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M. Fleckenstein, S. Schmitz-Valckenberg, A. Bindewald-Wittich, A. P. Göbel, C. Keilhauer, U. Mansmann, B. H. F. Weber, H. P. N. Scholl, F. G. Holz, FAM Study Group; Late-Onset Stargardt Macular Dystrophy Mimicking Atrophic Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2155.
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We have recently identified distinct patterns of abnormal fundus autofluorescence (FAF) in the junctional zone of geographic atrophy (GA) in patients with AMD (BJO 2005;89:874-8). A high degree of intra-individual symmetry in the FAF pattern, along with a high degree of inter-individual variability suggests genetic influence with underlying heterogeneity. Here we screened for mutations in the ABCA4 gene in patients displaying a distinct FAF pattern that shares phenotypic similarities with FAF findings in juvenile Stargardt macular dystrophy.
In the prospective, multicenter natural history FAM study (ClinicalTrials.gov ID: NCT00393692), FAF images were recorded with a confocal scanning laser ophthalmoscope (cSLO, exc 488 nm; em >500 nm) in a total of 590 patients with AMD. Abnormal FAF patterns outside GA areas were classified by two independent readers. Seven patients exhibiting the diffuse FAF pattern 'fine granular with peripheral punctate spots' ('GPS'), and 11 patients exhibiting other FAF patterns were screened for mutations in the ABCA4 gene by gene chip analysis of known mutations (ASPER Biotech, Tartu, Estonia). All changes were confirmed by direct sequencing.
All affected patients reported an onset of visual impairment beyond 50 years of age. In the group with the FAF pattern 'GPS', all patients had at least one mutated allele in the ABCA4 gene. In two patients both disease alleles were detected. In the control group of 11 AMD patients with GA, but a different pattern of abnormal FAF, only two patients showed one mutated allele.
These preliminary results indicate that the classification system of abnormal FAF has a genetic base and that the FAF pattern 'GPS' is caused by mutations in the ABCA4 gene implying that this distinct FAF phenotype represents late-onset Stargardt macular dystrophy rather than late atrophic AMD. Based on these findings expanded genotype-phenotype correlations are planned in our study population. The results reflect the importance of refined phenotyping using novel imaging methods for addressing genetic factors in AMD and related disorders.
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