Optic Neuropathy in Charcot-Marie-Tooth Disease

Background: Charcot-Marie-Tooth disease Type 2A (CMT2A) presents with optic atrophy in a subset of patients, but the prevalence and severity of optic nerve involvement in relation to other CMT subtypes has not been explored. Methods: Patients with genetically confirmed CMT2A (n = 5), CMT1A (n = 9) and CMTX1 (n = 10) underwent high- and low-contrast acuity testing using Sloan letter charts, and circumpapillary retinal nerve fiber layer (RNFL) and macular total retinal, RNFL, and ganglion cell layer/inner plexiform layer thickness was measured using spectral domain optical coherence tomography (OCT). We used age- and gender-adjusted linear regression to compare contrast acuity and retinal thickness between CMT groups. Results: One of 5 patients with CMT2A had optic nerve atrophy (binocular high-contrast acuity equivalent 20/160, mean circumpapillary RNFL 47.5 μm). The other patients with CMT2A had normal high- and low-contrast acuity and retinal thickness, and there were no significant differences between patients with CMT2A, CMT1A, and CMTX1. Conclusions: Optic atrophy occurs in some patients with CMT2A, but in others, there is no discernible optic nerve involvement. This suggests that optic neuropathy is specific to certain MFN2 mutations in CMT2A and that low-contrast acuity or OCT is of limited value as a disease-wide biomarker.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Optic Neuropathy in Charcot–Marie–Tooth Disease Ali G. Hamedani, MD, MHS, James A. Wilson, BS, Robert A. Avery, DO, MSCE, Steven S. Scherer, MD, PhD Background: Charcot–Marie–Tooth disease Type 2A (CMT2A) presents with optic atrophy in a subset of patients, but the prevalence and severity of optic nerve involvement in relation to other CMT subtypes has not been explored. Methods: Patients with genetically confirmed CMT2A (n = 5), CMT1A (n = 9) and CMTX1 (n = 10) underwent highand low-contrast acuity testing using Sloan letter charts, and circumpapillary retinal nerve fiber layer (RNFL) and macular total retinal, RNFL, and ganglion cell layer/inner plexiform layer thickness was measured using spectral domain optical coherence tomography (OCT). We used age- and gender-adjusted linear regression to compare contrast acuity and retinal thickness between CMT groups. Results: One of 5 patients with CMT2A had optic nerve atrophy (binocular high-contrast acuity equivalent 20/ 160, mean circumpapillary RNFL 47.5 mm). The other patients with CMT2A had normal high- and low-contrast acuity and retinal thickness, and there were no significant differences between patients with CMT2A, CMT1A, and CMTX1. Conclusions: Optic atrophy occurs in some patients with CMT2A, but in others, there is no discernible optic nerve involvement. This suggests that optic neuropathy is specific Department of Neurology (AGH, JAW, RAA, SSS), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Translational Center of Excellence for Neuroepidemiology and Neurology Outcomes Research (AGH), University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics (AGH), University of Pennsylvania, Philadelphia, Pennsylvania; Department of Ophthalmology (RAA), Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Division of Ophthalmology (RAA), Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania. The authors report no conflicts of interest. A. G. Hamedani receives grant funding from the NIH (NINDS T32 NS061779-10). S. S. Scherer is supported by the Judy Seltzer Levenson Memorial Fund for CMT Research and by the Inherited Neuropathy Consortium (U54 NS065712), which is a part of the NIH National Center for Advancing Translational Sciences (NCATS) Rare Disease Clinical Research Network, an initiative of the Office of Rare Disease Research. The remaining authors report no conflicts of interest. Address correspondence to Ali G. Hamedani, MD, MHS, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, 3 W. Gates Building, Philadelphia, PA 19104; E-mail: [e-mail] Hamedani et al: J Neuro-Ophthalmol 2021; 41: 233-238 to certain MFN2 mutations in CMT2A and that