Neuro-Ophthalmic Phenotype of OPA3

Background: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. Methods: Nine patients underwent meticulous visual function history and medical documents' review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. Results: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer-inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. Conclusions: This study compiled data regarding neuro-ophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Neuro-Ophthalmic Phenotype of OPA3 Ruth Huna-Baron, MD, Gilad Yahalom, MD, Yair Anikster, MD, PhD, Bruria Ben Zeev, MD, Chen Hoffmann, MD, Sharon Hassin-Baer, MD Background: Type III 3-methylglutaconic aciduria (OPA 3) is a neuro-ophthalmologic syndrome consisting of early-onset bilateral optic atrophy. Since Costeff described the phenotype of 19 patients in 1989, several reports described approximately 50 patients, but most of them lack details about neuro-ophthalmic phenotype. Our aim was to characterize the clinical neuro-ophthalmic phenotype of this syndrome. Methods: Nine patients underwent meticulous visual function history and medical documents’ review. Results of best-corrected visual acuity (VA), color vision, visual field (VF), ocular motility, pupillary reaction, slit-lamp, and dilated fundus examinations were recorded. Optical coherence tomography (OCT) was performed whenever possible. Results:: The average VA was 1.4 ± 0.8 logarithm of the minimum angle of resolution. Poor vision was the presenting symptom in 5 patients. Six patients had decreased VA and variable degrees of optic atrophy. Humphrey VF testing of 7 patients revealed generalized depression in 5 and a cecocentral defect in 2. All patients demonstrated dysmetric saccades. Four patients had strabismus, 3 with exotropia, and one with esotropia. Seven patients had nystagmus. Ocular motility abnormality is possibly the result of cerebellar atrophy that was found in MRI studies of our patients. OCT of the retina was possible in 6 patients and revealed retinal nerve fiber layer (RNFL) thinning as well as average retinal thinning. Three patients, in whom ganglion cell layer– inner plexiform layer (IPL) measurement was possible, also showed diffused thinning. Neuro-Ophthalmology Unit (RH-B), Goldschleger Eye Institute Chaim Sheba Medical Center, Tel-Hashomer, Israel; Department of Neurology (GY, SH-B), Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Israel; Movement Disorders Clinic and Department of Neurology (GY), Shaare Zedek Medical Center, Jerusalem, Israel; Metabolic Disease Unit Edmond and Lily Safra Children’s Hospital (YA), Chaim Sheba Medical Center, TelHashomer, Israel; Pediatric Neurology Unit (BBZ), Edmond and Lily Safra Children’s Hospital, Chaim Sheba Medical Center, TelHashomer, Israel; Radiology Department (CH), Chaim Sheba Medical Center, Tel-Hashomer, Israel; and Sackler Faculty of Medicine (RH-B, YA, BBZ, CH, SH-B), Tel-Aviv University, Tel-Aviv, Israel. G. Yahalom received consultation fee from AbbVie Inc. The remaining authors report no conflicts of interest. Address correspondence to Ruth Huna-Baron, MD, NeuroOphthalmology Unit, Goldschleger Eye Institute, Chaim Sheba Medical Center, Tel-Hashomer, Israel 5266202; E-mail: [e-mail] Huna-Baron et al: J Neuro-Ophthalmol 2022; 42: e147-e152 Conclusions: This study compiled data regarding neuroophthalmic manifestation of OPA 3 Type III patients. Contrary to established literature, poor vision was the presenting symptom in only 50% of our patients. This is the first report of OCT findings in 3MGA patients. The results demonstrated diffused thinning of the RNFL and ganglion cell complex-IPL with correlation to VA, which is in contrast to OPA1 patients in whom the most severe thinning is at the level of the papillomacular bundle. Average retinal thinning was identified at second and third decades of life, possibly resulting from early ganglion cell loss. These results may contribute to visual prognosis, and OCT may help monitor experimental therapies. Journal of Neuro-Ophthalmology 2022;42:e147–e152 doi: 10.1097/WNO.0000000000001249 © 2021 by North American Neuro-Ophthalmology Society C osteff syndrome (CS) is an autosomal recessive inherited disorder (OMIM #258501), originally described in patients of Iraqi-Jewish origin. CS is associated with increased urinary excretion of 3-methylglutaconic acid (3-MGA) (1,2). The disease manifests in early childhood with bilateral optic atrophy and later, usually in the second decade of life, coupled with motor deficits, including mainly spastic paraparesis, choreoathetosis, and ataxia (1,3). In 