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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 -
Annals of Translational Medicine Aug 2021Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic... (Review)
Review
Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic characterization over the past two decades have allowed identification of over 260 causative mutations associated with inherited retinal disorders. Thought to be incurable, gene supplementation therapy offers great promise in treating various forms of these blinding conditions. In gene replacement therapy, a disease-causing gene is replaced with a functional copy of the gene. These therapies are designed to slow disease progression and hopefully restore visual function. Gene therapies are typically delivered to target retinal cells by subretinal (SR) or intravitreal (IVT) injection. The historic Food and Drug Administration (FDA) approval of voretigene neparvovec for RPE65-associated Leber's congenital amaurosis (LCA) spurred tremendous optimism surrounding retinal gene therapy for various other monogenic IRDs. Novel disease-causing mutations continue to be discovered annually, and targeted genetic therapy is now under development in clinical and preclinical models for many IRDs. Numerous clinical trials for other IRDs are ongoing or have recently completed. Disorders being targeted for genetic therapy include retinitis pigmentosa (RP), choroideremia (CHM), achromatopsia (ACHM), Leber's hereditary optic neuropathy, usher syndrome (USH), X-linked retinoschisis, and Stargardt disease. Here, we provide an update of completed, ongoing, and planned clinical trials using gene supplementation strategies for retinal degenerative disorders.
PubMed: 34532415
DOI: 10.21037/atm-20-4726 -
The Neuroscientist : a Review Journal... Jun 2020Color provides valuable information about the environment, yet the exact mechanisms explaining how colors appear to us remain poorly understood. Retinal signals are... (Review)
Review
Color provides valuable information about the environment, yet the exact mechanisms explaining how colors appear to us remain poorly understood. Retinal signals are processed in the visual cortex through high-level mechanisms that link color perception with top-down expectations and knowledge. Here, we review the neuroimaging evidence about color processing in the brain, and how it is affected by acquired brain lesions in humans. Evidence from patients with brain-damage suggests that high-level color processing may be divided into at least three modules: perceptual color experience, color naming, and color knowledge. These modules appear to be functionally independent but richly interconnected, and serve as cortical relays linking sensory and semantic information, with the final goal of directing object-related behavior. We argue that the relations between colors and their objects are key mechanisms to understand high-level color processing.
Topics: Agnosia; Anomia; Cerebral Cortex; Color Perception; Color Vision Defects; Humans; Visual Pathways
PubMed: 31691627
DOI: 10.1177/1073858419882621 -
Wilderness & Environmental Medicine Dec 2023This Lessons from History article uses science, aviation, medicine, and mountaineering sources to describe some of the effects of hypoxia, illumination, and other...
This Lessons from History article uses science, aviation, medicine, and mountaineering sources to describe some of the effects of hypoxia, illumination, and other environmental conditions on the eye, the central nervous system, and light and color perception. The historical perspective is augmented by an analysis of an informal observation of the altered perception of red color on a deck of playing cards while climbing Mera Peak in the Himalaya. The appearance of a grayer red color on the cards was initially attributed to the effects of hypoxia alone. Instead, analysis of cards in combination with the low incidence of protan color vision defects at altitude indicated that glare and contrast effects in the extremely bright lighting environment combined with hypoxia likely caused the perception of a grayer red. The incident provides an educational opportunity for review, analysis, and commentary about some of the complex elements that impact color vision.
Topics: Humans; Color Vision; Color Perception; Altitude; Color Vision Defects; Hypoxia
PubMed: 37775373
DOI: 10.1016/j.wem.2023.08.003 -
Die Ophthalmologie Nov 2023Glaucoma is not a rare entity but because very few symptoms occur and visual field defects are frequently first recognized at a late stage, a large proportion of... (Review)
Review
BACKGROUND
Glaucoma is not a rare entity but because very few symptoms occur and visual field defects are frequently first recognized at a late stage, a large proportion of glaucoma diseases remain undetected. The aim of this study was to identify the proportion of undiagnosed glaucoma in German population-based cohort studies and to contextualize them in the context of the literature.
