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Leber congenital amaurosis (LCA) is the most common inherited cause of blindness in childhood and is characterised by a severe retinal dystrophy before the age of one year. Six genes have been identified that together account for approximately half of all LCA patients. These genes are expressed preferentially in the retina or the retinal pigment ep...
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Context 1
... in the six currently identified LCA genes are esti- mated to underlie approximately 50% of LCA cases (Table 1), although a comprehensive mutation analysis of all six genes in the same patient group has not been performed. The six LCA genes show a high degree of allelic heterogeneity with only a few mutations found recurrently (Fig. 2). ...
Context 2
... six genes that have been identified account for approximately half of all LCA cases. Single-strand conforma- tion analysis (SSCA) of these genes requires analysis of nearly 100 amplicons (Table 1). Routine mutation analysis of LCA patient samples using SSCA in standard DNA diagnostic facilities is therefore neither efficient nor cost-effective. ...
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Retinal dystrophies (RD) are major causes of familial blindness and are characterized by progressive dysfunction of photoreceptor and/or retinal pigment epithelium (RPE) cells. In this study, we aimed to evaluate and compare the therapeutic effects of two pluripotent stem cell (PSC)-based therapies. We differentiated RPE from human embryonic stem c...
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Aim:
To characterize by multimodal approach the phenotype of patients from a 3 generations pedigree, affected by autosomal dominant cone-rod dystrophy (CRD), found to carry a novel pathogenic variant in the cone-rod homeobox-containing (CRX) gene.
Methods:
Examination of the adult patients included the following tests: visual acuity, multicolour...
Leber congenital amaurosis (LCA) is an inherited retinal dystrophy that causes childhood blindness. Photoreceptors are especially sensitive to an intronic mutation in the cilia-related gene CEP290, which causes missplicing and premature termination, but the basis of this sensitivity is unclear. Here, we generated differentiated photoreceptors in th...
Citations
... It may manifest as a stand-alone ocular ailment or as a component of a syndrome, like Senior Loken or Joubert syndrome. Although autosomal dominant inheritance has been reported within some families, autosomal recessive inheritance is the usual mode of inheritance for LCA (61). Clinical Presentation People with LCA disease often have severe visual impairments from birth or early childhood. ...
... Approximately 10% of LCA patients have CRB1 variants. CEP290-LCA is a prevalent genetic cause, accounting for 15%-20% of cases (61). Patients with GUCY2D mutations typically have a stable vision, while those with RPE65 mutations may show some improvement followed by a decline. ...
Retinal dystrophies such as; Retinitis pigmentosa, Congenital Stationary Night Blindness, stargartds disease, lebers congenital amaurosis, and others; present with significant visual impairments due to various genetic mutations affecting retinal function and photoreceptor maintenance. This review explores the diverse landscape of retinal dystrophies, categorizing subtypes based on affected cell types. It sheds light on the clinical characteristics, diagnostic techniques, and complex genetic underpinnings of many illnesses. The study emphasizes the significance of the genetic landscape and enhanced diagnostic tools for prognosis. It also looks at newer forms of treatment, such as gene treatments and pharmaceutical approaches, providing a succinct summary of the developing field. This review, aimed at researchers and clinicians, is a useful tool for comprehending and treating retinal dystrophies.
... 1,2 The condition is analogous to retinitis pigmentosa (RP) and for early-onset forms, Leber congenital amaurosis (LCA) in humans. [3][4][5] The canine condition has been recognized in more than 100 breeds. Similar to the analogous conditions in humans, affected dogs may present with profound differences in clinical manifestations. ...
... The various forms of PRA can be further classified by factors such as age of onset, histopathological changes, mode of inheritance, and causal gene mutation. 3,5,[9][10][11][12][13][14][15][16][17][18][19] In some forms, such as rod-cone dysplasias, maturation of photoreceptors is halted and followed by a relatively rapid degeneration. 5,9 In later-onset forms, photoreceptors may develop to maturity but then go on to degenerate. ...
Objective:
To describe the clinical, preliminary electroretinographic and optical coherence tomography features of a newly identified form of progressive retinal atrophy (PRA) in German Spitzes, and identify the causal gene mutation.
Animals:
Thirty-three client-owned German Spitz dogs were included.
Procedures:
All animals underwent a full ophthalmic examination, including vision testing. In addition, fundus photography, ERG, and OCT were performed. A DNA-marker-based association analysis was performed to screen potential candidate genes and the whole genomes of four animals were sequenced.
