| 1. |
- Schatz, Patrik, et al.
(författare)
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Evaluation of Macular Structure and Function by OCT and Electrophysiology in Patients with Vitelliform Macular Dystrophy Due to Mutations in BEST1
- 2010
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783 .- 0146-0404. ; 51:9, s. 4754-4765
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To analyze retinal structure and function in vitelliform macular dystrophy (VMD) due to mutations in BEST1. METHODS. Patients from five Swedish and four Danish families were examined with electrooculography (EOG), full-field electroretinography (ffERG), multifocal ERG (mfERG), optical coherence tomography (OCT), and fundus autofluorescence photography (FAF). Genetic analysis of the BEST1 gene was performed by direct sequencing. RESULTS. Mutations in BEST1 have been reported previously in the Swedish families. In the Danish families, four disease-causing missense mutations were found, one of which is novel: c.936C>A (p.Asp312Glu). The mutation was homozygous in a 9-year-old boy and heterozygous in his father in a consanguineous family. ffERG rod response was reduced in the homozygous boy, but normal in the heterozygous father. EOG was reduced in all but two patients and did not correlate with the ffERG results. OCT ranged from normal to cystoid edema and thickening of the outer retina-choroid complex. Decreased mfERG amplitudes, increased mfERG latencies, and loss of integrity of the foveal photoreceptor inner/outer segment junction, correlated with decreased vision. FAF demonstrated hyperautofluorescence beyond the ophthalmoscopic changes in several patients. CONCLUSIONS. The finding of a homozygous dominant mutation in a patient with VMD and evidence of widespread retinal degeneration may imply that the pathogenesis of the generalized retinal degeneration differs from that of the macular degeneration. A relative agreement between hyperautofluorescence by FAF, reduced retinal function, and VMD implies that the hyperautofluorescence emanates from lipofuscin and A2E. A potential therapy for VMD, involving the inhibition of the retinoid cycle, is suggested. (Invest Ophthalmol Vis Sci. 2010;51:4754 - 4765) DOI:10.1167/iovs.10-5152
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| 2. |
- Zobor, Ditta, et al.
(författare)
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The clinical phenotype of CNGA3-related achromatopsia : Pretreatment characterization in preparation of a gene replacement therapy trial
- 2017
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 0146-0404. ; 58:2, s. 821-832
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. The purpose of this study was to clinically characterize patients with CNGA3-linked achromatopsia (CNGA3-ACHM) in preparation of a gene therapy trial. METHODS. Thirty-six patients (age 7-56 years) with complete (cACHM) or incomplete (iACHM) CNGA3-ACHM were examined, including detailed psychophysical tests, extended electrophysiology, and assessment of morphology by fundus autofluorescence and spectral-domain optical coherence tomography (SD-OCT). RESULTS. Mean best-corrected visual acuity was 0.78 ± 0.14 logMAR. Color vision tests were consistent with a rod-dominated function in every cACHM patient. Microperimetry indicated an overall lowered retinal sensitivity within 20° of visual field. In electroretinography (ERG), photopic responses were nondetectable in cACHM patients, but residual cone responses were observed in the iACHM patients. Scotopic responses were altered referring to anomalies of photoreceptor and postreceptor signaling, whereas in voltage versus intensity functions, V was significantly below normal values (P < 0.05). In contrast, slope (n) and semisaturation intensity (K) were found to be within normal limits. Spectral-domain OCT examination showed no specific changes in 14.7%, disruption of the ellipsoid zone (EZ) at the fovea in 38.2%, absent EZ in 17.7%, a hyporeflective zone in 20.5%, and outer retinal atrophy in 8.9% of all cases and foveal hypoplasia in 29 patients (85%). No correlation of retinal morphology with visual function or with a specific genotype was found. The severity of morphologic and functional changes lacked a robust association with age. CONCLUSIONS. Our extended investigations prove that even among such a genetically homogenous group of patients, no specific correlations regarding function and morphology severity and age can be observed. Therefore, the therapeutic window seems to be wider than previously indicated.
