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Annals of Eye Science Sep 2020Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology,...
Inherited retinal diseases (IRD) are a leading cause of blindness in the working age population. The advances in ocular genetics, retinal imaging and molecular biology, have conspired to create the ideal environment for establishing treatments for IRD, with the first approved gene therapy and the commencement of multiple therapy trials. The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD. Herein we present in a comprehensive and concise manner the imaging findings of: (I) macular dystrophies (MD) [Stargardt disease (), X-linked retinoschisis (), Best disease (), pattern dystrophy (), Sorsby fundus dystrophy (), and autosomal dominant drusen ()], (II) cone and cone-rod dystrophies (, , and ) (III) cone dysfunction syndromes [achromatopsia (], blue-cone monochromatism ( array), oligocone trichromacy, bradyopsia () and Bornholm eye disease (), (IV) Leber congenital amaurosis (, , , , , and ) (V) rod-cone dystrophies [retinitis pigmentosa, enhanced S-Cone syndrome (), Bietti crystalline corneoretinal dystrophy ()], (VI) rod dysfunction syndromes (congenital stationary night blindness, fundus albipunctatus () Oguchi disease (, ), and (VII) chorioretinal dystrophies [choroideremia (), gyrate atrophy ()].
PubMed: 33928237
DOI: 10.21037/aes-20-81 -
Klinische Monatsblatter Fur... Oct 2023Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper clinical and genetic diagnosis may allow an...
BACKGROUND
Achromatopsia (ACHM) as a hereditary cone disease might manifest in a stationary and progressive manner. The proper clinical and genetic diagnosis may allow an individual prognosis, accurate genetic counselling, and the optimal choice of low vision aids. The primary aim of the study was to determine the spectrum of clinical and genetic diagnostics required to characterize the ACHM.
METHODS
A retrospective analysis was performed in 8 patients from non-related families (5 ♀,3 ♂); age at diagnosis: 3 - 56 y, mean 18.13 (SD ± 18.22). Clinical phenotyping, supported by colour vision test, fundus photography-, autofluorescence- (FAF), infra-red- (IR), OCT imaging and electroretinography provided information on the current status and the course of the disease over the years. In addition, genetic examinations were performed with ACHM relevant testing ( and the transcription factor ).
RESULTS
All patients suffered photophobia and reduced visual acuity (mean: 0.16 [SD ± 0.08]). Nystagmus was identified in 7 from 8 subjects and in one patient a head-turn right helped to reduce the nystagmus amplitude. Colour vision testing confirmed complete achromatopsia in 7 out of 8 patients. Electrophysiology found severely reduced photopic- but also scotopic responses. Thinning and interruption of the inner segment ellipsoid (ISe) line within the macula but also FAF- and IR abnormalities in the fovea and/or parafovea were characteristic in all ACHM patients. Identification of pathogenic mutations in 7 patients helped to confirm the diagnosis of ACHM (3 adults, 4 children; 3 ♀ and 4 ♂). Achromatopsia was linked to (2 ♀, 1 ♂) and variants (2 ♀, 3 ♂). The youngest patient (♀, 10 y) had 3 different variants on different alleles. In a patient (♂, 29 y) carrying 2 pathogenic digenic-triallelic - and -mutations, a severe progression of ISe discontinuity to coloboma-like macular atrophy was observed during the 12-year follow-up. The oldest female (67 y) showed a compound homozygous - and heterozygous -, as well as a heterozygous variants. The destruction of her ISe line was significantly enlarged and represented a progressive cone-rod phenotype in comparison to other ACHM patients. In a patient (♂, 45 y) carrying a pathogenic and mutation, a severe macular oedema and a rod-cone phenotype was observed. In addition, two variants in considered as VOS were found. One patient showed the rare mutation, where a severe coloboma-like macular atrophy was observed on the left eye as early as at the age of three years.
CONCLUSION
Combining multimodal ophthalmological diagnostics and molecular genetics when evaluating patients with ACHM helps in characterizing the disease and associated modifiers, and is therefore strongly recommended for such patients.
PubMed: 37714190
DOI: 10.1055/a-2176-4233 -
Saudi Journal of Ophthalmology :... 2023Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus,...