Results:
Initial fundus changes were pale papilla and mild vascular attenuation. Oscillatory nystagmus was noted in 14 of 16 clinically affected puppies. Vision was impaired under both scotopic and photopic conditions. Rod-mediated ERGs were unrecordable in all affected dogs tested, reduced cone-mediated responses were present in one animal at 3 months of age and unrecordable in the other affected animals tested. Multiple small retinal bullae were observed in three clinically affected animals (two with confirmed genetic diagnosis). OCT showed that despite loss of function, retinal structure was initially well-preserved, although a slight retinal thinning developed in older animals with the ventral retina being more severely affected. Pedigree analysis supported an autosomal recessive inheritance. A mutation was identified in GUCY2D, which segregated with the disease (NM_001003207.1:c.1598_1599insT; p.(Ser534GlufsTer20)). Human subjects with GUCY2D mutations typically show an initial disconnect between loss of function and loss of structure, a feature recapitulated in the affected dogs in this study.
Conclusion:
We identified early-onset PRA in the German Spitz associated with a frameshift mutation in GUCY2D.
... La malattia fu analizzata per la prima volta da Leber nel 1869 venne riconosciuta come una patologia vera e propria (Leber, 1869). Questa patologia è caratterizzata da (Weleber et al., 2013, Fazzi et al., 2003, Cremers et al., 2002: ...
... La malattia fu analizzata per la prima volta da Leber nel 1869 venne riconosciuta come una patologia vera e propria (Leber, 1869). Questa patologia è caratterizzata da (Weleber et al., 2013, Fazzi et al., 2003, Cremers et al., 2002: ...
Relationship between autism and visual impairments.
... La malattia fu analizzata per la prima volta da Leber nel 1869 venne riconosciuta come una patologia vera e propria (Leber, 1869). Questa patologia è caratterizzata da (Weleber et al., 2013, Fazzi et al., 2003, Cremers et al., 2002: ...
Theoric and psychometric issues in the relationship between autism and visual impairments
... Luxturna (voretigene neparvovec) is an AAV2-based gene therapy for biallelic (homozygous or compound heterozygous) mutations in the rpe65 gene, such as Leber's Congenital Amaurosis type 2 (LCA2). RPE56 encodes a critical enzyme essential for phototransduction (process that converts energy contained in a photon of light to biochemical signals) to that mediates the transition of all-trans-retinyl esters to 11-cis-retinol [29]. In an open-label, randomised phase III study, no therapy-related serious adverse events or unacceptable immune responses occurred, whilst 65% of treated patients demonstrated improvements in visual function [30]. ...
Adeno-associated virus (AAV) is a viral vector that can be used to deliver therapeutic genes to diseased cells in the eye. Whilst some consider the eye to be an immuneprivileged organ, recent reports have begun to suggest that injection of AAV may elicit local and systemic immune activation. The objective of this thesis was to further our understanding of the nature of the immune response to intraocularly-delivered AAV vectors, and to develop strategies to achieve repeated gene transfer (i.e. successful follow-on injections) to the inner retina. A literature review was conducted into the role that pre-existing and induced neutralising antibody responses may play in the context of ocular gene therapy. This concluded that a multifaceted/comprehensive approach may be required to circumvent anti-capsid humoral immunity and enable repeated gene transfer in humans. As such, two possible components of this strategy were tested in this thesis. First, a capsid mutagenesis strategy was tested in which certain capsid residues, termed phosphodegrons, were mutated to attenuate cytosolic degradation of AAV. This was to enable robust transduction of the murine retina at low vector dose and thereby circumvent the generation of neutralising antibodies that is associated with injection of high doses of AAV. In fact, it was found that phosphodegron mutant AAV serotype 2 (AAV2) resulted in higher levels of immune activation across all tested parameters vs. wild-type AAV2, including neutralising and total AAV binding antibody levels, microglia activation, Muller glia activation, CD4+ and CD8+ T-cell infiltration into the retina, splenic germinal center B-cell activation and class-switching, and activation of conventional dendritic cells. Mechanistically, it was shown that the capsids demonstrated reduced binding affinity to the AAV2 primary receptor, heparan sulphate proteoglycan, and as such it was suggested that reduced sequestration of virions in the heparan-rich inner limiting membrane may increase cellular infection levels in the retina, thereby increasing overall immune activation. The phosphodegron mutant capsids also demonstrated that a slight escape from anti-AAV2 neutralising serum, suggesting they may be more refractory to pre-existing neutralising antibodies in seropositive patients. Second, an assessment was made as to whether perioperative administration of immunosuppressive glucocorticoid steroids would circumvent immune responses to AAV. It was found that prednisolone was effective at reducing anti-AAV neutralising and total AAV binding antibody titres. This effect may have occurred via the inhibition of splenic germinal center B-cell reactions and class-switching of immunoglobulin antibody isotypes, and reducing follicular helper T-cell levels. Despite the reduction in NAb and TAb titres, it was found that perioperative prednisolone administration was insufficient to enable repeated gene transfer following a second eye injection of AAV2. Interestingly, repeated bilateral AAV2 injections may have resulted in a slight reduction in electrophysiological activity in the retina compared to mice who received two control PBS injections. In conclusion, this thesis highlighted novel aspects of phosphodegron mutant AAV2 immunobiology and identified a possible utility for the administration of prednisolone as a tool for enabling repeated gene transfer of AAV gene therapy vectors.
