Non-syndromic retinitis pigmentosa Verbakel, Sanne K.; van Huet, Ramon A.C.; Boon, Camiel J.F. ...
Progress in retinal and eye research,
September 2018, 2018-09-00, 20180901, Volume:
66
Journal Article
Peer reviewed
Open access
Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, ...with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Fundus-controlled perimetry (FCP, also called ‘microperimetry’) allows for spatially-resolved mapping of visual sensitivity and measurement of fixation stability, both in clinical practice as well as ...research. The accurate spatial characterization of visual function enabled by FCP can provide insightful information about disease severity and progression not reflected by best-corrected visual acuity in a large range of disorders. This is especially important for monitoring of retinal diseases that initially spare the central retina in earlier disease stages. Improved intra- and inter-session retest-variability through fundus-tracking and precise point-wise follow-up examinations even in patients with unstable fixation represent key advantages of these technique. The design of disease-specific test patterns and protocols reduces the burden of extensive and time-consuming FCP testing, permitting a more meaningful and focused application. Recent developments also allow for photoreceptor-specific testing through implementation of dark-adapted chromatic and photopic testing. A detailed understanding of the variety of available devices and test settings is a key prerequisite for the design and optimization of FCP protocols in future natural history studies and clinical trials. Accordingly, this review describes the theoretical and technical background of FCP, its prior application in clinical and research settings, data that qualify the application of FCP as an outcome measure in clinical trials as well as ongoing and future developments.
•Fundus-controlled perimetry enables spatially-resolved testing of visual sensitivity.•Through fundus-tracking, even patients with unstable fixation may be examined.•Recent developments allow for partially photoreceptor-specific testing of function.•Reliability and ability to detect change is evident for multiple retinal diseases.•Applications include macular and retinal degenerations, dystrophies, toxic retinopathies and inflammatory diseases.
Unlike in the healthy mammalian retina, macrophages in retinal degenerative states are not solely comprised of microglia but may include monocyte-derived recruits. Recent studies have applied ...transgenics, lineage-tracing, and transcriptomics to help decipher the distinct roles of these two cell types in the diseasesettings of inherited retinal degenerations and age-related macular degeneration.Literature discussed here focuses on the ectopic presence of both macrophage types in the extracellular site surrounding the outer aspect ofphotoreceptor cells (i.e.,the subretinal space), which is crucially involved in the pathobiology. From these studies we propose a working model in which perturbed photoreceptor states cause microglial dominant migration to the subretinal space as a protective response, whereas the abundant presence ofmonocyte-derived cells there instead drives and accelerates pathology. The latter, we propose, is underpinned by specific genetic and nongenetic determinants that lead to a maladaptive macrophage state.
Mononuclear phagocytes (MNPs) are central players in retinal degeneration, as seen in age-related macular degenerationand inherited retinal degeneration.A key feature of retinal degeneration is the invasion of MNPs into the subretinal space (an extracellular site critical for vision).However, it remains debated whether these cells consist of microglia and/or monocyte-derived cells, and what are their respective roles.We argue that in retinal degeneration settingsin mouse models, ‘adaptive’ MNP responses are those in which reactive microglia migrate into the subretinal space and play a role in restricting diseaseprogression.‘Maladaptive’ response, by contrast, are seen, for example, in mice with certain deficiencies in MNP-expressed genes. There, a normally subthreshold insult can result in an abundance of pathogenic monocyte-derived cells in the subretinal space.We further lay out how these adaptive/maladaptive classifications may serve as a conceptual framework to help betterunderstand the complex roles of microglia versus monocytes in the human diseasecontext.
