No abstract

The aim of this study was to characterize the pathological and functional consequences of the G1961E mutant allele in the Stargardt disease gene ABCA4. Data from 15 patients were retrospectively reviewed and all the patients had at least one G1961E mutation. Comprehensive ophthalmic examination, full-field and pattern electroretinograms, and fundus autofluorescence (FAF) imaging were performed on all patients. Microperimetry, spectral-domain optical coherence tomography (OCT), and fluorescein angiography were performed in selected cases. Genetic screening was performed using the ABCR400 micro-array that currently detects 496 disctinct ABCA4 variants. All patients had normal full-field scotopic and photopic electroretinograms (ERGs) and abnormal pattern electroretinograms (PERGs) performed on both eyes, and all the fundi had bull's eye maculopathy without retinal flecks on FAF. On OCT, one patient had disorganization of photoreceptor outer segment, two had outer nuclear layer (ONL) thinning likely due to photoreceptor atrophy proximal to the foveal center, and three had additional retinal pigment epithelium (RPE) atrophy. On microperimetry, six patients had eccentric superior fixation and amongst this group, five had an absolute scotoma in the foveal area. DNA analysis revealed that three patients were homozygous G1961E/G1961E and the rest were compound heterozygotes for G1961E and other ABCA4 mutations. The G1961E allele in either homozygosity or heterozygosity is associated with anatomical and functional pathologies limited to the parafoveal region and a trend to delayed onset of symptoms, relative to other manifestations of ABCA4 mutations. Our observations support the hypothesis that the G1961E allele contributes to localized macular changes rather than generalized retinal dysfunction, and is a cause of bull's eye maculopathy in either the homozygosity or heterozygosity state. In addition, genetic testing provides precise diagnosis of the underlying maculopathy, and current non-invasive imaging techniques could be used to detect photoreceptor damage at the earliest clinical onset of the disease.Corresponding authors: 1 Dr.

To describe the phenotype and determine the genetic cause of autosomal dominant retinitis pigmentosa (adRP) in a large African American family. Methods: Fourteen members from 4 generations were evaluated clinically. Visual field measurements were made for most, and electroretinography, Tü binger perimetry, and optical coherence tomographic testing were done for individual family members. Genetic screening was performed on a recently introduced adRP microarray that contains approximately 400 mutations from 13 genes. Results: All of the affected members had a type 1 form of adRP, characterized by early onset of symptoms for visual impairment, marked central and peripheral vision loss, nondetectable electroretinographic responses, and decreased macular thickness on optical coherence tomographic testing. Two variants in the PRPF8 gene were identified in the proband, H2309R and IVS41-4G→A. The H2309R mutation segregated with the disease in the family, whereas the IVS41-4G→A variant did not. Conclusions: The severe form of adRP was caused by the PRPF8 H2309R variant, whereas the IVS41-4G→A variant was benign. Clinical Relevance: PRPF8 mutations should be suspected in patients with a type 1 form of adRP. A combination of advanced clinical workup and comprehensive genetic testing is essential for the precise diagnosis of diseases with high genetic heterogeneity such as RP.