... Luxturna (voretigene neparvovec) is an AAV2-based gene therapy for Leber's Congenital Amaurosis type 2 (LCA2). LCA2 is caused by biallelic (homozygous or compound heterozygous) mutations in the retinal pigment epithelium-65 (rpe65) gene, which encodes a critical enzyme essential for visual processing by converting alltrans-retinyl esters to 11-cis-retinol during phototransduction (Cremers, 2002). In an open-label, randomised phase III study, no therapy-related serious adverse events or unacceptable immune responses occurred, whilst 65% of treated patients demonstrated improvements in visual function (Russell et al., 2017). ...
Viral vectors can be utilised to deliver therapeutic genes to diseased cells. Adeno‐associated virus (AAV) is a commonly used viral vector that is favoured for its ability to infect a wide range of tissues whilst displaying limited toxicity and immunogenicity. Most humans harbour anti‐AAV neutralising antibodies (NAbs) due to subclinical infections by wild‐type virus during infancy and these pre‐existing NAbs can limit the efficiency of gene transfer depending on the target cell type, route of administration and choice of serotype. Vector administration can also result in de novo NAb synthesis that could limit the opportunity for repeated gene transfer to diseased sites. A number of strategies have been described in preclinical models that could circumvent NAb responses in humans, however, the successful translation of these innovations into the clinical arena has been limited. Here, we provide a comprehensive review of the humoral immune response to AAV gene therapy in the ocular compartment. We cover basic AAV biology and clinical application, the role of pre‐existing and induced NAbs, and possible approaches to overcoming antibody responses. We conclude with a framework for a comprehensive strategy for circumventing humoral immune responses to AAV in the future.
... L eber congenital amaurosis (LCA) is a group of inherited retinal disorders caused by loss-of-function mutations in several genes that are important for retinal function 1 . Most patients with LCA have severe visual impairment throughout infancy or childhood and become legally blind by the third or fourth decade of life due to progressing retinal degeneration 2 . ...
Cytosine base editors and adenine base editors (ABEs) can correct point mutations predictably and independent of Cas9-induced double-stranded DNA breaks (which causes substantial indel formation) and homology-directed repair (which typically leads to low editing efficiency). Here, we show, in adult mice, that a subretinal injection of an adeno-associated virus expressing an ABE and a single-guide RNA targeting a de novo nonsense mutation in the Rpe65 gene corrects the pathogenic mutation with up to 29% efficiency and with minimal formation of indel and off-target mutations, despite the absence of the canonical NGG sequence as a protospacer-adjacent motif. The ABE-treated mice displayed restored RPE65 expression and retinoid isomerase activity, and near-normal levels of retinal and visual functions. Our findings motivate the further testing of ABEs for the treatment of inherited retinal diseases and for the correction of pathological mutations with non-canonical protospacer-adjacent motifs.
... 9,30,45,48 On the other hand, some studies figured out that the other modifier genes and environmental factors may contribute to the phenotypic severity of the CRB1-associated retinopathy. 30,32,61 In the present study, patients with biallelic truncation variants presented an advanced NPD fundus change at a younger age (mostly less than five years of age) as compared to those with biallelic missense variants (Fig 3). Truncation variants played an essential role in patients' clinical performance, and the pathogenicity of the variants could influence the phenotype to some extent. ...
Purpose
To reveal the characteristics of ocular changes in patients with biallelic CRB1 mutations.
