| 1. |
- Areblom, Maria, et al.
(author)
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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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In: Genes. - 2073-4425. ; 14:7
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Journal article (peer-reviewed)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. |
- Almasoudi, Wejdan, et al.
(author)
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Co-occurrence of CLCN2-related leukoencephalopathy and SPG56
- 2023
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In: Clinical Parkinsonism and Related Disorders. - : Elsevier BV. - 2590-1125. ; 8
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Journal article (peer-reviewed)abstract
- Family Report: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. Conclusion: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant's pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance.
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| 3. |
- Ekesten, Björn, et al.
(author)
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Abnormal Appearance of the Area Centralis in Labrador Retrievers With an ABCA4 Loss-of-function Mutation
- 2022
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In: Translational Vision Science & Technology. - : Association for Research in Vision and Ophthalmology (ARVO). - 2164-2591. ; 11:2
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Journal article (peer-reviewed)abstract
- Purpose: To study retinal appearance and morphology in Labrador retrievers (LRs) heterozygous and homozygous for an ABCA4 loss-of-function mutation. Methods: Ophthalmic examination, including ophthalmoscopy and simple testing of vision, was performed in five ABCA4(wt/wt), four ABCA4(wt/InsC), and six ABCA4(InsC/InsC) LRs. Retinas were also examined with confocal scanning laser ophthalmoscopy (cSLO) and optical coherence tomography (OCT). Infrared and fundus autofluorescence (FAF) images were studied, and outer nuclear layer (ONL) and neuroretinal thickness were measured in the central and peripheral area centralis. Results: Clinical signs in young ABCA4(InsC/InsC) LRs were subtle, whereas ophthalmoscopic findings and signs of visual impairment were obvious in old ABCA4InsC/InsC LRs. Retinal appearance and vision testing was unremarkable in heterozygous LRs regardless of age. The cSLO/OCT showed abnormal morphology including ONL thinning, abnormal outer retinal layer segmentation, and focal loss of retinal pigment epithelium in the fovea equivalent in juvenile ABCA4(InsC/InsC) LRs. The abnormal appearance extended into the area centralis and visual streak in middle-aged ABCA4(InsC/InsC) and then spread more peripherally. A mild phenotype was seen on cSLO/OCT and FAF in middle-aged to old ABCA4(wt/InsC) LRs. Conclusions: Abnormal appearance and morphology in the fovea equivalent are present in juvenile ABCA4InsC/InsC. In the older affected LRs, the visual streak and then the peripheral retina also develop an abnormal appearance. Vision deteriorates slowly, but some vision is retained throughout life. Older heterozygotes may show a mild retinal phenotype but no obvious visual impairment. The ABCA4InsC/InsC LR is a potential model for ABCA4-mediated retinopathies/juvenile-onset Stargardt disease in a species with human-sized eyes. Translational Relevance: The ABCA4(InsC) mutation causes juvenile-onset abnormal appearance of the fovea equivalent in affected dogs that slowly spreads in the retina, while only a mild phenotype is seen in older carriers. This is the first non-primate, large animal model for ABCA4-related/STGD1 retinopathies in a species with a fovea equivalent.
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| 4. |
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| 5. |
- Kjellström, Ulrika, et al.
