Rigmor C. Baraas

Adaptive optics retinal imaging reveals S-cone dystrophy in tritan color-vision deficiency

Tritan color-vision deficiency is an autosomal dominant disorder associated with mutations in the short-wavelength-sensitive- (S-) cone-pigment gene. An unexplained feature of the disorder is that individuals with the same mutation manifest different degrees of deficiency. To date, it has not been possible to examine whether any loss of S-cone function is accompanied by physical disruption in the cone mosaic. Two related tritan subjects with the same novel mutation in their S-cone-opsin gene, but different degrees of deficiency, were examined. Adaptive optics was used to obtain high-resolution retinal images, which revealed distinctly different S-cone mosaics consistent with their discrepant phenotypes. In addition, a significant disruption in the regularity of the overall cone mosaic was observed in the subject completely lacking S-cone function. These results taken together with other recent findings from molecular genetics indicate that, with rare exceptions, tritan deficiency is progressive in nature.

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin

Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.

Variability in parafoveal cone mosaic in normal trichromatic individuals

Parafoveal function is important for daily visual tasks such as reading. Here the variability in cone density along the four cardinal meridians in parafoveal regions of the retina was investigated in vivo using an adaptive optics fundus camera. Ten healthy normal trichromatic individuals were included in the study. There were significant differences in cone density between individuals at all four tested eccentricities (0.5, 1, 2 and 3°) and meridians. Cone density ranged from 34,900 to 63,000 cones/mm2 at 1° horizontally, and from 31,600 to 60,700 at 1° vertically. The results were consistent with those of Curcio et al. (1990), although between-individual variability is greater than previously reported in the parafovea from 1 to 3.2°.

Integrity of the cone photoreceptor mosaic in oligocone trichromacy.

PURPOSE Oligocone trichromacy (OT) is an unusual cone dysfunction syndrome characterized by reduced visual acuity, mild photophobia, reduced amplitude of the cone electroretinogram with normal rod responses, normal fundus appearance, and normal or near-normal color vision. It has been proposed that these patients have a reduced number of normal functioning cones (oligocone). This paper has sought to evaluate the integrity of the cone photoreceptor mosaic in four patients previously described as having OT. METHODS Retinal images were obtained from two brothers (13 and 15 years) and two unrelated subjects, one male (47 years) and one female (24 years). High-resolution images of the cone mosaic were obtained using high-speed adaptive optics (AO) fundus cameras. Visible structures were analyzed for density using custom software. Additional retinal images were obtained using spectral domain optical coherence tomography (SD-OCT), and the four layers of the photoreceptor-retinal pigment epithelium complex (ELM, IS/OS, RPE1, RPE2) were evaluated. Cone photoreceptor length and the thickness of intraretinal layers were measured and compared to previously published normative data. RESULTS The adult male subject had infantile onset nystagmus while the three other patients did not. In the adult male patient, a normal appearing cone mosaic was observed. However, the three other subjects had a sparse mosaic of cones remaining at the fovea, with no structure visible outside the central fovea. On SD-OCT, the adult male subject had a very shallow foveal pit, with all major retinal layers being visible, and both inner segment (IS) and outer segment (OS) length were within normal limits. In the other three patients, while all four layers were visible in the central fovea and IS length was within normal limits, the OS length was significantly decreased. Peripherally the IS/OS layer decreased in intensity, and the RPE1 layer was no longer discernable, in keeping with the lack of cone structure observed on AO imaging outside the central fovea. CONCLUSIONS Findings are consistent with the visual deficits being caused by a reduced number of healthy cones in the two brothers and the adult female. In the unrelated adult subject, no structural basis for the disorder was found. These data suggest two distinct groups on the basis of structural imaging. It is proposed that the former group with evidence of a reduction in cone numbers is more in keeping with typical OT, with the latter group representing an OT-like phenotype. These two groups may be difficult to readily discern on the basis of phenotypic features alone, and high-resolution imaging may be an effective way to distinguish between these phenotypes.

Substitution of isoleucine for threonine at position 190 of S-opsin causes S-cone-function abnormalities

Five mutations in the S-cone-opsin gene (OPN1SW) that give rise to different single amino-acid substitutions (L56P, G79R, S214P, P264S, R283Q) are known to be associated with tritan color-vision deficiency. Here we report a sixth OPN1SW mutation (T190I) and the associated color vision phenotype. S-opsin genotyping and clinical evaluation of color vision were performed on affected and unaffected family members and normal controls. Chromatic contrast was tested at different levels of retinal illuminance. Affected family members were heterozygous for a nucleotide change that substituted the amino acid isoleucine (I) in place of threonine (T) that is normally present at position 190 of the S-opsin. The mutation is in extracellular loop II (EII). The association between making tritan errors and having the T190I mutant S opsin was strong (p>0.0001: Fishers exact test). The performance of subjects with the T190I mutation was significantly different from that of normal trichromats along the tritan vector under all conditions tested (Mann-Whitney U: p<0.05), but not along the protan or deutan vectors. Individuals with the T190I S-opsin mutation behaved as mild tritans at 12.3-92.3Td, but as tritanopes at 1.2-9.2Td, for both light-adapted and dark-adapted conditions. The results are consistent with the mutant opsin causing abnormal S-cone function.

