropathy of varying severity with predominantly motor symptoms compared with sensory (5). CMT can be classified as either demyelinating or axonal (2). CMT2A is the most common axonal form of CMT (6), and it is characterized by axonal degeneration without demyelination and preserved or mildly reduced motor conduction velocities (7). Mutations in the MFN2 gene account for 8%–30% of the disease (3). MFN2 encodes for a mitochondrial dynamin–related GTPase located on the outer mitochondrial membrane and the endoplasmic FIG. 2. A. Optic nerves: coronal T2 image with fat suppression through the orbits showing both optic nerves. There is mild thinning of the right optic nerve without signal abnormality (arrow heads). The left optic nerve shows moderate thinning of the nerve with T2 hyperintensity (arrow). B. Brachial plexus: coronal maximum intensity projection image of brachial plexus neurography showing bilateral mild to moderate smooth thickening of the brachial plexus (arrows). C. Lumbar plexus: coronal maximum intensity projection image of lumbar plexus neurography showing bilateral mild-to-moderate smooth thickening of the lumbar plexus (arrows). Chacko et al: J Neuro-Ophthalmol 2023; 43: e146-e148 e147 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence reticulum (2). MFN2 gene mutations commonly manifest as a peripheral neuropathy, but optic atrophy has been noted in a subset of patients (2). CMT2A with optic atrophy is also termed “hereditary sensory and motor neuropathy Type VI (HSMN6)” (2). In HSMN6, mutations in MFN2 can lead to retinal ganglion cell (RGC) axonal loss, and this ultimately results in optic nerve degeneration with the visual acuity reduced to 20/200 or worse (2). Optic nerve involvement has been seen in 10%–36% of patients with CMT2A (6). Patients with CMT2A and optic atrophy typically develop motor weakness, such as a flaccid tetraparesis, before the onset of visual symptoms (8). Our patient is unique as he presented with visual loss from optic neuropathy before other symptoms of CMT. He developed progressive vision loss in a short period of time highlighting the sensitivity of the RGC layer to mitochondrial dysfunction. Genetic testing revealed a pathogenic variant in MFN2 c.839G.A (p.Arg280His). Genetic testing also showed that he was negative for any mutations in LHON, OPA1, or OPA3 ruling out other common causes of optic atrophy. MRI of the entire spine revealed bilateral brachial plexus and lumbar plexus thickening. Chung et al (9) explained that nerve biopsy findings in patients with CMT2A have shown axonal cluster formation in addition to atrophy of thick myelinated nerve fibers. The bilateral brachial and lumbar plexus thickening seen in our patient may be due to Schwann cell proliferation in clusters of regenerating nerve fibers (9). EMG findings were consistent with a mild chronic axonal sensorimotor polyneuropathy. His bilateral optic atrophy, MFN2 gene mutation, and EMG results confirmed a diagnosis of CMT2A with optic atrophy (HSMN6). Rouzier et al (10) described a pedigree of 11 patients with CMT and optic atrophy. Three patients in this family had isolated optic atrophy; however, the association with CMT was evident from the family history. To the best of our knowledge, this is the first case of a patient with CMT2A who presented with visual loss from optic neuropathy before other symptoms of CMT and without a family history of neurologic disease. The diagnostic evaluation of a patient with an unexplained optic neuropathy should include a broad range of genetic etiologies, even when there is no family history of ophthalmologic or neurologic disease. There are many genetic panels from different laboratories to choose from when evaluating optic nerve atrophy. We recommend ordering a comprehensive gene panel on all patients with suspected genetic optic atrophy if testing for LHON, OPA1, and OPA3 does not yield a causative mutation. Testing should include entities that typically have associated non- e148 ocular findings, even if the patient has an isolated optic neuropathy and no family history of neurologic or ophthalmologic disease. This will allow for greater sensitivity to identify specific genetic causes that can lead to permanent blindness. Currently, treatment for CMT2A is limited to symptomatic care with hope for future disease-modifying therapies (2). STATEMENT OF AUTHORSHIP Conception and design: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat; Acquisition of data: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat; Analysis and interpretation of data: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat. Drafting the manuscript: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat; Revising it for intellectual content: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat. Final approval of the completed manuscript: J. A. Chacko, P. H. Phillips, R. H. Ramakrishnaiah, G. B. Schafer, S. H. Uwaydat. REFERENCES 1. Vaphiades MS, Brodsky MC. Pediatric optic atrophy. Int Ophthalmol Clin. 2012;52:17–28, xiii. 2. Burté F, Carelli V, Chinnery PF, Yu-Wai-Man P. Disturbed mitochondrial dynamics and neurodegenerative disorders. Nat Rev Neurol. 2015;11:11–24. 3. Bombelli F, Stojkovic T, Dubourg O, Echaniz-Laguna A, Tardieu S, Larcher K, Amati- Bonneau P, Latour P, Vignal O, Cazeneuve C, Brice A, Leguern E. Charcot-Marie-Tooth disease type 2A: from typical to rare phenotypic and genotypic features. JAMA Neurol. 2014;71:1036–1042. 4. Voo I, Allf BE, Udar N, Silva-Garcia R, Vance J, Small KW. Hereditary motor and sensory neuropathy type VI with optic atrophy. Am J Ophthalmol. 2003;136:670–677. 5. Newman NJ, Biousse V. Hereditary optic neuropathies. Eye. 2004;18:1144–1160. 6. Hamedani AG, Wilson JA, Avery RA, Scherer SS. Optic neuropathy in charcot-marie- tooth disease [published online ahead of print, 2020 apr 16]. J Neuroophthalmol. 2020. doi: 10.1097/WNO.0000000000000965. 7. Zhu D, Kennerson ML, Walizada G, Züchner S, Vance JM, Nicholson GA. Charcot-Marie- Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology. 2005;65:496–497. 8. Guerriero S, D’Oria F, Rossetti G, Favale R, Zoccolella S, Alessio G, Petruzzella V. CMT2A harboring mitofusin 2 mutation with optic nerve atrophy and normal visual acuity. Int Med Case Rep J. 2020;13:41–45. 9. Chung KW, Kim SB, Park KD, Choi KG, Lee JH, Eun HW, Suh JS, Hwang JH, Kim WK, Seo BC, Kim SH, Son IH, Kim SM, Sunwoo IN, Choi BO. Early onset severe and late-onset mild Charcot-Marie- Tooth disease with mitofusin 2 (MFN2) mutations. Brain. 2006;129:2103–2118. 10. Rouzier C, Bannwarth S, Chaussenot A, Chevrollier A, Verschueren A, Bonello-Palot N, Fragaki K, Cano A, Pouget J, Pellissier JF, Procaccio V, Chabrol B, Paquis-Flucklinger V. The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy “plus” phenotype. Brain. 2012;135:23–34. Chacko et al: J Neuro-Ophthalmol 2023; 43: e146-e148 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.