(author)
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A five-year follow-up of ABCA4 carriers showing deterioration of retinal function and increased structural changes
- 2022
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In: Molecular Vision. - 1090-0535. ; 28, s. 300-316
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Journal article (peer-reviewed)abstract
- Purpose: To investigate whether the reduced retinal function and morphological retinal changes previously demonstrated in ABCA4 carriers had remained stationary or had deteriorated over time at 5-year follow-up to further explore if carriers of an autosomal recessive trait also express a weak phenotype, although this is not expected for an autosomal recessive disorder. Methods: Thirteen ABCA4 carriers from a previous study that included parents to patients with well known genetically verified ABCA4-associated retinal degenerations were reexamined 5 years after the initial examination. As novel genes and new variants in already established genes are continuously reported, all subjects underwent renewed genetic testing with a next-generation sequencing (NGS) panel that included 288 genes associated with retinal dystrophies and an analysis of deep intronic mutations and copy number variations in the ABCA4 gene. Moreover, to evaluate any changes in retinal function and/or structure over time, clinical reassessment with Goldmann perimetry, visual acuity testing, fundus photography, fundus autofluorescence (FAF) imaging, optical coherence tomography (OCT), full-field electro-retinography (ffERG), and multifocal ERG (mf ERG) were performed 5 years after the initial investigation. The values of the ffERG parameters were compared between the two time points (the measurements obtained in the initial study versus the measurements at 5-year follow-up) and with the controls. The mf ERG results of the carriers were compared with those of the controls. Results: The renewed genetic testing confirmed the previously established ABCA4 mutations but also revealed the hypomorph ABCA4 variant c.5603A>T in five ABCA4 carriers. In three of them, the variant was found to be associated with known disease-causing alleles that always carry the c.5603A>T in cis. According to recent publications, the subjects could still be considered ABCA4 carriers because both variants are on the same allele. In the remaining two subjects, c.5603A>T could be in trans with the previously known ABCA4 variant, and the subjects were therefore excluded from the study since they could no longer be considered as carriers only. Statistical comparison of ffERG parameters showed significant reduction of the isolated rod,-as well as the combined rod-cone amplitudes over the five years of follow-up, but not compared with the controls. Concerning macular function, mf ERG amplitudes were reduced for all rings in the carriers compared with the controls. Fundus photographs demonstrated morphological changes in 64% of the carriers, and 36% of them had further changes at follow-up. FAF images showed alterations in 55% of the carriers, with increased changes in 36% of them. Abnormalities on OCT were observed in 82% of the carriers, of whom 9% had newly found abnormalities at follow-up. Conclusions: At 5-year follow-up, the ABCA4 carriers, who previously demonstrated reduced macular function, presented with deterioration of general retinal function, including reduced isolated rod and mixed rod-cone ffERG responses combined with a slight increase in morphological changes in some subjects. This indicates that carriership of at least some ABCA4 variants may cause a condition similar to a subgroup of dry age-related macular degeneration (AMD). In the long run, this might be of importance concerning the possibilities to also treat this subgroup of AMD patients with future gene-based and pharmacological drugs targeting ABCA4-associated disorders.
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| 6. |
- Kjellström, Ulrika, et al.
(author)
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Autosomal recessive Stickler syndrome associated with homozygous mutations in the COL9A2 gene
- 2021
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In: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 42:2, s. 161-169
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Journal article (peer-reviewed)abstract
- Background: Stickler syndrome is a hereditary disorder of collagen tissues causing ocular, auditory, orofacial, and joint manifestations. Ocular findings typically include vitreous degeneration, high myopia, retinal detachment, and cataract. Many subjects demonstrate sensorineural or conductive hearing loss. The inheritance is autosomal dominant with mutations in COL2A1, COL11A1, or COL11A2 or autosomal recessive due to mutations in COL9A1, COL9A2, or COL9A3. We describe a family with Stickler syndrome caused by homozygous loss-of-function mutations in COL9A2. Methods: Two brothers from a consanguineous family were examined with genetic testing, visual acuity, Goldmann perimetry, full-field and multifocal electroretinography (ffERG, mERG), optical coherence tomography (OCT), fundus autofluorescence (FAF), fundus photography, and pure-tone audiograms. Results: Both subjects were homozygous for the mutation c.1332del in COL9A2. Their parents were heterozygous for the same mutation. The boys demonstrated reduced visual acuity, vitreous changes and myopia. The proband was operated for retinal detachment and cataract in one eye. FfERG revealed reduced function of both rods and cones and mERG showed reduced macular function. No morphological macular changes were found by OCT or FAF. Both brothers have severe sensorineural hearing loss with down-sloping audiograms but only subtle midface hypoplasia and no, or mild joint problems. Conclusion: Only a few families with Stickler syndrome caused by COL9A2 mutations have been reported. We confirm previous descriptions with a severe ocular and auditory phenotype but mild orofacial and joint manifestations. Moreover, we demonstrate reduced macular and overall retinal function explaining the reduced visual acuity in patients with Stickler syndrome also without retinal complications.
