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A pair of identical twins with cone-rod dystrophy and 1 patient with dominant retinitis pigmentosa are reported who had a peculiar vascular retinopathy characterised by perivenous accumulation of fluorescein in the temporal periphery. Other retinal dystrophies associated with leaking retinal vessels are discussed.
In retinas of rats (RCS) with inherited retinal dystrophy, cells interpreted as macrophages infiltrate the outer nuclear layer and subsequently appear in the interphotoreceptor space, where they accummulate during the course of the disease. The morphology and distribution of these cells and their relations to the pigment epithelial cells were investigated. Macrophages, regardless of their location, possessed morphological features that distinguished them from the pigment epithelial cells. Premelanosomes and melanosomes, typical of pigment epithelial cells, were never observed in macrophages. There was no evidence to indicate that, during the period studied, the pigment epithelial cells had become dedifferentiated or had migrated from Bruch's membrane. Macrophages, like pigment epithelial cells, phagocytized little or no outer segment material. The findings indicate that, at least during the interval studied, the cells that infiltrate the retina and interphotoreceptor space are macrophages rather than pigment epithelial cells.
Four acid hydrolase activities are demonstrable by light microscopy in pigment epithelial cell lysosomes of rats (Royal College of Surgeons--RCS) with inherited retinal dystrophy and in control (Fischer) rats. The enzymes include acid phosphatase, aryl sulfatase, N-acetyl-beta-glucosaminidase, and esterase activities. No marked differences are observed in distribution or staining intensity of lysosomes in the two strains of rat. Acid hydrolase activities are not localized in sites other than lysosomes. Acid phosphatase and aryl sulfatase activities are also demonstrable by electron microscopy. In both strains, acid phosphatase reaction product is localized to various forms of lysosomes in pigment epithelial cells. A diffuse precipitate, considered to be nonspecific in origin, is seen in the cytoplasm, apical processes, outer segments (control), and outer segment debris (RCS). The precipitate is probably due to adsorption of lead from the incubation medium or of lead phosphate that diffuses from heavy accumulations in nearby lysosomes. Aryl sulfatase reaction product, in contrast to acid phosphatase, is localized to far fewer lysosomes and there is virtually no nonspecific precipitate. The findings indicate that lysosomes of RCS pigment epithelial cells possess several cytochemically demonstrable acid hydrolase activities. There is no evidence for the localization of acid phosphatase (or aryl sulfatase) activities in sites other than lysosomes.
Resynthesis of rhodopsin both in the retina and the eye cup was studied in albino rats (Campbell line) and in rats with pigmented eyes (Hunter line) with hereditary retinal dystrophy. Wistar rats and those of MSU line were used as controls, respectively. The rate of resynthesis of rhodopsin after its bleaching in the retina of dystrophic animals appeared to be much less than that in the normal ones, and decreased during the disease. When clear morphological changes were seen, only 50% of the previously bleached pigment was capable of regeneration during 2 hours of dark adaptation, the time being quite adequate for complete regeneration of rhodopsin in normal animals. It was found that in Campbell and Hunter rats breakdown and resynthesis of rhodopsin takes place not only in the retina but also in the layer of outer segment debris of photoreceptors located between the pigment epithelium cells and the retina.