MATERIAL AND METHODS
The prevalence of glaucoma in the Gutenberg Health Study (GHS) and the age-related investigations on health of the University of Regensburg (AugUR) was evaluated based on visual field examinations and optic disc color photography according to the ISGEO criteria. Furthermore, the self-reported glaucoma diagnoses were collected and the proportion of undiagnosed glaucoma was determined.
RESULTS
The proportion of undiagnosed glaucoma was 55% in the GHS, and 53% in the AugUR study. The results correlate with results from previous studies from other countries in which the proportion of unrecognized glaucoma ranged from 33% to 78%. In the GHS and the AugUR study the proportion of undiagnosed glaucoma was higher in younger age groups and in women.
DISCUSSION
Roughly every second case of glaucoma is undetected. As the symptoms are often nonspecific or take a long time to appear, there is a risk of advanced glaucomatous visual field defects or blindness due to a lack of glaucoma awareness. Studies have shown that a systematic screening can halve this risk.
Topics: Humans; Female; Intraocular Pressure; Glaucoma; Visual Field Tests; Visual Fields; Optic Disk; Vision Disorders
PubMed: 37847376
DOI: 10.1007/s00347-023-01943-0 -
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 -
Journal of Perinatal Medicine Jul 2023The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal...
The mammalian retina lacks regenerative potency to replace damaged or degenerated cells. Therefore, traumatic or genetic insults that lead to the degeneration of retinal neurons or retinal pigment epithelium (RPE) cells alter visual perception and ultimately can lead to blindness. The advent of human stem cells and their exploitation for vision restoration approaches has boosted the field. Traditionally, animal models - mostly rodents - have been generated and used to mimic certain monogenetic hereditary diseases. Of note, some models were extremely useful to develop specific gene therapies, for example for Retinitis Pigmentosa, Leber congenital amaurosis and achromatopsia. However, complex multifactorial diseases are not well recapitulated in rodent models such as age-related macular degeneration (AMD) as rodents lack a macula. Here, human stem cells are extremely valuable to advance the development of therapies. Particularly, cell replacement therapy is of enormous importance to treat retinal degenerative diseases. Moreover, different retinal degenerative disorders require the transplantation of unique cell types. The most advanced one is to substitute the RPE cells, which stabilize the light-sensitive photoreceptors. Some diseases require also the transplantation of photoreceptors. Depending on the disease pattern, both approaches can also be combined. Within this article, I briefly feature the underlying principle of cell replacement therapies, demonstrate some successes and discuss certain shortcomings of these approaches for clinical application.
Topics: Animals; Humans; Retinal Degeneration; Retinal Pigment Epithelium; Retina; Macular Degeneration; Stem Cells; Mammals
PubMed: 36474335
DOI: 10.1515/jpm-2022-0510 -
Survey of Ophthalmology 2023Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor... (Review)
Review
Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor disruption may occur in a variety of hereditary, degenerative, traumatic, and toxic chorioretinal diseases. These have been known previously by multiple synonyms including macular microhole, foveal spot, and outer foveal microdefects. A common clinical feature underlying these conditions is the presence of apparently normal fovea or subtle hypopigmented lesion at the foveal or juxtafoveal area. A detailed history along with high-resolution optical coherence tomography is often helpful to derive a conclusive diagnosis in majority of these cases. Focal photoreceptor disruption usually involves loss or rarefaction of ellipsoid/interdigitation zone, either in isolation or associated with external limiting membrane or retinal pigment epithelium disruption in the fovea. Vitreomacular interface (VMI) disorders including vitreomacular traction, posterior vitreous detachment, epiretinal membrane, and impending macular hole possibly remain the most common cause. Retinal dystrophies such as cone dystrophy, occult macular dystrophy, and achromatopsia may present with diminution of vision and normal appearing fundus in a younger age group. Other causes include photic retinopathy (e.g., from a history of sun gazing or laser pointer exposure), blunt trauma, drug exposure (e.g., poppers maculopathy or tamoxifen retinopathy), and acute retinal pigment epitheliopathy (ARPE). Visual prognosis depends on the underlying etiology with complete recovery common in the subset of patients with VMI, and ARPE, whereas persistent outer retinal defects are the rule in other conditions. We discuss the differential diagnoses that lead to isolated foveal photoreceptor defects. Identifying and understanding the underlying disease processes that cause foveal photoreceptor disruption may help predict visual prognosis.
