Best vitelliform macular dystrophy (BVMD) is caused by mutations in BEST1 (also known as VMD2; OMIM 153700) on the long arm of chromosome 11.1 An array of BEST1 phenotypes have now been characterized, including microcornea, rod-cone dystrophy, early-onset cataract, posterior staphyloma syndrome, vitreoretinochoroidopathy, and adult-onset foveomacular vitelliform dystrophy. BEST1 encodes bestrophin, a 585–amino acid protein with more than 120 described mutations.2 We herein present 2 siblings with bilateral retinoschisis and electroretinography (ERG) consistent with BVMD associated with a novel mutation in BEST1. Report of Cases Report of Cases An 8-year-old Jamaican girl presented with a several-week history of blurry vision in both eyes. Best-corrected visual acuity (BCVA) at presentation was 20/40 OD and 20/60 OS. Fundus examination of the right (Figure 1A) and left (Figure 1B) eyes was significant for bilateral macular retinoschisis and serous retinal detachments. Ocular coherence tomography demonstrated central macular thickness to be 381 μm OD (Figure 2A) and 430 μm OS (Figure 2B). Fluorescein angiography demonstrated multiple hyperfluorescent spots in the periphery with central leakage in both eyes (Figure 3). Indocyanine green angiography revealed multiple hypofluorescent spots in the periphery with hyperfluorescence centrally. Electroretinography demonstrated normal rod, rod-cone, high-intensity rod-cone, oscillatory, cone, and cone flicker responses in the patient's right and left eyes (Figure 4). Multifocal ERG demonstrated severely impaired central macular function in the right eye (Figure 5A and B) and left eye (Figure 5C and D). An electrooculogram demonstrated severely subnormal light response of the standing potential in both eyes, with an Arden ratio of 1.27 and 1.26 in the right and left eyes, respectively (Figure 6). The patient's blood was sent for genotypic analysis (the John and Marcia Carver Nonprofit Genetic Testing Laboratory, University of Iowa) and direct genetic sequencing of the entire coding region of BEST1 revealed a novel mutation with probable high penetrance.3 Specifically, a heterozygous GAG to AAG nucleotide substitution in the coding sequence of BEST1 was identified. Notably, sequencing of the entire coding region of XLRS1 demonstrated no disease-causing variations. Follow-up at 2 years demonstrated stable BCVA, fundus examination, and ocular coherence tomography findings. View LargeDownload Figure 1. Fundus photographs of case 1. Montage fundus images of the right (A) and left (B) eyes revealing bilateral yellow foveal clusters within a coarsened vitelliform lesion, well circumscribed by a pigment line and surrounding striae. Additional perifoveal as well as peripheral nasal semicircinate vitelliform lesions are also seen bilaterally. View LargeDownload Figure 2. Optical coherence tomography of case 1. Optical coherence tomography of the right (A) and left (B) eyes with foveal sectioning reveals splitting at the outer plexiform layer. Also seen are symmetric cystic changes in the inner nuclear layer with no retinal break. Additionally, bilateral subfoveal serous retinal detachments are present. View LargeDownload Figure 3. Fluorescein angiography of case 1. Fluorescein angiography of the right (A) and left (B) eyes demonstrates bilateral, heterogeneous, central fluorescein staining that mimics a fluid level. Late hyperfluorescence peripherally, corresponding to vitelliform lesions seen in Figure 1, is also noted. View LargeDownload Figure 4. Electroretinogram of case 1. Scotopic electroretinogram responses of the right (OD) (A) and left (OS) (B) eyes demonstrate a-wave amplitudes of −9.36 and −8.70 μV, b-wave amplitudes of 213.7 and 209 μV, and implicit times of 28 and 27 and 115 and 119 milliseconds, respectively. Maximal combined response of the right and left eyes demonstrates a-wave amplitudes of −123 and −117 μV, b-wave amplitudes of 318 and 276 μV, and implicit times of 18 and 18 and 63 and 64 milliseconds, respectively. Oscillatory potentials of the right and left eyes are −38.8 and −43.5 μV, respectively. Photopic responses of the right and left eyes demonstrate a-wave amplitudes of −25.7 and −33.3 μV, b-wave amplitudes of 145 and 143 μV, and implicit times of 15 and 16 and 34 and 34 milliseconds, respectively. The 30-Hz flicker responses of the right and left eyes demonstrate b-wave amplitudes of 130 and 128 μV with implicit times of 30 and 30 milliseconds, respectively. Div indicates division; F, flicker; and OP, oscillatory potential. View LargeDownload Figure 5. Multifocal electroretinogram of case 1. Multifocal electroretinogram of the control right eye (A), the patient's right eye (B), the control left eye (C), and the patient's left eye (D) demonstrates severe macular dysfunction in both eyes. Both eyes demonstrate central depression of cone responses with P1 amplitudes reduced by approximately 71% of reference values in both eyes. View LargeDownload Figure 6. Electrooculogram of case 1. Electrooculogram of the right (A) and left (B) eyes demonstrates an attenuated light response of the standing potential in both eyes, with an Arden ratio of 1.27 and 1.26 in the right and left eyes, respectively. Downward arrowheads indicate a dark trough and upward arrowheads, a light peak. Report of Cases The brother of case 1, a 12-year-old Jamaican boy, reported difficulty reading for 3 years. His BCVA at presentation was 20/80 OD and 20/40 OS. Fundus examination was significant for vessel sheathing in both eyes (though most prominent at the superior arcuate fibers in his left eye), central retinal pigment epithelial (RPE) changes, bilateral macular retinoschisis, and serous retinal detachments. Fluorescein angiography