Unfavorable effect of photodynamic therapy for late subretinal neovascularization with chorioretinal anastomoses associatedwith idiopathic multiple serous detachments of the retinal pigment epithelium.

PURPOSE: To describe a case of a 46-year-old woman with an asymptomatic history of unilateral multiple serous detachments of the retinal pigment epithelium (PED) in the right eye, treated with photodynamic therapy (PDT) with verteporfin for recent onset of subfoveal choroidal neovascularization (CNV) with chorioretinal anastomoses (CRA). RESULTS: Fluorescein and indocyanine green (ICG) angiography, performed with a Heidelberg scanning laser ophthalmoscope (SLO), demonstrated a predominantly classic foveal choroidal neovascular membrane associated with a PED and 1 one retinal and 2 two venous chorioretinal anastomoses. The left fundus was normal. PDT therapy was performed according to standard techniques. Three PDT treatments were performed at an interval of 3 months. Three months after the second PDT, visual acuity dropped to 20/200, with an en-largement of the neovascular network. One month after the third treatment, visual acuity deteriorated further and the CRA appeared enlarged, associated with a dense fibrotic re-action in the centere of the lesion. CONCLUSIONS: This clinical observation demonstrates that idiopathic serous detachments of the retinal pigment epithelium may represent predisposing changes to CNV development, and in the case CNV is associated with CRA, PDT may be unsuccessful. (Eur J Ophthalmol 2004; 14: 568-71).

Unfavorable effect of photodynamic therapy for late subretinal neovascularization with chorioretinal anastomoses associated with idiopathic multiple serous detachments of the retinal pigment epithelium.

PURPOSE: To describe a case of a 46-year-old woman with an asymptomatic history of unilateral multiple serous detachments of the retinal pigment epithelium (PED) in the right eye, treated with photodynamic therapy (PDT) with verteporfin for recent onset of subfoveal choroidal neovascularization (CNV) with chorioretinal anastomoses (CRA). METHODS: Case report. RESULTS: Fluorescein and indocyanine green (ICG) angiography, performed with a Heidelberg scanning laser ophthalmoscope (SLO), demonstrated a predominantly classic foveal choroidal neovascular membrane associated with a PED and 1 one retinal and 2 two venous chorioretinal anastomoses. The left fundus was normal. PDT therapy was performed according to standard techniques. Three PDT treatments were performed at an interval of 3 months. Three months after the second PDT, visual acuity dropped to 20/200, with an enlargement of the neovascular network. One month after the third treatment, visual acuity deteriorated further and the CRA appeared enlarged, associated with a dense fibrotic reaction in the centere of the lesion. CONCLUSIONS: This clinical observation demonstrates that idiopathic serous detachments of the retinal pigment epithelium may represent predisposing changes to CNV development, and in the case CNV is associated with CRA, PDT may be unsuccessful.

A homozygous deletion in RPE65 in a small Sardinian family with autosomal recessive retinal dystrophy.

PURPOSE: We have been engaged in an ongoing study to screen candidate genes for mutations in small families with various forms of autosomal recessive retinal dystrophy. Here we report the screening of a cohort of 14 families from Sardinia for mutations in the genes encoding the alpha- and beta-subunits of cGMP-phosphodiesterase and RPE65 (PDE6A, PDE6B, and RPE65). METHODS: Haplotype analysis was performed on each family using simple sequence repeat markers closely flanking or within each of the three gene candidates. For families in which a gene could not be ruled out from segregating with disease, exons of the gene from proband DNAs were screened for mutations by SSCPE (single strand conformation polymorphism electrophoresis). All variants found by SSCPE were sequenced directly. RESULTS: By haplotype analysis, 6/14, 11/14, and 4/13 families were ruled out for PDE6A, PDE6B, and RPE65, respectively. A few variants were found in the proband DNAs of the remaining families, but only one was significant: a 20 bp deletion in exon 4 of RPE65. The deletion co-segregated with disease in one family and caused a frame shift that produces a stop codon downstream. It was absent from the other Sardinian families that we tested, and from Sardinian and North American controls. Results of studies of phenotype in homozygotes and heterozygotes in this Sardinian family are compared with those from a non-Sardinian family recently reported to have the same RPE65 mutation. CONCLUSIONS: This RPE65 mutation, which appears to be quite restricted in its occurrence in Sardinia, leads to childhood onset severe retinal dystrophy or Leber congenital amaurosis. Affecteds of the other 13 plus two additional families were diagnosed with arRP. This family lived in an area of Sardinia where none of the others lived suggesting different ancestral origins.