1997, Nystuen et al (4) demonstrated linkage to chromosome 19q13.2-q13.3 and, in 2001, Anikster et al identified mutation c.143-1G . C variant in DNA samples obtained from Iraqi-Jewish patients with CS. This intron 1 acceptor splice-site mutation has been shown to abolish production of the mRNA of the OPA3 gene (5,6). To date, the function of the OPA3 protein, which is 179 amino acids long, is yet unknown, as are the metabolic basis and pathophysiology of CS. Several studies demonstrated that the OPA3 protein localized to the mitochondrial inner membrane produced both direct and indirect evidence of involvement of mitochondrial dysfunction in this disorder (7,8). Since Costeff et al first described the phenotype of 19 patients with CS in 1989 (3), several reports described approximately 50 patients, including recent reports from e147 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Demographic, clinical, and OCT findings Patient Age (y)/sex Visual Acuity Color Vision 1 2 3 4 5 6 7 8 9 20/F 30/F 33/F 37/F 57/M 21/M 33/F 69/F 42/M 20/100 20/1,000 20/400 20/400 20/5,000 20/32 20/5,000 20/1,000 20/80 0/12 0/12 NA 0/12 NA 4/12 NA NA 0/12 Strabismus Nystagmus Optic Disc RNFL/GCC (mm) Average Retinal Thickness (mm) ET — + + + + + 2 + + 2 2 3 3 3 3 1 3 3 2 NA 48/38 NA NA NA 60/53 NA NA 60/52 183 237 157 216 NA 234 NA NA 254 — XT — XT XT — ET, esotropia; F, female; GCC, ganglion cell complex; M, male; NA, not available; OCT, optical coherence tomography; Optic disc, 1, temporal pallor, 2, mild pallor, 3, severe atrophy; RNFL, retinal nerve fiber layer; XT, exotropia; y, years; mm, micrometer. our medical center (1,2,9–12). These reports, however, lack details about the neuro-ophthalmic phenotype, specifically in association with visual field (VF), ocular motility, MRI, and optical coherence tomography (OCT), as well as longitudinal information. Our study was designed to better characterize the neuro-ophthalmic phenotype of CS. METHODS The study patients were evaluated at the neuro-ophthalmology unit as part of an ongoing clinical and natural history study of CS. The neurologic and cognitive manifestations of CS were recently reported in detail as part of a clinical and natural history study of the syndrome (11,12). The comprehensive neuro-ophthalmic evaluations included meticulous visual function history and review of the medical documents. Bestcorrected visual acuity (VA) was measured using Snellen chart. Color vision evaluation was performed by Ishihara pseudoisochromatic plate 24-plate edition of the Ishihara test book published in 1997 by Kanehara & Co, Ltd (Tokyo, Japan), and scored by the number of plates identified out of the first 12 screening plates. VF testing was performed using Humphrey computerized VF 24-2 stimulus V when III could not be performed due to low VA. In addition, the findings of ocular motility, pupillary reaction, slit-lamp biomicroscopy, and dilated fundus examination were recorded. OCT was performed using Cirrus HD-OCT (Carl Zeiss Meditec, Inc, Dublin, CA) unless it was precluded by the patient’s poor fixation. Consenting patients underwent MRI in 1.5‐Tesla system (GE Healthcare Technologies, Milwaukee, WI). All patients signed informed consent, and the study was approved by the Sheba Medical Center’s Institutional Review Board. Data were analyzed using a Student t test. All statistical tests were 2-sided, and those with a P value ,0.05 were considered significant. Data are expressed as mean ± SD. The relationships between the patient’s age and VA, neurological manifestation, and OCT results were assessed with Pearson’s correlations. No multivariate analysis was applicable due to the small sample size. RESULTS Demographics Nine patients (6 females and 3 males) aged 20–68 years (mean38 ± 20 years) comprised the study group. Two patients were siblings (Table 1, Patients #3 and #4). All were of Iraqi FIG. 1. Visual acuity (LogMAR) and age at evaluation. LogMAR, logarithm of the minimum angle of resolution. e148 Huna-Baron et al: J Neuro-Ophthalmol 2022; 42: e147-e152 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Mild temporal pallor. B. Mild diffuse pallor. C. Diffuse atrophy. origin, and they all had urinary methylglutaconic aciduria. Eight patients who underwent molecular diagnosis were found to harbor the previously described c.143-1G . C mutation in a homozygous state (5). Demographic and clinical data are presented in Table 1. Three patients had other systemic conditions: one patient (Table 1. #7) had hypothyroidism, another patient had (Table1. #8) atrial fibrillation, and one patient (Table 1. #5) had