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Genes Mar 2023Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are...
Achromatopsia is a rare congenital condition with cone photoreceptor dysfunction causing color blindness, reduced vision, nystagmus and photophobia. New treatments are being developed, but the current evidence is still conflicting regarding possible progression over time, and there is no clear genotype-phenotype correlation. This natural history study aimed to further explore the course of disease and potential clinical differences between various genotypes. The retrospective design allowed for the study of a large cohort with a long follow-up. Patients were identified from the Danish national registries. If not already available, genetic analysis was offered to the patient. Clinical data from 1945-2022 were retrieved from medical records and included best-corrected visual acuity (BCVA), color vision, refractive error, nystagmus, visual fields and fundoscopic findings. We identified variants believed to be disease causing in five of the known achromatopsia genes: ; ; ; and ; and novel variants were identified in and . Progressive deterioration of BCVA only attributable to achromatopsia was found in three of 58 patients. Progressive phenotype was seen with variants in and The results indicate that myopia could be more frequently occurring with variants in , and and support the evidence that achromatopsia is a predominantly stationary condition with respect to BCVA. Although a clear genotype-phenotype correlation can still not be concluded, there may be differences in phenotypical characteristics with variants in different genes.
Topics: Humans; Color Vision Defects; Retrospective Studies; Cyclic Nucleotide-Gated Cation Channels; Denmark
PubMed: 36980963
DOI: 10.3390/genes14030690 -
Progress in Retinal and Eye Research Jan 2024The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding,... (Review)
Review
The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.
Topics: Humans; Retinal Degeneration; Diabetic Retinopathy; Unfolded Protein Response; Endoplasmic Reticulum Stress; Retina; Endoplasmic Reticulum; Homeostasis
PubMed: 38092262
DOI: 10.1016/j.preteyeres.2023.101231 -
Investigative Ophthalmology & Visual... Mar 2020The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic...
PURPOSE
The purpose of this study was to report GNAT2-associated achromatopsia (GNAT2-ACHM) natural history, characterize photoreceptor mosaic, and determine a therapeutic window for potential intervention.
METHODS
Patients with GNAT2-ACHM were recruited from a single tertiary referral eye center (Moorfields Eye Hospital, London, UK). We performed longitudinal clinical evaluation and ophthalmic examination, and multimodal retinal imaging, including adaptive optics scanning light ophthalmoscopy, quantitative analysis of the cone mosaic, and outer nuclear layer (ONL) thickness, including cone densities evaluation in selected regions of interest and comparison with reported healthy controls.
RESULTS
All nine subjects (3 women) presented with nystagmus, decreased visual acuity (VA), light sensitivity, and highly variable color vision loss. One patient had normal color vision and better VA. Mean VA was 1.01 (±0.10) logarithms of the minimal angle of resolution (LogMAR) at baseline, and 1.04 (±0.10) LogMAR after a mean follow-up (range) of 7.6 years (1.7-12.8 years). Optical coherence tomography showed preservation of the foveal ellipsoid zone (EZ; n = 8; 88.9%), and EZ disruption (n = 1; 11.1%). Mean ONL thickness (range, ± SD) was 84.72 µm (28.57-113.33, ± 25.46 µm) and 86.47 µm (28.57-113.33, ± 24.65 µm) for right and left eyes, respectively. Mean cone densities (±SD) at 190 µm, 350 µm, and 500 µm from the foveal center, were 48.4 (±24.6), 37.8 (±14.7), and 30.7 (±9.9), ×103 cones/mm2, respectively. Mean cone densities were lower than these of unaffected individuals, but with an overlap.
CONCLUSIONS
The cone mosaic in GNAT2-ACHM is relatively well preserved, potentially allowing for a wide therapeutic window for cone-directed interventions.