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| 3. |
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| 4. |
- Branham, Kari, et al.
(författare)
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Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative Disease
- 2012
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 53:13, s. 8232-8237
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2. METHODS. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS. We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region). CONCLUSIONS. This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (Invest Ophthalmol Vis Sci. 2012;53:8232-8237) DOI:10.1167/iovs.12-11025
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| 5. |
- Kjellström, Ulrika, et al.
(författare)
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Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene
- 2016
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Ingår i: Investigative Ophthalmology and Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 57:14, s. 6048-6057
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To describe genotype and phenotype in a family with autosomal recessive retinitis pigmentosa (arRP) carrying homozygous mutations in the gene for the α-subunit of cyclic guanosine monophosphate (cGMP)-hydrolyzing phosphodiesterase 6 (PDE6A). Moreover, to compare their plasma cGMP levels to controls, exploring the possible role for cGMP in RP diagnostics.Methods: Seven siblings and their parents were recruited. Microarray, verified by Sanger sequencing, was used for genotyping. Investigations included slit lamp and fundus examination, Goldmann perimetry, full-field and multifocal electroretinography (ERG), and optical coherence tomography (OCT). Cyclic GMP was measured with an immunoassay kit.Results: All siblings and their father were homozygous, and the mother heterozygous, for IVS6+1G>A in PDE6A. Seven family members also carried c1532G>A in ABCA4. Visual fields were constricted with mere central remnants in older subjects and additional temporal crescents in younger subjects. Visual acuity ranged from 0.8 to amaurosis. Full-field ERGs showed extinguished rod responses and minimal cone responses. Multifocal ERGs were severely reduced. Optical coherence tomography revealed either general attenuation or central macular edema. Mean plasma cGMP in patients was approximately twice that in controls.Conclusions: To our knowledge, this is the first phenotypic description of arRP due to homozygous IVS6+1G>A mutations in PDE6A and these seem here to be associated with severe RP leading to early extinction of rod responses as well as reduced macular function. Additionally, patients showed increased plasma levels of cGMP, indicating a possible role for cGMP measurements as part of the clinical tests for this and, after further investigations, maybe other forms of RP.
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| 6. |
- Morén, Håkan, et al.
(författare)
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Angiography and mfERG show that blood supply to the pig retina may be both ipsilateral and contralateral.
- 2013
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 54:9, s. 6112-6117
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We recently presented a transfemoral endovascular coiling technique for inducing experimental retinal ischemia in pigs. Substantial variation was seen in the degree of ischemia. It was hypothesized that the blood supply to the retina may originate from both the ipsi- and contralateral ophthalmic arteries, and that there may be an interconnecting artery between the eyes. Methods: The external carotid system of ten pigs was catheterized using a fluoroscopy- monitored, transfemoral, endovascular approach. Vascular occlusion was achieved in the ophthalmic artery using coils. The effect of occlusion was examined using angiography and multifocal electroretinography (mfERG). Results: During angiography of the ophthalmic artery on one side, contrast filling was seen in the retinas on both sides, suggesting that the ophthalmic artery on one side may supply both retinas. A blood vessel connecting the eyes was visualized. mfERG recordings showed that the use of coiling to occlude the ophthalmic artery had greater ischemic effects in eyes that depended mainly on the ipsilateral ophthalmic artery for blood supply and smaller ischemic effect in retinas that received blood from both the ipsilateral and contralateral ophthalmic artery via the interconnecting vessel. Conclusions: The blood supply to the retina may originate from both the ipsi- and contralateral ophthalmic artery in the pig. There is an interindividual variability in the ischemic effect of occlusion depending on the architecture of the vasculature. These findings may be important in the development of new animal models of experimental retinal ischemia, since arterial occlusion in one eye may affect the blood supply to the contralateral eye.
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| 7. |
- Morén, Håkan, et al.