PurposeEye inflammation may occur in patients with inherited retinal dystrophies (IRDs) and is seen frequently in IRDs associated with mutations in the CRB1 gene. The purpose of this study was to ...determine the types of inflammatory cells involved in IRDs, by deep profiling the composition of peripheral blood mononuclear cells of patients with a CRB1-associated IRD.MethodsThis study included 33 patients with an IRD with confirmed CRB1 mutations and 32 healthy controls. A 43-parameter flow cytometry analysis was performed on peripheral blood mononuclear cells isolated from venous blood. FlowSOM and manual Boolean combination gating were used to identify and quantify immune cell subsets.ResultsComparing patients with controls revealed a significant increase in patients in the abundance of circulating CD4+ T cells and CD8+ T cells that express sialyl Lewis X antigen. Furthermore, we detected a decrease in plasmacytoid dendritic cells and an IgA+CD24+CD38+ transitional B-cell subset in patients with an IRD.ConclusionsPatients with a CRB1-associated IRD show marked changes in blood leukocyte composition, affecting lymphocyte and dendritic cell populations. These results implicate inflammatory pathways in the disease manifestations of IRDs.
To describe the phenotype and clinical course of patients with RPGR-associated retinal dystrophies, and to identify genotype-phenotype correlations.
A multicenter medical records review of 74 male ...patients with RPGR-associated retinal dystrophies.
Patients had retinitis pigmentosa (RP; n = 52; 70%), cone dystrophy (COD; n = 5; 7%), or cone-rod dystrophy (CORD; n = 17; 23%). The median follow-up time was 11.6 years (range 0-57.1). The median age at symptom onset was 5.0 years (range 0-14 years) for patients with RP and 23.0 years (range 0-60 years) for patients with COD/CORD. The probability of being blind (best-corrected visual acuity <0.05) at the age of 40 was 20% and 55% in patients with RP and COD/CORD, respectively. RPGR-ORF15 mutations were associated with high myopia (P = 0.01), which led to a faster best-corrected visual acuity decline in patients with RP (P < 0.001) and COD/CORD (P = 0.03). Patients with RP with RPGR-ORF15 mutations had a faster visual field decline (P = 0.01) and thinner central retina (P = 0.03) than patients with mutations in exon 1 to 14.
Based on best-corrected visual acuity survival probabilities, the intervention window for gene therapy for RPGR-associated retinal dystrophies is relatively broad in patients with RP. RPGR-ORF15 mutations were associated with COD/CORD and with a more severe phenotype in RP. High myopia is a risk factor for faster best-corrected visual acuity decline.
Purpose
To report clinical features and potential disease markers of inherited retinal dystrophy (IRD) caused by the biallelic c.148delG variant in the tubby‐like protein 1 (TULP1) gene.
Methods
A ...retrospective observational study of 16 IRD patients carrying a homozygous pathogenic TULP1 c.148delG variant. Clinical data including fundus spectral‐domain optical coherence tomography (SD‐OCT) were assessed. A meta‐analysis of visual acuity of previously reported other pathogenic TULP1 variants was performed for reference.
Results
The biallelic TULP1 variant c.148delG was associated with infantile and early childhood onset IRD. Retinal ophthalmoscopy was primarily normal converting to peripheral pigmentary retinopathy and maculopathy characterized by progressive extra‐foveal loss of the ellipsoid zone (EZ), the outer plexiform layer (OPL), and the outer nuclear layer (ONL) bands in the SD‐OCT images. The horizontal width of the foveal EZ showed significant regression with the best‐corrected visual acuity (BCVA) of the eye (p < 0.0001, R2 = 0.541, F = 26.0), the age of the patient (p < 0.0001, R2 = 0.433, F = 16.8), and mild correlation with the foveal OPL‐ONL thickness (p = 0.014, R2 = 0.245, F = 7.2). Modelling of the BCVA data suggested a mean annual loss of logMAR 0.027. The level of visual loss was similar to that previously reported in patients carrying other truncating TULP1 variants.
Conclusions
This study describes the progression of TULP1 IRD suggesting a potential time window for therapeutic interventions. The width of the foveal EZ and the thickness of the foveal OPL‐ONL layers could serve as biomarkers of the disease stage.