Topics: Adolescent; Adult; Child; Color Perception Tests; Color Vision Defects; Electroretinography; Female; Follow-Up Studies; GTP-Binding Protein gamma Subunits; Humans; Male; Middle Aged; Multimodal Imaging; Nystagmus, Pathologic; Ophthalmoscopy; Optical Imaging; Pedigree; Phenotype; Retinal Cone Photoreceptor Cells; Tomography, Optical Coherence; Visual Acuity; Young Adult
PubMed: 32203983
DOI: 10.1167/iovs.61.3.40 -
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 -
Indian Journal of Ophthalmology Jun 2022To determine the pattern of refractive error among commercial drivers in north India.
PURPOSE
To determine the pattern of refractive error among commercial drivers in north India.
METHODS
Descriptive study with convenient sampling conducted among commercial drivers of north India.
RESULTS
A total of 213 (75.8%) heavy-vehicle and 68 (24.2%) light-vehicle drivers were screened for eye diseases. Refractive error for distance was reported in 44 (15.7%; 95% CI: 11.6-20.4) drivers. Hyperopia was reported in 23 (8.2%; 95% CI: 5.2-12) drivers, followed by myopia in 15 (5.3%; 95% CI: 3-8.6) drivers and astigmatism in six (2.1%; 95% CI: 0.7-4.5) drivers. Presbyopia was reported in 157 (55.8%) drivers. Dry eye was reported in 70 (24.9%), stereo deficiency in 77 (27.4%), and color vision deficiency in 11 (3.9%) drivers. Three drivers were diagnosed with cataract, and two were referred for retina evaluation.
CONCLUSION
Hyperopia in both eyes was the most common refractive error. Dry eye disease and color vision deficiency were also reported. Most of the drivers were not using spectacles for refractive error correction. Due to their mobile nature, drivers with cataract and retina diseases did not turn up for follow-up.
Topics: Cataract; Color Vision Defects; Humans; Hyperopia; Prevalence; Refractive Errors
PubMed: 35647994
DOI: 10.4103/ijo.IJO_2510_21 -
Taiwan Journal of Ophthalmology 2018Foveal hypoplasia is a retinal disorder in which there is a lack of full development of the morphology of the fovea. The optical coherence tomography (OCT) and... (Review)
Review
Foveal hypoplasia is a retinal disorder in which there is a lack of full development of the morphology of the fovea. The optical coherence tomography (OCT) and functional findings are presented in relation to the underlying genetic and developmental conditions. Recent advancements of high-resolution OCT imaging have unveiled characteristics of foveal hypoplasia that were not detected by conventional imaging methods. An absence of a foveal pit does not necessarily imply poor visual acuity, and the maturation of the cone photoreceptors is important for the visual acuity. Regardless of the degree of the development of the inner retinal layers, the visual acuity can be preserved as in diseases such as Stickler syndrome that is a newly identified retinal disorder associated with foveal hypoplasia.
PubMed: 30637189
DOI: 10.4103/tjo.tjo_101_18 -
Expert Opinion on Biological Therapy Jan 2018The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight... (Review)
Review
INTRODUCTION
The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity.
AREAS COVERED
This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis.
EXPERT OPINION
Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.
Topics: Choroideremia; Clinical Trials as Topic; Color Vision Defects; Dependovirus; Genetic Therapy; Genetic Vectors; Humans; Lentivirus; Macular Degeneration; Nerve Degeneration; Stargardt Disease; Usher Syndromes; cis-trans-Isomerases
PubMed: 29057663
DOI: 10.1080/14712598.2018.1389886 -
European Journal of Ophthalmology Nov 2023Achromatopsia is an autosomal recessive cone dysfunction syndrome, characterized by absence of color discrimination, low visual acuity, photophobia, and nystagmus....
BACKGROUND
Achromatopsia is an autosomal recessive cone dysfunction syndrome, characterized by absence of color discrimination, low visual acuity, photophobia, and nystagmus. Achromatopsia constitutes a common cause of visual impairment in children, with a prevalence of 1:30,000 worldwide.
OBJECTIVE
To characterize the clinical characteristics of achromatopsia, the main genes causing the disease in our population and the clinical course of the disease, with an emphasis on visual function stability with increasing age.
METHODS
Retrospective study based on medical charts of patients with achromatopsia. Patients were divided into two groups according to their age at last follow-up: older and younger than 10 years. A subset of patients with long term follow-up were analyzed separately, with patients being described in both age groups.
