Prevalence of the EFEMP1 R345W mutation in patients with presumed AMD originating from the endemic area of Malattia Leventinese and evidence for lack of genetic heterogeneity.

Abstract

Abstract: : Purpose:ML is an inherited autosomal dominant macular dystrophy first described in the Leventina valley in Switzerland. A single mutation in EFEMP1 has been reported in all but one affected families (Toto et al. 2002). The phenotype is characterized by early peripapillary and macular radial drusen and the disease progresses towards geographic atrophy by the fifth or sixth decade mimicking AMD. The aim of this study was to determine the prevalence of R345W in patients with presumed AMD originating from the Leventina valley. Methods: 280 unrelated patients with presumed AMD, referred for angiographic examination, were invited by mail to participate. EFEMP1 exon 10 was PCR–amplified and screened by DHPLC for the presence of the R345W mutation. Variants were confirmed by direct bidirectional sequencing and MspI digestion. Results: : Fifty patients accepted to participate to the study (18 men, 32 women; mean age 71.0 ± 9.5 years). The R345W mutation was identified in 3 patients (6 %).The first patient (53 years old), presented with clinical and angiographic evidence of hemorrhagic choroidal neovascular membrane in the right eye. The second patient, a myopic 59–year–old woman, presented with bilateral degenerative macular lesions with macular edema in the left eye. The third patient was a 78 years old woman with chorioretinal atrophy of the macular area with bilateral subretinal fibrosis. Interestingly she belonged to the same family reported by Toto et al. Conclusion:Our results suggest that end–stage Malattia Leventinese significantly contributes to the population of presumed AMD in this endemic area of Switzerland. In addition the third R345W–positive patient corresponded to the oldest patient of the family with Malattia Leventinese for which linkage apparently excluded the EFEMP1 locus (Toto et al. 2002). The phenotype of all family members was reappraised, showing fortuitous aggregation of radial and unspecific juvenile drusen in the same family. Genotypic data were consistent with linkage to the EFEMP1 locus after exclusion of the phenocopies. DHPLC–based detection of the R345W mutation represents a simple, cost–effective and rapid screening method allowing for the discrimination of the underlying genotype of patients with presumed AMD.

Keywords: retinal degenerations: hereditary • genetics • clinical (human) or epidemiologic studies: prevalence/incidence