Design
Comparative exome sequencing and retrospective case series on clinical data.
Methods
Seventy-four patients from 63 families with biallelic potential pathogenic variants in CRB1 were selected from our in-house exome sequencing. The clinical data were reviewed and evaluated in detail, including best corrected visual acuity, fundus photography, OCT, and ERG.
Results
Biallelic CRB1 variants, involving 45 variants including 23 novel, were identified in 40 novel families based on exome sequencing. Analysing clinical data of the 74 individuals from 63 families revealed the following CRB1-associated phenotypes: 1) early-onset reduced visual acuity with congenital nystagmus; 2) two types of characteristic retinal changes including yellowish geographic macular degeneration (YMD) or nummular pigment deposits (NPD) at posterior retina with bone-spicule pigmentation at mid-peripheral; 3) undetectable rod and cone responses on electroretinogram; 4) cystoid macular edema or macular atrophy on OCT. YMD and NPD are unique and CRB1-associated. Long-term follow-up examination as well as age- and variant-dependent phenotypic analysis suggested YMD is the early fundus change that would gradually progress to NPD.
Conclusions
YMD and NPD are two major characteristic CRB1-associated fundus changes and the former one will advance to the latter with age. Recognizing such characteristic signs associated with biallelic CRB1 variants may be of value in areas without widespread access to genetic testing where a more targeted approach is needed and might be biomarkers for evaluation of effects for future intervention.
... Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal degeneration (IRD), characterized by blindness or severe visual impairment from birth [1,2]. It is clinically diagnosed as bilateral congenital blindness, with a diminished or absent electroretinogram (ERG) before the age of 6 m, and shows clinical and genetic heterogeneity [1,2]. ...
... Leber congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal degeneration (IRD), characterized by blindness or severe visual impairment from birth [1,2]. It is clinically diagnosed as bilateral congenital blindness, with a diminished or absent electroretinogram (ERG) before the age of 6 m, and shows clinical and genetic heterogeneity [1,2]. Recently, 14 causative genes of LCA were listed in the RetNet (Retinal Information Network) database [3]. ...
Background:
Leber congenital amaurosis (LCA) is the earliest onset and the most severe form of all inherited retinal degenerative disorders, characterized by blindness, or severe visual impairment from birth, and typically exhibits clinical and genetic heterogeneity. Recently, 14 causative genes of LCA were reported. We performed whole-exome sequencing (WES) for Japanese siblings, and identified a novel homozygous nonsense mutation in the RPGR-interacting protein 1 (RPGRIP1) gene. We also report their follow-up data over 27 years.
Case presentation:
Patient 1 is a 37-year-old male. In 1992, his eye position indicated orthophoria, however, horizontal nystagmus was evident, and he complained of photophobia. His best corrected decimal visual acuity (BCVA) was 0.2 (S + 6.5/C-3.5/170°) OD and 0.1 (S + 6.0/C-2.5/10°) OS. Fundus examination revealed bisymmetrical inferior focal retinal pigment epithelium (RPE) mottling. Bright-flash electroretinogram (ERG) revealed a subnormal pattern, while 30 Hz flicker ERG was non-recordable in both eyes. At his final visit in 2019, his BCVA was 0.09 (S + 3.5/C-3.5/180°) OD and 0.09 (S + 3.0/C-4.0/10°) OS. Patient 2, a 34-year-old female, is the sibling of patient 1. In 1992, her BCVA was 0.05 (S + 6.0) OD and 0.06 (S + 5.0) OS. She was in a chin-up position during visual acuity testing. Horizontal nystagmus was evident, and she also complained of photophobia. Bright-flash ERG was severely attenuated, and 30 Hz flicker ERG was non-recordable in both eyes. At her final visit in 2019, her BCVA was 0.02 (uncorrectable) OD and 0.03 (uncorrectable) OS. There were no other patients with LCA in their family and their parents were non-consanguineous. WES revealed a homozygous, consecutive, two-nucleotide variation in the RPGRIP1 gene (NM_020366: exon15:c.G2294A and c.C2295A, p.C765X), resulting in a premature stop codon. We interpreted this variation as a novel pathogenic mutation of RPGRIP1 that contributes to LCA6 development.
Conclusions:
Herein, we report a novel nonsense mutation of RPGRIP1 in two patients with LCA6 and present their long-term follow-up data. These clinical data linked to genotypes provide important information for the development of new treatments, such as gene therapy, as well as for genetic counseling.