Complete congenital stationary night blindness maps on Xp11.4 in a Sardinian family.

X-linked congenital stationary night blindness (CSNBX) is a hereditary non-progressive retinal disorder, which can appear in two different clinical forms, complete and incomplete, associated with CSNB1 and CSNB2 loci on Xp. We describe a Sardinian family with complete CSNBX and define better the limits of the CSNB1 genetic locus on Xp11.4 through linkage analysis. Haplotype analysis showed two key recombinants, which restrict the CSNB1 locus to a region of about 3 cM limited by markers DSX1068 and DSX6810 respectively. The locus that we describe is included in the CSNB1 locus defined by previous reports referring to the same clinical form of the disease. These results, in addition to other recent mapping reports about families from different geographical areas, confirm the genetic homogeneity of X-linked complete CSNB.

A novel mutation in the GLC1A gene causes juvenile open-angle glaucoma in 4 families from the Italian region of Puglia.

BACKGROUND: Primary open-angle glaucoma encompasses a complex of potentially blinding ocular diseases characterized by a normal-appearing angle of the anterior chamber, a characteristic degeneration of the optic nerve with resultant typical visual field defects, and usually, an elevated intraocular pressure. It can be subdivided into 2 groups according to the age at onset: the more prevalent chronic open-angle glaucoma diagnosed after 40 years of age, and the less common juvenile form, which occurs between 3 years of age and early adulthood. A locus for primary open-angle glaucoma (GLC1A) has been mapped to a 3-centimorgan region of the long arm of chromosome 1 (1q23-25). Recently, the myocilin (MYOC) gene, located in this chromosomal interval, has been found mutated in several patients affected by primary open-angle glaucoma. OBJECTIVE: To describe the clinical and molecular genetic features of 4 pedigrees affected by autosomal dominant juvenile open-angle glaucoma, all from the Italian region of Puglia. METHODS: Clinical study, gonioscopy, automated perimetry, and DNA analysis were performed on several members of the 4 families. RESULTS: We identified a new molecular defect (1177GACA-->T) in the third exon of the GLC1A gene. This mutation is present in all affected persons and in 2 still phenotypically normal persons. CONCLUSION: Our results are important for diagnostic purposes because it is now possible to identify asymptomatic carriers, for whom clinical surveillance for the early detection and treatment of glaucoma may be suggested.

Molecular basis of open-angle glaucoma in Italy.

Glaucoma is a group of ocular diseases characterized by an optic neuropathy in which degeneration of retinal ganglion cells leads to a characteristic excavation of the optic nerve head. Primary open-angle glaucoma (POAG) can be subdivided into two groups according to age of onset:- 1. the more common middle- to late-age onset, chronic open-angle glaucoma (COAG) diagnosed after the age of 40 years; 2. the rarer juvenile open-angle glaucoma (JOAG), which is diagnosed between the age of 3 years and early adulthood. Recently, the gene coding for the trabecular meshwork-induced glucocorticoid response protein (TIGR), located in chromosome 1 (1q23-25), was found mutated in patients affected by POAG. In this work we describe the clinical and molecular genetic features of several Italian families affected by autosomal dominant POAG, collected in various regions of Italy.

Blue-yellow perimetry in patients with ocular hypertone.

The authors report the data of the blue-yellow (B-Y) perimetry compared with the Standard perimetry in normal subjects with endocular hypertension or with initial glaucoma. With the aim of evaluating the relationship with chromatic sense deficits, precociously found in glaucoma, the F-M 100 Hue test and Lanthony D 15 Desaturé test were done. Checks were made of refraction, visual acuity, pupil diameter and assumption of medications. Sensitivity reduction in eyes with initial glaucoma is highly significant with the B-Y perimetry. Pupil diameter reduction is quite uninfluential while the chromatic sense shows some quantitative and qualitative deficits.

A common beta ig-h3 gene mutation (delta f540) in a large cohort of Sardinian Reis Bücklers corneal dystrophy patients. Mutations in brief no. 180. Online.

