Absent Foveal Avascular Zone in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Gour Wang, MD Absent Foveal Avascular Zone in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay Vivian Paraskevi Douglas, MD, DVM, MBA, Konstantinos A. A. Douglas, MD, DVM, MBA, John B. Miller, MD, Eric D. Gaier, MD, PhD A utosomal recessive spastic ataxia of CharlevoixSaguenay (ARSACS) is an inherited neurodegenerative disorder characterized by early onset ataxia, spasticity, amyotrophy, and dysarthria. Ophthalmic manifestations of ARSACS include nystagmus, oculomotor neuropathies, macular microcysts, and increased thickness of the inner retinal layers (1–3). Although the pathogenesis of ARSACS has been attributed to mitochondrial dysfunction, the pathophysiology of the hallmark funduscopic changes remains unclear (1–3). Optical coherence tomographic angiography (OCT-A) is a recently developed technology that allows for noninvasive imaging of the retinal and choroidal microvasculature. Application of OCT-A to macular and neuroophthalmic disease has uncovered new insights in many diseases of the posterior pole. In this article, we used OCT-A to gain new insights into the hallmark funduscopic findings in ARSACS. A 19-year-old French Canadian man with a history of ARSACS and pathogenic compound heterozygous mutations in the SACS gene [c.4744G.A (p.Asp1582Asn); c.7205_7206delTT (p.Leu2402Argfs*6)] was referred by his neurologist for evaluation of visual function. The patient denied any changes or difficulty with his vision. He had a long-standing history of spasticity and peripheral neuropathy consistent with a generalized sensorimotor polyneuropathy with mixed axonal and demyelinating features on previous electromyography. MRI of the brain had demonstrated linear striations within the pons, atrophic changes of the cerebellar vermis, and a retrocerebellar arachnoid cyst. Harvard Retinal Imaging Lab (VPD, KAAD, JBM), Boston, Massachusetts; Department of Ophthalmology (VPD, KAAD, JBM, EDG), Harvard Medical School, Boston, Massachusetts; Retina Service (JBM), Massachusetts Eye and Ear, Boston, Massachusetts; Department of Ophthalmology (EDG), Boston Children’s Hospital, Boston, Massachusetts; and Department of Brain and Cognitive Sciences (EDG), Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts. Supported by E. D. Gaier: NIH K08 EY030164. The authors report no conflicts of interest. Address correspondence to Eric D. Gaier, MD, PhD, Assistant Professor of Ophthalmology, Pediatric Neuro-Ophthalmology Service, Pediatric Ophthalmology and Adult Strabismus, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115; E-mail: [e-mail] e166 On examination, best-corrected visual acuities (Snellen) were 20/20-2 in the right eye and 20/25 in the left eye without dyschromatopsia. Examination of the pupils revealed normal and symmetric responses to light. There was conjugate, right-beating nystagmus on right gaze and subtle left-sided appendicular ataxia, consistent with asymmetric cerebellar disease. Automated static perimetry (Humphrey 24-2, SITA) showed diffuse mild reductions in sensitivity for the right and left eyes with mean deviations of 22.91 and 23.66 dB, respectively. Dilated funduscopy revealed thickened peripapillary nerve fibers in both eyes (Fig. 1A). OCT quantitatively confirmed the increased thickness of the retinal nerve fiber layer (RNFL) in both eyes (Fig. 1B, C). OCT of the macula revealed dentate thickening of the inner retina that was most prominent in the peripapillary macula in both eyes (Fig. 2A, B). OCT-A of the optic nerve head showed prominence of the peripapillary retinal vasculature and increased retinal capillary density in both eyes (Fig. 2C, D). OCT-A of the macula showed absence of the foveal avascular zone (FAZ) in both eyes (Fig. 2E, F). Segmentation of the choroid and choriocapillaris for the peripapillary region and macula, respectively, showed no abnormalities (not shown). ARSACS, first described in 1978 in the CharlevoixSaguenay region of Quebec, is a slowly progressive neurodegenerative disorder with the characteristic ophthalmic finding of increased peripapillary inner retinal thickness (1–3). Visual function is relatively well preserved with typically only mild diffuse deficits on visual field testing. Increased retinal nerve fiber thickness, previously mischaracterized as myelinated nerve fiber layer, is a hallmark of ARSACS (1–3). Neurodegenerative ataxias sharing clinical overlap with ARSACS, including Friedreich’s ataxia and spinocerebellar ataxia Types 1–3, 6, and 7, are characterized by normal or thin RNFL measurements (1). Thus, the characteristic fundus finding in ARSACS holds a diagnostic value. Not all patients with ARSACS demonstrate clinically appreciable increased nerve fiber thicknesses (3). If confirmed in other patients with ARSACS, the finding of an absent