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| 7. |
- Magnusson, Gunilla, 1968, et al.
(author)
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The prevalence of visual axis opacification in the Swedish Pediatric Cataract Register
- 2024
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In: ACTA OPHTHALMOLOGICA. - 1755-375X .- 1755-3768.
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Journal article (peer-reviewed)abstract
- Purpos o report on the occurrence of postoperative visual axis opacification (VAO) in children younger than 5 years of age operated for cataract in Sweden, and to analyse correlations with age at surgery and surgical method.Methods Data were derived from the Swedish Pediatric Cataract Register (PECARE). All children operated on between 1 January 2007 and 31 December 2020 were included. Follow-ups at 1, 2 and 5 years of age were analysed.Results Cataract surgery were performed on 770 eyes belonging to 549 children (n = 282 boys, 51.4%); 327/770 (42.5%) of the children underwent surgery before 3 months of age and 216/770 (28%) before 6 weeks of age. Data on 881 follow-up visits were registered. At the follow up-visits at 1, 2 and 5 years of age, VAO was present in 154/349 (44.1%), 41/323 (12.7%) and 25/208 (12%). The majority of the children with VAO underwent cataract surgery before age 6 months, with a predominance before age 2 months. Primary IOL was implanted in 601/770 (78%) of eyes; 40.8% had an acrylic one-piece lens, 31.8% had a bag-in-the-lens IOL, 21.9% were aphakic and 5.2% had an acrylic three-piece lens. Implantation of a bag-in-the-lens IOL was related to a significantly lower occurrence of VAO compared to other types of IOL, including aphakia (p < 0.0002).Conclusion Our results are in accordance with the literature. Primary bag-in-the-lens IOL implantation before 2 years of age seems adequate and safe, with a low occurrence of VAO, and can thus be continued as routine in Sweden.
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| 8. |
- Panneman, Daan M., et al.
(author)
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Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis
- 2023
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In: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 11
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Journal article (peer-reviewed)abstract
- Introduction: Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) are two groups of inherited retinal diseases (IRDs) where the rod photoreceptors degenerate followed by the cone photoreceptors of the retina. A genetic diagnosis for IRDs is challenging since >280 genes are associated with these conditions. While whole exome sequencing (WES) is commonly used by diagnostic facilities, the costs and required infrastructure prevent its global applicability. Previous studies have shown the cost-effectiveness of sequence analysis using single molecule Molecular Inversion Probes (smMIPs) in a cohort of patients diagnosed with Stargardt disease and other maculopathies. Methods: Here, we introduce a smMIPs panel that targets the exons and splice sites of all currently known genes associated with RP and LCA, the entire RPE65 gene, known causative deep-intronic variants leading to pseudo-exons, and part of the RP17 region associated with autosomal dominant RP, by using a total of 16,812 smMIPs. The RP-LCA smMIPs panel was used to screen 1,192 probands from an international cohort of predominantly RP and LCA cases. Results and discussion: After genetic analysis, a diagnostic yield of 56% was obtained which is on par with results from WES analysis. The effectiveness and the reduced costs compared to WES renders the RP-LCA smMIPs panel a competitive approach to provide IRD patients with a genetic diagnosis, especially in countries with restricted access to genetic testing.
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| 9. |
- Schroeder, Marion, et al.
