| 1. |
- Areblom, Maria, et al.
(författare)
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A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing
- 2023
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Ingår i: Genes. - 2073-4425. ; 14:7
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Tidskriftsartikel (refereegranskat)abstract
- In the present era of evolving gene-based therapies for inherited retinal dystrophies (IRDs), it has become increasingly important to verify the genotype in every case, to identify all subjects eligible for treatment. Moreover, combined insight concerning phenotypes and genotypes is crucial for improved understanding of thevisual impairment, prognosis, and inheritance. The objective of this study was to investigate to what extent renewed comprehensive genetic testing of patients diagnosed with IRD but with previously inconclusive DNA test results can verify the genotype, if confirmation of the genotype has an impact on the understanding of the clinical picture, and, to describe the genetic spectrum encountered in a Swedish IRD cohort. The study included 279 patients from the retinitis pigmentosa research registry (comprising diagnosis within the whole IRD spectrum), hosted at the Department of Ophthalmology, Skåne University hospital, Sweden. The phenotypes had already been evaluated with electrophysiology and other clinical tests, e.g., visual acuity, Goldmann perimetry, and fundus imaging at the first visit, sometime between 1988–2015 and the previous—in many cases, multiple—genetic testing, performed between 1995 and 2020 had been inconclusive. All patients were aged 0–25 years at the time of their first visit. Renewed genetic testing was performed using a next generation sequencing (NGS) IRD panel including 322 genes (Blueprint Genetics). Class 5 and 4 variants, according to ACMG guidelines, were considered pathogenic. Of the 279 samples tested, a confirmed genotype was determined in 182 (65%). The cohort was genetically heterogenous, including 65 different genes. The most prevailing were ABCA4 (16.5%), RPGR (6%), CEP290 (6%), and RS1 (5.5%). Other prevalent genes were CACNA1F (3%), PROM1 (3%), CHM (3%), and NYX (3%). In 7% of the patients there was a discrepancy between the diagnosis made based on phenotypical or genotypical findings alone. To conclude, repeated DNA-analysis was beneficial also in previously tested patients and improved our ability to verify the genotype–phenotype association increasing the understanding of how visual impairment manifests, prognosis, and the inheritance pattern. Moreover, repeated testing using a widely available method could identify additional patients eligible for future gene-based therapies.
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| 2. |
- Cardiakidis Myers, Anna, et al.
(författare)
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Rifabutin accumulates in the lens and reduces retinal function in the rabbit eye
- 2009
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Ingår i: Retina. - 0275-004X. ; 29:1, s. 106-111
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To study the toxicology of rifabutin in the rabbit eye with emphasis on retinal function and histopathology.METHODS: Seven rabbits received a daily dose of rifabutin during 15 months. Six rabbits receiving only the vehicle were used as controls. Repeated standardized full-field electroretinograms (ERG) were assessed. After discontinuing treatment, the rabbits were killed and the cornea, the lens, and the sectioned retina was studied. Immunhistochemistry directed against vimentin, glial fibrillaryacidic protein (GFAP), protein kinase C (PKC), and peanut agglutinin (PNA) was performed.RESULTS: Rifabutin was detected in serum of the treated rabbits. During treatment, the full-field ERG demonstrated significantly reduced b-wave amplitudes in the total rod-cone response as well as in the isolated rod and cone response compared with the recordings before treatment. The control rabbits did not demonstrate a reduction of the ERG amplitudes. The treated rabbits developed a discoloration of the lens, not seen in the control group. No retinal pathology was demonstrated using immunohistochemical methods.CONCLUSION: Rifabutin causes a discoloration of the lens and reduces both rod and cone function in rabbits, but does not alter retinal morphology. Previous reports on ocular side effects caused by rifabutin are supported by the results of this study.
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| 3. |
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| 4. |
- Kjellström, Sten, et al.
(författare)
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Long-term 12 year follow-up of X-linked congenital retinoschisis.
