Antisense oligonucleotide-based splicing correction in individuals with leber congenital amaurosis due to compound heterozygosity for the c.2991+1655A>G mutation in CEP290

Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant

Indirect exclusion of four candidate genes for generalized progressive retinal atrophy in several breeds of dogs

BACKGROUND: Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina (ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs. RESULTS: Mutation screening was performed initially by PCR and single strand conformation polymorphism (SSCP) analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4, CX36, MERTK and RDH12 in 71 affected dogs of 29 breeds. Yet 30 new sequence variations were identified, both, in the coding regions and intronic sequences. Many of the sequence variations were in heterozygous state in affected dogs. CONCLUSION: Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK (for all 29 breeds) and RDH12 (for 9 breeds)

Clinical characteristics of rod and cone photoreceptor dystrophies in patients with mutations

METHODS. Eight patients-four diagnosed with retinitis pigmentosa (RP) and four with conerod dystrophy (CRD), carrying causal C8orf37 mutations-were clinically evaluated, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, kinetic perimetry, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), autofluorescence (AF) imaging, and fundus photography. RESULTS. In families A and D, respectively, one and three patients showed a classic RP phenotype with night blindness followed by concentric loss of visual field. Severe visual loss to light perception occurred early in the course of the disease. The symptoms initiated during infancy (family A) or adolescence (family D). Ophthalmoscopy revealed macular atrophy, bone spicules, attenuated vessels, and waxy pale optic discs. SD-OCT showed profound photoreceptor degeneration and AF demonstrated atrophy of the retinal pigment epithelium (RPE). ERG responses were nonrecordable in these patients. In families B and C, the patients were diagnosed with CRD. Initial symptoms were photophobia or loss of visual acuity and occurred during infancy (family B) or adolescence (family C). Ophthalmoscopy and AF revealed profound macular RPE atrophy and SD-OCT demonstrated macular photoreceptor degeneration. ERG responses were severely reduced in a cone-rod pattern or were nonrecordable. Interestingly, both patients in family B demonstrated polydactyly. CONCLUSIONS. Mutations in C8orf37 give rise to an early or adolescent-onset autosomal recessive CRD or RP phenotype with early macular atrophy. The occurrence of postaxial polydactyly in one family suggests a syndromic phenotype, which may indicate C8orf37 has a ciliary function

Near-infrared reflectance imaging of neovascular age-related macular degeneration

Contains fulltext : 81007.pdf (publisher's version ) (Closed access)PURPOSE: To evaluate various types of neovascular age-related macular degeneration (AMD) by near-infrared fundus reflectance (NIR) as compared to fundus fluorescein angiography (FFA) and to test NIR for assessment of leakage due to choroidal neovascularization (CNV). PATIENTS AND METHODS: Thirty-three patients with neovascular AMD (cases) and 20 age-matched patients with non-exudative AMD and healthy subjects (controls) were examined with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2). NIR images of neovascular AMD were qualitatively compared to the corresponding FFA and to age-matched controls. CNV membranes and exudation areas were manually segmented on FFA and NIR and analyzed quantitatively. Results : Of all cases included, five eyes had classic CNV, six had minimal classic lesions, 15 occult CNV's and seven eyes had retinal angiomatous proliferation (RAP). A dark halo on NIR was found in all cases and showed high correspondence to leakage on FFA (r (2) = 0.93; p < 0,0005). In classic CNV and minimal classic CNV, the classic part of the lesion on FFA revealed strong correlation to a dark core surrounded by a bright reflecting ring on NIR (r (2) = 0.88; p < 0.0005). Occult parts on FFA of minimal classic CNV and occult CNV lesions appeared as poorly demarcated, jagged areas of increased NIR. RAP was characterized by speckled NIR located at the intraretinal neovascular complex. CONCLUSIONS: NIR imaging in neovascular AMD revealed characteristic alterations depending on the type of CNV. These changes may reflect histological differences of the lesions. Leakage caused local darkening of NIR, presumably originating from increased light-scattering and absorbance by fluid accumulation and sub-cellular structure alterations

Risk factors for development and progression of diabetic retinopathy in Dutch patients with type 1 diabetes mellitus

Purpose: To investigate risk factors for the development and progression of diabetic retinopathy (DR) and long-term visual outcomes in Dutch patients with type 1 diabetes mellitus (T1DM). Methods: Cumulative incidences were calculated for DR, vision-threatening DR (VTDR), defined as (pre)proliferative DR and diabetic macular oedema, and best-corrected visual acuity (BCVA) <0.5 and <0.3 at the most recent eye examination. The fo

Cone rod dystrophies

Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness

Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3–p21.2 between D1S2896 and D1S457 but outside ABCA4

