Henry, Matt

Kitchens, John

Maldonado, Ramiro S.

Pascual, Juan M.

English

University of Kentucky

University of Kentucky UKnowledge Ophthalmology and Visual Science Faculty Publications Ophthalmology and Visual Science 8-1-2020 GLUT1 Deficiency: Retinal Detrimental Effects of Gliovascular Modulation Matt Henry The University of Texas Southwestern Medical Center John Kitchens University of Kentucky Juan M. Pascual The University of Texas Southwestern Medical Center Ramiro S. Maldonado University of Kentucky, Ramiro.Maldonado@uky.edu Follow this and additional works at: https://uknowledge.uky.edu/ophthalmology_facpub  Part of the Medical Physiology Commons, Neurology Commons, and the Ophthalmology Commons Right click to open a feedback form in a new tab to let us know how this document benefits you. Repository Citation Henry, Matt; Kitchens, John; Pascual, Juan M.; and Maldonado, Ramiro S., "GLUT1 Deficiency: Retinal Detrimental Effects of Gliovascular Modulation" (2020). Ophthalmology and Visual Science Faculty Publications. 17. https://uknowledge.uky.edu/ophthalmology_facpub/17 This Article is brought to you for free and open access by the Ophthalmology and Visual Science at UKnowledge. It has been accepted for inclusion in Ophthalmology and Visual Science Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact UKnowledge@lsv.uky.edu. GLUT1 Deficiency: Retinal Detrimental Effects of Gliovascular Modulation Digital Object Identifier (DOI) https://doi.org/10.1212/nxg.0000000000000472 Notes/Citation Information Published in Neurology: Genetics, v. 6, no. 4. Copyright © 2020 The Author(s) This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. This article is available at UKnowledge: https://uknowledge.uky.edu/ophthalmology_facpub/17 CLINICAL/SCIENTIFIC NOTES OPEN ACCESSGLUT1 deficiencyRetinal detrimental effects of gliovascular modulationMatt Henry, MD, John Kitchens, MD, Juan M. Pascual, MD, PhD, and Ramiro S. Maldonado, MDNeurol Genet 2020;6:e472. doi:10.1212/NXG.0000000000000472CorrespondenceDr. Maldonadoramiro.maldonado@uky.eduMost patients with glucose transporter type 1 (GLUT1) deficiency syndrome (G1D) experienceanticonvulsant-refractory epilepsy and abnormal cognitive and motor development.1 Ninetypercent of patients withG1Dharbor a causative loss-of-functionmutation in the SLC2A1 gene; inthe others, brain fluorodeoxyglucose (FDG) PET can confirm the diagnosis.G1D investigation has centered on the cerebral aspects of the disease, but extracerebral mani-festations are plausible.1 The eye is a likely substrate: retinal GLUT1 sustains ocular glucosetransport based on its expression in Müller, vascular endothelial, and pigmentary epithelial cells.Notably, GLUT1 is a target for diabetic retinopathy drugs.2,3 We describe retinal abnormalities ina patient with G1D in the broader context of the plausible mechanisms and consequences ofretinal GLUT1 loss of function or therapeutic inhibition.Case reportA 20-year-old woman with the common epileptic form of G1D reported subnormal visual acuityuncorrectable with glasses and harbored a de novo pathogenic SLC2A1 variant (c.1454C>T;P485L).1,4 The mutation introduced a dileucine motif in GLUT1 associated with clathrin re-cruitment and excessive internalization of cell membrane GLUT1.5Her visual acuity was 20/40 (OD) and 20/30 (OS) with no other obvious ocular abnormalities.Optical coherence tomography (OCT) revealed retinal thinning in the posterior pole respectingthe fovea (figure 1, A and B) and absence of the interdigitation band peripherally with moderatephotoreceptor layer thinning (figure 1, C and D). Swept source OCT demonstrated significantchoroidal thickening (571 and 495 μm in the OD and OS, respectively; normal for age:;330–400 μm). Retinal fundus autofluorescence (FAF) demonstrated hyperautofluorescenceoutside the fovea and an unusual hyperautofluorescence in the central fovea (figure 1, E and F).OCT-angiography (OCTA) showed a paucity of perimacular vessels (figure 1, G and H).There were functional correlates to these findings, including multiple D-15 