Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion.

Inherited retinal dystrophies are the most common cause of childhood blindness in the developed world. Cone-rod retinal dystrophies are severe examples of this group of disorders. Analysis of a large cone-rod dystrophy pedigree suggested that inheritance within the family was influenced by meiotic drive (p = 0.008), a rare segregation distortion in human genetics. Two-point linkage analysis showed significant linkage with three markers mapping to chromosome 19q. Multipoint analysis gave a maximum lod score of 10.08 (theta = 0.05) distal to D19S47. Cone-rod dystrophy is therefore assigned to 19q13.1-q13.2 and a new candidate locus for other retinal dystrophies is identified.

Chromosome 19q cone-rod retinal dystrophy. Ocular phenotype.

OBJECTIVE: To describe the phenotype in a family with dominantly inherited cone-rod dystrophy with chromosome assignment to a 19q locus, and to correlate this with current classifications of this retinal dystrophy. DESIGN: A detailed clinical examination including Goldmann perimetry was undertaken in all family members. Six members under the age of 30 years underwent dark-adapted electroretinography, color contrast-sensitivity measurement, dark-adapted static perimetry, and dark adaptometry. PATIENTS: The study included 34 affected and 22 unaffected patients in four generations of a pedigree that manifested autosomal dominant cone-rod retinal dystrophy linked to a chromosome 19q locus by genetic linkage analysis. RESULTS: Loss of visual acuity occurred in the first decade of life, onset of night blindness occurred after 20 years of age, and little visual function remained after the age of 50 years. Central and, later, peripheral retinal fundus changes were associated with central scotoma, pseudoaltitudinal field defects, and finally global loss of function. Psychophysical and electrophysiologic testing before the age of 26 years showed more marked loss of cone than rod function. CONCLUSIONS: The phenotype associated with this mutation does not fit well into previous subtypes of cone-rod dystrophy. Further studies will be needed to correlate specific genetic mutations in this group of conditions with the various clinical phenotypes.

Fundus changes in mesangiocapillary glomerulonephritis type II: vitreous fluorophotometry.

We have described a complex abnormality of retinal pigment epithelium, Bruch's membrane, and choriocapillaris in mesangiocapillary glomerulonephritis (MCGN) type II. Patients with MCGN type II were examined by vitreous fluorophotometry which reveals that there is a breakdown of the blood retinal barrier (BRB) in those patients with the typical fundus lesions. The function of this barrier was calculated as a penetration ratio and was statistically greater in these patients when compared with a group of (a) normal persons, (b) patients with drusen, and (c) patients with other forms of glomerulonephritis.

Fundus changes in (type II) mesangiocapillary glomerulonephritis simulating drusen: a histopathological report.

We report for the first time to our knowledge the histopathological findings in the eye of a patient with type II mesangiocapillary glomerulonephritis (dense deposit disease) in which a deposit of material morphologically very similar to that which is pathognomonic for the disease in the kidney was demonstrated in Bruch's membrane. The nature of the deposit in the renal lesion is unknown but is considered to represent a structural alteration secondary to a reaction with anticomplement antibody. Clinically the fundus appearance resembled that seen in drusen.

Immunocytochemical study of retinal diode laser photocoagulation in the rat.

AIM: To determine the nature of the cellular infiltrate, alterations in cell adhesion molecules, and MHC II antigen expression in the rat retina following diode laser retinal photocoagulation. METHOD: 20 normal Lister rats underwent diode laser photocoagulation of the retina. Frozen sections from eyes enucleated at 0, 1, 5, 13, and 33 days post laser were examined for T cells (R7.3), CD4 T cells (W3/25), activated CD4 T cells (OX-40), CD8 T cells (OX-8), B cells (OX-33), and macrophages (OX-42), MHC II antigen (OX-6), and E-Selectin-1, VCAM-1, and ICAM-1. RESULTS: Retinal diode laser photocoagulation stimulated a wound healing response in the outer retina and choroid. The cellular infiltrate included macrophages and activated CD4 T cells at 13 and 33 days post laser. Glial cells in the inner plexiform and inner nuclear layers expressed MHC II antigen at 24 hours only. ICAM-1 antigen was induced in RPE cells and in Muller cells in the inner retina at all time intervals post laser and intense staining for ICAM-1 was present around intraretinal migrated cells at 13 and 33 days post laser. VCAM-1 antigen expression was induced in the choroidal vascular endothelium and RPE at 13 and 33 days after laser as was E-Selectin-1 antigen expression which was also evident focally at the external limiting membrane in association with migrated cells adjacent to the burn. CONCLUSIONS: These results suggest that alterations in cell adhesion molecules may regulate the migration and activation of retinal pigment epithelium, macrophages and CD4 T cells at the outer blood-retinal barrier and choroid following diode laser photocoagulation of the normal Lister rat retina.

Fundus changes in mesangiocapillary glomerulonephritis type II: clinical and fluorescein angiographic findings.

Previously we have demonstrated a deposit in Bruch's membrane in a single case of mesangiocapillary glomerulonephritis type II. We studied a group of patients with this disease and described extensive clinical and fluorescein angiographic abnormalities, which were in marked contrast to the findings in a group of patients with other forms of glomerulonephritis. This finding contributes to our understanding of the pathophysiology of the complex of the retinal pigment epithelium, Bruch's membrane, and choriocapillaris.

Electrophysiology of type II mesangiocapillary glomerulonephritis with associated fundus abnormalities.

The retinal electrophysiology is reported in four patients with type II mesangiocapillary glomerulonephritis and partial lipodystrophy with associated fundus abnormalities and no visual symptoms. The histological hallmark of the condition is that of widespread electron dense deposits in the renal glomerulus and in the choriocapillaris and Bruch's membrane of the eye. Three of the four patients had the typical fundal appearance of multiple, yellow, drusen-like lesions at the posterior pole of the eye with normal visual acuity. These three patients had abnormally low Arden ratios on electro-oculography with normal electroretinography responses. This is the first clinical model of disease known to be isolated to the choriocapillaris and Bruch's membrane causing an electro-oculographic abnormality without any clinically detectable deficit in visual function.

Traumatic retinal angiopathy and seat belts: pathogenesis of whiplash injury.

Three cases of traumatic retinal angiopathy associated with whiplash injury are presented. The pathogenesis of the fundal appearances is discussed. Local microcirculatory disturbances are postulated as the cause of the retinopathy as opposed to the systemic disturbance associated with Purtscher's retinopathy. This condition may be underdiagnosed as there may be few abnormal signs on funduscopy. Fluorescein angiography may be very helpful. The incidence may be increasing as a result of legislation concerning the wearing of seat belts, and the condition has medico-legal significance. Increasing awareness may increase diagnosis.

The role of molecular genetics in the prenatal diagnosis of retinal dystrophies.

Inherited retinal dystrophies are important causes of incurable blindness in developed countries. Advances in molecular genetics promise significant improvements in their management. Immediate benefits of present knowledge are presymptomatic and prenatal diagnosis in selected cases. To study the predictive power of these techniques a simulated genetic risk estimation was undertaken in a cone-rod retinal dystrophy pedigree known to be linked to chromosome 19. Using data on five fully informative, flanking DNA markers, phenotype was correctly assigned with only a 2% probability of error. If the two most closely linked markers were found to be uninformative, this error probability remained unchanged. Using genetic risk calculations and direct mutation detection many retinal dystrophies could now be identified by prenatal diagnosis.