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Molecular Diagnosis & Therapy Jan 2022Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the... (Review)
Review
Achromatopsia (ACHM), also known as rod monochromatism or total color blindness, is an autosomal recessively inherited retinal disorder that affects the cones of the retina, the type of photoreceptors responsible for high-acuity daylight vision. ACHM is caused by pathogenic variants in one of six cone photoreceptor-expressed genes. These mutations result in a functional loss and a slow progressive degeneration of cone photoreceptors. The loss of cone photoreceptor function manifests at birth or early in childhood and results in decreased visual acuity, lack of color discrimination, abnormal intolerance to light (photophobia), and rapid involuntary eye movement (nystagmus). Up to 90% of patients with ACHM carry mutations in CNGA3 or CNGB3, which are the genes encoding the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel, respectively. No authorized therapy for ACHM exists, but research activities have intensified over the past decade and have led to several preclinical gene therapy studies that have shown functional and morphological improvements in animal models of ACHM. These encouraging preclinical data helped advance multiple gene therapy programs for CNGA3- and CNGB3-linked ACHM into the clinical phase. Here, we provide an overview of the genetic and molecular basis of ACHM, summarize the gene therapy-related research activities, and provide an outlook for their clinical application.
Topics: Animals; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Genetic Therapy; Humans; Mutation; Retinal Cone Photoreceptor Cells
PubMed: 34860352
DOI: 10.1007/s40291-021-00565-z -
The Yale Journal of Biology and Medicine Dec 2017Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal... (Review)
Review
Achromatopsia is a rare congenital cause of vision loss due to isolated cone photoreceptor dysfunction. The most common underlying genetic mutations are autosomal recessive changes in , , , , , or . Animal models of , , and have been rescued using AAV gene therapy; showing partial restoration of cone electrophysiology and integration of this new photopic vision in reflexive and behavioral visual tests. Three gene therapy phase I/II trials are currently being conducted in human patients in the USA, the UK, and Germany. This review details the AAV gene therapy treatments of achromatopsia to date. We also present novel data showing rescue of a mouse model using an rAAV.CBA.CNGA3 vector. We conclude by synthesizing the implications of this animal work for ongoing human trials, particularly, the challenge of restoring integrated cone retinofugal pathways in an adult visual system. The evidence to date suggests that gene therapy for achromatopsia will need to be applied early in childhood to be effective.
Topics: Animals; Circadian Rhythm; Clinical Trials as Topic; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Dependovirus; Disease Models, Animal; Dogs; Genetic Therapy; Humans; Mice; Retina
PubMed: 29259520
DOI: No ID Found -
The British Journal of Ophthalmology Jan 2016The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision and varying... (Review)
Review
The cone dysfunction syndromes are a heterogeneous group of inherited, predominantly stationary retinal disorders characterised by reduced central vision and varying degrees of colour vision abnormalities, nystagmus and photophobia. This review details the following conditions: complete and incomplete achromatopsia, blue-cone monochromatism, oligocone trichromacy, bradyopsia and Bornholm eye disease. We describe the clinical, psychophysical, electrophysiological and imaging findings that are characteristic to each condition in order to aid their accurate diagnosis, as well as highlight some classically held notions about these diseases that have come to be challenged over the recent years. The latest data regarding the genetic aetiology and pathological changes observed in the cone dysfunction syndromes are discussed, and, where relevant, translational avenues of research, including completed and anticipated interventional clinical trials, for some of the diseases described herein will be presented. Finally, we briefly review the current management of these disorders.
Topics: Color Vision Defects; Genotype; Humans; Phenotype; Retinal Cone Photoreceptor Cells; Retinal Diseases; Syndrome
PubMed: 25770143
DOI: 10.1136/bjophthalmol-2014-306505 -
Vision Research May 2019Retinal and cortical signals initiated by a single cone type can be recorded using the spectral compensation (or silent substitution) paradigm. Moreover, responses to...