low-contrast acuity or OCT is of limited value as a disease-wide biomarker. Journal of Neuro-Ophthalmology 2021;41:233–238 doi: 10.1097/WNO.0000000000000965 © 2020 by North American Neuro-Ophthalmology Society C harcot–Marie–Tooth (CMT) disease is a group of genetically and clinically heterogeneous inherited neuropathies affecting approximately 1 in 2,500 individuals (1). Mutations in over 100 different genes have been identified, causing autosomal dominant demyelinating (CMT1), autosomal dominant axonal (CMT2), X-linked (CMTX), and autosomal recessive neuropathies (2). Of particular relevance to neuro-ophthalmologists is CMT disease Type 2A (CMT2A), the most common axonal form of CMT (3), which is accompanied by optic atrophy in a subset of patients, and sometimes termed CMT or hereditary sensory and motor neuropathy Type VI. Other complex neurogenetic phenotypes (spasticity, cerebellar ataxia, etc.) can include both neuropathy and optic atrophy as well (4). The association between CMT and optic atrophy was first reported in 1889, and the first detailed description of its neuro-ophthalmic phenotype was published by Hoyt in 1960 (5). More recent case series have documented optic nerve involvement in 10%–36% of patients with CMT2A (6–8), but these cases were characterized by severe vision loss and optic atrophy, and because subjects did not undergo systematic neuro-ophthalmic evaluation, mild optic nerve involvement (which might only be apparent on optical coherence tomography [OCT]) could have been missed due to selection or recall bias. The presence of intermediate or subclinical optic nerve phenotypes in other patients with CMT2A would provide novel insight into the molecular pathogenesis of CMT2A, inform clinical care, and have a potential role as disease biomarker. To date, only 2 patients with CMT2A have been evaluated with OCT in the literature, and both had retinal nerve fiber layer (RNFL) and ganglion cell layer (GCL) thinning corresponding to significant visual acuity and field loss (9). 233 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution The other common forms of CMT are not commonly recognized as having clinical optic nerve involvement. However, previous studies have found abnormal visual evoked potentials in patients with CMT1 (exact type unknown) (10–13), and transient white matter changes on MRI occur in CMTX1 (14) and may even be present to a lesser degree in other forms of CMT (15). The objective of this study was to determine the prevalence and extent of optic nerve involvement in the 3 most common forms of CMT (CMT1A, CMT2A, and CMTX1) using a prospective natural history cohort. We hypothesized that low-contrast acuity and OCT parameters would be abnormal in CMT2A patients both with and without vision loss. We also hypothesized that contrast acuity and OCT parameters would be lower in CMTX1 than CMT1A, which we expected to be normal. This study was approved by the University of Pennsylvania institutional review board, and informed consent was obtained from prospective study subjects before enrollment. acquired in high-speed mode using 768 a-scans per b-scan. Measures of the circumpapillary RNFL (cpRNFL) thickness were acquired using the standard 3.4-mm circle around the optic nerve head at a diameter of 12°. Three scans were performed for each eye, and the scan with the greatest quality for each eye (minimum: .20 dB) was selected. Macular imaging included 61 horizontal b-scans spaced equally apart over a 9.2 · 7.6-mm area centered over the fovea. Scans were immediately reviewed for mirror, edge, or other artifacts and repeated as needed (minimum quality .20 dB). Retinal layers were automatically segmented using manufacturer-provided software, and all b-scans were individually reviewed for segmentation error and manually adjusted as needed. For individual layer thickness calculations, macular images were divided according to the Early Treatment of Diabetic Retinopathy Study grid (superior, inferior, nasal, and temporal quadrants of the inner 3-mm and outer 6-mm regions). Circumpapillary RNFL and macular