Elsevier

Experimental Eye Research

Volume 76, Issue 2, 1 February 2003, Pages 203-211
Experimental Eye Research

In vivo micropathology of Best macular dystrophy with optical coherence tomography

https://doi.org/10.1016/S0014-4835(02)00280-4Get rights and content

Abstract

Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5–61), representing four families with known VMD2 mutations, were included. OCT scans were recorded in the central retina and longitudinal reflectivity profiles were analysed. The central retina in BMD showed different OCT abnormalities at or near the level of the highly reflective deep retinal band termed the outer retina-choroid complex (ORCC). Two types of ORCC change were noted to occur either separately or together: (1) splitting with or without intervening hyporeflective areas; and (2) elevation. Longitudinal study of a BMD patient indicated that such abnormalities were dynamic and changed in type and degree with time. The pathogenetic sequence in BMD may begin with defective fluid transport across the RPE secondary to the channelopathy in the basolateral membrane. In the macula, this leads to an abnormal interface with adjacent structures at both apical and basal surfaces of the RPE. The disease process results in detachments of the neurosensory retina, such as in central serous chorioretinopathy, and sub-RPE pathology resembling some stages of age-related macular degeneration, with eventual loss of photoreceptors, inner retina and central vision.

Introduction

Best macular dystrophy (BMD) is an autosomal dominant macular degeneration caused by mutations in the VMD2 gene, which encodes the protein bestrophin (Petrukhin et al., 1998). Bestrophin is an integral membrane protein primarily expressed in the retinal pigment epithelium (RPE) (Petrukhin et al., 1998, Marquardt et al., 1998) and localized to its basolateral plasma membrane (Marmorstein et al., 2000). Recently, it was demonstrated that bestrophin forms a chloride channel responsible for maintaining chloride conductance across the basolateral membrane of the RPE (Sun et al., 2002). These discoveries elucidate the mechanism of the diagnostic retina-wide RPE dysfunction measured by electro-oculography (EOG) in BMD patients that is detectable even in the absence of macular abnormalities (Francois et al., 1966, Cross and Bard, 1974).

The maculopathy in BMD has attracted the interest of clinical investigators since its recognition (Best, 1905). The prominent yellow macular lesions evolve in ophthalmoscopic appearance and may be accompanied by excellent visual acuity or lead to major declines in central vision (Fishman et al., 1993, Park et al., 1999). Pathogenetic sequences have been proposed to help understand the maculopathy in BMD (Mohler and Fine, 1981, Gass, 1997) and there have been clues to the disease process at a microscopic level from histopathological studies (Frangieh et al., 1982, Weingeist et al., 1982, O'Gorman et al., 1988).

Optical coherence tomography (OCT) can provide cross-sectional images of the retina in vivo. As a supplement to knowledge from histopathology and the wealth of clinical observations of BMD, we determined the OCT micropathology in BMD patients in order to gain greater understanding of the process leading to loss of central vision in this disease.

Section snippets

Materials and methods

Ten patients with BMD, representing four families, were studied clinically and with OCT. DNA was analyzed for VMD2 gene mutations according to published methods (Lotery et al., 2000, Li et al., 2000). A patient with central serous chorioretinopathy (CSCR) and a patient with age-related macular degeneration (AMD) were also included. Consent for all procedures was obtained from subjects after the nature of the studies had been explained. Research procedures were in accordance with institutional

Clinical and OCT spectrum

Table 1 shows some clinical characteristics of the BMD patients in this study. Three missense mutations in the VMD2 gene were identified in the four families; two of the mutations have been reported in molecular surveys of BMD (Marquardt et al., 1998, Wadelius et al., 1998, Caldwell et al., 1999, Bakall et al., 1999, Lotery et al., 2000, Marchant et al., 2001). By history, there was no known relationship between Families 1 and 3. The third change resulting in the substitution of arginine for

OCT micropathology in BMD: clinical and histopathological correlates

BMD patients show a spectrum of OCT patterns across the macula. The normal OCT scans in VMD2 mutation-positive BMD patients correspond to the previtelliform clinical stage (reviewed in Gass (1997)). The dramatic OCT thinning in regions of the macula would correspond to the atrophic clinical stage. Between these extremes of disease expression, there were patients with vitelliform, pseudohypopyon or vitelliruptive macular lesions. Patients at these intermediate clinical stages shared the OCT

Acknowledgements

This study was supported by National Institutes of Health (EY-05627; EY-13203; EY-13365); Foundation Fighting Blindness, Inc.; Macula Vision Research Foundation; The Chatlos Foundation, Inc., F.M. Kirby Foundation; The Macular Disease Foundation; and the Mackall Trust. S.G.J. is a Research to Prevent Blindness (RPB) Senior Scientific Investigator; J.S.S. was the James S. Adams R.P.B. Special Scholar; A.V.C. is an RPB Special Scholar. We thank J. Emmons, E. Smilko, S. Schwartz, J. Chico, M.

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