PURPOSE
Achromatopsia is a rare stationary retinal disorder that primarily affects the cone photoreceptors. Individuals with achromatopsia present with photophobia, nystagmus, reduced visual acuity (VA), and color blindness. Multiple genes responsible for achromatopsia have been identified (e.g. cyclic nucleotide-gated channel subunit alpha 3 [CNGA3] and activating transcription factor 6). Studies have assessed the role of gene therapy in achromatopsia. Therefore, for treatment and prevention, the identification of phenotypes and genotypes is crucial. Here, we described the clinical manifestations and genetic mutations associated with achromatopsia in patients from Saudi Arabia.
METHODS
This case series study included 15 patients with clinical presentations, suggestive of achromatopsia, who underwent ophthalmological and systemic evaluations. Patients with typical achromatopsia phenotype underwent genetic evaluation using whole-exome testing.
RESULTS
All patients had nystagmus ( = 15) and 93.3% had photophobia ( = 14). In addition, all patients ( = 15) had poor VA. Hyperopia with astigmatism was observed in 93.3% ( = 14) and complete color blindness in 93.3% of the patients ( = 14). In the context of family history, both parents of all patients ( = 15) were genetic carriers, with a high consanguinity rate (82%, = 9 families). Electroretinography showed cone dysfunction with normal rods in 66.7% ( = 10) and both cone-rod dysfunction in 33.3% ( = 5) patients. Regarding the genotypic features, 93% of patients had variants in ( = 14) categorized as pathogenic Class 1 (86.7%, = 13). Further, 66.7% ( = 10) of patients also harbored the c.661C>T DNA variant. Further, the patients were homozygous for these mutations. Three other variants were also identified: c.1768G>A (13.3%, = 2), c.830G>A (6.6%, = 1), and c. 822G >T (6.6%, = 1).
CONCLUSION
Consanguinity and belonging to the same tribe are major risk factors for disease inheritance. The most common genotype was with the c.661C>T DNA variant. We recommend raising awareness among families and providing genetic counseling for this highly debilitating disease.
PubMed: 38155673
DOI: 10.4103/sjopt.sjopt_108_23 -
Optometry and Vision Science : Official... Apr 2022This case report discusses a case of suspected occult macular dystrophy, which is an underrecognized but not rare subtype of cone dystrophy. Increasing clinician...
SIGNIFICANCE
This case report discusses a case of suspected occult macular dystrophy, which is an underrecognized but not rare subtype of cone dystrophy. Increasing clinician recognition of occult macular dystrophy will lead to increased accurate diagnosis of affected patients.
PURPOSE
A clinical presentation and diagnosis of a case of suspected occult macular dystrophy, as well as background information and management, are reported.
CASE REPORT
A 44-year-old White man reported long-standing decreased vision and photophobia in both eyes. Examination revealed a bilateral reduction in best-corrected visual acuity, abnormal color vision, central visual field defects, and subtle disruption of subfoveal photoreceptor integrity on optical coherence tomography with a normal fundus appearance. The multifocal electroretinogram showed decreased perifoveal responses, whereas both the photopic and scotopic full-field electroretinograms were normal. This distinctive electroretinogram response pattern was critical in the diagnosis of occult macular dystrophy.
CONCLUSIONS
Reduced visual acuity with a normal clinical examination result is commonly encountered in patients with occult macular dystrophy. Therefore, clinicians must be aware of occult macular dystrophy and order appropriate testing to accurately identify cases of occult macular dystrophy. Without thorough evaluation, patients may be easily misdiagnosed with other etiologies of vision loss.
Topics: Adult; Electroretinography; Fluorescein Angiography; Humans; Macular Degeneration; Male; Retinal Dystrophies; Tomography, Optical Coherence; Visual Acuity
PubMed: 35001063
DOI: 10.1097/OPX.0000000000001858 -
American Journal of Ophthalmology Sep 2023To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). (Clinical Trial)
Clinical Trial
PURPOSE
To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM).
DESIGN
Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial.
METHODS
The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months.
RESULTS
AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23).
CONCLUSIONS
AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.
Topics: Humans; Adult; Child; Child, Preschool; Color Vision Defects; Prospective Studies; Cyclic Nucleotide-Gated Cation Channels; Genetic Therapy; Inflammation
PubMed: 37172884
DOI: 10.1016/j.ajo.2023.05.009 -
Genes Jun 2024Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults.... (Review)
Review
Inherited cone disorders (ICDs) are a heterogeneous sub-group of inherited retinal disorders (IRDs), the leading cause of sight loss in children and working-age adults. ICDs result from the dysfunction of the cone photoreceptors in the macula and manifest as the loss of colour vision and reduced visual acuity. Currently, 37 genes are associated with varying forms of ICD; however, almost half of all patients receive no molecular diagnosis. This review will discuss the known ICD genes, their molecular function, and the diseases they cause, with a focus on the most common forms of ICDs, including achromatopsia, progressive cone dystrophies (CODs), and cone-rod dystrophies (CORDs). It will discuss the gene-specific therapies that have emerged in recent years in order to treat patients with some of the more common ICDs.
