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Genetic variation in the ABCA4 (ABCR)gene has been associated with several distinct retinal phenotypes, including Stargardt disease/fundus flavimaculatus (STGD/FFM), cone-rod dystrophy (CRD), retinitis pigmentosa (RP) and age-related macular degeneration. The current model of genotype/phenotype association suggests that patients harboring deleterious mutations in both ABCR alleles would develop RP-like retinal pathology. Here we describe ABCA4-associated phenotypes, including a proband with a homozygous nonsense mutation in a family from Southern Italy. The proband had been originally diagnosed with STGD. Ophthalmologic examination included kinetic perimetry, electrophysiological studies and fluorescein angiography. DNA of the affected individual and family members was analyzed for variants in all 50 exons of the ABCA4gene by screening on the ABCR400 microarray. A homozygous nonsense mutation 2971G>T (G991X) was detected in a patient initially diagnosed with STGD based on funduscopic evidence, including bull’s eye depigmentation of the fovea and flecks at the posterior pole extending to the mid-peripheral retina. Since this novel nucleotide substitution results in a truncated, nonfunctional, ABCA4 protein, the patient was examined in-depth for the severity of the disease phenotype. Indeed, subsequent electrophysiological studies determined severely reduced cone amplitude as compared to the rod amplitude, suggesting the diagnosis of CRD. ABCR400 microarray is an efficient tool for determining causal genetic variation, including new mutations. A homozygous protein-truncating mutation in ABCA4 can cause a phenotype ranging from STGD to CRD as diagnosed at an early stage of the disease. Only a combination of comprehensive genotype/phenotype correlation studies will determine the proper diagnosis and prognosis of ABCA4-associated pathology.

Objective:Apolipoprotein E (apoE) is an important regulator of cholesterol and lipid transport during compensatory synaptogenesis. Our purpose was to investigate the role of apoE gene polymorphisms in Italian patients with age-related macular degeneration (AMD). Methods:We used the polymerase chain reaction technique to analyze apoE genotypes in 87 patients with AMD, in 47 age-matched controls and in 1,287 individuals from a general reference population. Results:The frequency of allele Ε4 carriers was significantly higher (p = 0.002) in the general population than in AMD patients, while the frequency of allele Ε2 was higher in the patients (p = 0.069) with an increased risk for AMD in the patients versus the population-based controls (odds ratio = 1.7; 95% confidence interval: 1.0–2.9). Allele Ε4 was associated with a decreased risk for AMD in the patients versus the population-based controls (odds ratio = 0.3; 95% confidence interval: 0.1–0.8). Clinical Relevance:These data suggest that apoE testing may represent a tool for the evaluation of the relative risk of AMD. Consequently, a preventive strategy can be initiated at an early stage of the disorder. Conclusion:The apoE gene polymorphism showed a significant association with the risk of AMD. The lower frequency of the Ε4 allele in AMD patients suggests that the apoE gene could play a protective role in the pathogenesis of the disease. In contrast, the Ε2 allele was found associated with a slightly increased risk of AMD, although we did not find a statistically significant effect.

It was evaluated whether ArF 193 nm excimer laser corneal surgery represents a risk factor in cataractogenesis. For this purpose, 20 male albino rabbits underwent a photorefractive keratectomy and biochemical analyses on aqueous humour (hydrogen peroxide, ascorbic acid, and reduced and oxidized glutathione) and on lens (malondialdehyde, reduced and oxidized glutathione) were performed. In the aqueous humour of all treated animals a significant increase in hydrogen peroxide and in oxidized glutathione and a concomitant decrease in ascorbic acid and reduced glutathione concentration were observed. Moreover, all these variations were significantly correlated with the cumulative UV dose used. In the lens, after excimer laser corneal surgery, there was a dramatic loss of reduced glutathione and a parallel increase in oxidized glutathione levels. Malondialdehyde concentration was also increased, but only at the highest UV exposure. Moreover, all these variations were significantly correlated with the cumulative UV dose used. These findings demonstrate that the exposure of aqueous humour and lens to the secondary radiation generated after ArF 193 nm excimer laser corneal photoablative keratectomy induces biochemical modifications which are known to be markers of cataractogenesis. Copyright 1994, 1999 Academic Press