A severe form of autosomal recessive retinitis pigmentosa (arRP) was identified in a large Pakistani family ascertained in the Punjab province of Pakistan. All affected individuals in the family had night blindness in early childhood, early complete loss of useful vision, and typical RP fundus changes plus macular degeneration. After exclusion of known arRP loci, a genome-wide scan was performed using microsatellite markers at about 10 cM intervals and calculating two-point lod scores. PCR cycle dideoxynucleotide sequencing was used to sequence candidate genes inside the linked region for mutations. RP in this family shows linkage to markers in a 10.5 cM (8.9 Mbp) region of chromosome 1p13.3–p21.2 between D1S2896 and D1S457. D1S485 yields the highest lod score of 6.54 at θ=0. Sequencing the exons and intron–exon boundaries of five candidate genes and six ESTs in this region, OLFM3, GNAI3, LOC126987, FLJ25070, DKFZp586G0123, AV729694, BU662869, BU656110, BU171991, BQ953690, and CA397743, did not identify any causative mutations. This novel locus lies approximately 4.9 cM (7.1 Mbp) from ABCA4, which is excluded from the linked region. Identification and study of this gene may help to elucidate the phenotypic diversity of arRP mapping to this region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47597/1/439_2005_Article_54.pd

Acute Endophthalmitis after Cataract Surgery: Clinical Characteristics and the Role of Intracameral Antibiotic Prophylaxis

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Low vision rehabilitation for better quality of life in visually impaired adults

Contains fulltext : 218889.pdf (Publisher’s version ) (Open Access)BACKGROUND: Low vision rehabilitation aims to optimise the use of residual vision after severe vision loss, but also aims to teach skills in order to improve visual functioning in daily life. Other aims include helping people to adapt to permanent vision loss and improving psychosocial functioning. These skills promote independence and active participation in society. Low vision rehabilitation should ultimately improve quality of life (QOL) for people who have visual impairment. OBJECTIVES: To assess the effectiveness of low vision rehabilitation interventions on health-related QOL (HRQOL), vision-related QOL (VRQOL) or visual functioning and other closely related patient-reported outcomes in visually impaired adults. SEARCH METHODS: We searched relevant electronic databases and trials registers up to 18 September 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating HRQOL, VRQOL and related outcomes of adults, with an irreversible visual impairment (World Health Organization criteria). We included studies that compared rehabilitation interventions with active or inactive control. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 44 studies (73 reports) conducted in North America, Australia, Europe and Asia. Considering the clinical diversity of low vision rehabilitation interventions, the studies were categorised into four groups of related intervention types (and by comparator): (1) psychological therapies and/or group programmes, (2) methods of enhancing vision, (3) multidisciplinary rehabilitation programmes, (4) other programmes. Comparators were no care or waiting list as an inactive control group, usual care or other active control group. Participants included in the reported studies were mainly older adults with visual impairment or blindness, often as a result of age-related macular degeneration (AMD). Study settings were often hospitals or low vision rehabilitation services. Effects were measured at the short-term (six months or less) in most studies. Not all studies reported on funding, but those who did were supported by public or non-profit funders (N = 31), except for two studies. Compared to inactive comparators, we found very low-certainty evidence of no beneficial effects on HRQOL that was imprecisely estimated for psychological therapies and/or group programmes (SMD 0.26, 95% CI -0.28 to 0.80; participants = 183; studies = 1) and an imprecise estimate suggesting little or no effect of multidisciplinary rehabilitation programmes (SMD -0.08, 95% CI -0.37 to 0.21; participants = 183; studies = 2; I(2) = 0%); no data were available for methods of enhancing vision or other programmes. Regarding VRQOL, we found low- or very low-certainty evidence of imprecisely estimated benefit with psychological therapies and/or group programmes (SMD -0.23, 95% CI -0.53 to 0.08; studies = 2; I(2) = 24%) and methods of enhancing vision (SMD -0.19, 95% CI -0.54 to 0.15; participants = 262; studies = 5; I(2) = 34%). Two studies using multidisciplinary rehabilitation programmes showed beneficial but inconsistent results, of which one study, which was at low risk of bias and used intensive rehabilitation, recorded a very large and significant effect (SMD: -1.64, 95% CI -2.05 to -1.24), and the other a small and uncertain effect (SMD -0.42, 95%: -0.90 to 0.07). Compared to active comparators, we found very low-certainty evidence of small or no beneficial effects on HRQOL that were imprecisely estimated with psychological therapies and/or group programmes including no difference (SMD -0.09, 95% CI -0.39 to 0.20; participants = 600; studies = 4; I(2) = 67%). We also found very low-certainty evidence of small or no beneficial effects with methods of enhancing vision, that were imprecisely estimated (SMD -0.09, 95% CI -0.28 to 0.09; participants = 443; studies = 2; I(2) = 0%) and multidisciplinary rehabilitation programmes (SMD -0.10, 95% CI -0.31 to 0.12; participants = 375; studies = 2; I(2) = 0%). Concerning VRQOL, low-certainty evidence of small or no beneficial effects that were imprecisely estimated, was found with psychological therapies and/or group programmes (SMD -0.11, 95% CI -0.24 to 0.01; participants = 1245; studies = 7; I(2) = 19%) and moderate-certainty evidence of small effects with methods of enhancing vision (SMD -0.24, 95% CI -0.40 to -0.08; participants = 660; studies = 7; I(2) = 16%). No additional benefit was found with multidisciplinary rehabilitation programmes (SMD 0.01, 95% CI -0.18 to 0.20; participants = 464; studies = 3; I(2) = 0%; low-certainty evidence). Among secondary outcomes, very low-certainty evidence of a significant and large