Topics: Humans; Fovea Centralis; Tomography, Optical Coherence; Diagnosis, Differential; Retinal Diseases; Retinal Perforations; Eye Diseases; Retrospective Studies
PubMed: 36934831
DOI: 10.1016/j.survophthal.2023.03.003 -
Cortex; a Journal Devoted To the Study... Jan 2024The famous "Piazza del Duomo" paper, published in Cortex in 1978, inspired a considerable amount of research on visual mental imagery in brain-damaged patients. As a...
The famous "Piazza del Duomo" paper, published in Cortex in 1978, inspired a considerable amount of research on visual mental imagery in brain-damaged patients. As a consequence, single-case reports featuring dissociations between perceptual and imagery abilities challenged the prevailing model of visual mental imagery. Here we focus on mental imagery for colors. A case study published in Cortex showed perfectly preserved color imagery in a patient with acquired achromatopsia after bilateral lesions at the borders between the occipital and temporal cortex. Subsequent neuroimaging findings in healthy participants extended and specified this result; color imagery elicited activation in both a domain-general region located in the left fusiform gyrus and the anterior color-biased patch within the ventral temporal cortex, but not in more posterior color-biased patches. Detailed studies of individual neurological patients, as those often published in Cortex, are still critical to inspire and constrain neurocognitive research and its theoretical models.
Topics: Humans; Imagination; Temporal Lobe; Cerebral Cortex; Brain Injuries; Imagery, Psychotherapy; Visual Perception
PubMed: 37926612
DOI: 10.1016/j.cortex.2023.10.002 -
World Neurosurgery Aug 2019Hemangioblastomas of the optic nerve are very rare tumors. They occur in association with Von Hippel-Lindau (VHL) syndrome; however, sporadic occurrences have been... (Review)
Review
BACKGROUND
Hemangioblastomas of the optic nerve are very rare tumors. They occur in association with Von Hippel-Lindau (VHL) syndrome; however, sporadic occurrences have been reported. We describe here a case of optic nerve hemangioblastoma in the absence of VHL and review the pertinent literature.
CASE DESCRIPTION
A 33-year-old woman presented with gradually progressive vision loss in the right eye. On examination, the visual acuity on the right was hand movement close to face in all quadrants. Color discrimination was impaired. Fundoscopy revealed optic atrophy and no other retinal pathology. There was relative afferent pupillary defect in the right eye. No neurocutaneous markers were found. Imaging revealed lesion isointense on T1, hyperintense on T2/fluid-attenuated inversion recovery, and showing relatively homogenous enhancement on postcontrast study. Multiple flow voids were seen in the intracranial part of the lesion. The proximal part of the intraorbital right optic nerve was enlarged and tortuous with distended optic nerve sheath. A right single-piece fronto-orbital craniotomy was done. A reddish lesion seen involving the right optic nerve just proximal to the chiasm with multiple vessels and a distinct feeding vessel was seen supplying the tumor. The lesion was excised and the optic nerve was sacrificed approximately 1 cm proximal to the chiasm. The postoperative course was uneventful.
CONCLUSIONS
Conclusions: Optic nerve hemangioblastoma is a rare occurrence and a high level of suspicion is required preoperatively in the absence of VHL syndrome.
Topics: Adult; Color Vision Defects; Female; Hemangioblastoma; Humans; Magnetic Resonance Imaging; Optic Nerve Neoplasms; Perfusion Imaging; Tomography, X-Ray Computed; Vision Disorders; von Hippel-Lindau Disease
PubMed: 31054346
DOI: 10.1016/j.wneu.2019.04.224