hypertension and hypercholesterolemia. All 9 patients denied alcohol abuse and 2 reported light smoking. The educational status range was 8–18 years (mean 11.6 ± 2.3 years), and 7 were unemployed due to their motor and vision disability. Five were single, 2 were married with no children, 1 was married with 3 children, and 1 was divorced with 3 children. Vision and Ocular Assessment The presenting symptom was poor vision in 5 patients and motor developmental delay in the other 4 patients. The mean VA for the group was 1.4 ± 0.8 LogMAR, which corresponds to an approximate Snellen VA of 20/500 (range 0.2–2.5 LogMAR). The mean difference between eyes was 0.05 LogMAR. Refraction was mild myopia (#22.00) in 5 patients and plano in 2 others. Two of the patients could not be refracted due to coarse nystagmus. VA correlated with age, possibly implying slow progression over time (Fig. 1). Data on VA from past medical records were available for 3 patients (Table 1 Patients #2, #6, and #9) and demonstrated deterioration of 0.1 LogMAR during a period of 15–20 years (Patients #6 and #9) and deterioration of 0.9 LogMAR in Patient #2. Two patients (#1 and #8) were followed for 1 and 6 years, respectively, without change in VA. Color vision testing was possible only in 5 patients due to poor VA; among them, 4 patients recognized only the Ishihara control plate and the one with the best VA recognized 4 plates out of 12. Seven patients underwent the Humphrey VF test, and the results revealed generalized depression in 5 and a cecocentral defect in 2. The average mean deviation of the 3 patients who underwent the stimulus III test was 14.5 ± 4.5 dB in the right eye and 17.6 ± 6.0 dB in the left eye. There was no correlation between VA and other neurologic manifestations, such as ataxia and pyramidal involvement. There was some correlation between ambulation and VA (R = 0.5, P = 0.1), as could be expected for visually compromised persons. The mean intraocular pressure was 14.4 ± 2.4 mm Hg (range 10–18 mm Hg). The 2 oldest patients (age 57 and 69 years) had nuclear sclerosis cataract. FIG. 3. Diffuse thinning of ganglion cell and inner plexiform layer (GCC–IPL). Huna-Baron et al: J Neuro-Ophthalmol 2022; 42: e147-e152 e149 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Visual acuity (LogMAR) and average retinal thickness by optical coherence tomography in micrometers (mm). LogMAR, logarithm of the minimum angle of resolution. Fundus examination revealed optic disc temporal pallor in one 21-year-old patient who had a relatively good VA of 0.6 LogMAR (Fig. 2A), general mild pallor in 2 patients (Fig. 2B), and severe atrophy in the rest (Fig. 2C). No overt retinal abnormality was detected in any of the patients. All the study patients demonstrated unsmooth pursuit and dysmetric saccades. Seven patients had manifest binocular conjugate horizontal nystagmus, 4 had strabismus, 3 had large angle comitant exotropia, and 1 had comitant esotropia of 8 prism diopter. thinning of average retinal thickness was found in all 6. This thinning correlated with VA, R = 20.65 (P = 0.05) (Fig. 4). Table 1 lists the OCT values of the right eye of each testable patient. The average difference between the 2 eyes was 6.5 mm (range 3–18 mm). The MRI performed on 5 patients showed chiasmal thinning and cerebellar atrophy (Fig. 5), with no evidence of white matter abnormality. Optic nerve thinning was observed on 3 patients who underwent orbital MRI scans, and extraocular muscle atrophy was also noted in 1 of those patients. Ancillary Tests OCT testing was partially possible in 6 patients due to poor fixation in the other 3. Retinal nerve fiber layer (RNFL) and ganglion cell complex–inner plexiform layer (GCC–IPL) could be accurately measured in only 3 of those 6 patients, and it demonstrated thinning of the RNFL (mean 53 ± 5 mm) and diffuse thinning of (GCC–IPL; mean 48 ± 6 mm) (Fig. 3). Foveal retinal thickness and average retinal thickness were measured in 6 patients, and thinning of foveal thickness was demonstrated in 3 patients, whereas DISCUSSION There are scant data on the characteristics of the clinical neuroophthalmic phenotype of CS. This study compiled information on neuro-ophthalmic manifestations of OPA 3 type III of 9 patients. This syndrome is called optic atrophy plus, but low vision was the presenting symptom in only 5 of the 9 patients in this group. VA is affected with great variability and seems to have some correlation with age, as demonstrated in Figure 1. Six FIG. 5. A. T2 coronal MRI with chiasmal thinning (black arrow). B. T1 sagittal MRI with cerebellar