Retinal and cortical signals initiated by a single cone type can be recorded using the spectral compensation (or silent substitution) paradigm. Moreover, responses to instantaneous excitation increments combined with gradual excitation decreases are dominated by the response to the excitation increment. Similarly, the response to a sudden excitation decrement dominates the overall response when combined with a gradual excitation increase. Here ERGs and VEPs were recorded from 34 volunteers [25.9 ± 10.4 years old (mean ± 1 SD); 25 males, 9 females] to sawtooth flicker (4 Hz) stimuli that elicited L- or M-cone responses using triple silent substitution. The mean luminance (284 cd/m) and the mean chromaticity (x = 0.5686, y = 0.3716; CIE 1931 color space) remained constant and thus the state of adaptation was the same in all conditions. Color discrimination thresholds along protan, deutan, and tritan axes were obtained from all participants. Dichromatic subjects were genetically characterized by molecular analysis of their opsin genes. ERG responses to L-cone stimuli were absent in protanopes whereas ERG responses to M-cone stimuli were strongly reduced in deuteranopes. Dichromats showed generally reduced VEP amplitudes. Responses to cone-specific stimuli obtained with standard electrophysiological methods may give the same classification as that obtained with the Cambridge Colour Test and in some cases with the genetic analysis of the L- and M-opsin genes. Therefore, cone-specific ERGs and VEPs may be reliable methods to detect cone dysfunction. The present data confirm and emphasize the potential use of cone-specific stimulation, combined with standard visual electrodiagnostic protocols.
Topics: Adolescent; Adult; Color Perception Tests; Color Vision; Color Vision Defects; Cone Opsins; Electroretinography; Evoked Potentials, Visual; Female; Humans; Male; Young Adult
PubMed: 30844384
DOI: 10.1016/j.visres.2019.02.011 -
The Journal of Physiology Sep 1953
Topics: Color Perception; Color Vision; Color Vision Defects; Humans
PubMed: 13097391
DOI: 10.1113/jphysiol.1953.sp004964 -
PloS One 2021Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a...
SIGNIFICANCE
Horizontal visual field extension was assessed for red and white stimuli in subjects with protanopia using semi-automated kinetic perimetry. In contrast to a conventional anomaloscope, the "red/white dissociation ratio" (RWR) allows to describe protanopia numerically. For the majority of subjects with protanopia a restriction for faint red stimuli was found.
PURPOSE
Comparing the horizontal visual field extensions for red and white stimuli in subjects with protanopia and those with normal trichromacy and assessing the related intra-subject intra-session repeatability.
METHODS
The subjects were divided into groups with protanopia and with normal trichromacy, based on color vision testing (HMC anomaloscope, Oculus, Wetzlar/FRG). Two stimulus characteristics, III4e and III1e, according to the Goldmann-classification, were presented with semi-automated kinetic perimetry (Octopus 900 perimeter, Haag-Streit, Köniz/CH). They moved along the horizontal meridian, with an angular velocity of 3°/s towards the visual field center, starting from either the temporal or nasal periphery. If necessary, a 20° nasal fixation point offset was chosen to capture the temporal periphery of the visual field. For each condition the red/white dissociation ratio (RWR); Pat Appl. DPMA DRN 43200082D) between the extent of the isopter for red (RG610, Schott, Mainz/ FRG) and white stimuli along the horizontal meridian was determined.
RESULTS
All data are listed as median/interquartile range: Five males with protanopia (age 22.1/4.5 years) and six males with normal trichromacy (control group, age 30.5/15.2 years) were enrolled. The RWR is listed for the right eye, as no clinically relevant difference between right and left eye occurred. Protanopes' RWR for mark III4e (in brackets: control group) was 0.941/0.013 (0.977/0.019) and for mark III1e 0.496/0.062 (0.805/0.051), respectively.
