| Name | Francesca |
| Surname | Simonelli |
| Institution | Università degli Studi della Campania Luigi Vanvitelli |
| francesca.simonelli@unicampania.it | |
| Address | Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Naples, Italy |
Autosomal recessive Stargardt disease (STGD) has been associated with substantial genetic and phenotypic heterogeneity. By systematic clinical analyses of STGD patients with complete genetic data (i.e. identified mutations on both alleles of the ABCA4 gene), we set out to determine phenotypic subtypes and to correlate these with specific ABCA4 alleles. Twenty-eight patients from 18 families with STGD/fundus flavimaculatus were investigated. All patients were submitted to complete ophthalmologic examination, electrophysiology, fluorescein angiography and ABCA4 gene chip analysis. Two main clinical phenotypes were observed among the examined patients. The severe phenotype was characterized by the onset of the disease <20 years and reduced ERG response, whereas the mild phenotype presented with later onset of the disease and a normal ERG response. Genetic analysis of the ABCA4 gene revealed, in the severe group, more frequently deletions, stop codons and insertions as compared to the mild phenotype group (p=0.0113 by Fisher's exact test). Moreover, the compound heterozygous mutations G1961E/5018+2T-->C found in 7 patients from 3 unrelated STGD families were associated with a mild phenotype in all subjects, except 1. This study documented variability of the clinical expression of STGD in relation to the age of onset of the disease, fundus appearance and the ERG response and allowed to subdivide patients into a severe and a mild phenotype group. These findings suggest that an extensive and comprehensive genetic analysis of STGD patients combined with thorough clinical evaluation, including the careful recording of the age of onset of the disease, would allow a more precise prognostic evaluation.
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 ABCA4 gene 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.
To describe the clinical phenotype of X linked juvenile retinoschisis in eight Italian families with six different mutations in the XLRS1 gene.
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).
To assess the mutation spectrum in the ABCR gene and clinical phenotypes in Italian families with autosomal recessive Stargardt disease (STGD1) and fundus flavimaculatus (FFM).
Since many years experimental evidences have suggested an association between nutrition and lens opacities. A dietary deficiency of antioxidants and reactive oxygen scavengers may be involved in the pathogenesis of the "idiopathic" human senile cataract, as it has been demonstrated in some experimental cataracts. We tested the levels of ascorbic acid (vit. C), alpha-tocopherol (vit. E), reduced glutathione (GSH) and malondialdehyde (MDA) in the plasma or in the red blood cells (RBC) of 42 patients who were affected by surgically significant cataract and of 40 age-matched controls. Plasma vit. C mean level was 4.46 gamma/ml in cataracts and 4.62 gamma/ml in controls, while vit. E level was 7.70 and 7.09 gamma/ml respectively. RBC GSH was found to be 342 gamma/ml in cataracts and 346 in controls, while the MDA content was 4.06 picoMol/ml and 4.08 picoMol/ml respectively. The level of each tested nutrient or metabolite was not found to be statistically different between cataractous patients and controls, nor any significant trend was found to be present when the nutrients and metabolites were correlated to each other. Our results do not support the hypothesis of a nutritional deficiency in human senile cataracts. However, a defect in the antioxidative metabolism pathways could be present either systemically or at lens level.