Farnsworth colortesting defects in the protan axis bilaterally and suppressed cone flicker amplitudes with normalrod system electroretinography (ERG) responses (figure e-1, links.lww.com/NXG/A276). Re-peat testing over 1 year was invariant.DiscussionOur patient with G1D exhibited structural and functional retinal dysfunction. The retinal changeswere congruent across all imaging modalities: the retinal thinning noted on macular colorthickness maps correlated with the hyperautofluorescence on FAF and with the area of reducedFrom the University of Kentucky College of Medicine (M.H.); Retina Associates of Kentucky (J.K.), Lexington; Rare Brain Disorders Program (J.M.P.), Department of Neurology andNeurotherapeutics, Department of Physiology (J.M.P.), Department of Pediatrics (J.M.P.), Eugene McDermott Center for Human Growth & Development/Center for Human Genetics(J.M.P.), The University of Texas Southwestern Medical Center, Dallas; and Ophthalmic Genetics Program (J.K., R.S.M.), Department of Ophthalmology, University of Kentucky,Lexington.Go to Neurology.org/NG for full disclosures. Funding information is provided at the end of the article.The Article Processing Charge was funded by The GLUT1 Foundation.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloadingand sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1vessel density on OCTA. Together with the thickened choroidand decreased cone flicker, the simplest interpretation of ourfindings is early onset photoreceptor degeneration.In the retina, Glut1-mediated transport occurs across capil-lary endothelial cells of the inner blood-retinal barrier andthe retinal pigment epithelium (RPE). This implies that ourpatient’s de novo somatic (and therefore uniformly vascularand glial because there is no reason to suspect mosaicism)mutation exerts secondary consequences on neurons (whichare largely devoid of GLUT1). This likely stems from re-duced glucose (or another mediator) flux across retinal celltypes.Modest GLUT1 expression changes are functionally relevant:increased renal GLUT1 has deleterious consequences in di-abetic nephropathy.6 Conversely, GLUT1 small interferingRNAs (siRNAs) reduce retinal glucose and ameliorate di-abetic retinopathy, which is accompanied by reduced ERGsignal amplitude and outer nuclear layer thinning.3 This isanalogous to our patient’s diminished cone flicker amplitudeand retinal thickness. Furthermore, diabetic mice exhibit in-creased RPE GLUT1 expression after prolonged exposure tohyperglycemia and hypoxia. The resulting elevated RPE glu-cose can be associated with impaired pigment epithelium-derived (PEDF) secretion, leading to imbalanced vascularendothelial growth factor (VEGF)/PEDF and stimulatedneovascularization.3 Our patient exhibited reduced capillarydensity, which may reflect altered VEGF/PEDF release as indiabetic retinopathy.Some diabetic retinopathy therapies target GLUT1, in-cluding angiotensin-converting enzyme inhibitors such ascaptopril. This occurs, in part, via decreased retinal glucoseafter the reduction of GLUT1-mediated glucose transport(despite unaltered GLUT1 expression). Intraocular siRNAdiminishes GLUT1 expression in the inner blood-retinalbarrier of streptozotocin-diabetic mice and decreases retinalglucose.3 Last, GLUT1 inhibition by forskolin or genistein indiabetic mice leads to similar results. In all these contexts,retinal glucose decreases after treatment, suggesting thatGLUT1 inhibition can counteract the end result of multi-factorial diabetic retinopathy.However, GLUT1 inhibition may be detrimental to photo-receptor and RPE cells. In mice, reduction of RPE glucosevia GLUT1 knockout results in outer segment shortening,photoreceptor cell death, and Müller cell activation. Thisunderscores the importance of near-constant GLUT1 ac-tivity in the retina.7 Our findings suggest that these experi-mental observations are likely relevant in humans,suggesting that therapeutic GLUT1 inhibition may result inundesired effects.ConclusionsOur case demonstrates the contribution of nonneural GLUT1to retinal cell (including