drug therapies,andgenetherapy. avenues includenutritionalsupplementation, Stargardt’s maculardystrophy, cur­ approved treatments orcures forpatientswith ABCA4 gene. Although there are no cur­ dys­ Vision Development & Rehabilitation Vision Vision Dev&Rehab 2020;6(3):237-42. Vision a patientwithgenetically confirmedAbca4mutations. Cure forStargardts”: Theprognosis and rehabilitation of Meyer J,SchmiedeckeS,Sanchez-DiazP. “There isNo covd.org. https://doi.org/10.31707/VDR2020.6.3.p237. of OpenAccessJournals.Onlineaccessisavailable at Development.VDRisindexedin the DirectoryVision editor. Copyright2020CollegeofOptometristsin use reprints of this article must be obtained from the which theauthorsmaybeaffiliated. Permissionto Rehabilitation oranyinstitu­ Development& Development,Vision in Vision reflect theopinionsofCollegeOptometrists ments are theauthors’personalopinionsandmaynot to JackelynMeyer, OD, at [email protected]­ Correspondence regarding thisarticleshouldbeemailed Keywords: trophy associatedwith mutation inthe Low Vision Rehabilitation, StargardtsLow Vision

auto­ CASEStargardt’s macular dystrophy isan Background ABSTRACT REPORT “ Confirmed A Confirmed Genetically Patient with of a Rehabilitation and Prognosis Stargardt’s”: The for No Cure is There Mutations San Antonio,Texas Rosenberg SchoolofOptometry, WordUniversity oftheIncarnate FAAO Patricia Sanchez-Diaz,PhD,DVM, FAAO, AMCMO,DipLV Stephanie Schmiedecke,OD, Jackelyn Meyer, OD ABCA4, Bioptic,GeneTherapy, somal recessive inherited retinal tion ororganization to bca rent research 4 rent FDA

237 most commoncauseofStargardt’s disease. binding cassettetransporterABCA4are the Autosomal recessive mutationsintheATP- a juvenileformofmaculardegeneration. dystrophy thatiscommonlyreferred toas INTRODUCTION individuals. provides significant rehabilitation tothese phenotype andmagnificationdetermination Genetic testingprovides insighttothe Conclusion macular dystrophy. genetic counselingofapatientwithStargardt’s including magnificationassessmentand reports forcomprehensive rehabilitation, presents withsuspectedStargardt’s withvisual A 58yearoldAfricanAmericanfemale Case Report killing off thephotoreceptor cellsoftheretina. leave toxicbyproducts in theretina, eventually RPE andPRdegeneration.ABCA4mutations oxidative damagetoRPEcellsandeventual toxic A2Eretionoid withinRPEcellsleadsto pigment epithelial[RPE]cells.Thebuildupof [PR] andinthephagolysosomesofretinal within theoutersegmentsofphotoreceptors the accumulationoftoxicretinoid compounds Pathogenic variants in ABCA4 gene lead to sound FDA approved treatments, patients therapies, andgene therapy. So,without include nutritional supplementation, drug macular dystrophy. Current research avenues treatments orcures forpatientswith Stargardt’s [RPE] atrophy. There are no FDAapproved extensive fleckingthathave resorbed. the posteriorpole.Stage3isdefined as Stage 2presents withtheseflecksthroughout with yellowish “fleck” in theparafoveal area. stages ofStargardt’s disease.Stage1appears the diseaseprocess. gresses through different stagesthroughout Stargardt’s diseaseisaninheritedretinal Stage 4 shows retinal pigment epithelium Funduscopically, Stargardt’s diseasepro­ Volume 6,Issue3• September 2020 2,3 Fishmandescribed4 2 1 with Stargardt’s disease management focuses CASE PRESENTATION on low vision rehabilitation. RA, a 58 year old African American woman, Rehabilitation success rates are high within presents for a second opinion and ocular health Stargardt’s patients because of the relative examination. She was clinically diagnosed stability of visual acuity at 20/200 and the ability with Stargardt’s and was told by several eye of these patients to use both preferential retinal doctors she would “never see 20/20”. She first locus [PRL] in combination with magnification noticed vision changes when she was nine to aid in viewing tasks.4,5 Patients who have years old. Her ocular history is also positive Stargardt’s disease generally maintain a for primary open angle glaucoma in both stable Visual Acuity [VA] between 20/200 and eyes (OU), and takes two medications for this: 20/400. In a study done at University of Illinois dorzolamide dosed three times a day, and at Chicago, 97.5% of Stargardt’s patients latanoprost at night OU. She denies any family maintained a VA of 20/200 or better.3 This case history of glaucoma or Stargardt’s disease. will look at the comprehensive rehabilitation, Systemically, she has both hypothyroidism, including magnification assessment and hypercholesterolemia and takes levothyroxine genetic counseling of a patient with Stargardt’s 112 mg tab daily. macular dystrophy.