Topics: Humans; Color Vision Defects; Cone-Rod Dystrophies; Retinal Cone Photoreceptor Cells; Cone Dystrophy; Blindness; Animals; Genetic Therapy
PubMed: 38927662
DOI: 10.3390/genes15060727 -
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 -
American Journal of Clinical Pathology Oct 2022To learn what color vision-deficient pathologists and cytotechnologists consider their most significant problems and advantages as well as any accommodations.
OBJECTIVES
To learn what color vision-deficient pathologists and cytotechnologists consider their most significant problems and advantages as well as any accommodations.
METHODS
An anonymous online survey developed for practicing pathologists and cytotechnologists regarding their experiences with stains was sent to the members of 4 national societies.
RESULTS
We received 377 responses. Twenty-three people, all men, identified themselves as color vision deficient, with 22 reporting red-green color vision deficiency and 1 reporting uncertain type. Eight pathologists and cytotechnologists indicated that they thought that their color vision deficiency conferred advantages to them, including a greater appreciation of morphology, with less confusion resulting from variations in stain quality or intensity. Nineteen pathologists and cytotechnologists thought that their color vision deficiency conferred disadvantages; the most common disadvantages stated were the identification of eosinophils and acid-fast bacilli. Other difficulties included interpretation of RBCs and nucleoli and sometimes Alcian blue, Brown and Brenn, Congo red, crystal violet, Fite, Giemsa, mucicarmine, periodic acid-Schiff, and fluorescence in situ hybridization stains. Only 2 of the color vision-deficient pathologists and cytotechnologists found digital slides more difficult than glass slides.
CONCLUSIONS
Color vision-deficient pathologists and cytotechnologists report that they have developed approaches to viewing slides that do not compromise their interpretations. Digital pathology may provide several approaches for aiding color vision-deficient pathologists with the interpretation of certain stains.
Topics: Alcian Blue; Color Vision Defects; Congo Red; Gentian Violet; Humans; In Situ Hybridization, Fluorescence; Male; Pathology, Clinical; Periodic Acid
PubMed: 35913114
DOI: 10.1093/ajcp/aqac081 -
Proceedings of the National Academy of... Sep 2021Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR...
Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying disease variants and from gene-edited null hESCs. We found that achromatopsia patient and null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.
Topics: Activating Transcription Factor 6; Color Vision Defects; Cone Opsins; Gene Expression; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Organoids; Retina; Retinal Cone Photoreceptor Cells; Vision, Ocular
PubMed: 34561305
DOI: 10.1073/pnas.2103196118 -
Human Mutation Jul 2022Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To... (Review)
Review
Achromatopsia (ACHM) is a congenital cone photoreceptor disorder characterized by impaired color discrimination, low visual acuity, photosensitivity, and nystagmus. To date, six genes have been associated with ACHM (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6), the majority of these being implicated in the cone phototransduction cascade. CNGA3 encodes the CNGA3 subunit of the cyclic nucleotide-gated ion channel in cone photoreceptors and is one of the major disease-associated genes for ACHM. Herein, we provide a comprehensive overview of the CNGA3 variant spectrum in a cohort of 1060 genetically confirmed ACHM patients, 385 (36.3%) of these carrying "likely disease-causing" variants in CNGA3. Compiling our own genetic data with those reported in the literature and in public databases, we further extend the CNGA3 variant spectrum to a total of 316 variants, 244 of which we interpreted as "likely disease-causing" according to ACMG/AMP criteria. We report 48 novel "likely disease-causing" variants, 24 of which are missense substitutions underlining the predominant role of this mutation class in the CNGA3 variant spectrum. In addition, we provide extensive in silico analyses and summarize reported functional data of previously analyzed missense, nonsense and splicing variants to further advance the pathogenicity assessment of the identified variants.
Topics: Color Vision Defects; Cyclic Nucleotide-Gated Cation Channels; Humans; Mutation; Retinal Cone Photoreceptor Cells
PubMed: 35332618
DOI: 10.1002/humu.24371