RESULTS
Seventy-six patients were included in the study. The mean age was 14.28 years. Variants in the CNGA3 gene were the most common (73.6%). Clinical characteristics included photophobia (96.2%), nystagmus (93.6%), hypermetropia (72.3%) and strabismus (51.1%). In the large cohort there was no correlation of age with visual acuity ( = 0.129). In the separate subset cohort with long follow-up there was a relative improvement in visual acuity with age ( < 0.001).
CONCLUSIONS
CNGA3 is the main gene associated with achromatopsia in our population (around ∼ 73%), which is in contrast to the distribution worldwide (∼ 25%). Most achromats suffer from photophobia and nystagmus, and the main refractive error is hypermetropia. Achromatopsia's natural course seems to be stationary, and there may even be a slight improvement in visual acuity with time.
PubMed: 37920903
DOI: 10.1177/11206721231212768 -
Current Biology : CB Apr 2023Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of...
Most defects causing retinal degeneration in retinitis pigmentosa (RP) are rod-specific mutations, but the subsequent degeneration of cones, which produces loss of daylight vision and high-acuity perception, is the most debilitating feature of the disease. To understand better why cones degenerate and how cone vision might be restored, we have made the first single-cell recordings of light responses from degenerating cones and retinal interneurons after most rods have died and cones have lost their outer-segment disk membranes and synaptic pedicles. We show that degenerating cones have functional cyclic-nucleotide-gated channels and can continue to give light responses, apparently produced by opsin localized either to small areas of organized membrane near the ciliary axoneme or distributed throughout the inner segment. Light responses of second-order horizontal and bipolar cells are less sensitive but otherwise resemble those of normal retina. Furthermore, retinal output as reflected in responses of ganglion cells is less sensitive but maintains spatiotemporal receptive fields at cone-mediated light levels. Together, these findings show that cones and their retinal pathways can remain functional even as degeneration is progressing, an encouraging result for future research aimed at enhancing the light sensitivity of residual cones to restore vision in patients with genetically inherited retinal degeneration.
Topics: Humans; Retinal Degeneration; Retinal Cone Photoreceptor Cells; Retina; Retinitis Pigmentosa; Color Vision
PubMed: 36977418
DOI: 10.1016/j.cub.2023.03.007 -
Irish Journal of Medical Science Oct 2023Emergency service vehicle (ESV) drivers are an important part of the health, fire and police services. ESV driving is associated with increased crash risk, but little... (Review)
Review
BACKGROUND
Emergency service vehicle (ESV) drivers are an important part of the health, fire and police services. ESV driving is associated with increased crash risk, but little guidance exists in the literature on relevant medical conditions among drivers and their potential for adding to higher crash risks.
AIMS
We undertook a narrative review to examine the role of medical and other conditions in crash risk of ESV drivers.
METHOD
A literature search was conducted using the ScienceDirect and Transport Research International Documentation (TRID) databases. There was no time frame for the search, and results were restricted to review and research articles.
RESULTS
Of 570 papers identified, 13 remained after screening and full-text review. A range of factors have been shown to have an impact on increased crash risk, including the nature of the task, physical features of the equipment, training, experience, environmental conditions and secondary tasks. There was scant information on medical conditions other than alcohol use disorders.
CONCLUSIONS
Given issues of speed, vehicle and environment, it would seem prudent to mandate levels of medical fitness to drive similar to and sometimes exceeding (i.e. colour blindness for traffic signals and alerts, hearing impairment as first responders) those for group 2 drivers with extra stipulations relating to specific service needs such as enhanced visual (such as colour blindness and contrast sensitivity) and auditory function. Further research is needed on the prevalence and emergence of relevant medical conditions among ESV drivers, with due consideration of their application to the driving tasks in each service.
Topics: Humans; Automobile Driving; Accidents, Traffic; Alcoholism; Color Vision Defects; Ambulances
PubMed: 36752949
DOI: 10.1007/s11845-023-03301-0