Retinitis pigmentosa (RP) is an inherited pigmentary retinal dystrophy where patients experience poor peripheral, night, and eventually central vision. There are statements in the literature which ...suggest visual acuity loss can progress to total blindness in these patients. This study sought to examine these statements by performing a retrospective analysis of the visual acuity measured in a large cohort of RP patients.
The charts of 1,095 RP patients were reviewed in this retrospective cross-sectional analysis. They included all of the RP patients examined by one of the authors (G.A.F.). Patients with sector RP or a delimited form of this disease were not included. The review was focused on the analysis of patients with 20/200 or worse vision in the better-seeing eye (N = 215).
We determined that 0.46% of the enrolled patients progressed to no light perception in each eye. Ninety-two percent of the 1,095 patients examined were able to read a visual acuity chart. There were 6.8% who saw only hand motion, count fingers, or light perception.
No light perception was measured in only 0.46% of patients. Thus, only a very small number of the RP patients in our cohort progressed to total blindness.
To analyze demographic and ophthalmic data in patients with and without chorioretinal atrophy after voretigene neparvovec-rzyl (VN) to identify possible causes for this phenomenon.
Retrospective ...cohort study with longitudinal follow-up.
A total of 71 eyes of 38 patients aged 2 to 44 years with RPE65-mediated retinal dystrophy treated with VN across 2 large gene therapy centers in the United States and Germany.
Patients treated with VN who developed atrophy were compared with those who did not.
Gender, age, surgical center, spherical equivalent refraction, best-corrected visual acuity (BCVA), baseline full-field scotopic threshold testing (FST), and posttreatment change in FST.
A total of 20 eyes of 12 patients developed atrophy after treatment with VN (28% of all eyes). There was no significant difference in gender, age, surgical center, or spherical equivalent refraction between the atrophy group and the no atrophy group. However, patients between school age and young adulthood were predominantly affected, whereas the youngest and the oldest patients did not develop atrophy. Baseline BCVA was better in patients who developed atrophy than those who did not (P = 0.006). The postoperative improvement in FST at 1 month was significantly higher in the atrophy group than in the no atrophy group (P = 0.0005), and this difference remained statistically significant at 1 year (P = 0.0001). There was no correlation to baseline FST, to inflammation, or to which eye was treated first.
The degree of FST improvement after VN appears to be strongly correlated with the development of VN-related chorioretinal atrophy. This finding raises the possibility that atrophy may develop as a toxic or metabolic sequela of vector-mediated RPE65 expression. In light of the expanding number of retinal gene therapy clinical trials, this complication warrants further study because it may not be limited to VN.
Proprietary or commercial disclosure may be found after the references.
Usher Syndrome: Genetics of a Human Ciliopathy Fuster-García, Carla; García-Bohórquez, Belén; Rodríguez-Muñoz, Ana ...
International journal of molecular sciences,
07/2021, Volume:
22, Issue:
13
Journal Article
Peer reviewed
Open access
Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical ...types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation.
The human retina is a highly complex tissue that makes up an integral part of our central nervous system. It is astonishing that our retina works seamlessly to provide one of our most critical ...senses, and it is equally devastating when a disease destroys a portion of the retina and robs people of their vision. After decades of research, scientists are beginning to understand retinal cells in a way that can benefit the millions of individuals suffering from inherited blindness. This understanding has come about in part with the ability to culture human embryonic stem cells and the innovation of induced pluripotent stem cells, which can be cultured from patients and used to model their disease. In this review, we highlight the successes of specific disease modelling studies and resulting molecular discoveries. The greatest strides in cellular modelling have come from mutations in genes with established and well-understood cellular functions in the context of the retina. We believe that the future of cellular modelling depends on emphasising reproducible production of retinal cell types, demonstrating functional rescue using site-specific programmable nucleases, and shifting towards unbiased screening using next generation sequencing.
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