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W. P. Cella, V. C. Greenstein, J. Zernant-Rajang, R. T. Smith, G. R. Barile, N.-K. Wang, J. Tosi, S. Chang, S. H. Tsang, R. Allikmets; The G1961E Mutant Allele in the Stargardt Disease Gene ABCA4 Causes Bull’s Eye Maculopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4491.
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To characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4.
Fifteen patients were enrolled in the study. All patients had at least one G1961E mutation. The following procedures were performed: a comprehensive ophthalmic examination, fundus autofluorescence imaging (FAF), full-field scotopic and photopic electroretinograms (ERGs) and pattern ERGs. In addition fundus tracking microperimetry, spectral-domain optical coherence tomography (SD-OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR500 micro-array that currently detects 496 distinct ABCA4 variants.
All patients (30 eyes) had normal full-field scotopic and photopic ERGs and abnormal PERGs. On FAF all eyes had bull’s eye maculopathy without retinal flecks. Of the 6 patients (12 eyes) examined with SD-OCT, horizontal mid-line scans showed that one had disorganization of photoreceptor outer segments in the fovea, 2 had outer nuclear layer thinning probably due to photoreceptor atrophy proximal to the foveal center, and 3 had additional retinal pigment epithelium atrophy. On microperimetry, 6 patients (12 eyes) had eccentric fixation superior to the fovea and 5 of these patients had an absolute scotoma in the foveal area. DNA analysis revealed that 3 patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and another ABCA4 mutation. The G1961E alleles in either homozygosity or heterozygosity were associated with anatomical and functional pathologies limited to the parafoveal region and with a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations.
The G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull’s eye maculopathy in either the homozygous or heterozygous state. Genetic testing is imperative for precise diagnosis of the underlying maculopathy. Current non-invasive imaging techniques can be used to detect photoreceptor damage at the earliest clinical onset of the disease.
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