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.
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.
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.
Sequence variants in Eyes Shut Homolog (EYS) gene are one of the most frequent causes of autosomal recessive retinitis pigmentosa (RP). Herein, we describe an Italian RP family characterized by ...EYS-related pseudodominant inheritance. The female proband, her brother, and both her sons showed typical RP, with diminished or non-recordable full-field electroretinogram, narrowing of visual field, and variable losses of central vision. To investigate this apparently autosomal dominant pedigree, next generation sequencing (NGS) of a custom panel of RP-related genes was performed, further enhanced by bioinformatic detection of copy-number variations (CNVs). Unexpectedly, all patients had a compound heterozygosity involving two known pathogenic EYS variants i.e., the exon 33 frameshift mutation c.6714delT and the exon 29 deletion c.(5927þ1_5928-1)_(6078þ1_6079-1)del, with the exception of the youngest son who was homozygous for the above-detailed frameshift mutation. No pathologic eye conditions were instead observed in the proband’s husband, who was a heterozygous healthy carrier of the same c.6714delT variant in exon 33 of EYS gene. These findings provide evidence that pseudodominant pattern of inheritance can hide an autosomal recessive RP partially or totally due to CNVs, recommending CNVs study in those pedigrees which remain genetically unsolved after the completion of NGS or whole exome sequencing analysis.
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.
Inherited retinal diseases (IRDs) are a leading cause of irreversible visual loss in the developed world. The primary driver of pathology in IRDs is pathogenic genetic variant. However, there is ...increasing evidence, from recent studies, for a role of the immune system in disease mechanism, particularly retinal microglia. Microglia are the primary immune cells in the retina and actively contribute to disease pathogenesis when activated locally by phagocytosing photoreceptors, inducing inflammation and signaling infiltration of circulating monocytes. In this article, we discuss the evidence for the contribution of retinal microglia to IRD pathogenesis reported so far using mice model.
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