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- Kuehlewein, Laura, et al.
(författare)
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Clinical phenotype and course of PDE6A-associated retinitis pigmentosa disease, characterized in preparation for a gene supplementation trial
- 2020
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Ingår i: JAMA Ophthalmology. - : American Medical Association (AMA). - 2168-6165. ; 138:12, s. 1241-1250
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Treatment trials require sound knowledge on the natural course of disease. OBJECTIVE To assess clinical features, genetic findings, and genotype-phenotype correlations in patients with retinitis pigmentosa (RP) associated with biallelic sequence variations in the PDE6A gene in preparation for a gene supplementation trial. DESIGN, SETTING, AND PARTICIPANTS This prospective, longitudinal, observational cohort study was conducted from January 2001 to December 2019 in a single center (Centre for Ophthalmology of the University of Tübingen, Germany) with patients recruited multinationally from 12 collaborating European tertiary referral centers. Patients with retinitis pigmentosa, sequence variants in PDE6A, and the ability to provide informed consent were included. EXPOSURES Comprehensive ophthalmological examinations; validation of compound heterozygosity and biallelism by familial segregation analysis, allelic cloning, or assessment of next-generation sequencing-read data, where possible. MAIN OUTCOMES AND MEASURES Genetic findings and clinical features describing the entire cohort and comparing patients harboring the 2 most common disease-causing variants in a homozygous state (c.304C>A;p.(R102S) and c.998 + 1G>A;p.?). RESULTS Fifty-seven patients (32 female patients [56%]; mean [SD], 40 [14] years) from 44 families were included. All patients completed the study. Thirty patients were homozygous for disease-causing alleles. Twenty-seven patients were heterozygous for 2 different PDE6A variants each. The most frequently observed alleles were c.304C>A;p.(R102S), c.998 + 1G>A;p.?, and c.2053G>A;p.(V685M). The mean (SD) best-corrected visual acuity was 0.43 (0.48) logMAR (Snellen equivalent, 20/50). The median visual field area with object III4e was 660 square degrees (5th and 95th percentiles, 76 and 11 019 square degrees; 25th and 75th percentiles, 255 and 3923 square degrees). Dark-adapted and light-adapted full-field electroretinography showed no responses in 88 of 108 eyes (81.5%). Sixty-nine of 108 eyes (62.9%) showed additional findings on optical coherence tomography imaging (eg, cystoid macular edema or macular atrophy). The variant c.998 + 1G>A;p.? led to a more severe phenotype when compared with the variant c.304C>A;p.(R102S). CONCLUSIONS AND RELEVANCE Seventeen of the PDE6A variants found in these patients appeared to be novel. Regarding the clinical findings, disease was highly symmetrical between the right and left eyes and visual impairment was mild or moderate in 90% of patients, providing a window of opportunity for gene therapy.
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- Meyer, Linda M, et al.
(författare)
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Bilateral cataract induced by unilateral UVR-B exposure : evidence for an inflammatory response
- 2013
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Ingår i: Acta Ophthalmologica. - : Wiley. - 1755-375X .- 1755-3768. ; 91:3, s. 236-242
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate whether unilateral in vivo UVR-B exposure of one eye affects the fellow eye in a co-cataractogenic, sympathetic reaction and to determine whether an inflammatory response could be involved in the pathogenesis.Methods: C57BL/6 mice were unilaterally exposed in vivo to UVR-B for 15 min. In the group of 24 animals each received 0×/2×/3×/or 4× cataract threshold equivalent dose. Following 48-hr UVR-B exposure, cataract morphology was documented in dark-field illumination photography, and light scattering was quantified, in both lenses in vitro. Serum levels of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α were analysed with ELISA. Immunohistochemistry was performed for inflammatory infiltration in exposed and contralateral eyes.Results: UVR-B exposure induced cataract in all exposed lenses. There was additionally a significant UVR dose-dependent increase in light scattering in the lenses of the non-exposed fellow eye. Inflammatory infiltration was detected immunohistochemically in the anterior segment of both eyes. IL-1β serum concentration increased with increasing UVR-B exposure dose. There was a similar trend for serum IL-6 but not for TNF-α.Conclusion: Unilateral UVR-B exposure to one eye is associated with intraocular inflammation and an increase in lens light scattering also in the unexposed, fellow eye. A resulting systemic inflammatory response might be mediated by IL-1β and possibly IL-6. The finding that an inflammatory response may play a role in UVR-B-induced cataract development might initiate new strategies in the prevention of the disease.
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- Stahl, Andreas, et al.
(författare)
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Lipid metabolites in the pathogenesis and treatment of neovascular eye disease.
- 2011
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Ingår i: The British journal of ophthalmology. - : BMJ. - 0007-1161. ; 95:11, s. 1496-1501
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Tidskriftsartikel (refereegranskat)abstract
- Lipids and lipid metabolites have long been known to play biological roles that go beyond energy storage and membrane structure. In age-related macular degeneration and diabetes, for example, dysregulation of lipid metabolism is closely associated with disease onset and progression. At the same time, some lipids and their metabolites can exert beneficial effects in the same disorders. This review summarises our current knowledge of the contributions of lipids to both the pathogenesis and treatment of neovascular eye disease. The clinical entities covered are exudative age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity, with a special emphasis on the potential therapeutic effects of ω3- (also known as n-3) polyunsaturated fatty acids.
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