Novel Mutation in BEST1 Associated With Retinoschisis

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.

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.

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).

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.

Correspondence: Dr Albini, Department of Ophthalmology, Bascom Palmer Eye Institute, 900 17th St NW, Miami, FL 33136 (talbini@med.miami.edu).

Published Online: April 9, 2013. doi:10.1001/jamaophthalmol.2013.2047

This article was corrected for errors on July 10, 2013.