total retinal, RNFL, GCL, and inner plexiform layer (IPL) layer thickness was recorded. Ganglion cell layer and IPL thickness measures were summed and reported as a single measure of GCL/IPL thickness. Study Population Statistical Analyses Subjects were recruited from an established natural history study at the inherited neuropathy clinic at the University of Pennsylvania. The CMT Examination Score (CMTES), which measures neuropathy severity on a 26-point scale (16), was performed as part of this study. Using the natural history study database, we contacted all subjects with a clinical diagnosis of CMT2A or CMTX1 and a similar number with CMT1A, confirmed by genetic testing either of the proband or an affected relative, without any knowledge of their current visual function. We excluded patients with a known history of secondary optic nerve or retinal disease such as glaucoma, optic neuritis, ischemic optic neuropathy, or age-related macular degeneration. Descriptive statistics were summarized in tables, and ageand gender-adjusted linear regression was used to compare contrast acuity and OCT measurements between CMT2A and CMTX1 relative to CMT1A. For visual acuity, binocular acuity at 100%, 2.5%, and 1.25% was analyzed. For macular OCT, the superior, inferior, nasal, and temporal quadrants at 3 mm were averaged. Thickness measurements of the right eye and left eye were then averaged for analysis except for 3 subjects who had unilateral epiretinal membranes that limited accurate measurement of total retinal and RNFL thickness; for these subjects, only data from the unaffected eye were used. Statistical analyses were performed using STATA version 15 (College Station, TX), and statistical significance was defined at the P , 0.05 level. METHODS Low-Contrast Acuity We measured high- and low-contrast visual acuity using a protocol previously developed to measure visual dysfunction in multiple sclerosis and Friedreich ataxia (17). Highcontrast acuity was tested both monocularly and binocularly, and low-contrast acuity (2.5% and 1.25%) was tested binocularly using retroilluminated Sloan letter charts (Precision Vision, LaSalle, IL) from a distance of 2 m. The total number of letters correctly identified at each level of contrast was recorded. Contrast acuity was measured by a trained technician, and participants wore their standard refractive correction for distance. Optical Coherence Tomography All subjects underwent nonmydriatic spectral domain OCT imaging of both optic nerves and maculae (Heidelberg SPECTRALIS, Heidelberg, Germany). All scans were 234 RESULTS We included 24 patients with CMT: 9 with CMT1A (7 women and 2 men), 5 with CMT2A (1 woman and 4 men), and 10 with CMTX1 (3 women and 7 men). The median age was 58.0 years (interquartile range: 53.9–71.0), and all but one were Caucasian. The results of binocular high- and low-contrast acuity testing are presented in Figure 1. Median binocular high-contrast (100% contrast) acuity was 54 letters for CMT1A, 55 letters for CMT2A, and 57 letters for CMTX1 (all roughly corresponding to a Snellen equivalent of 20/25). In age- and gender-adjusted linear regression models, there was no difference in high- or low-contrast acuity (2.5% or 1.25% contrast) for CMT2A or CMTX1 compared to CMT1A. However, inspection of the data revealed Hamedani et al: J Neuro-Ophthalmol 2021; 41: 233-238 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Boxplot of binocular high- and low-contrast acuity by CMT subtype. Boxes denote the interquartile range (25th–75th) percentile, with a horizontal line inside each box indicating the median. CMT, Charcot–Marie–Tooth. an outlying individual with CMT2A whose binocular highcontrast acuity was only 9 letters (corresponding to a Snellen equivalent of 20/160) and who was unable to see any letters at 2.5% or 1.25% contrast. Circumpapillary RNFL thickness by CMT subtype is presented in Figure 2. Mean global cpRNFL thickness was 91.9 mm for CMT1A (SD 11.2 mm), 74.6 mm for CMT2A (SD 16.9 mm), and 87.9 mm for CMTX1 (SD 9.9 mm). After adjusting for age and gender, RNFL thickness