Visual function and genetic analysis of families with a progressive Stargardt–like disease

Abstract

Abstract: : Purpose: To characterize ocular function and to identify the genetic cause of disease in 3 families residing in the same village and suffer from a unique progressive Stargardt–like disease. Methods: Clinical evaluation included, among others, refractive error, visual acuity, a full ocular exam, color vision testing, perimetry, and electroretinography (ERG). Haplotype analysis was performed by studying microsatellite markers flanking the ABCA4 gene and single nucleotide polymorphisms (SNPs) within the gene. Microarray analysis was performed at Asper Biotech. Results: Nine affected and 13 unaffected individuals were recruited from three apparently unrelated consanguineous Muslim–Arab families who live in the same village. Two of these families (#6 and #33) are large, with multiple consanguineous marriages. During the early stages of disease, fundoscopic, angiographic and retinal function studies in patients from all three families resemble those of classic Stargardt disease. Color vision is impaired and focal foveal cone ERG responses are severely reduced and delayed. However, later in life, a severe, widespread cone–rod degeneration ensues. Full–field cone and rod ERGs are affected in a cone>rod pattern, and visual field testing reveals central scotomas and constricted peripheral fields. The marked progressive involvement of the periphery distinguishes this phenotype from classic Stargardt disease. A linkage haplotypes analysis with ABCA4 markers revealed cosegregation with the disease assuming two different causative mutations. This is in contrast with the high consanguinity level in these families. A microarray analysis of all 437 known ABCA4 sequence changes in two of these patients did not reveal any possible pathogenic mutations. Conclusions:Our data indicate that this unique phenotype, similar to Stargardt class III, is probably caused by mutations in the ABCA4 gene. It perhaps involves new mutations that have not been described thus far. These mutations apparently cause a severe form of Stargardt disease which progresses to marked impairment of peripheral as well as central retinal function. We are now in the process of screening all 50 ABCA4 exons aiming to identify these mutations.

Keywords: retina • mutations • macula/fovea