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Investigative Ophthalmology and Visual Science

The gene for autosomal dominant retinitis pigmentosa in a large pedigree of Irish origin has recently been found to be linked to an anonymous polymorphic sequence, D3S47 (C17), from the long arm of chromosome 3. As the gene coding for rhodopsin is also assigned to the long arm of chromosome 3 and is expressed in rod photoreceptors that are affected early in this blinding disease, we searched for a mutation of the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. We found a C----A transversion in codon 23 (corresponding to a proline----histidine substitution) in 17 of 148 unrelated patients and not in any of 102 unaffected individuals. This result, coupled with the fact that the proline normally present at position 23 is highly conserved among the opsins and related G-protein receptors, indicates that this mutation could be the cause of one form of autosomal dominant retinitis pigmentosa.

A point mutation of the rhodopsin gene in one form of retinitis pigmentosa

Purpose Because previous studies suggested degeneration and loss of photoreceptors in aged human retina, the spatial density of cones and rods subserving the central 43 degrees of vision as a function of age was determined. Methods Cones and rods were counted in 27 whole mounted retinas from donors aged 27 to 90 years with macroscopically normal fundi. Photoreceptor topography was analyzed with new graphic and statistical techniques. Results Changes in cone density throughout this age span showed no consistent relationship to age or retinal location, and the total number of foveal cones was remarkably stable. In contrast, rod density decreased by 30%, beginning inferior to the fovea in midlife and culminating in an annulus of deepest loss at 0.5 to 3 mm eccentricity by the ninth decade. Space vacated by dying rods was filled in by larger rod inner segments, resulting in a similar rod coverage at all ages. At the temporal equator, cone density declined by 23%, but rods were stable throughout adulthood. Conclusions The stability of both rod coverage and rhodopsin content despite decreasing cell number suggests plasticity of the adult rod system and that age-related declines in scotopic sensitivity may be due to postreceptoral factors. There is no evidence for the massive loss of foveal cones required to explain even modest decrements in acuity, consistent with evidence that visual deficits at high photopic levels may be largely due to optical factors. Why the rods of central retina, which share a common support system and light exposure with the neighboring cones, are preferentially vulnerable to aging remains to be determined.

Aging of the human photoreceptor mosaic: evidence for selective vulnerability of rods in central retina.

Retinitis pigmentosa. The Friedenwald Lecture.

Diabetic retinopathy (DR) causes significant visual loss on a global scale. Treatments for the vision-threatening complications of diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) have greatly improved over the past decade. However, additional therapeutic options are needed that take into account pathology associated with vascular, glial, and neuronal components of the diabetic retina. Recent work indicates that diabetes markedly impacts the retinal neurovascular unit and its interdependent vascular, neuronal, glial, and immune cells. This knowledge is leading to identification of new targets and therapeutic strategies for preventing or reversing retinal neuronal dysfunction, vascular leakage, ischemia, and pathologic angiogenesis. These advances, together with approaches embracing the potential of preventative or regenerative medicine, could provide the means to better manage DR, including treatment at earlier stages and more precise tailoring of treatments based on individual patient variations.

/pdf/diabetic-retinopathy-current-understanding-mechanisms-and-2mleh6waux.pdf

Diabetic retinopathy: current understanding, mechanisms, and treatment strategies

• Four color vision tests were used to assess color vision in 51 insulin-dependent diabetic patients and 41 normal controls. Right and left eyes of diabetic patients, selected because they had minimal retinopathy, had significantly more color vision defects than controls on Lanthony desaturated D-15, Farnsworth-Munsell 100-Hue, and chromagraph tests. The 100-Hue scores were significantly higher in both right and left eyes of diabetic patients than in controls. There were no significant associations between presence or absence of a color vision defect and age, sex, age at onset, duration of diabetes, or its metabolic control.

Color Vision Defects in Early Diabetic Retinopathy

Psychophysical and electrophysiological methods are used to evaluate retinal function in a family with dominantly inherited retinitis pigmentosa. Techniques of full-field (ganzfeld) stimulation, scotopically balanced lights, and a ganzfeld adapting field are introduced to analyze the electroretinogram (ERG). Rod ERG responses, reduced in amplitude and delayed in latency, are detectable in the early stages of the disease. Cone ERG responses are normal. Dark adaptation testing shows normal cone but abnormal rod function with a slight delay in the rate of rod recovery. Scotopic luminosity curves and ERG responses to scotopically matched lights suggest that the rhodopsin present has a normal absorption spectrum. A reduction in the amount or effectiveness of rhodopsin in each rod throughout the entire retina can explain the findings. The literature on light-induced retinal degenerations is reviewed, and the effects of light exclusion on this disease are considered.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=ophth&articleId=629212&pdfFileName=archopht_80_1_009.pdf

Rod Responses in Retinitis Pigmentosa, Dominantly Inherited

Three adults with macular dysfunction and peripheral pigmentary retinal degeneration are described as one clinical entity called progressive cone-rod degeneration, based on their psychophysical and electrophysiological findings. These patients had diminishing visual acuity, abnormal color vision, monophasic dark-adaptation curves with slightly elevated rod thresholds, and markedly decreased or absent cone components in the presence of reduced rod components in the electroretinogram (ERG). Scotopic luminosity curves and ERGs with scotopically balanced lights suggest that the rhodopsin present has a normal absorption spectrum. Cone-rod degeneration is differentiated from dominanty inherited retinitis pigmentosa although both are associated with bone spicule pigmentation and retinal arteriolar attenuation. A recessive mode of inheritance is suggested, and the relationship of cone-rod degeneration to the retinal manifestations of the Laurence-Moon-Biedl syndrome is discussed.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=ophth&articleId=629213&pdfFileName=archopht_80_1_010.pdf

Progressive cone-rod degeneration

A family with autosomal dominant retinitis pigmentosa showing reduced penetrance is described. Reduced penetrance is established in patients who transmitted the gene defect to their offspring but are themselves clinically normal and beyond the age of risk for the disease. The electroretinograms (ERG) demonstrate rod responses reduced in amplitude and delayed in implicit time at an early stage similar to those seen in dominant retinitis pigmentosa with complete penetrance. Cone responses are also delayed in implicit time even when response amplitudes are normal. This cone ERG abnormality has not been found in dominant retinitis pigmentosa with complete penetrance.

Dominant Retinitis Pigmentosa With Reduced Penetrance

Psychophysical and electrophysiological testing are used to examine a family with sex-linked retinitis pigmentosa. Marked changes in the electroretinogram (ERG) precede any abnormalities visible with the ophthalmoscope. Both cone and rod responses are reduced in amplitude and delayed in implicit time. Cone responses are detectable after rod responses have disappeared. When rod function can be measured, scotopic luminosity curves and ERG responses to scotopically balanced lights indicate a normal rod action spectrum. The disease in males is widespread, whereas carrier females show loss of retinal function only in limited areas. Comparison of findings in carrier females with those in affected males provides support for the Lyon hypothesis.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=OPHTH&articleId=629425&pdfFileName=archopht_81_2_012.pdf

Ralph D. Gunkel

Papers

Color Vision Defects in Early Diabetic Retinopathy

Rod Responses in Retinitis Pigmentosa, Dominantly Inherited

Progressive cone-rod degeneration

Dominant Retinitis Pigmentosa With Reduced Penetrance

Rod and cone responses in sex-linked retinitis pigmentosa.