CONCLUSIONS
In this exploratory "proof-of-concept study" red/white dissociation ratio perimetry is introduced as a novel technique aiming at assessing and quantifying the severity of protanopia. Further effort is needed to understand the magnitude of the observed red-/white dissociation and to extend this methodology to a wider age range of the sample and to anomalous trichromacies (protanomalia) with varying magnitude.
Topics: Adolescent; Adult; Color Perception; Color Vision Defects; Humans; Male; Photic Stimulation; Reaction Time; Visual Field Tests; Young Adult
PubMed: 34928982
DOI: 10.1371/journal.pone.0260362 -
The Journal of Physiology Feb 19831. A subject who has suffered from central serous chorio-retinopathy in his left eye noticed differences in the colour of a given light as perceived by each eye alone....
1. A subject who has suffered from central serous chorio-retinopathy in his left eye noticed differences in the colour of a given light as perceived by each eye alone. Standard screening tests (colour order and colour matching) indicated a tritan defect in the left eye; the right eye was normal on these tests.2. The subject was dichromatic in his left eye, trichromatic in his right. The left-eye distimulus colour-matching functions, spectral luminosity, and wave-length discrimination functions were indistinguishable from corresponding data for congenital tritanopia. Comparable right-eye data were normal.3. Spectral dichromatic colour matches were invariant under changes of intensity and under addition of a common light to both halves of the field. (Grassmann's laws of linearity are satisfied.)4. Increment threshold versus intensity (t.v.i.) curves for a blue (481.9 nm) test on a yellow background yielded the normal three branches (for Pi(4)(mu), Pi(1)(mu) and Pi(3)(mu) respectively) in the trichromatic eye. In the dichromatic eye a single mechanism was found. It had the field sensitivity of Pi(4)(mu) whether measured with the blue, or with a violet (429.5 nm) test. No trace of Pi(3)(mu) or Pi(1)(mu) was ever discovered in the tritanopic eye. Both are normal in the trichromatic eye.5. The field sensitivities of Pi(4), Pi(5) and Pi(3) of the normal eye are well fitted by linear combinations of the spectral colour-matching functions of the trichromatic eye. Pi(4) and Pi(5) of the dichromatic eye are well fitted by linear combinations of the tritanopic matching functions.6. Colour matches made by the trichromatic eye do not match when viewed by the tritanopic eye, almost certainly because the ocular media of the two eyes have wave-length-dependent differences in absorption. For the largest difference (430 nm) the trichromatic eye transmits about 2.2 times more light than its fellow. When allowance is made for these differences, the field sensitivities of Pi(4) and Pi(5) of the two eyes do not differ. The field sensitivities of Pi(4) and Pi(5) of the normal eye, on the other hand, differ significantly from those of the average spectra obtained on four normal trichromats by Stiles, in a way that cannot be attributed to differences in transmittance of ocular media.7. It is concluded that classical (or acquired) tritanopia is not distinguishable in its manifestations from congenital tritanopia; furthermore, tritanopia can be regarded as a reduced form of normal trichromacy, once allowances are made for absorption of the ocular media and for variations among normal trichromats.8. Despite extensive search no evidence could be uncovered which might exclude the hypothesis that the colour vision in tritanopia depends exclusively upon absorption in only two foveal cone pigments, one long-wave-absorbing and one medium-wave-absorbing.
Topics: Adult; Choroid; Color Perception; Color Perception Tests; Color Vision Defects; Humans; Light; Male; Retinal Diseases; Sensory Thresholds; Uveal Diseases
PubMed: 6603508
DOI: 10.1113/jphysiol.1983.sp014557 -
Investigative Ophthalmology & Visual... Dec 2019To perform deep phenotyping of subjects with PDE6C achromatopsia and examine disease natural history.
PURPOSE
To perform deep phenotyping of subjects with PDE6C achromatopsia and examine disease natural history.
METHODS
Eight subjects with disease-causing variants in PDE6C were assessed in detail, including clinical phenotype, best-corrected visual acuity, fundus autofluorescence, and optical coherence tomography. Six subjects also had confocal and nonconfocal adaptive optics scanning light ophthalmoscopy, axial length, international standard pattern and full-field electroretinography (ERG), short-wavelength flash (S-cone) ERGs, and color vision testing.
