Clinical and Genetic Characterization of Patients With Pseudo–Vitellifom Macular Dystrophy and Cuticular Drusen

Abstract

Abstract: : Purpose: To study the possible role of the ABCA4, VMD2, TIMP–3, peripherin/RDS and fibulin 5 genes in the disease phenotype of patients with pseudo–vitelliform macular dystrophy and cuticular drusen. Methods: Thirty patients, ages 40–87, diagnosed with pseudo–vitelliform macular dystrophy were ascertained at MEETH and Columbia University. The presence of cuticular drusen was confirmed by clinical examination and fundus photography; fluorescein angiography and autofluorescence images were analyzed when available. DNA samples were obtained from all study subjects and screened for mutation in the ABCA4, VMD2, TIMP–3, peripherin/RDS and fibulin 5 genes by a combination of DHPLC, microarray screening and direct sequencing. Results: All patients presented with cuticular drusen and pseudo–vitelliform detachment (n = 22) or atrophic changes following regression of the detachment (n = 8). In addition, 4 patients presented with geographic atrophy, three patients presented with choroidal neovascularization and 1 patient was diagnosed with both. Twelve patients had not only cuticular, but also soft indistinct drusen. Visual acuity ranged from 20/20 to CF. The screening of 30 patients revealed the I32V mutation in peripherin /RDS in one patient and 2 ABCA4 variants, T897I and G1961E, in 2 more patients. All three variants have been considered disease–associated in multiple earlier studies. No amino acid–altering variants were detected in VMD2, TIMP–3, and fibulin 5 genes in the 30 patients. Conclusions:Possibly disease–associated mutations were detected in 3/30 (10%) of patients presenting with pseudo–vitellifom macular dystrophy and cuticular drusen; therefore, ABCA4 and RDS mutations may be involved in a small fraction of the described (sub)–phenotype. Fibulin 5 mutations have been recently linked to patients with cuticlar drusen and macular degeneration however, this study, although relatively small, did not confirm this observation.

Keywords: gene screening • retinal degenerations: hereditary