was lower for CMT2A, borderline globally (adjusted difference 216.5 mm, 95% CI: 233.2 to 0.08) and significantly inferiorly (adjusted difference 228.1 mm, 95% CI: 253.5 to 22.8), but not for CMTX1 (global 23.7, 95% CI: 217.2 to 9.8; inferior 26.3, 95% CI: 226.9 to 14.3) compared to CMT1A. However, inspection of the data again revealed a significant outlier with CMT2A whose global cpRNFL thickness was only 47.5 mm, which corresponded to the individual with 20/160 acuity (Fig. 3). When this outlier was excluded, there was no significant difference in global or quadrant-specific cpRNFL thickness between CMT2A and CMT1A. Macular total retinal, RNFL, and GCL/ IPL thickness are summarized in Table 1. After adjusting for age and gender, there were no significant differences FIG. 2. Boxplot of global and quadrant-specific circumpapillary retinal nerve fiber layer thickness by CMT subtype. Boxes denote the interquartile range (25th–75th) percentile, with a horizontal line inside each box indicating the median. CMT, Charcot–Marie–Tooth; PMB, papillomacular bundle. Hamedani et al: J Neuro-Ophthalmol 2021; 41: 233-238 235 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Circumpapillary retinal nerve fiber layer (RNFL) thinning in a patient with CMT2A and vision loss due to optic atrophy. Spectral domain optical coherence tomographic images acquired in high-speed mode using standard 3.4-mm circle with 12° diameter and automatic RNFL segmentation demonstrate severe bilateral retinal nerve fiber layer thinning predominantly affecting the temporal, superior, and inferior quadrants. OD, right eye; OS, left eye. in average total retinal, RNFL, or GCL/IPL thickness between CMT2A or CMTX1 compared to CMT1A. Given the known association of CMT2A with optic atrophy, we examined these 5 patients in further detail (Table 2). Each CMT2A subject had a unique MFN2 mutation. The subject with optic atrophy (#5) had the second-earliest age of onset and the second-highest CMTES (higher scores mean more severe neuropathy). TABLE 1. Age- and gender-adjusted difference in macular (3 mm) total retinal, RNFL, and GCL/IPL thickness between CMT2A and CMTX1 compared to CMT1A CMT1A CMT2A CMTX1 Mean Difference in Total Thickness (95% CI) Mean Difference in RNFL Thickness (95% CI) Mean Difference in GCL/IPL Thickness (95% CI) Ref 3.8 (234.7 to 42.2) 5.7 (218.4 to 30.0) Ref 21.1 (25.4 to 3.3) 2.1 (20.6 to 4.9) Ref 2.2 (29.4 to 13.9) 4.7 (24.1 to 13.5) GCL, ganglion cell layer; IPL, inner plexiform layer; RNFL, retinal nerve fiber layer. 236 Hamedani et al: J Neuro-Ophthalmol 2021; 41: 233-238 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Clinical, genetic, and OCT characteristics of patients with CMT2A Subject Number 1 2 3 4 5 Optic Atrophy Mutation Age of Onset (yrs) Disease Duration (yrs) CMTES No No No No Yes p.Leu741Trp p.Ala100Ser p.Arg707Trp p.Arg468His p.Arg259Cys 20 25 61 11 16 37 31 11 66 39 15 20 4 14 16 OCT, optical coherence tomography. DISCUSSION In prospectively recruited CMT natural history cohort, we found optic atrophy in only one patient with CMT2A due to different MFN2 mutations. Furthermore, there were no differences in high- and low-contrast acuity or OCT measurements between the remaining CMT2A subjects and a representative sample of subjects CMTX1 and CMT1A. This suggests that optic neuropathy is specific to certain MFN2 mutations in CMT2A and that low-contrast acuity or OCT is of limited value as a disease-wide biomarker. CMT2A is caused by mutations in the Mitofusin 2 gene (MFN2) (18), which encodes MFN2, an intrinsic membrane protein of the outer mitochondrial membrane. MFN2 plays an important role in mitochondrial fusion through its interactions with MFN1 on apposed mitochondrial membrane, and with the OPA1 gene product at the inner mitochondrial membrane (19). OPA1 mutations are the most common cause of dominant optic atrophy (20), so it is not surprising that optic neuropathy occurs in CMT2A due to MFN2 mutations. MFN2 mutations can cause optic atrophy that is indistinguishable from OPA1associated dominant optic atrophy (21), and other