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Variable Expressivity in Multifocal Best´s Disease with VMD2 Gene Mutation (T299>G)

1Frisch I. B., 2Weber B. H. F., 1Holz F. G.,
1Ruprecht-Karls-Universität Heidelberg, Universitäts-Augenklinik (Heidelberg)
2Julius-Maximilians-Universität Würzburg, Institut für Humangenetik, Biozentrum (Würzburg)

Purpose: Best´s disease (vitelliform macular dystrophie - VMD) is an autosomal dominant retinal dystrophy, caused by mutations in the VMD2 gene. Apart from the typical macular yellowish lesions, multiple discrete vitelliform lesions may occur. We characterized the phenotype in a family with multifocal Best´s disease and an identified mutation in the VMD2 gene.
Methods: Besides standardized measurements of visual acuity examinations included electrophysiology (EOG), fluorescein angiography, fundus autofluorescence and visual field investigations. The mutation analysis was done by PCR amplification of the 10 coding exons of the VMD2 gene with exon-flanking primer sets, and subsequent sequencing of the PCR products.
Results: Propositus was a 55-year-old male patient with a history of gradual visual loss. His 88-year old mother and 48- and 55-year old sisters had a unilateral loss of visual acuity for years. The visual acuity of the patient was 20/60 OD and 20/25 OS. Perimacular multiple yellowish lesions were seen corresponding to increased autofluoescence. The two sisters had additional disciform scars and areas of geographic atrophy. Sequence analysis of the VMD2 exon 4 revealed a thymine to guanine transition at nucleotide 299 (299T>G) in all affected family members. This results in a leucine to arginine substitution at position 100 in the corresponding protein (L100A). In all genotypes with this mutation the EOG was pathological.
Conclusions: In this family several affected members had multifocal vitelliform lesions. The diagnosis of Best´s disease was confirmed by molecular analysis. The phenotypical spectrum in presence of an identical phenotype underscores of the considerable variable expressivity in this disease. Although a diffuse expression of the abnormal gene product in the retinal pigment epihelium must be assumed, it is still unknown which factors determine the appearance of unifocal versus multifocal lesions with excessive lipofuscin accumulations.