Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of cone photoreceptors. As a result of photoreceptor degeneration, affected individuals experience gradual loss of visual function, with primary symptoms of progressive nyctalopia, constricted visual fields and, ultimately, central vision loss. The onset, severity and clinical course of RP shows great variability and unpredictability, with most patients already experiencing some degree of visual disability in childhood. While RP is currently untreatable for the majority of patients, significant efforts have been made in the development of genetic therapies, which offer new hope for treatment for patients affected by inherited retinal dystrophies. In this exciting era of emerging gene therapies, it remains imperative to continue supporting patients with RP using all available options to manage their condition. Patients with RP experience a wide variety of physical, mental and social-emotional difficulties during their lifetime, of which some require timely intervention. This review aims to familiarize readers with clinical management options that are currently available for patients with RP.

Purpose: Eye 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. Methods: This 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. Results: Comparing 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. Conclusions: Patients 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 determine the profile of inflammation-related proteins and complement system factors in the plasma of CRB1-associated inherited retinal dystrophies (CRB1-IRDs). We used the Olink Explore 384 Inflammation II panel for targeted proteomics in 30 cases and 29 controls (cohort I) to identify immune pathways involved in CRB1-IRDs. Genotyping was performed in cohort I and a second cohort of 123 patients from 14 countries and 1292 controls (cohort II). A significant shift in complement cascade factors was observed in plasma proteomes of CRB1-IRD patients (enrichment for complement cascade, Padj = 3.03 × 10-15). We detected higher plasma levels of complement factor I and complement factor H [CFH] (q = 0.008 and q = 0.046, respectively, adjusted for age and sex), inhibitors of complement component 3 (C3), which correlated significantly (Pearson's coefficient >0.6) with elevated levels of C3 (q = 0.064). The CRB1 missense variants frequently found in patients showed a strong linkage disequilibrium with the common CFH variant rs7535263 (D' = 0.97 for p.(Cys948Tyr); D' = 1.0 for p.(Arg764Cys)), known to be linked with altered plasma CFH-related protein levels. Correction for the CFH genotype revealed significantly elevated plasma levels of CFH-related 2 (CFHR2) in CRB1-IRD patients (q = 0.041). CRB1-IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, and linkage between CRB1 and CFH genes implicates functional variants of the CFH-CFHR locus with specific pathogenic variants of CRB1.

To compare the plasma metabolic profile of patients with a Crumbs homolog 1-associated inherited retinal degeneration (CRB1-IRD) with that of healthy controls (HCs). A case-control study. A cohort of 30 Dutch patients with CRB1-IRD and 29 Dutch HCs. The MxP Quant 500 Kit was used for measuring metabolite concentrations. We fitted a linear regression model with adjustments for age and sex based on the concentration of metabolites in micromolar (micromoles per liter) or on the sums and ratios of metabolites to determine differences between patients and controls. Plasma concentration of 619 metabolites. Overrepresentation of pathways among metabolites associated strongest to CRB1-IRDs (P < 0.05, n = 62) identified amino acid pathways (such as β-alanine, histidine, and glycine/serine) and bile acid biosynthesis, driven by a decrease in deoxycholic acid derivatives produced by gut microbiota. Enrichment analysis of metabolic classes across the plasma metabolic profile further identified significant positive enrichment for lipid metabolites glycerophospholipids, cholesterol esters, and ceramides, and significant depletion for bile acid metabolites. Further investigation of the sums and ratios (i.e., metabolism indicators) ascertained a significant decrease in intestinal microbial-dependent secondary bile acid classes. Lipid metabolic alterations and decreased microbiota-related secondary bile acid concentrations indicate significant alterations in gut metabolism in patients with a CRB1-IRD. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Purpose: To compare the plasma metabolic profile of patients with a CRB1 -associated inherited retinal degeneration ( CRB1 -IRD) with healthy controls (HCs). Design: A case-control study. Methods: Plasma concentration of 619 metabolites was measured with the MxP ^® Quant 500 Kit in 30 patients with a CRB1 -IRD and 29 HCs. We fitted a linear regression model with adjustments for age and sex based on the concentration of metabolites in µM (µmol/L), or on the sums and ratios of metabolites, to determine differences between patients and controls. Results: Over-representation of pathways among metabolites associated strongest to CRB1 -IRDs ( P < 0.05, n = 62) identified amino acid pathways (such as beta-alanine, histidine, and glycine/serine) and bile acid biosynthesis, driven by a decrease in deoxycholic acid derivatives produced by gut microbiota. Enrichment analysis of metabolic classes across the plasma metabolic profile further identified significant positive enrichment for lipid metabolites glycerophospholipids, cholesterol esters, and ceramides, and significant depletion for bile acid metabolites. Further investigation of the sums and ratios (i.e., metabolism indicators) ascertained a significant decrease in intestinal microbial-dependent secondary bile acid classes. Conclusions: Lipid metabolic alterations and decreased microbiota-related secondary bile acid concentrations indicate significant alterations in gut metabolism in patients with a CRB1 -IRD.

Objective: To determine the profile of inflammation-related proteins and complement system factors in serum of CRB1 -associated inherited retinal dystrophies ( CRB1 -IRDs). Design: A case-control study. Subjects, Participants, and/or Controls: A cohort of 30 Dutch CRB1 -IRD patients and 29 Dutch healthy controls (HC) (Cohort I), and a second cohort of 123 CRB1 -IRD patients from 14 countries and 1292 controls (Cohort II) were used in this study. Methods: Quantitative 370-plex targeted proteomics in blood plasma and genotyping of the single nucleotide variant (SNV) rs7535263 in the CFH gene. Main Outcome Measures: Plasma concentrations of inflammation-related proteins and the genotype of the SNV rs7535263. Results: CRB1 -IRD patients showed increased plasma levels of complement system and coagulation cascade proteins compared to healthy controls. Complement Factor I [CFI], Serpin Family D1 [SERPIND1], and Complement Factor H [CFH] were significantly elevated (q0.6) with higher levels of plasma Complement Component 3 [C3] (q = 0.064). The most enriched pathway in patients was the “Complement cascade” (R-HSA-166658, Padj = P = 3.03 × 10 ^-15 ). An analysis of the genotype of CFH variant rs7535263, which is in close physical proximity to the CRB1 gene and is associated with other retinal conditions by influencing plasma complement levels, revealed significantly skewed allele distribution specifically in Dutch patients (A allele of rs7535263, odds ratio (OR) [95%CI = 2.85 [1.35-6.02], P = 6.19 × 10 ^-3 ), but not in a global case-control cohort ( P = 0.12). However, CRB1 missense variants that are common in patients display strong linkage disequilibrium (LD) with rs7535263 in CFH in the UK Biobank (D’ = 0.97 for p.(Cys948Tyr); D’ = 1.0 for p.(Arg764Cys)), indicating that genetic linkage may influence plasma complement factor levels in CRB1 -IRD patients. After accounting for the CFH genotype in the proteomic analyses, we also detected significantly elevated plasma levels of Complement Factor H Related 2 [CFHR2] in CRB1 -IRD patients (q = 0.04). Conclusions: CRB1 -IRDs are characterized by changes in plasma levels of complement factors and proteins of the innate immune system, which is influenced by common functional variants in the CFH-CFHR locus. This indicates that innate immunity is implicated in CRB1 -IRDs.