features of mitochondrial disease, such as sensorineural hearing loss and leukoencephalopathy, have also been described (22). The one patient with CMT2A and optic atrophy in our cohort had a c.775C.T mutation predicted to cause a p.Arg259Cys change. This mutation has been described in 3 other individuals, all of whom had CMT2A with optic atrophy (6) and is consistent with previous studies that have found optic atrophy repeatedly associated with particular MFN2 mutations (23). Why particular MFN2 mutations cause optic atrophy is not resolved. It does not seem to be only related to the severity of neuropathy: optic neuropathy is reported in cases of severe, early-onset CMT2A (p.Met21Val, p.Arg94Trp, p.Arg94Gln, p.Arg104Trp, p.His361Tyr, p.Arg364Trp, p.Arg364Pro, and p.Glu418ter) as well as milder cases with later disease onset (p.Thr206Ile, p.Asp210Val, p.Arg250Cys, p,Asn276Arg, and p.Thr206Ile). Some mutations (p.Arg94Gln, p.Arg104Trp, p.Thr206Ile, p.Asp210Val, p.Arg250Cys, p.Arg259Cys, and p.Asn276Arg) are in the GTPase domain (residues 103–309), mutations of which have hypothesized to increase the likelihood of central nervous system involvement, including optic neuropathy (21). However, mutations outside Hamedani et al: J Neuro-Ophthalmol 2021; 41: 233-238 the GTPase domain (p.Met21Val, p.Arg94Trp, p.Arg94Gln, p.His361Tyr, p.Arg364Trp, p.Arg364Pro, and p.Glu418ter) also cause optic neuropathy. The p.Asp210Val mutation, which is unusual in that the optic atrophy can begin in early childhood and precede the clinical onset of neuropathy, causes deleterious effects in mitochondria, but it remains to be shown that these defects are the cause of optic neuropathy (21). A limitation of the literature on optic nerve involvement in MFN2 mutations is the lack of systematic assessment of visual acuity and optic nerve structure and morphology. We addressed this limitation by measuring both high- and low-contrast acuity and OCT in all patients with CMT2A. Aside from the one patient with clinically manifest optic atrophy, we did not observe any intermediate or subclinical optic nerve phenotypes, which supports the hypothesis that optic neuropathy in CMT2A is specific to certain MFN2 mutations. We also did not observe any differences between CMT2A, CMT1A, and CMTX1. Our small sample size (especially for CMT2A) limited the detection of small differences in contrast acuity or retinal thickness, and given that mean high- and low-contrast acuity was slightly lower in CMT2A compared to CMT1A and CMTX1, it is possible that large multicenter cohorts will have greater power to detect subtle optic nerve dysfunction in other MFN2 mutations. However, given the lack of clear difference in cpRNFL or macular RNFL or GCL/IPL thickness (which have much less variability than low-contrast acuity), we think that this is unlikely and that optic neuropathy is not a feature of CMT1A, CMTX1, or most CMT2A patients. Although lowcontrast acuity and OCT may be useful for investigating specific MFN2 mutations when there is an a priori suspicion of optic nerve disease (including genetic carriers who have a relative with CMT2A and optic atrophy), we do not advocate for their use as a research biomarker for CMT2A as a whole or other inherited neuropathies. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. G. Hamedani, R. A. Avery, and S. S. Scherer; b. Acquisition of data: A. G. Hamedani and J. A. Wilson; c. Analysis and interpretation of data: A. G. Hamedani. Category 2: a. Drafting the manuscript: A. G. Hamedani; b. Revising it for intellectual content: A. G. Hamedani, R. A. Avery, and S. S. Scherer. Category 3: a. Final approval of the completed manuscript: A. G. Hamedani, J. A. Wilson, R. A. Avery, and S. S. Scherer. 237 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution REFERENCES 1. Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet. 1974;6:98–118. 2. Rossor AM, Polke JM, Houlden H, Reilly MM. Clinical implications of genetic advances in Charcot-Marie-Tooth disease. Nat Rev Neurol. 2013;9:562–571. 3. 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