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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 -
EMBO Molecular Medicine Apr 2021Gene therapy using recombinant adeno-associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful...
Gene therapy using recombinant adeno-associated virus (rAAV) vectors to treat blinding retinal dystrophies has become clinical reality. Therapeutically impactful targeting of photoreceptors still relies on subretinal vector delivery, which detaches the retina and harbours substantial risks of collateral damage, often without achieving widespread photoreceptor transduction. Herein, we report the development of novel engineered rAAV vectors that enable efficient targeting of photoreceptors via less invasive intravitreal administration. A unique in vivo selection procedure was performed, where an AAV2-based peptide-display library was intravenously administered in mice, followed by isolation of vector DNA from target cells after only 24 h. This stringent selection yielded novel vectors, termed AAV2.GL and AAV2.NN, which mediate widespread and high-level retinal transduction after intravitreal injection in mice, dogs and non-human primates. Importantly, both vectors efficiently transduce photoreceptors in human retinal explant cultures. As proof-of-concept, intravitreal Cnga3 delivery using AAV2.GL lead to cone-specific expression of Cnga3 protein and rescued photopic cone responses in the Cnga3 mouse model of achromatopsia. These novel rAAV vectors expand the clinical applicability of gene therapy for blinding human retinal dystrophies.
Topics: Animals; Capsid; Color Vision Defects; Dependovirus; Dogs; Genetic Therapy; Genetic Vectors; Mice; Retina
PubMed: 33616280
DOI: 10.15252/emmm.202013392 -
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 -
Ophthalmology Jun 2022To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). (Observational Study)
Observational Study
PURPOSE
To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH).
DESIGN
Multicenter, observational study.
PARTICIPANTS
A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384).
METHODS
Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans.
MAIN OUTCOME MEASURES
Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA).
RESULTS
The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH.
CONCLUSIONS
We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.
Topics: Albinism; Albinism, Ocular; Albinism, Oculocutaneous; Color Vision Defects; Cytoskeletal Proteins; Fovea Centralis; Humans; Membrane Proteins; Vision Disorders
PubMed: 35157951
DOI: 10.1016/j.ophtha.2022.02.010 -
Communications Biology Mar 2022Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often...
Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.
Topics: Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Humans; Light Signal Transduction; Mutation, Missense; Retinal Cone Photoreceptor Cells
PubMed: 35233102
DOI: 10.1038/s42003-022-03120-6 -
Investigative Ophthalmology & Visual... Feb 2021Emmetropization is the process of adjusting ocular growth to the focal plane in order to achieve a clear image. Chromatic light may be involved as a cue to guide this...
PURPOSE
Emmetropization is the process of adjusting ocular growth to the focal plane in order to achieve a clear image. Chromatic light may be involved as a cue to guide this process. Achromats are color blind and lack normal cone function; they are often described as being hyperopic, indicating a failure to emmetropize. We aim to describe the refraction and refractive development in a population of genetically characterized achromats.
METHODS
Refractive error data were collected retrospectively from 28 medical records of CNGB3 c.1148delC homozygous achromats. The distribution of spherical equivalent refractive error (SER) and spherical error was analyzed in adults. The refractive development in children was analyzed by documenting astigmatic refractive error and calculating median SER in 1-year age groups and by analyzing the individual development when possible.
RESULTS
The distribution of SER and spherical error resembled a Gaussian distribution, indicating that emmetropization was disturbed in achromats, but we found indication of some decrease in SER during the first years of childhood. The prevalence of refractive errors was high and broadly distributed. Astigmatic refractive errors were frequent but did not seem to increase with age.
CONCLUSIONS
Refractive development in achromats is more complicated than a complete failure to emmetropize. The spread of refractive errors is larger than previously documented. Results presented here support the theory that chromatic cues and cone photoreceptors may play a role in emmetropization in humans but that it is not essential.
Topics: Accommodation, Ocular; Adolescent; Adult; Aged; Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Female; Follow-Up Studies; Humans; Male; Middle Aged; Refraction, Ocular; Refractive Errors; Retrospective Studies; Time Factors; Young Adult
PubMed: 33560291
DOI: 10.1167/iovs.62.2.10 -
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 -
The British Journal of Ophthalmology Feb 2004The cone dystrophies comprise a heterogeneous group of disorders characterised by visual loss, abnormalities of colour vision, central scotomata, and a variable degree... (Review)
Review
The cone dystrophies comprise a heterogeneous group of disorders characterised by visual loss, abnormalities of colour vision, central scotomata, and a variable degree of nystagmus and photophobia. They may be stationary or progressive. The stationary cone dystrophies are better described as cone dysfunction syndromes since a dystrophy often describes a progressive process. These different syndromes encompass a wide range of clinical and psychophysical findings. The aim is to review current knowledge relating to the cone dysfunction syndromes, with discussion of the various phenotypes, the currently mapped genes, and genotype-phenotype relations. The cone dysfunction syndromes that will be discussed are complete and incomplete achromatopsia, oligocone trichromacy, cone monochromatism, blue cone monochromatism, and Bornholm eye disease. Disorders with a progressive cone dystrophy phenotype will not be discussed.
Topics: Color Vision Defects; Genotype; Humans; Mutation; Phenotype; Psychophysics; Scotoma; Syndrome
PubMed: 14736794
DOI: 10.1136/bjo.2003.027102