RESULTS
All subjects presented with early-onset nystagmus, decreased best-corrected visual acuity, light sensitivity, and severe color vision loss, and five of them had high myopia. We identified three novel disease-causing variants and provide phenotype data associated with nine variants for the first time. No subjects had foveal hypoplasia or residual ellipsoid zone (EZ) at the foveal center; one had an absent EZ, three had a hyporeflective zone, and four had outer retinal atrophy. The mean width of the central EZ lesion on optical coherence tomography at baseline was 1923 μm. The mean annual increase in EZ lesion size was 48.3 μm. Fundus autofluorescence revealed a central hypoautofluorescence with a surrounding ring of increased signal (n = 5). The mean hypoautofluorescent area at baseline was 3.33 mm2 and increased in size by a mean of 0.13 mm2/year. Nonconfocal adaptive optics scanning light ophthalmoscopy revealed residual foveal cones in only one of two cases. Full-field ERGs were consistent with severe generalized cone system dysfunction but with relative preservation of S-cone sensitivity.
CONCLUSIONS
PDE6C retinopathy is a severe cone dysfunction syndrome often presenting as typical achromatopsia but without foveal hypoplasia. Myopia and slowly progressive maculopathy are common features. There are few (if any) residual foveal cones for intervention in older adults.
Topics: Adolescent; Adult; Child; Color Vision; Color Vision Defects; Cyclic Nucleotide Phosphodiesterases, Type 6; Electroretinography; Eye Proteins; Female; Follow-Up Studies; Forecasting; Humans; Male; Middle Aged; Ophthalmoscopy; Phenotype; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 31826238
DOI: 10.1167/iovs.19-27761 -
Clinical & Experimental Optometry Jul 2004The structure and function of the available and significant clinical colour vision tests are reviewed in the light of the needs in the clinical examination of congenital... (Review)
Review
The structure and function of the available and significant clinical colour vision tests are reviewed in the light of the needs in the clinical examination of congenital and acquired colour vision deficiencies. The tests are grouped and described as pseudo-isochromatic plates, arrangement tests, matching tests and vocational tests. The colorimetric constructions of the test types are described and the efficiency of their performance and usefulness discussed. Recommendations are made for basic and extended test batteries, when examining of congenital and acquired colour vision deficiencies in the consulting room.
Topics: Color Perception Tests; Color Vision Defects; Equipment Design; Humans
PubMed: 15312031
DOI: 10.1111/j.1444-0938.2004.tb05057.x -
Journal of Visualized Experiments : JoVE Apr 2017Many techniques have been developed to visualize how an image would appear to an individual with a different visual sensitivity: e.g., because of optical or age...
Many techniques have been developed to visualize how an image would appear to an individual with a different visual sensitivity: e.g., because of optical or age differences, or a color deficiency or disease. This protocol describes a technique for incorporating sensory adaptation into the simulations. The protocol is illustrated with the example of color vision, but is generally applicable to any form of visual adaptation. The protocol uses a simple model of human color vision based on standard and plausible assumptions about the retinal and cortical mechanisms encoding color and how these adjust their sensitivity to both the average color and range of color in the prevailing stimulus. The gains of the mechanisms are adapted so that their mean response under one context is equated for a different context. The simulations help reveal the theoretical limits of adaptation and generate "adapted images" that are optimally matched to a specific environment or observer. They also provide a common metric for exploring the effects of adaptation within different observers or different environments. Characterizing visual perception and performance with these images provides a novel tool for studying the functions and consequences of long-term adaptation in vision or other sensory systems.
Topics: Adaptation, Physiological; Aging; Color Perception; Color Perception Tests; Color Vision; Color Vision Defects; Humans; Retina; Visual Cortex
PubMed: 28518063
DOI: 10.3791/54038