- 2010
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Ingår i: Ophthalmic Genetics. - : Informa UK Limited. - 1744-5094 .- 1381-6810. ; Jul 1, s. 114-125
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the retinal structure and function during the progression of X-linked retinoschisis (XLRS) from childhood to adulthood. Methods: Ten patients clinically diagnosed with XLRS were investigated at 6-15 years of age (mean age 9 years) with a follow-up 8 to 14 years later (mean 12 years). The patients underwent regular ophthalmic examination as well as testing of best corrected visual acuity (BCVA), visual field (VF) and assessment of full-field electroretinography (ERG) during their first visit. During the follow-up, the same clinical protocols were repeated. In addition, macular structure and function was examined with multifocal electroretinography (mfERG) and optical coherence tomography (OCT). The patients were 18-25 years of age (mean age 21 years) at the follow-up examination. All exons and exon-intron boundaries of RS1-gene were sequenced for gene mutations in 9 out of the 10 patients. Results: Best corrected VA and VF were stable during this follow-up period. No significant progression in cone or rod function could be measured by full-field ERG. Multifocal electroretinography and OCT demonstrated a wide heterogeneity of macular changes in retinal structure and function at the time of follow-up visit. Three different mutations were detected in these nine patients, including a known nonsense mutation in exon 3, a novel insertion in exon 5 and an intronic mutation at 5' splice site of intron 3. Conclusions: Clinical follow-up (mean 12 years) of ten young XLRS patients (mean age of 9 years) with a typical congenital retinoschisis phenotype revealed no significant decline in retinal function during this time period. MfERG and OCT demonstrated a wide variety of macular changes including structure and dysfunction. The XLRS disease was relatively stable during this period of observation and would afford opportunity for therapy studies to judge benefit against baseline and against the fellow eye.
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| 5. |
- Kjellström, Sten, et al.
(författare)
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Retinal function and histopathology in rabbits treated with Topiramate.
- 2006
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Ingår i: Documenta Ophthalmologica. - : Springer Science and Business Media LLC. - 1573-2622 .- 0012-4486. ; 113:3, s. 179-186
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate retinal function and histopathology in rabbits treated orally with the antiepileptic drug topiramate. Methods Six rabbits were treated with a daily oral dose of topiramate during a period of eight months. Six rabbits receiving water served as controls. Blood samples were analyzed for determination of topiramate serum levels in order to ensure successful drug exposition. Standardized full-field electroretinograms (ERGs) were performed before treatment and then at 2, 3 and 8 months during the treatment period. After terminating treatment the rabbits were sacrificed and the morphology of the sectioned retina was studied. Results After eight months of treatment the fullfield ERG demonstrated normal rod function in treated and control rabbits, but the light adapted 30 Hz flicker b-wave amplitude was significantly reduced in the treated rabbits. This was the case for both the light adapted (Wilcoxon signed ranks test, P=0.046) and the dark adapted (Wilcoxon signed ranks test, P=0.028) 30 Hz flicker response from the treated rabbits. Retinal immunohistology revealed a severe accumulation of GABA in amacrine cells and in the inner plexiform layer in 4 of 6 treated rabbits compared to the controls. Conclusions Topiramate, orally administrated to rabbits, may cause a significant reduction of the retinal function demonstrated by the reduced b-wave amplitude in the full-field ERG, as well as changes in immunohistology characterized by a severe accumulation of GABA in the inner retina. The retinal dysfunction and the morphological changes indicate that topiramat may damage the retina, similarly to vigabatrin (another antiepileptic drug).
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| 6. |
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| 7. |
- Ponjavic, Vesna, et al.