Color Constancy of Red-Green Dichromats and Anomalous Trichromats

Purpose. Color-vision deficiency is associated with abnormalities in color matching and color discrimination, but its impact on the ability of people to judge the constancy of surface colors under different lights (color constancy) is less clear. This work had two aims: first, to quantify the degree of color constancy in subjects with congenital red-green color deficiency; second, to test whether the degree of color constancy in anomalous trichromats can be predicted from their Rayleigh anomaloscope matches. Methods. Color constancy of red-green color-deficient subjects was tested in a task requiring the discrimination of illuminant changes from surface-reflectance changes. Mondrian-like colored patterns, generated on the screen of a computer monitor, were used as stimuli to avoid the spatial cues provided by natural objects and scenes. Spectral reflectances were taken from the Munsell Book of Color and from natural scenes. Illuminants were taken from the daylight locus. Results. Protanopes and deuteranopes performed more poorly than normal trichromats with Munsell spectral reflectances but were less impaired with natural spectral reflectances. Protanomalous and deuteranomalous trichromats performed as well as, or almost as well as, normal trichromats, independent of the type of reflectance. Individual differences were not correlated with Rayleigh anomaloscope matches. Conclusions. Despite the evidence of clinical color-vision tests, red-green color-deficient persons are less disadvantaged than might be expected in their judgments of surface colors under different lights.

Poorer color discrimination by females when tested with pseudoisochromatic plates containing vanishing designs on neutral backgrounds

It might be expected that normal trichromatic females would perform as well as normal trichromatic males of the same age when tested with standard clinical color-vision tests that use pseudoisochromatic vanishing designs on neutral gray backgrounds such as the Hardy-Rand-Rittler (HRR) pseudoisochromatic plates and the Neitz Test of Color Vision (NTCV). Here 2966 children aged 6-13 years from four municipalities in Norway were tested in their school classrooms with the NTCV. Children who made errors on the test were retested. 187 males and 152 females made one or more errors on retest, and each was tested individually on the Richmond HRR Fourth Edition. 8% of the males were defined as color deficient when a double criterion for failing was applied, that is, one or more errors on the NTCV and two or more errors on the HRR. The calculated frequency of color-deficient females (homozygotes) for the same criterion is 0.42%. By contrast, 3% of females failed the criterion that gave a stable population of color-deficient males. This result is considered in relation to reports of female carriers of color-vision deficiency having problems with the Ishihara test and of females having poorer color discrimination than males.

The influence of L-opsin gene polymorphisms and neural ageing on spatio-chromatic contrast sensitivity in 20–71 year olds

Chromatic contrast sensitivity may be a more sensitive measure of an individuals visual function than achromatic contrast sensitivity. Here, the first aim was to quantify individual- and age-related variations in chromatic contrast sensitivity to a range of spatial frequencies for stimuli along two complementary directions in color space. The second aim was to examine whether polymorphisms at specific amino acid residues of the L- and M-opsin genes (OPN1LW and OPN1MW) known to affect spectral tuning of the photoreceptors could influence spatio-chromatic contrast sensitivity. Chromatic contrast sensitivity functions were measured in 50 healthy individuals (20-71 years) employing a novel pseudo-isochromatic grating stimulus. The spatio-chromatic contrast sensitivity functions were found to be low pass for all subjects, independent of age and color vision. The results revealed a senescent decline in spatio-chromatic contrast sensitivity. There were considerable between-individual differences in sensitivity within each age decade for individuals 49 years old or younger, and age did not predict sensitivity for these age decades alone. Forty-six subjects (including a color deficient male and eight female carriers) were genotyped for L- and M-opsin genes. The Ser180Ala polymorphisms on the L-opsin gene were found to influence the subjects color discrimination and their sensitivity to spatio-chromatic patterns. The results expose the significant role of neural and genetic factors in the deterioration of visual function with increasing age.

The relationship between perifoveal achromatic, L- and M-cone acuity and retinal structure as assessed with multimodal high resolution imaging

HIGHLIGHTSCone density correlates with L‐cone logMAR at 5 deg eccentricity.L‐cone acuity is a useful indicator of the perifoveal structure‐function relationship.Cone density cannot be characterized by a scalar factor across eccentricity. ABSTRACT The relationships between perifoveal measures of achromatic‐, L‐ and M‐cone acuity and retinal structure were investigated in healthy young males. Thirty‐two males, aged 20–39 years, with normal foveal logMAR letter acuity and no observed ocular abnormalities participated in the study. Achromatic and isolated L‐ and M‐cone spatial acuity was measured in the dominant eye with a Sloan E letter of 90% achromatic decrement contrast or 23% increment cone contrast, respectively. Separately, the central part of the same eye was imaged with high‐resolution spectral‐domain optical coherence tomography (SD‐OCT) and adaptive optics ophthalmoscopy (AOO). Thickness measures and cone density in the fovea and parafoveal region were not correlated with perifoveal structural measures. A significant correlation was observed between thicker retinal pigment epithelium (RPE) complex, higher cone density and better L‐cone logMAR at 5 deg eccentricity, but not for achromatic or M‐cone logMAR. The results imply that single letter perifoveal L‐cone acuity, rather than achromatic acuity, may provide a useful measure for assessing the structure‐function relationship and detecting early changes in the perifoveal cone mosaic.

The genetics of congenital aniridia-a guide for the ophthalmologist

Congenital aniridia is a rare panocular disease caused by fundamental disturbances in the development of the eye, characterized primarily by hypoplasia of the iris and macula. Severe secondary complications such as keratopathy, cataract, and glaucoma are common and often lead to considerable visual impairment or blindness. Many complications in aniridia patients are difficult to treat and present a challenge for the ophthalmologist. Increasingly, associated nonocular features of the disease are also being recognized. Over the past decades, major steps have been made in the understanding of the genetic basis of aniridia. Moreover, recent studies have prepared the ground for future treatment options based on specific mutations. Therefore, specific knowledge about genetics in aniridia has become more important than ever. We provide an overview of the field of aniridia genetics and its clinical implications.