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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 -
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 -
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 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 -
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 -
The Journal of Physiology Sep 1953
Topics: Color Perception; Color Vision; Color Vision Defects; Humans
PubMed: 13097391
DOI: 10.1113/jphysiol.1953.sp004964 -
Scientific Reports Jul 2023To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and...
To report the association of autoimmune polyglandular syndrome type 1 (APS1) with cone dystrophy in a large Saudi family. This is a Retrospective chart review and prospective genetic testing and ophthalmic examination of a large multiplex consanguineous family. Genetic testing was performed on 14 family members, seven of whom had detailed ophthalmic examinations. Medical history, ocular history and evaluation, visual field testing, full-field electroretinogram (ERG), and Whole Exome Sequencing (WES) results were analyzed. Three family members were homozygous for c.205_208dupCAGG;p.(Asp70Alafs*148) in AIRE and homozygous for c.481-1G>A in PDE6C. One additional family member was homozygous for only the AIRE variant and another additional family member was homozygous for only the PDE6C variant. All patients with homozygosity for the PDE6C variant had cone dystrophy, and all patients with homozygosity for the AIRE variant had APS1. In addition, two of the family members who were homozygous for the PDE6C and AIRE variants had reduced rod function on ERG. We report the co-inheritance for APS1 and PDE6C-related cone dystrophy, an unusual example of two seemingly independent recessive conditions coinciding within a family. Dual molecular diagnosis must be taken into account by ophthalmologists facing unusual constellations of findings, especially in consanguineous families.
Topics: Humans; Cone Dystrophy; Prospective Studies; Retrospective Studies; Genetic Testing; Homozygote
PubMed: 37433860
DOI: 10.1038/s41598-023-38419-9 -
American Journal of Ophthalmology Oct 2020To characterize the progression of optical gaps and expand the known etiologies of this phenotype.
PURPOSE
To characterize the progression of optical gaps and expand the known etiologies of this phenotype.
DESIGN
Retrospective cohort study.
METHODS
Thirty-six patients were selected based on the identification of an optical gap on spectral-domain optical coherence tomography (OCT) from a large cohort of patients (N = 746) with confirmed diagnoses of inherited retinal dystrophy. The width and height of the gaps in 70 eyes of 36 patients were measured by 2 independent graders using the caliper tool on Heidelberg Explorer. Measurements of outer and central retinal thickness were also evaluated and correlated with gap dimensions.
RESULTS
Longitudinal analysis confirmed the progressive nature of optical gaps in patients with Stargardt disease, achromatopsia, occult macular dystrophy, and cone dystrophies (P < .003). Larger changes in gap width were noted in patients with Stargardt disease (78.1 μm/year) and cone dystrophies (31.9 μm/year) compared with patients with achromatopsia (16.2 μm/year) and occult macular dystrophy (15.4 μm/year). Gap height decreased in patients with Stargardt disease (6.5 μm/year; P = .02) but increased in patients with achromatopsia (3.3 μm/year) and occult macular dystrophy (1.2 μm/year). Gap height correlated with measurements of central retinal thickness at the fovea (r = 0.782, P = .00012). Interocular discordance of the gap was observed in 7 patients. Finally, a review of all currently described etiologies of optical gap was summarized.
CONCLUSION
The optical gap is a progressive phenotype seen in an increasing number of etiologies. This progressive nature suggests a use as a biomarker in the understanding of disease progression. Interocular discordance of the phenotype may be a feature of Stargardt disease and cone dystrophies.
Topics: Adolescent; Adult; Aged; Biomarkers; Calcium-Binding Proteins; Child; Color Vision Defects; Cone-Rod Dystrophies; Disease Progression; Electroretinography; Female; Humans; Macular Degeneration; Male; Membrane Proteins; Middle Aged; Phenotype; Retina; Retinitis Pigmentosa; Retrospective Studies; Stargardt Disease; Tomography, Optical Coherence; Visual Acuity; rab GTP-Binding Proteins
PubMed: 32445700
DOI: 10.1016/j.ajo.2020.05.016 -
Ophthalmic Research 2015Achromatopsia (ACHM) is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1 in 30,000. It presents at birth or early infancy and... (Review)
Review
Achromatopsia (ACHM) is a rare autosomal recessive inherited retinal disorder with an incidence of approximately 1 in 30,000. It presents at birth or early infancy and is typically characterized by reduced visual acuity, nystagmus, photophobia, and very poor or absent color vision. The symptoms arise from isolated cone dysfunction, which can be caused by mutations in the crucial components of the cone phototransduction cascade. Although ACHM is considered a functionally nonprogressive disease affecting only the cone system, recent studies have described progressive age-dependent changes in retinal architecture. Currently, no specific therapy is available for ACHM; however, gene replacement therapy performed on animal models for three ACHM genes has shown promising results. Accurate genetic and clinical diagnosis of patients may therefore enhance and enable therapeutic intervention in the near future. This short review summarizes the genetic background, pathophysiology, clinical findings, diagnostics, and therapeutic perspectives in ACHM.
Topics: Animals; Color Vision Defects; Disease Models, Animal; Drug Evaluation, Preclinical; Electroretinography; Eye Proteins; Genetic Therapy; Humans; Mutation; Pedigree; Retinal Cone Photoreceptor Cells; Retinal Degeneration
PubMed: 26304472
DOI: 10.1159/000435957 -
Cold Spring Harbor Perspectives in... Oct 2014Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2... (Review)
Review
Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies. Curr Opin Genet Dev 11: 307-316.). IRDs may be inherited as Mendelian traits or through mitochondrial DNA, and may affect the entire retina (e.g., rod-cone dystrophy, also known as retinitis pigmentosa, cone dystrophy, cone-rod dystrophy, choroideremia, Usher syndrome, and Bardet-Bidel syndrome) or be restricted to the macula (e.g., Stargardt disease, Best disease, and Sorsby fundus dystrophy), ultimately leading to blindness. IRDs are a major cause of severe vision loss, with profound impact on patients and society. Although IRDs remain untreatable today, significant progress toward therapeutic strategies for IRDs has marked the past two decades. This progress has been based on better understanding of the pathophysiological pathways of these diseases and on technological advances.
Topics: Animals; Bardet-Biedl Syndrome; Choroideremia; Clinical Trials as Topic; Color Vision Defects; Disease Models, Animal; Eye Diseases, Hereditary; Genetic Diseases, X-Linked; Genetic Heterogeneity; Genetic Therapy; Humans; Leber Congenital Amaurosis; Macular Degeneration; Myopia; Night Blindness; Optogenetics; Retinal Degeneration
PubMed: 25324231
DOI: 10.1101/cshperspect.a017111