Disease asymmetry and hyperautofluorescent ring shape in retinitis pigmentosa patients

Abstract

Retinitis pigmentosa (RP) is described as a bilateral disease with inter-eye symmetry that presents on short-wavelength fundus autofluorescence (SW-AF) imaging with hyperautofluorescent (hyperAF) rings with an ellipsoid shape and regular borders. Nevertheless, both asymmetry and irregular ring morphologies are also observed. In this retrospective study of 168 RP patients, we characterize the degree of inter-eye asymmetry and frequency of irregular hyperAF ring morphologies according to mode of inheritance and disease-causing gene by using SW-AF imaging and spectral-domain optical coherence tomography (SD-OCT) scans. We observed that from 336 eyes, 290 (86%) presented with regular hyperAF rings and 46 (14%) presented with irregular shapes. From the 168 patients, 23 (14%) presented with asymmetric disease, with 16 (70%) of these patients also presenting with irregular ring shapes. Patients with autosomal dominant RP (adRP) had the highest proportion of irregular ring shapes (21%) and disease asymmetry (23%) in comparison to other modes of inheritance. Furthermore, both RP1 and RHO-adRP had the highest proportions of both disease asymmetry and irregular ring morphology. Our results suggest that in patients presenting with either irregular ring shapes or asymmetric disease, emphasis should be placed in targeted gene sequencing of genes known to cause adRP, such as RHO and RP1. Retinitis pigmentosa (RP) is a group of heterogenous rod-cone retinal dystrophies caused at a cellular level by the degeneration of photoreceptors 1,2. In most cases, the genetic defect is exclusive to the rods, whose degeneration leads to secondary cone death 2,3. Patients clinically present with night blindness, constricted visual fields, and an eventual decrease in central vision that ultimately leads to blindness in the late stages. Other clinical findings on examination of the posterior pole include intraretinal pigment migration associated with retinal pigment epithelium (RPE) thinning, attenuated blood vessels, and pallor of the optic nerve 4. The prevalence of RP is estimated to be 1 in 4,000, and the disease can be inherited in an autosomal dominant (30-40%), autosomal recessive (50-60%), or X-linked (5-15%) manner 1. RP is often described as a bilateral disease that presents and progresses symmetrically between both eyes. Exceptions are rare, but unilateral RP may account for 5% of the total population of RP patients 5. Other pathologies that have been reported to cause unilateral pigmentary retinopathy include infection, inflammation, and trauma 6-9. Nevertheless, few studies exist that analyze the degree of disease asymmetry among RP patients. An early study by Biro et al. suggested that a feature of RP is the symmetrical development of pigmentation, while a study by Massof et al. reported a high degree of symmetry as measured by visual fields 10,11. More recent studies by Sujirakul et al. and Fakin et al. have also reported a high degree of symmetry, although asymmetry does occur 12,13. Nevertheless, these studies did not explore t...

Outer retinal degeneration in a non-human primate model using temporary intravitreal tamponade with N-methyl-N-nitrosourea in cynomolgus monkeys

“…AF examination revealed a hyper-AF ring at the perifovea and various island-shaped hypo-AF dots at the periphery. The AF findings of RP vary according to genotype, but most cases show a perifoveal ringshaped hyper-AF lesion [35] similar to our present results. The lesions imaged by OCT demonstrated that hyper-AF lesions exhibited ellipsoid zone loss and an external limiting membrane [36].…”

Identification of a novel large multigene deletion and a frameshift indel inPDE6Bas the underlying cause of early-onset recessive rod–cone degeneration

“…Evidence of this variant was found through detailed manual review of the ES reads and was only clearly identified with GS. The RCD phenotype of these patients is consistent with the one associated with PDE6B in the literature, and it matches with the phenotype of patients harboring the known p.Asn643Glyfs*29 variant (Shen et al 2014;Ellingford et al 2016;Haer-Wigman et al 2017;Carss et al 2017;Jespersgaard et al 2019;Khateb et al 2019;Jauregui et al 2020;Weisschuh et al 2020;Kuehlewein et al 2021).…”

“…Exome sequencing (ES) analysis of affected twins initially detected only one heterozygous pathogenic variant in PDE6B, c.1923_1969delinsTCTGGG, resulting in a frameshift and premature stop codon formation (p.Asn643Glyfs*29) within the phosphodiesterase catalytic domain (Table 1). This variant was absent in gnomAD and previously reported in several IRD patients (Supplemental Table S1) (Shen et al 2014;Ellingford et al 2016;Haer-Wigman et al 2017;Carss et al 2017;Jespersgaard et al 2019;Khateb et al 2019;Jauregui et al 2020;Weisschuh et al 2020;Kuehlewein et al 2021). We have classified it as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines using the following criteria (loss-of-function variant, PVS1, detected in trans with a pathogenic variant, PM3, absent in population databases, PM2_SUPP) (Table 1).…”

Clinical/Demographic Functional Testing and Multimodal Imaging Differences between Genetically Solved and Unsolved Retinitis Pigmentosa

“…Asymmetric disease presentation has been recognized in 3.7–14% of nsRP cases. Both Jauregui et al [5] and Sujirakul et al [3] reported that disease asymmetry was highest in AD-RP, especially in association with RP1 and RHO disease-causing variants. In our cohort, asymmetric disease presentation was observed in 3.2% and 6.1% of cases in groups 1 and 2, respectively.…”

“…These changes are usually bilateral with a high degree of inter-eye symmetry [3]. However, phenotypic variability is common, and several atypical RP phenotypes have been described, including unilateral or asymmetric cases [3][4][5]. One contributing factor is genetic heterogeneity, but the influence of disease modifiers cannot be excluded in face of the variable expressivity observed both between and within families.…”