FAZ by OCT-A may be an even more specific diagnostic testing result to implicate ARSACS in the differential diagnosis of ataxia. Douglas et al: J Neuro-Ophthalmol 2021; 41: e166-e168 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Increased peripapillary retinal nerve fiber layer (RNFL) thickness in a patient with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). A. Fundus photographs of the right and left eyes, respectively (Topcon, Oakland, NJ). B, C. Optical coherence tomography (OCT; Cirrus, Carl Zeiss Meditec, Inc, Dublin, CA) of the peripapillary retinal nerve fiber layer (RNFL) with depictions of thickness heat maps for the right and left eyes, respectively, (B), and thickness for both eyes plotted as a function of disc sector (C). The case presented in this article also serves as an example of how OCT-A can provide valuable insights into ocular and/or systemic disorders beyond what was previously possible with dilated fundus examination and standard OCT. Absence of the FAZ is not unique to ARSACS, as it has been demonstrated in the context of foveal hypoplasia associated with aniridia and albinism. Shah et al (4) described “foveal hypoplasia” in a 14-year-old boy with presumed ARSACS, referring to attenuation of the normal foveal depression. Importantly, true foveal hypoplasia causes significant impairment in central visual acuity, whereas ARSACS does not. One might attribute this finding to the accompanying increased thickness of the peripapillary inner retinal layers (4). However, the increased inner retinal thickness typically does not track into the fovea (Fig. 2A, B insets). Disruption of normal foveal architecture in FIG. 2. OCT-A findings in a patient with ARSACS. A, B. En face OCT images of the right (A) and left (B) eyes (RTVue-XR Avanti; Optovue, Fremont, CA). Insets below depict horizontal macular B-scan OCT images taken through the fovea (Zeiss). C, D. OCT-A (Optovue) 6 x 6 mm images with retinal segmentation centered on the right (C) and left (D) optic discs. Insets below depict corresponding B-scan images with anterior and posterior retinal segmentation boundaries (red). E, F. OCT-A 8 · 8 mm images with retinal segmentation centered on the fovea for the right (E) and left (F) eyes. Insets below depict corresponding B-scan images with the posterior retinal segmentation boundary (red). OCT-A, Optical coherence tomography angiography. Douglas et al: J Neuro-Ophthalmol 2021; 41: e166-e168 e167 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence patients with ARSACS may instead result from maldevelopment rather than crowding by a thickened inner retina (4). The absent FAZ on OCT-A presented for the first time in this article supports this hypothesis because crowding by thickened inner retina would not be expected to alter the foveal vasculature once developed. This finding also raises the possibility that microvascular changes could be present in other areas of the brain and may play a role in the pathophysiology of ARSACS. ARSACS is caused by loss-of-function mutations in the SACS gene, which encodes sacsin (5). Sacsin is highly expressed in cerebellar Purkinje cells and shows predominantly cytoplasmic and mitochondrial localization. Sacsin dysfunction in mice and ARSACS patients results in an abnormally interconnected mitochondrial network, possibly secondary to disrupted mitochondrial fission (5). Transport of mitochondria in cultured hippocampal neuronal dendrites is impaired in sacsin knockout mice (5). Sacsin knockout also reduces the number of dendrites, and dendritic arbors are thicker and disorganized (5). Although changes to axonal morphology were not evaluated in this study, the morphologic changes in dendrites parallel those in retinal ganglion cell axons that is observed funduscopically in ARSACS patients (2). No pathologic analyses of the retina have been reported in ARSACS, limiting our ability to further characterize the nature of nerve fiber layer thickening and to assess mitochondrial localization and network morphology. Experiments aimed at characterizing the retinal morphologic changes in ARSACS and/or sacsin deficient mice are needed. Given our ability to image and e168 pharmacologically and genetically manipulate retinal ganglion cells in vivo using intravitreal injections in mice, a focus on retinal ganglion cells in the context of sacsin dysfunction would significantly advance our understanding of ARSACS pathophysiology (5). In conclusion, we present a novel OCT-A finding of absent FAZ in a patient with ARSACS that supports maldevelopment as the mechanism for disrupted foveal architecture and may suggest microvascular changes in ARSACS pathophysiology. Further study will reveal whether OCT-A could serve as an additional noninvasive diagnostic tool in the evaluation of ataxia. 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