D

Figure 1: Funduscopic view of patient RA. Figure 1A: Heavy pigmentation over macula with surrounding RPE dropout, pisciform flecks throughout the periphery, R eye. Figure 1B: Heavy pigmentation over macula with surrounding RPE dropout, pisciform flecks throughout the periphery, L eye. Figure 1C: Macular hypo-reflectivity with pisciform hyper/hypo fluorescence throughout the periphery, R eye. Figure 1D: Macular hyporeflectivity with pisciform hyper/hypo fluorescence throughout the periphery, L eye.

238 Vision Development & Rehabilitation Volume 6, Issue 3 • September 2020

1 2 3 4 5 6 7 A. B. 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 Figure 2: 120 dB visual field of patient RA. Figure 2A: Peripherally full field with central 14 degree loss horizontally and 12 degree loss vertically, R eye. Figure 2B: Peripherally full field with central 8 degree loss horizontally and 12 degree loss 26 vertically, L eye. 27 28 29 Ocular Health Examination included reading street signs and bus numbers 30 Upon ocular health exam, her entering at distance. RA had a moderate contrast 31 acuities were: right eye (OD) 20/200 PHNI impairment, log 1.05 reduction in both left 32 and left eye (OS) 20/150 PHNI. Preliminary and right eyes. A 120 point visual field was 33 testing and anterior slit lamp exam was within peripherally full, with central five degrees of 34 35 normal limits. Posteriorly, each optic nerve absolute loss as seen in Figure 2. Amsler grid 36 head was labeled with a cup-to-disc ratio of revealed central scotomas in both left and 37 0.7vertical/0.7horizontal with mild pallor OU. right eyes with rivalry present; RA preferred 38 Fundus photos were taken (see Figure 1). her left eye. 39 The maculae in both eyes had pigmented 40 41 scars, lacked a foveal light reflex, and had Device Evaluation 42 extensive flecking throughout the posterior For the goal of spotting distance tasks, 43 pole and periphery. Fundus autofluorescence using a 4x Keplerian telescope held over RA’s 44 showed dense hyperintense and hypointense left eye with her best correction spectacles on, 45 pigment clumping in the macula with white- she obtained a visual acuity of 20/40 (previously 46 47 hyperintense flecks throughout the periphery. 20/140). RA was trained how to localize, focus, spot, track, and trace with device. An initial 48 49 Functional Vision Evaluation training session was completed and 8 weeks 50 RA received a low vision examination with later a second training session was completed 51 ultimate goals to see bus numbers, navigate to ensure RA was comfortable, and competent 52 53 transportation independently, spot people with the telescope tasks. After successful 54 from across the room, read medication training, RA was fit in a 4x Ocutech Sport 55 labels, and be comfortable in outdoor, sunny, bioptic over the left eye. The prescription in 56 conditions. A Visual Functioning Questionnaire the carrier lens was OD: -3.00 -0.50 x080 and 57 [VFQ] was completed and she reported that OS: -3.00 -0.75 x015. The pupillary distance 58 59 reading mail, menus, and small labels were was 65mm. She was trained how to spot in 60 most challenging for her. Other difficulties and out of the bioptic and could do so with 61 62 239 Vision Development & Rehabilitation Volume 6, Issue 3 • September 2020 63 64 65 ease. The bioptic was fit properly with the been reported primarily in patients of African telescope mount so that the bottom of the American ancestry. The third variant ABCA4 telescope eyepiece aligned with the base of c.294C>G is another missense variant previously the patient’s upper lid. This allowing for RA to described in a compound heterozygous state easily drop her chin to align the telescope in with known pathogenic variants in patients with her angle of vision.6 Stargardt’s disease. This genetic variant has A filter evaluation was done to alleviate been classified as “probably damaging”. The RA’s veiling glare complaint. RA appreciated fourth ABCA4 variant c.1927G>A had been the NoIR 533nm lens, amber-orange filter as reported in heterozygosity in 452 individuals fit over glasses for outdoor purposes. For her of predominantly African ancestry as well. bioptic, a slip behind filter was evaluated of Although, based on bioinformatics predictions, the same caliber and was ordered for visual this amino acid change seemed to be comfort while using the bioptic outdoors. deleterious, there is not enough clinical data to For near, a Ruby XL HD portable electronic demonstrate the pathogenicity of this ABCA4 video magnifier [EVM] was evaluated. RA read c.1927G>A missense variant and is classified as 0.8M which is equivalent to reading small a variant of “uncertain significance” (VUS). RA newspaper headlines. She used the device with was heterozygous for three pathogenic changes an effective add of +3.00D and an enlargement that cause the loss of functional ABCA4 protein ratio of screen to print ration of 2. Her preferred and confirms the clinical findings. The patient contrast was the camera option. did not have children or siblings and her parents were deceased. Family testing would have Genetic Testing demonstrated the compound heterozygous RA underwent genetic testing using the state compatible with Stargardt’s disease. Blueprint Genetics Retinal Dystrophy Panel and a saliva sample. The genetic test was sponsored Management within the program My Retina Tracker. This In our case, low vision rehabilitation was genetic test evaluates a panel of over 250 essential for keeping RA completing her genes linked to inherited retinal dystrophies.14 activities of daily living [ADLs] with success. The test identified four pathogenic variants Patients with Stargardt’s have large central (one nonsense and the other three missense) scotomas and decreased contrast due to in ABCA4 gene. The four variants identified in their large foveal scars. They learn to use RA were inherited with a recessive pattern. She PRL’s that push the damaged area of the was heterozygous for the following four variants retina away, attempting to use intact retina ABCA4 c.1496G>A p.(Trp499*), c.926C>G to see.7 Magnification is then added so that p. (Pro309Arg), c.294C>G p. Asn98Lys), and the less sensitive peripheral retina detect c.1927G>A p. (VAL643Met). ABCA4 c.1496G>A larger stimulus and the brain can interpret causes a premature stop codon and the loss of the image.7 Our patient read 0.8M, (ie small normal protein function, by either the formation newspaper headlines), with an equivalent of a truncated protein or loss of protein function viewing power of +6.00D. via nonsense-mediated mRNA. The ABCA4 Magnification was applied for distance c.1496 mutation is inherited with a recessive using her 4x hand held telescope as well as pattern. The second genetic variant identified her bioptic. With her 4x Sport Ocutech bioptic in RA (ABCA4 c.926C>G) was classified as mounted over the left eye, she could read a “likely pathogenic” based on frequency 20/40 on the Snellen acuity chart. With this allele and on predictions of protein function. device, she can see adequately at distance This second missense ABCA4 variant has to see street signs, as well as bus numbers. In

