Ophthalmic Genetics, Early Online, 1–5, 2014 ! Informa Healthcare USA, Inc. ISSN: 1381-6810 print / 1744-5094 online DOI: 10.3109/13816810.2014.889171

C ASE REPORT

Progressive Cone Dysfunction and Geographic Atrophy of the Macula in Late Stage Autosomal Dominant Vitreoretinochoroidopathy (ADVIRC) Connie June Chen and Morton F. Goldberg

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Wilmer Eye Institute, Ophthalmology, Baltimore, MD, USA

ABSTRACT Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare inherited ocular disease associated with distinct mutations in the BEST1 gene. Typically, patients have only mild visual impairment, and rarely do patients have moderate or severe visual impairment, often as a result of vitreous hemorrhage. We now describe progressive central macular atrophy and cone dysfunction leading to visual loss in an elderly ADVIRC patient 33 years after initial presentation. Keywords: Autosomal dominant vitreoretinochoroidopathy; inherited; retinal disease

INTRODUCTION

CASE REPORT

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare inherited ocular disease associated with distinct mutations in the BEST1 gene. The characteristic appearance includes peripheral chorioretinal atrophy and a distinctive annular pattern of peripheral coarse hyperpigmentation between the vortex veins and ora serrata.1–3 Typically, patients have only mild visual impairment as a result of presenile cataracts or cystoid macular edema. Rarely do patients have moderate or severe visual impairment, often as a result of vitreous hemorrhage.4 Excellent visual acuity is usually retained into the ninth decade of life, because most clinical and histopathological changes are limited to the periphery of the fundus.5 We now describe progressive central macular atrophy and cone dysfunction leading to visual loss in an elderly ADVIRC patient 33 years after initial presentation.

The patient is a Caucasian female with a welldocumented family history of ADVIRC, who first presented at age 46 for pre-senile cataracts. She underwent uncomplicated cataract surgery with placement of anterior chamber intraocular lenses bilaterally, as reported by Traboulsi and co-authors in 1993.2 Full field photopic and scotopic electroretinograms were normal at the initial presentation. She then returned at age 57 years with complaints of mild difficulties with night vision. At that time visual acuity was 20/25 in the right eye and 20/30 in the left eye, and full field electroretinograms revealed slightly subnormal photopic responses with single flash stimulus but normal scotopic responses. Retinal examination revealed only coarse annular hyperpigmentation in the peripheral retina, but no clinical evidence of macular edema or atrophy (Figure 1).

Received 5 January 2014; accepted 25 January 2014; published online 24 February 2014 Correspondence: Connie June Chen, MD, Wilmer Eye Institute, Ophthalmology, 600 North Wolfe Street, Woods Building, Baltimore, MD 21287, USA. E-mail: [email protected]

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C. J. Chen & M. F. Goldberg

FIGURE 1. At age 57, fundus photographs demonstrate a normal macular appearance in the right eye with no pigmentary or atrophic changes (A), and a relatively normal macular appearance in the left eye with lack of any atrophic changes (B). There are characteristic annular peripheral pigmentary changes with a sharp transition between areas of normal and abnormal peripheral retina in the right eye (C) and left eye (D).

FIGURE 2. At age 79, an Optos wide-field fundus photograph of the right eye demonstrates drusen (arrows) along the superotemporal arcade (A). In the left eye, an Optos photograph demonstrates central macular atrophy (asterisk) as well as drusen (arrow) along the superotemporal arcade (B). Thirty degree fundus photo of the left eye highlights the drusen along the superotemporal arcade (C, arrow). Ophthalmic Genetics

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Progressive Cone Dysfunction in ADVIRC

FIGURE 3. At age 79, fundus autofluorescence photography demonstrates hypoautofluorescence in the areas of perifoveal retinal pigment epithelial atrophy with hyperautofluorescence in the superior and nasal macula of the right eye (A, arrowheads). Fundus autofluorescence photography reveals hypoautofluorescence in the area of foveal retinal pigment epithelial atrophy and mild hyperautofluorescence in the superior, nasal, and inferior macula in the left eye (B, arrowhead). Fluorescein angiography demonstrates a transmission defect in the area of retinal pigment epithelial atrophy in both eyes and no leakage (C, D). Spectral domain OCTs of the right eye (E) and the left eye (F) demonstrate thinning of the outer retinal layers and no cystoid macular edema.

The patient was lost to follow up until age 70 years.6 She then described slow, progressive loss of central vision in the left eye, associated with a ‘‘donut-shaped’’ scotoma. At that time, she had best !

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corrected visual acuity of 20/50 in the right eye and 20/100- in the left eye. Examination showed perifoveal retinal pigment epithelial atrophy in both eyes. Full field electroretinogram revealed normal

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C. J. Chen & M. F. Goldberg

scotopic responses bilaterally and borderline responses with single flash and flicker stimuli. A multifocal electroretinogram, however, showed severely reduced central amplitudes, left greater than right. At age 79 she returned with further decline of her vision in both eyes and stable nyctalopia. At this visit, her corrected visual acuity was 20/63 in the right eye and 1/200 in the left eye. She was noted to have stable vitreous fibrillar condensations as well as stable chorioretinal atrophy and coarse hyperpigmention in the periphery for 360 degrees in both eyes. She also had extramacular drusenoid deposits in both eyes along the superotemporal arcade and attenuated retinal arterioles (Figure 2). She also demonstrated patchy hypoautofluorescence in the area of perifoveal retinal pigment epithelial atrophy with accumulation of hyperautofluorescent material in the superior and nasal macula in the right eye (Figure 3). Ophthalmoscopic examination of the left eye revealed retinal pigment epithelial atrophy involving the fovea. There was accumulation of hyperautofluorescent material at the superior, nasal, and inferior border of atrophy. There was no evidence of leakage on fluorescein angiogram to suggest any cystoid macular edema. Spectral domain optical coherence tomography showed corresponding central photoreceptor loss in both eyes and confirmed no evidence of epiretinal membrane, subretinal fluid or intraretinal fluid.