photoreceptor) activity and vision.Although diabetic retinopathy therapies that inhibit GLUT1are plausible, this inhibition may be detrimental. This casealso illustrates the value of retinal assessment in G1D and inthose receiving GLUT1-related diabetes therapies.Figure 1 Retinalmultimodal imaging in apatientwithGLUT1deficiency(A and B) Optical coherence tomography (OCT) total macular color thick-nessmaps (in microns) showing marked retinal thinning (blue-purple area)outside the fovea in the right and left eyes, respectively. (C andD)OCT b-scansat the foveal centers demonstrate thickened retinal pigment epithelial layerinterdigitation bands (red arrows) only at the foveal centers; the bands dis-appear in the periphery of the scans. (E and F) Wide-field fundus auto-fluorescence (FAF) images of the right and left eye, respectively, showingincreased FAF in the perifoveal area corresponding to the area of retinalthinning depicted in (A and B). Note that the fovea demonstrates subtle butabnormal hyperautofluorescence centrally; this area normally shows hypo-autofluorescence because of macular pigment AF blockage. (G and H) OCTangiography (OCTA) of the superficial capillary plexus demonstrates de-creased perimacular vessel density. (A–F) See figure e-2 (links.lww.com/NXG/A276) for comparison of all images to those of a normal subject.2 Neurology: Genetics | Volume 6, Number 4 | August 2020 Neurology.org/NGAcknowledgmentThe authors acknowledge the collaboration of the patientdescribed and her legally consenting family. The support ofthe Glucose Transporter Type 1 Deficiency Foundation andof the NIH (grant NS077015 to J.M.P.) is also acknowledged.Study fundingSupported by Glut1 Deficiency Foundation.DisclosureThe authors report no disclosures relevant to the manuscript.Go to Neurology.org/NG for full disclosures.Publication historyReceived byNeurology: Genetics January 16, 2020. Accepted in final formJune 1, 2020.References1. Pascual JM, Ronen GM. Glucose transporter type I deficiency (G1D) at 25(1990–2015): presumptions, facts, and the lives of persons with this rare disease.Pediatr Neurol 2015;53:379–393.2. Calado SM, Alves LS, Simao S, Silva GA. GLUT1 activity contributes to the im-pairment of PEDF secretion by the RPE. Mol Vis 2016;22:761–770.3. You ZP, Zhang YL, Shi K, et al. Suppression of diabetic retinopathy with GLUT1siRNA. Sci Rep 2017;7:7437.4. Slaughter L, Vartzelis G, Arthur T. New GLUT-1 mutation in a child with treatment-resistant epilepsy. Epilepsy Res 2009;84:254–256.5. Meyer K, Kirchner M, Uyar B, et al. Mutations in disordered regions can cause diseaseby creating dileucine motifs. Cell 2018;175:239–253.e17.6. Heilig CW, Liu Y, England RL, et al. D-glucose stimulates mesangial cellGLUT1 expression and basal and IGF-I-sensitive glucose uptake in ratmesangial cells: implications for diabetic nephropathy. Diabetes 1997;46:1030–1039.7. Swarup A, Samuels IS, Bell BA, et al. Modulating GLUT1 expression in retinalpigment epithelium decreases glucose levels in the retina: impact on photo-receptors and Muller glial cells. Am J Physiol Cell Physiol 2019;316:C121–C133.Appendix AuthorsName Location ContributionMatt Henry,MDUniversity ofKentucky,LexingtonData acquisition and drafted themanuscript for intellectual contentJohnKitchens,MDUniversity ofKentucky,LexingtonDesign and conceptualization, dataacquisition, critical review, anddrafting of the manuscriptAppendix (continued)Name Location ContributionJuan M.Pascual,MD, PhDUniversity of TexasSouthwestern,DallasData acquisition, interpreted thedata, and revised the manuscriptfor intellectual contentRamiro S.Maldonado,MDUniversity ofKentucky,LexingtonDesign and conceptualization,data acquisition, critical review,and drafting of themanuscriptNeurology.org/NG Neurology: Genetics | Volume 6, Number 4 | August 2020 3

GLUT1 Deficiency: Retinal Detrimental Effects of Gliovascular Modulation

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GLUT1 Deficiency: Retinal Detrimental Effects of Gliovascular Modulation

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