240 Vision Development & Rehabilitation Volume 6, Issue 3 • September 2020 fact, by the Texas state recommendations, she recruiting patients with two mutant ABAC4 meets driving requirements with her bioptic as alleles in the hopes of injecting a normal gene she is 20/40 in her better seeing eye through via a viral vector through subretinal injection, the bioptic and has 140 degrees of visual in hopes that transcriptional machinery of the field.8 RA was referred to occupational therapy host cell would re-integrate non-diseased for intensive behind-the-wheel training using gene into diseased RPE.11 her bioptic before receiving a modified Texas Genetic testing identified genes for class­ state driver’s license. ification, allowing further phenotypic expression The prognosis of Stargardt’s is relatively of the disease to be classified genotypically. stable as visual acuity normally stabilizes Plotting genetic abnormalities provides better between Snellen 20/200-20/400. With magnifi­ insight to the genotype of the disease.12 A cation, RA was able to accomplish her activities study by Schulz et al looked at 335 Stargardt’s of daily living. patients from a multicenter cohort to identify Although there are no current FDA variant genes, giving researchers more data to approved treatments or cures for patients with determine gene variant and protein variants. Stargardt’s macular dystrophy, current research Schulz’s study revealed 48 novel pathogenic avenues include nutritional supplementation, gene variations in the ABCA4 gene alone.13 It drug therapies, and gene therapy. One is therefore of critical importance that genetic promising study done by Prokopiou et. al, testing is done. Genetic confirmation not revealed that Omega-3 supplementation may only yields a diagnosis for patients, but also be therapeutic in decreasing the oxidative provides hope for future research toward the stress in the photoreceptors in the retina in a development of a cure. mouse model. The hypothesis concludes that there may be a therapeutic effect on patients Conclusion with Stargardt’s disease and current clinical Stargardt’s is a genetic disease that affects trials are undergoing.9 an individual’s retina at a measurable cellular Another promising clinical trial is through level. Although diagnosing patients at a Acucela Inc. Currently a drug, Emixustat cellular level is not immediately life changing, hydrochloride, is undergoing phase III clinical science continues to press forward and the trials for individuals with genetically confirmed potential of future gene therapy is a possibility. ABCA4 Stargardt’s disease. This drug, taken Identifying pathogenic genes makes a 10mg orally each day, has been hypothesized database to help identify other patients, as to slow the progression of macular atrophy. well as qualify patients for future gene therapy. The drug works to inhibit RPE65, a critical Patients with this disease, however, function protein in the visual pathway, and reducing at a very high level when provided with low the availability of vitamin A derivatives in vision rehabilitation. the visual cycle, limiting buildup of toxic Until an answer is found these patients need A2E retinoid to prevent oxidative damage to to be assisted with appropriate rehabilitation. RPE cells and photoreceptor degeneration.10 Gene therapy does not help individuals Current subjects enrolled in the study must complete ADLs, therefore, low vision (LV) have mutation in the ABCA4 gene. This referrals and rehabilitation are necessary. solidifies the importance that patient inherited These patients respond well to magnification retinal conditions are genetically confirmed so and eccentric viewing changing and maintain participants can be properly selected. a high level of functionality, as seen in our Gene therapy studies have also been case example. established. One study in clinical phase I/II was