atrophy (white arrow). e150 Huna-Baron et al: J Neuro-Ophthalmol 2022; 42: e147-e152 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution of the 9 study patients were legally blind, while the VAs of the other 3 were mildly affected. Although longitudinal information on VA was available for only 3 patients, it would appear that their disease progression is very slow, as seen in both Figure 1 and from the analysis of the patients’ documents. Information on VA that spanned 2-3 decades was available for 3 patients: 1 sustained significant deterioration of 0.9 LogMAR (9 lines) over a period of 16 years, and there was a worsening of 0.1 LogMAR (1 line during 15 and 26 years) in the other 2. Dilated fundi examinations revealed variable degrees of optic atrophy, as previously reported (1–3). The ocular movement evaluation revealed the presence of nystagmus, as had also been reported earlier (1–3) in 78% of our study patients. The conjugate binocular horizontal nystagmus in adults may result from a combination of poor vision and cerebellar abnormality. In the MRI of 4 patients with nystagmus, both chiasmal and cerebellar atrophy were observed. Pursuit and saccade abnormalities had not been detailed in previous reports, and 4 (44%) of our patients had some sort of strabismus compared with a 4% prevalence in the general population (13). Because comitant exotropia was seen in 3 patients with the worst VA, we may assume that this is sensory exotropia. The cause for this phenotypic variability is unclear because the 8 patients tested were all known to be carriers of the c.143-1G . C mutation. The exact role of OPA3 in mitochondrial metabolism is still unknown, and advances in mitochondrial research may shed light on this issue (8). We succeeded in quantitatively evaluating the VF by means of computerized VF testing, which was not described before (1–3). This is also the first report of OCT findings in 3-MGA patients. The average retinal thickness of 6 patients, in whom accurate measurement could be obtained, demonstrated thinning that correlated with VA and probably represents atrophy of the retinal ganglion cell. This could be evaluated directly only in 3 patients who managed to undergo reliable RNFL and GCC–IPL measurements. The results demonstrated diffuse thinning of the RNFL and the GCC–IPL, with correlation to VA. The GCC–IPL diffuse thinning is different than that described in OPA1 patients in whom the thinning is most severe at the level of the papillomacular bundle (14–16). No correlation was found between VA and other neurologic manifestations, such as ataxia and pyramidal involvement, further emphasizing the variability of the phenotype. Cerebellar and chiasmal atrophy were observed in our patients’ MRIs, in contrast to earlier reports of normal MRI findings by others (1–3). This is in line with the reports on patients with dominant optic atrophy whose MRIs were reported as being normal or as demonstrating optic nerve atrophy (17). Contrary to the lack of white matter changes in our patients, bilateral small-vessel ischemic white matter changes were found by Yu-Wai-Man in their OPA1 patients (18). The phenotype variability in the same mutation warrants further study using advanced OCT and MRI Huna-Baron et al: J Neuro-Ophthalmol 2022; 42: e147-e152 methodologies aimed at finding correlations between structure, function, and molecular correlation. Similarly, OCT may help in the monitoring of experimental therapies when they become available, and the results may assist in predicting prognosis of young patients. Our study has several limitations. The small number of patients in the study group and the even smaller number of patient undergoing VF and OCT precluded our ability to establish putative genotype–phenotype correlations. Nevertheless, we were able to provide a comprehensive analysis of the afferent and efferent visual systems in CS (OPA3 Type III) by OCT and MRI when possible. Retinal thinning, possibly resulting from the ganglion cell loss also found in OPA1, was identified even at the second and third decades of life of patients with CS. These results provide novel data that may contribute to our ability to estimate visual prognosis. Finally, OCT may add valuable information to help in the monitoring of experimental therapies for CS. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. Huna-Baron, G. Yahalom Y. Anikster, B. Ben Zeev, C. Hoffmann, and S. Hassin-Baer; b. Acquisition of data: R. Huna-Baron, G. Yahalom, Y. Anikster, B. Ben Zeev, C. Hoffmann, and S. Hassin-Baer; c. 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