(författare)
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Endovascular Coiling of the Ophthalmic Artery in Pigs to Induce Retinal Ischemia
- 2011
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 52:7, s. 4880-4885
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. The authors recently showed that the retinal circulation can be accessed by transfemoral endovascular catheterization. The purpose of this study was to examine whether endovascular coiling can be used to induce different degrees of ischemic injury. The possibility of creating occlusions at different sites in the vasculature to cause retinal ischemia with different degrees of severity was investigated. METHODS. The ophthalmic artery was catheterized through the external carotid system using a fluoroscopy-monitored, transfemoral, endovascular approach in 12 pigs (mean weight, 70 kg). The effects were evaluated using angiography and multifocal electroretinography. RESULTS. Occlusion of arteries supplying the retina was established using endovascular coiling. Coiling in the proximal part of the ophthalmic artery caused no or little ischemia, presumably because of collateral blood supply. Coiling in the distal part of the ophthalmic artery, over the branching of the main ciliary artery, caused more severe retinal ischemia. Multifocal electroretinography recordings, which reflect retinal function in an area close to the visual streak, showed decreased amplitudes and increased implicit times after distal occlusion, but not after proximal occlusion of the ophthalmic artery. The responses were similar 1 hour and 72 hours after coiling, indicating that a permanent ischemic injury was established. CONCLUSIONS. The porcine ophthalmic artery can be occluded using an endovascular coiling technique. This provides an experimental animal model of retinal ischemia in which occlusion at different sites of the vasculature produces different degrees of severity of the ischemic damage. (Invest Ophthalmol Vis Sci. 2011;52:4880-4885) DOI:10.1167/iovs.11-7628
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| 8. |
- Morén, Håkan, et al.
(författare)
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The porcine retinal vasculature can be accessed using an endovascular approach, a new experimental model for retinal ischemia.
- 2009
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Ingår i: Investigative Ophthalmology & Visual Science. - : Association for Research in Vision and Ophthalmology (ARVO). - 1552-5783. ; 50:11, s. 5504-5510
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. The aim was to examine if the retinal circulation in the pig can be accessed using interventional neuroradiology and to explore the possibility to create occlusions that result in experimental retinal ischemia. Methods. Six experiments were performed using 100 kg pigs. The external carotid system was catheterizised using fluoroscopy monitored, transfemoral, endovascular approach. Transient and permanent vascular occlusions were performed using an angioplasty balloon catheter or a liquid embolic agent that was administered via an injection-catheter. Results. A technique for transfemoral catheterization of arteries supplying the retina was established. The ophthalmic artery was demonstrated to give rise to the main ciliary artery, from which the retinal artery branched as a single or several arteries. A balloon-catheter could be introduced into the ophthalmic artery, but not into the main ciliary artery. An injection-catheter could, in all experiments, be introduced into the main ciliary artery and, in some experiments, into the retinal artery. Occlusion of the ophthalmic artery, over the branching of the main ciliary artery, caused incomplete ischemia, presumably due to collaterals feeding the distal parts of the vasculature. mfERG recordings showed decreased amplitudes and increased implicit times, indicating retinal ischemia. Occlusion of the ciliary and retinal arteries caused complete ischemia, as shown by complete flattening of the mfERG recordings and, by indirect ophthalmoscopy, blanching of the retinal arteries and a pale retina Conclusions. We prove for the first time that the ophthalmic and retinal artery can be catheterizised using a transfemoral endovascular approach. This technique may be useful to produce clear-cut experimental retinal ischemia.
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| 9. |
- Sharon, D, et al.