Reis-Bücklers' corneal dystrophy (RBCD) is a relatively rare autosomal dominant disease originating in the Bowman's membrane, which causes severe visual impairment. Recently RBCD, together with lattice corneal dystrophy type I (LCDI), granular corneal dystrophy (CDGG1) and Avellino stromal dystrophy (ASD), all mapped on 5q31, were found to be associated to four different mutations in the beta ig-h3 gene which codify for kerato-epithelin. We identified several cases of RBCD in Sardinia. We reconstructed through genealogical search two eight generation-families, originating from the same village (Arbus), indicating a common ancestor for RBCD in Sardinia. Linkage studies on these families confirmed the association of the disease with the 5q31 region. Sequence analysis of beta ig-h3 gene revealed a trinucleotide deletion in exon 12, corresponding to the loss of F540 in the protein sequence (delta F540). Our data describe a new mutation in the beta ig-h3 gene causing RBCD. This dominant negative mutation is located in the fourth internal repeat of kerato-epithelin which is a protein domain highly conserved across species. This suggests the basic role of this domain in maintaining the proper kerato-epithelin structure which when altered can cause the typical precipitates in the RBCD cornea.

The influence of diabetes mellitus on primary open angle glaucoma perimetry.

We have carried out a study into retinal sensitivity alterations in the course of primary open angle glaucoma to see if their appearance and evolution might be influenced by concomitant diabetes mellitus. The visual field examination (Perimeter Octopus 500 EZ, programme G1) indicated prevalent sensitivity defects in the superior hemifield, both in glaucoma only subjects and in those with diabetes as well. As to the inferior hemifield, a greater, statistically significant, retinal sensitivity defect was found in the inferior temporal quadrant of the left eye in the group of diabetics.

[Human dirofilariasis in Sardinia: 4 new cases. Review of published cases]. / Dirofilariasi umana in Sardegna: 4 nuovi casi. Revisione dei casi pubblicati.

Four new cases of Human Dirofilariasis in Sardinia are described: I subconjunctival and 3 subcutaneous. The patients were men in 3 cases and woman in the other one. The age of the subjects varied from 35 to 58 years. The parasite, Dirofilaria repens, was in all the cases a female. From the review of the literature only 3 other cases were reported in the island. Due to the diffuse presence of both the causal agent, D. repens, in dogs and many species of Culicidae that can transmit the infection to man, it is possible that human cases are more common than reported, many cases passing undiagnosed or simply not published.

Deletion in the peripherin/RDS gene in two unrelated Sardinian families with autosomal dominant butterfly-shaped macular dystrophy.

BACKGROUND: Autosomal dominant butterfly-shaped macular dystrophy is associated with different mutations of the peripherin/RDS gene. We studied the phenotype of two families with a novel large deletion in the peripherin/RDS gene. METHODS: Clinical study, fluorescein angiography, color vision testing, automatic perimetry, electrophysiologic studies, and DNA analysis were performed on all the members of the two families. RESULTS: Fundus examination in patients aged 30 to 60 years showed yellow deposits in the macula with a butterfly-shaped pattern. Central choroidal atrophy was present in the older patients only. Macular visual function tests (color vision and central visual field) were abnormal, and electro-oculograms were slightly subnormal in five individuals tested. Electroretinograms and results of dark adaptometry were normal. Linkage analysis with intragenic polymorphic markers and quantitative polymerase chain reaction showed heterozygosity for a large deletion that removed exons 2 and 3 of the peripherin/RDS gene in all affected members of two families. CONCLUSIONS: This deletion escaped detection by direct analysis of amplified exons and was identified by intragenic polymorphic markers analysis, resulting in loss of heterozygosity from affected parents to affected children, and by quantitative polymerase chain reaction. The delineation of the molecular defect associated with the disease in these two families allows us to verify the presence or absence of the disease in clinically unaffected members.

Genetic mapping of autosomal dominant primary open-angle glaucoma (POAG) in Sardinia.

Primary open-angle glaucoma (POAG) can be subdivided into two groups according to age of onset: (1) the more prevalent middle to late-age-onset chronic open-angle glaucoma (COAG) diagnosed after age 40, and (2) the less common form, juvenile open-angle glaucoma (JOAG), which occurs between 3 years of age and early adulthood. Susceptibility to either COAG or JOAG has been found to be inherited. The discovery of several genetic markers spanning the region 1q21-q24 in genetic linkage with autosomal dominant juvenile open-angle glaucoma (adJOAG) represents a major breakthrough towards the localisation of gene(s) responsible for the disease. Linkage analysis is a powerful means of distinguishing disease loci in large families with dominant disease. However the size of the group of families may represent a crucial factor for the linkage analysis. Sardinia is an island with a relatively isolated ethnic group showing a relatively high frequency of ad JOAG and COAG (Fossarello et al, 1994) and it is genetically more homogeneous than most Western populations. Therefore it represents an ideal ethnic group to search for linkage. We identified 18 families affected by POAG in which the disease appears to be inherited as autosomic dominant trait. In all families but two, occurrence of both JOAG and COAG in the same kindred was observed. Identification of adPOAG locus was performed by linkage analysis using 9 microsatellite markers spanning the region 1q21-q24. No significant linkage was observed. Our findings provide further evidence for genetic heterogeneity in autosomal dominant primary open angle glaucoma, even in a geographic area where a relatively homogeneous genetic background exists.