(författare)
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Alterations in electroretinograms and retinal morphology in rabbits treated with vigabatrin
- 2004
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Ingår i: Documenta Ophthalmologica. - 1573-2622. ; 108:2, s. 125-133
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To determine whether long-term treatment with the anti-epileptic drug vigabatrin causes damage to rabbit retina.METHODS: Five rabbits were treated continuously with a daily dose of vigabatrin solution per orally during a period of 1-8 months. Two rabbits receiving water were used as controls. Repeated full-field electroretinograms (every two weeks) were assessed during this period. Vigabatrin serum concentration was repeatedly measured for securing successful drug administration. After termination of treatment the rabbits were sacrificed and the morphology of the sectioned retina was studied.RESULTS: In all rabbits treated with vigabatrin the serum analyses repeatedly demonstrated elevated drug concentration. Full-field electroretinograms demonstrated normal rod function in all treated rabbits, but reduced cone function in two of the five treated rabbits verified by 30Hz flicker stimulation. Morphologic studies of the sectioned retina demonstrated GFAP immunoactivity of the glial cells localized in the retinal periphery in all five treated rabbits, one of which had staining also in the centrally localized glial cells. The treated rabbits also demonstrated a weaker GAD staining in the IPL and less positive amacrine cells, compared to the controls. Only two treated rabbits had normal GABA staining while three had an enhanced GABA immunoreactivity and undistinguishable fibers in the IPL. In three out of five treated rabbits the Müller cells were short, stubby and fragmented, with swollen endfeet.CONCLUSION: This study demonstrates changes in histopathology caused by vigabatrin in an animal model, which has not been reported previously. We have found that vigabatrin orally administrated to rabbits does not affect rod function but may reduce cone function in the full-field electroretinogram, which is similar to the previously reported vigabatrin effect on the human ERG. The results indicate that vigabatrin may damage or influence, at least one cell type in the rabbit retina.
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| 8. |
- Abdulridha-Aboud, Wissam, et al.
(författare)
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Characterization of macular structure and function in two swedish families with genetically identified autosomal dominant retinitis pigmentosa
- 2016
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Ingår i: Molecular Vision. - 1090-0535. ; 22, s. 362-373
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods: Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results: The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions: These two families demonstrate the extreme inter-and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype.
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| 9. |
- Acar, C, et al.
(författare)
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Mutation screening of patients with Leber congenital amaurosis or the enhanced S-cone syndrome reveals a lack of sequence variations in the NRL gene
- 2003
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Ingår i: Molecular Vision. - 1090-0535. ; 9:3-4, s. 14-17
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To determine if mutations in the retinal transcription factor gene NRL are associated with retinopathies other than autosomal dominant retinitis pigmentosa (adRP). Methods: Genomic DNA was isolated from blood samples obtained from 50 patients with Leber Congenital Amaurosis (LCA), 17 patients with the Enhanced S-Cone Syndrome (ESCS), and a patient with an atypical retinal degeneration that causes photoreceptor rosettes with blue cone opsin. The 5' upstream region (putative promoter), untranslated exon 1, coding exons 2 and 3, and exon-intron boundaries of the NRL gene were analyzed by direct sequencing of the PCR-amplified products. Results: Complete sequencing of the NRL gene in DNA samples from this cohort of patients revealed only one nucleotide change. The C->G transversion at nucleotide 711 of NRL exon 3 was detected in one LCA patient; however, this change did not alter the amino acid (L237L). Conclusions: No potential disease causing mutation was identified in the NRL gene in patients with LCA, ESCS, or the atypical retinal degeneration. Together with previous studies, our results demonstrate that mutations in the NRL gene are not a major cause of retinopathy. To date, only missense changes have been reported in adRP patients, and sequence variations are rare. It is possible that the loss of NRL function in humans is associated with a more complex clinical phenotype due to its expression in pineal gland in addition to rod photoreceptors.
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| 10. |
- Andreasson, Jakob, 1975, et al.
(författare)
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Electron-lattice interactions in the perovskite LaFe0.5Cr0.5O3 characterized by optical spectroscopy and LDA plus U calculations
- 2009
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X .- 2469-9950 .- 2469-9969. ; 80:7, s. 075103-
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Tidskriftsartikel (refereegranskat)abstract
- We use resonance Raman scattering (incident photon energies between 1.8 and 4.13 eV), LDA+U calculations, spectroscopic ellipsometry, and oblique IR reflectivity to characterize the strong electron-phonon interactions in the disordered perovskite LaFe0.5Cr0.5O3. When the photon energy coincides with a Cr to Fe Mott-Hubbard transfer gap around 2.4 eV the electron-phonon interaction is manifested by a Franck-Condon effect with exceptional first-and higher order scattering of a local oxygen breathing mode. At higher incident energies we observe a superposition of Franck-Condon scattering and Frohlich interaction induced infrared active longitudinal optical two-phonon scattering activated mainly by O to Fe charge transfer. Our results establish LaFe0.5Cr0.5O3 as a model compound for research on electron-phonon interactions in strongly correlated complex systems and show that Franck-Condon scattering in complex solids is not limited to Jahn-Teller active compounds.
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