demonstrated multiple hyperfluorescent spots in the periphery with central leakage while indocyanine green angiography yielded significant multiple hypofluorescent spots in the periphery with hyperfluorescence centrally. Genotypic analysis of the patient's blood revealed the same mutation in BEST1 demonstrated in his sister. Also like his sister, sequencing of the entire coding region of XLRS1 in this patient also demonstrated no disease-causing variations. Follow-up at 2 years demonstrated stable visual acuity, fundus examination, and ocular coherence tomography findings of the right eye and worsening visual acuity (20/100 BCVA) with a new full-thickness macular hole in the left eye (Figure 7). View LargeDownload Figure 7. Optical coherence tomography of case 2. Optical coherence tomography of the left eye with foveal sectioning reveals retinoschisis with an extensive serous retinal detachment. Also seen is a full-thickness macula hole at the fovea. Comment These 2 cases exhibit clinical findings consistent with BVMD: bilateral symmetric multifocal macular lesions, suggestions of a central vitelliform lesion on fluorescein angiography, and a normal full-field ERG with an abnormal electrooculogram. The unusual aspect of the cases is the presence of subretinal fluid and retinoschisis associated with a novel mutation in BEST1. Fluorescein angiography in BVMD varies by stage but classically demonstrates early hyperfluorescence (from RPE atrophy) with late pooling.2 This is demonstrated in the central macula in our patients (Figure 3), with fluorescein angiography of the left eye of case 1 consistent with a pseudohypopyon lesion. Full-field photopic and scotopic ERG responses in BVMD are usually normal in a-wave and b-wave amplitude, dark adaption, and recovery time, reflecting mostly extramacular photoreceptor function.4 Multifocal ERG, however, may demonstrate variable central loss (depending on the stage of the vitelliform lesion) generally believed to be a reflection of abnormal macular cone and bipolar cell function. In the case of the first sibling, the severity of her phenotype expectedly produced this central attenuation on multifocal ERG (Figure 5), with no abnormalities on full-field ERG. The characteristic electrooculogram finding in BVMD is a decreased Arden ratio, noted even in asymptomatic carriers. The electrooculogram in case 1 demonstrated a reduction in the Arden ratio to a level consistent with BVMD (Figure 6). Wild-type BEST1 encodes a transmembrane protein localized to the basolateral plasma membrane of the RPE cell, which probably functions as a Ca +2–sensitive chloride channel.5 In our siblings, 6 separate polymorphisms were identified in sequencing BEST1. Only 2 of these were deemed phenotypically significant: a single guanine to adenosine substitution resulting in a Glu213Lys amino acid change and a frameshift mutation at amino acid position 404 (Pro404 del1cctC). The exact effect of the amino acid substitution, from glutamic acid (which has a negative charge at physiologic pH) to lysine (which has a positive charge), is unclear. However, a similar missense mutation in hemoglobin (specifically a glutamic acid to valine substitution) retards ionic cross-linking and results in altered tertiary protein structure to yield, most famously, the “sickling” of erythrocytes characteristic of sickle cell anemia. Dysfunction of bestrophin likely indirectly impairs apical fluid transport. This then indirectly impairs RPE phagocytosis of photoreceptor outer segments, lysosomal function, and regulation of subretinal fluid, yielding the characteristic vitelliform lesions and serous retinal detachments characteristic of BVMD.6 Similarly, the phenotypic severity of the siblings we describe, particularly serous retinal detachments and retinoschisis, suggests the mutation they harbor grossly affects chloride transport and Ca +2 signaling, both thought to underlie RPE ionic transport and fluid homeostasis. In summary, we herein present 2 siblings with BVMD, both exhibiting a previously unreported missense mutation in BEST1 as well as the novel findings of retinoschisis and a full-thickness macular hole. Back to top Article Information Correspondence: Dr Albini, Department of Ophthalmology, Bascom Palmer Eye Institute, 900 17th St NW, Miami, FL 33136 (firstname.lastname@example.org). Published Online: April 9, 2013. doi:10.1001/jamaophthalmol.2013.2047 Conflict of Interest Disclosures: None reported. This article was corrected for errors on July 10, 2013. References 1. Petrukhin K, Koisti MJ, Bakall B, et al. Identification of the gene responsible for Best macular dystrophy. Nat Genet. 1998;19(3):241-2479662395PubMedGoogle ScholarCrossref 2. Boon CJ, Klevering BJ, Leroy BP, Hoyng CB, Keunen JE, den Hollander AI. The spectrum of ocular phenotypes caused by mutations in the BEST1 gene. Prog Retin Eye Res. 2009;28(3):187-20519375515PubMedGoogle ScholarCrossref 3. Stone EM. Leber congenital amaurosis: a model for efficient genetic testing of heterogeneous disorders. LXIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 2007;144(6):791-81117964524PubMedGoogle ScholarCrossref 4. Birch DG, Anderson JL. Standardized full-field electroretinography: normal values and their variation with age. Arch Ophthalmol. 1992;110(11):1571-15761444914PubMedGoogle ScholarCrossref 5. Hartzell HC, Qu Z, Yu K, Xiao Q, Chien LT. Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol Rev. 2008;88(2):639-67218391176PubMedGoogle ScholarCrossref 6. Xiao Q, Hartzell HC, Yu K. Bestrophins and retinopathies. Pflugers Arch. 2010;460(2):559-56920349192PubMedGoogle ScholarCrossref
JAMA Ophthalmology – American Medical Association
Published: Jun 1, 2013
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