The relationship between glucose-6-phosphate dehydrogenase deficiency and cataracts in Sardinia. An epidemiological and biochemical study.

The Italian island of Sardina occupies an important position on the map of glucose-6-phosphate dehydrogenase (G6PD)-deficiency distribution throughout the world, since in this region the condition is particularly frequent and severe (erythrocytes show only 0-7% of G6PD normal activity, while people result affect up to 35% depending on the district). In order to investigate the relationship between the deficiency of G6PD in erythrocytes and in lens, and cataractogenesis, we studied 2125 idiopathic cataractous and non-cataractous subjects, both G6PD-deficient and normal, males and females. Parameters investigated included incidence, distribution and type of cataracts, age at the moment of the first observation, geographical provenance, and G6PD activity in erythrocytes. Moreover, G6PD activity and glutathione (GSSG)-reducing activity was assessed in cataractous lenses obtained from deficient and normal individuals. G6PD deficiency was found to be significantly more frequent in males of the age-group 40-49 years (P = 0.025), while the frequency of G6PD deficiency was decisively lower in the older age-groups. In females, mainly heterozygotes, no evidence of such a relation was found. Cataractous lenses obtained from male patients with no G6PD activity in erythrocytes showed undetectable levels of G6PD activity, and lowered, but not extinguished, levels of GSSG-reducing activity. Cataractous lenses from heterozygous females showed intermediate levels of G6PD activity and GSSG-reducing activity. A preliminary study of 182 diabetic, G6PD-deficient and non-deficient subjects, failed to demonstrate that Sardinian variants of G6PD deficiency provide protection against cataract formation in diabetic patients.

Identification and distribution of coated vesicles in the retinal pigment epithelium of man and rabbit.

Coated pits (CPs) and coated vesicles (CVs) were investigated in the retinal pigment epithelium (RPE) of man and rabbit. In both species CPs and CVs show the typical coat of bristles radiating from their convex surface. CPs originate only from invaginations of the basal and apical cell membrane. The bipolar distribution of CPs is reflected in the distribution of CVs, which are most concentrated near the basal and apical cell boundaries. Neither fusion of CVs with the cytoplasmic organelles nor the presence of receptosomes could be demonstrated. The distribution patterns of CPs, CVs, Golgi apparatus, and mitochondria are very similar in RPE of man and rabbit. Moreover, as compared with other ocular tissues. CVs found in RPE differ both in size and distribution from those found in the pigment epithelium of the pars plana ciliaris and in trabecular endothelial cells. This peculiarity might indicate that receptor-mediated endocytosis via CVs plays a role in the transport across RPE of substances that are specific to this epithelium. Some analogies between the specificity of size and distribution of CVs in RPE and the process of internalization and transport of retinal are suggested.

Coated pits and coated vesicles in the endothelial cells of trabecular meshwork.

Coated pits (CPs) and coated vesicles (CVs) were investigated in the trabecular meshwork of man and rabbit. In both man and rabbit CPs and CVs appear to be randomly distributed throughout the trabecular tissue. CVs are located in the peripheral cytoplasm of the trabecular endothelial cells and show an average diameter of 0 . 16 micron. The ratio between the number of CPs and CVs ranges from 0 . 53 (rabbit) to 0 . 6 (man). The number of CPs and CVs is higher in rabbit than in man. Consequently, the overall CPs surface and CVs volume density estimates are higher in rabbits, where CPs represent about 1% of the cell surface and CVs account for about 0 . 4% of the cell cytoplasm. In man these percentages are 0 . 46 and 0 . 17%, respectively. No significant changes of CPs and CVs were found in rabbits with corticosteroid-induced ocular hypertension. However, changes in length of boundary membrane of CPs, though not statistically significant, were accompanied by proportional changes in CVs diameter.