IMPORTANCE: Substantial unexplained heritability remains for pathogenic inherited retinal disease (IRD) variants. Application of genome-wide association studies (GWAS) could help identify causal genes in rare diseases. OBJECTIVE: To leverage a GWAS for the discovery of IRD-associated genes. DESIGN, SETTING, AND PARTICIPANTS: This GWAS analysis was combined with replication of findings in 2 independent IRD cohorts. The study was conducted from January 2024 to December 2025 in a multicenter setting through FinnGen, 100 000 Genomes Project, and the National Health Service Genomic Medicine Service combined with clinical cohort from the Oulu University Hospital. Using IRD criteria from the International Classification of Diseases, 9th and 10th Revisions, 540 individuals with IRD and 473 945 control individuals were identified in the FinnGen study. For validation of FinnGen results, 49 patients were recruited from Oulu University Hospital. Results were further validated in 2 individuals identified from the UK cohort. MAIN OUTCOMES AND MEASURES: The GWAS and proteomics analysis were performed in the FinnGen cohort. Sanger and whole-genome sequencing and RNA approaches were used in a clinical IRD cohort to validate pathogenicity of the identified XXYLT1 variant. RESULTS: This GWAS identified 13 recessive loci reaching genome-wide significance (defined as P < 5 × 10-8). Of these, 4 (near or within XXYLT1, ANKRD10, DYM, and CBLN4) had not been associated with IRD, including the XXYLT1 c.505-1G>C founder variant. This variant was further genotyped in the clinical replication cohort, leading to identification of 5 more homozygous individuals from 4 families. The phenotype was consistent with a cone-rod or macular dystrophy, with visual deterioration, cystoid macular edema and/or schisislike macular abnormalities. The effect of the XXYLT1 c.505-1G>C variant was further investigated using RNA sequencing and complementary DNA amplicon sequencing, demonstrating exon 2 skipping and a loss-of-function effect. These findings were replicated in an independent population identifying 2 patients from the UK harboring a homozygous XXYLT1 c.766G>A, p.(Glu256Lys) missense variant. CONCLUSIONS AND RELEVANCE: This GWAS identified an association between XXYLT1 and IRD. These results affirm that GWAS in a founder population can be used as a potential tool for the discovery of rare mendelian disease genes and that XXYLT1 should be considered in clinical IRD gene panels.
PURPOSE: To identify the genetic cause for disease in individuals affected with inherited retinal disease and to characterize their retinal phenotype and the properties of the underlying gene. METHODS: Participants underwent a comprehensive ophthalmological evaluation, including best-corrected visual acuity, visual field testing, fundus autofluorescence, optical coherence tomography, and electroretinography. Genetic analyses included exome, genome, and Sanger sequencing. Gene expression pattern was analyzed by reverse transcription-polymerase chain reaction. Localization of the encoded protein in cells and in the human retina was examined by immunofluorescence staining. RESULTS: Four different pathogenic variants in C19orf44 were identified in 15 biallelic individuals from 11 unrelated families. The most common variant was c.549_550del p.(Ser185ProfsTer2). Most individuals were affected with a unique clinical phenotype characterized by late-onset patchy perifoveal chorioretinal atrophy and electroretinographic features of rod-cone degeneration. C19orf44 is expressed in various human tissues, including the retina, where it was found in the outer nuclear layer and in the outer plexiform layer. In cultured cells (hTERT RPE-1 and HeLa) and in human primary fibroblasts, C19orf44 is found in the nucleus, and it is downregulated during mitosis. CONCLUSION: Based on our results, C19orf44 is crucial for normal human retinal function, and pathogenic variants in this gene are associated with autosomal recessive inherited retinal disease.
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A 40-year-old patient with a bilateral posterior uveitis is presented and it is suggested that this may be a reflection of an underlying dystrophy.
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Neurological, ophthalmological and genetic investigations were performed on a family, a member of which presented with a rare association of tapeto-retinal degeneration, protanopia and Charcot-Marie-Tooth disease (CMT), and asked for genetic counseling. The neurological enquiry was completed by measurement of motor nerve conduction velocity in several completed by measurement of motor nerve conduction velocity in several members of the family. The propositus was submitted to a muscle biopsy. The ophthalmological examination included ophthalmoscopy, fluorescein angiography, electroretinogram and electrooculogram. The propositus, a woman aged 40, had typical CMT disease and her father also had a mild form of it. She had protanopia as had her father, her son and her nephew. In addition she had large macular pigmented changes, described as retinal dystrophy, "flavus flavimaculatus." Her mother had only senile pigmented modification of the fundus and her three daughters had mild macular pigmented changes, like "salt and pepper." Two genes are probably involved: one for protanopia with X linked recessive inheritance, the other responsible of CMT and tapeto-retinal degeneration, with an autosomal dominant inheritance, giving a 50% risk of recurrence.