(author)
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A novel phenotype associated with the R162W variant in the KCNJ13 gene
- 2022
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In: Ophthalmic Genetics. - : Informa UK Limited. - 1381-6810 .- 1744-5094. ; 43:4, s. 500-507
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Journal article (peer-reviewed)abstract
- Background: Pathogenic variants in KCNJ13 have been associated with both autosomal dominant Snowflake vitreoretinal degeneration (SVD) and autosomal recessive Leber congenital amaurosis. SVD is characterized by aberrant vitreoretinal interface leading to increased risk of retinal detachment, crystalline retinal snowflake deposits, optic disc abnormalities, early-onset cataract, and cornea guttae. Reduced dark adaptation and reduced scotopic rod b-waves have also been described. We report a novel phenotype associated with the R162W variant in KCNJ13. Methods: Four affected members of a Swedish family were included. Three of them were examined with best corrected visual acuity, Goldmann perimetry, full-field—and multifocal electroretinography, optical coherence tomography, fundus color photographs, fundus autofluorescence images, slit lamp inspection, and genetic testing. The fourth subject only managed genetic testing. Results: All subjects carry the pathogenic missense variant; c.484C>T (NM_002242.4), R162W, in KCNJ13. ERG measurements revealed reduced macular—as well as general retinal function. Two of the subjects had a history of retinal detachment and the two younger subjects demonstrated early onset cataract. They all had structural macular changes and slightly gliotic optic discs. Conclusion: In this family, the R162W variant in KCNJ13, previously described in association with SVD, causes a somewhat novel phenotype including macular dystrophy and moderate reduction of general retinal function as the main features combined with disc abnormalities, retinal detachment, and presenile cataract that has been described before. In times of up-coming gene-based therapies, it is important to report new genotype—phenotype associations to improve the possibilities to identify future treatment candidates.
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| 10. |
- Schroeder, Marion, et al.
(author)
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Electrophysiological evaluation and 18-month follow-up of two regimens with aflibercept for neovascular age-related macular degeneration
- 2022
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In: Documenta Ophthalmologica. - : Springer Science and Business Media LLC. - 1573-2622 .- 0012-4486. ; 144:2, s. 99-115
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Journal article (peer-reviewed)abstract
- PURPOSE: To compare two aflibercept treatment regimens and the electrophysiological outcome concerning cone and rod function in age-related macular degeneration (nAMD) over 18 months.METHODS: 41 patients with treatment-naïve nAMD were randomized 1:1 to either arm 1 or 2. Arm 1 received three consecutive monthly aflibercept injections, followed by bimonthly treatment until week 52. Thereafter, a treat-and-extend (TAE) regimen was applied. Arm 2 was treated according to a TAE protocol throughout the 18-month follow-up. We assessed visual acuity (VA), central retinal thickness (CRT), injection rate and interval, and evaluated cone and rod function with full-field and multifocal electroretinography (ffERG, mERG).RESULTS: There were no statistically significant differences in mean baseline VA, lesion type, age, gender, or symptom duration between the two arms. During the 18-month follow-up, mean VA improved in arm 1 (n = 19) from 63.5 ± 10.5 to 69.1 ± 9.2 letters; p = 0.098; and in arm 2 (n = 20) from 66.8 ± 13.6 to 73.9 ± 9.0 letters; p = .002. In both arms, mean CRT was significantly reduced; p < 0.000. At month 18, we found no significant difference in the number of injections or injection intervals between groups. Arm 1 had received 11.3 ± 1.7 injections vs. 10.9 ± 2.0 in arm 2. The mean injection interval was 9.2 ± 3.4 weeks vs. 9.5 ± 3.1, with 52% (n = 10) on the maximum 12-week interval in arm 1, and 50% (n = 10) in arm 2. The combined rod-cone a-wave amplitude significantly decreased over time; p = 0.043. The isolated rod b-wave amplitude showed a statistically significant decline; p = 0.026. The overall mERG amplitude and implicit time remained unchanged over time; p = 0.878 vs. p = 0.922. The central ring 1 mERG amplitude improved; p = 0.041, with an unaffected implicit time.CONCLUSIONS: After 18 months, both treatments arms have received a similar number of injections at comparable intervals. Electrophysiological evaluation shows no signs of toxicity concerning cone function. But ffERGs for the combined and isolated rod response have declined, possibly reflecting either toxic effects of the drug to rods or the natural course of the disease itself.
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