(författare)
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Mutated alleles of the rod and cone Na-Ca+K-exchanger genes in patients with retinal diseases
- 2002
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Ingår i: Investigative Ophthalmology & Visual Science. - 1552-5783. ; 43:6, s. 1971-1979
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To study the possible involvement of the rod (SLC24A1) and cone (SLC24A2) Na-Ca+K exchanger (NCKX) genes in retinal diseases. METHODS. DNA was collected from unrelated patients with retinal disease, mainly from North America. A human genomic library was screened with the cone NCKX cDNA, and hybridizing clones were sequenced to determine the genomic organization of the SLC24A2 gene. The single-strand conformation polymorphism (SSCP) technique and direct sequencing were used to screen the patients' DNA for mutations in SLC24A1 and SLC24A2. The effect of selected missense changes on protein function was tested by measuring potassium-dependent Na-Ca exchange of the mutant proteins expressed in insect cells. RESULTS. Twenty-seven novel sequence changes were found in the rod NCKX gene, 21 of which are unlikely to be pathogenic, because they did not cosegregate with the disease or did not affect conserved regions of the protein. Of the remaining six, two were frameshift mutations found in one patient each. If translated, these alleles would encode nonfunctional proteins. Three of the six possibly pathogenic mutations were missense changes located in conserved regions, and their protein functions were assayed. Only one (Ile992Thr) had a significantly low level of exchanger function, but it was found in two unrelated patients who were heterozygotes with different retinal diseases, and this mutation could not be unequivocally associated with either disease. The last of the six changes is likely to create a new splice acceptor site. The genomic organization of the cone NCKX gene was determined, and it contained 11 exons with a few splice variants. Fifteen novel sequence changes were identified in the cone exchanger gene in patients with a cone dysfunction or degeneration. Only three of these sequence changes, all missense changes found in heterozygous patients, were considered possibly pathogenic. Functional analysis showed only a slight reduction in the activity of the corresponding mutant proteins. CONCLUSIONS. Although variant alleles of the rod and cone NCKX genes were found, none could be definitively associated with a specific retinal disease. The human phenotype associated with mutant exchanger alleles remains unknown.
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| 10. |
- Thiselton, DL, et al.
(författare)
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A comprehensive survey of mutations in the OPA1 gene in patients with autosomal dominant optic atrophy
- 2002
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Ingår i: Investigative Ophthalmology & Visual Science. - 1552-5783. ; 43:6, s. 1715-1724
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE. To characterize the spectrum of mutations in the OPA1 gene in a large international panel of patients with autosomal dominant optic atrophy (adOA), to improve understanding of the range of functional deficits attributable to sequence variants in this gene, and to assess any genotype-phenotype correlations. METHODS. All 28 coding exons of OPA1, intron-exon splice sites, 273 bp 5' to exon 1, and two intronic regions with putative function were screened in 94 apparently unrelated white patients of European origin with adOA by single-strand conformational polymorphism (SSCP)-heteroduplex analysis and direct sequencing. Clinical data were collated, and putative mutations were tested for segregation in the respective families by SSCP analysis or direct sequencing and in 100 control chromosomes. Further characterization of selected splice site mutations was performed by RT-PCR of patient leukocyte RNA. Staining of mitochondria in leukocytes of patients and control subjects was undertaken to assess gross differences in morphology and cellular distribution. RESULTS. Twenty different mutations were detected, of which 14 were novel disease mutations (missense, nonsense, deletion-frameshift, and splice site alterations) and six were known mutations. Mutations were found in 44 (47%) of the 94 families, included in the study. Ten new polymorphisms in the OPA1 gene were also identified. Mutations occur throughout the gene, with three clusters emerging: in the mitochondrial leader, in the highly conserved guanosine triphosphate (GTP)-binding domain, and in the -COOH terminus. Examination of leukocyte mitochondria from two unrelated patients with splice site mutations in OPA1 revealed no abnormalities of morphology or cellular distribution when compared with control individuals. CONCLUSIONS. This study describes 14 novel mutations in the OPA1 gene in patients with adOA, bringing the total number so far reported to 54. It is likely that many cases of adOA are due to mutations outside the coding region of OPA1 or to large-scale rearrangements. Evaluation of the mutation spectrum indicates more than one pathophysiological mechanism for adOA. Preliminary data suggests that phenotype-genotype correlation is complex, implying a role for other genetic modifying or environmental factors. No evidence was found of pathologic changes in leukocyte mitochondria of patients with adOA.
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