DISCUSSION ADVIRC is a rare, autosomal dominantly inherited retinal dystrophy that is attributed to mutations in the pre-mRNA splicing sites in the BEST1 gene. These mutations lead to exon skipping and shortened and internally deleted bestrophin-1 isoforms.3 ADVIRC is the sole known phenotype resulting from altered splicing of BEST1,3 whereas Best vitelliform macular dystrophy is the result of missense mutations in BEST1.7 The functional consequences of the altered bestrophin-1 isoforms in ADVIRC remain unclear. However, the anterior segment abnormalities that have also been seen with ADVIRC (i.e. presenile cataract and incomplete anterior segment development, such as hypoplastic ciliary processes, shallow anterior chambers, and microcornea)1,8,9 and the high expression of bestrophin mRNA observed during the late phase of mouse embryonic development suggest that the altered isoforms have widespread impact on ocular development.10 Interestingly, the central retinal pigment epithelial atrophy can be clinically apparent late in the disease course of ADVIRC, as in our patient, and somewhat resembles the later onset atrophic stage of Best vitelliform macular dystrophy. Lefaut and colleagues

have reported a 61-year-old ADVIRC patient who had chorioretinal atrophy involving the macula in both eyes, and severely reduced rod and cone responses, and moderately increased latencies bilaterally. The initial presenting visual acuity was 20/60 in the right eye and 20/25 in the left eye. The 37-yearold nephew also demonstrated increasing macular chorioretinal atrophy and progressively reduced cone and rod amplitudes. It is possible that there are mild, subclinical abnormalities in retinal pigment epithelial development early in the course of ADVIRC, and more obvious central cone dysfunction and RPE atrophy may develop later in life, as in our elderly patient. Prior presentations of ADVIRC patients have not included relevant data in patients as old as our proband. Subclinical histopathologic abnormalities of the macula may occur during decades of aging before they appear clinically. ADVIRC may be considered on a spectrum of bestrinopathies that affect embryonic development of anterior segment structures and peripheral retinal pigment epithelium early in life, but that can also present late in life with central atrophic retinal pigment epithelial changes resulting in macular dysfunction. It is likely that the BEST1 mutation is directly responsible for the macular changes, because episodes of cystoid macular edema and other macular diseases were not observed in any of the previous visits. Furthermore, these changes do not appear typical for age-related geographic atrophy, because the atrophy has an initial moth-eaten appearance rather than the well-demarcated circumscribed lobules of RPE loss that are usually seen in AMD. Based on our and others’ observations, we believe the phenotypic description of ADVIRC should be expanded to include macular and posterior pole abnormalities.

DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

REFERENCES 1. Kaufman SJ, Goldberg MF, Orth DH, et al. Autosomal dominant vitreoretinochoroidopathy. Arch Ophthalmol 1982;100:272–278. 2. Traboulsi EI, Payne JW. Autosomal dominant vitreoretinochoroidopathy. Report of the third family. Arch Ophthalmol 1993;111:194–196. 3. Burgess R, MacLaren RE, Davidson AE, et al. ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing. J Med Genet 2009;46:620–625. Ophthalmic Genetics

Progressive Cone Dysfunction in ADVIRC

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4. Blair NP, Goldberg MF, Fishman GA, et al. Autosomal dominant vitreoretinochoroidopathy (ADVIRC). Br J Ophthalmol 1984;68:2–9. 5. Goldberg MF, Lee FL, Tso MO, et al. Histopathologic study of autosomal dominant vitreoretinochoroidopathy. Peripheral annular pigmentary dystrophy of the retina. Ophthalmology 1989;96:1736–1746. 6. Oh KT, Vallar C. Central cone dysfunction in autosomal dominant vitreoretinochoroidopathy (ADVIRC). Am J Ophthalmol 2006;141:940–943. 7. Boon CJ, Klevering BJ, Leroy BP, et al. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res 2009;28:187–205.

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8. Yardley J, Leroy BP, Hart-Holden N, et al. Mutations of VMD2 splicing regulators cause nanophthalmos and autosomal dominant vitreoretinochoroidopathy (ADVIRC). Invest Ophthalmol Vis Sci 2004;45: 3683–3689. 9. Lefaut BA, Loeys B, Leroy BP, et al. Clinical and electrophysiological findings in autosomal dominant vitreoretinochoroidopathy: report of a new pedigree. Graefes Arch Clin Exp Ophthalmol 2001;239:575–582. 10. Bakall B, Marmorstein LY, Hoppe G, et al. Expression and localization of bestrophin during normal mouse development. Invest Ophthalmol Vis Sci 2003;44: 3622–3628.

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