241 Vision Development & Rehabilitation Volume 6, Issue 3 • September 2020 References 9. Prokopiou, E. et al. Omega-3 Fatty Acids Supple­ ment­ation: Therapeutic Potential in a Mouse Model of 1. Maeda A, Maeda T, Golczak M, Palczewski K. Stargardt Disease. Invest Opthalmol Visi Sci 2018 Jun Retinopathy in mice induced by disrupted all-trans- 1;59(7):2757-2767. https://doi.org/gdnqzg retinal clearance. J Biol Chem. 2008;283(39):26684– 26693. https://doi.org/frnh7z 10. Gregory, J. Acucela Inc.Safety and Efficacy of Emixustat in Stargardt Disease (SeaSTAR). February 13,2020. 2. Stargardt macular degeneration. National Library of https://bit.ly/2FJ91vK Medicine. Nov 2010. https://bit.ly/2FIZox9 11. Weleber, R; Sahel J.A., Sanofi. Phase I/II Study 3. Fishman, GA. Fundus Flavimaculatus: a clinical of SAR422459 in Patient with Stargardt’s Macular classification. Arch Ophthalmolo 1976; 94: 2061-7 Degeneration. January 2020. https://bit.ly/3hzAQ7g 4. Kim, L. Comparison of Visual Acuity in Patients with 12. Kumara, N. Retinal Gene Therapy. British Medical Different Stages of Stargardt’s Disease. Ophthalmology Bulletin, 2018, 126:13-25 2006: 113: 1748-1751. https://bit.ly/3c0O3oh 13. Schulz HL et al. Mutation spectrum of the ABCA4 gene 5. Shah M. Vision Rehabilitation of patients with Stargardt’s in 335 Stargardt disease patients from a multicenter disease. J Coll Physicians Surg Pak. 2008 May;18(5):294. german cohort-impact of selected deep intronic variants https://bit.ly/2FHh2Bn and common SNPs. Invest Ophthalmol Vis Sci. 2017; 58: 6. Ocutech; Telescopic Low Vision Aides for the Visually 394–403. Imapaired; 2020. https://bit.ly/3hvSybO 7. Ratra, D et al. Factors influencing the choice of low- AUTHOR BIOGRAPHY: vision devices for visual rehabilitation in Stargardt Jackelyn Meyer, OD disease. Clinical and Experimental Optometry, 2019: San Antonio, Texas 102.4 426-433 Jackelyn Meyer, OD, completed her low vision residency 8. “Vision Requirements for Driving Safety with Emphasis at the University of Incarnate Word, Rosenberg School of on Individual Assessment.” International Council of Optometry. Among her special interests are considerations in Ophthalmology, Feb. 2006. driving with low vision, and the diagnosis and management of patients with Leber’s Hereditary Optic Neuropathy.

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242 Vision Development & Rehabilitation Volume 6, Issue 3 • September 2020