Multimodal structural disease progression of retinitis pigmentosa according to mode of inheritance

Due to the genotype–phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype–phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.

Section: Discussioncontrasting

confidence: 84%

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients

Kim

Song

et al. 2020

“…The presentation of patients with asymmetric RP was also similar to patients with symmetric RP in regards to age of disease onset and severity of disease. It has been widely reported that XLRP is more severe than adRP 31 . This was also observed in our patient cohort, regardless of whether the patient presented with asymmetric disease or not.…”

Section: Discussionmentioning

confidence: 99%

Disease asymmetry and hyperautofluorescent ring shape in retinitis pigmentosa patients

Jauregui

Chan

et al. 2020

Self Cite

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...

“…Movement of TZ over time is likely driven by non-autonomous cell death mechanisms acting within or across photoreceptor types [75][76][77][78][79][80][81][82][83][84] . Importantly, definition of the TZ varies across investigations and can include some aspect of visual function 11,52,[85][86][87] , RPE atrophy or demelanization 13,73,[88][89][90] , extent of normal ONL thickness 71,87,91 , or the extent of the IS/OS signal detectability on OCT which demarcates severe OS abnormality 12,13,89,[92][93][94][95] . In a previous investigation, we showed that spatial progression of TZ as defined by the detectability of the IS/OS signal was greatest in the superior retina over a 2-year interval in Class B RHO-adRP 13 .…”

Section: Natural History Of Rod Photoreceptor Dysfunction In Human Irdsmentioning

confidence: 99%

Rod function deficit in retained photoreceptors of patients with class B Rhodopsin mutations

Cideciyan

Jacobson

Román

et al. 2020

A common inherited retinal disease is caused by mutations in RHO expressed in rod photoreceptors that provide vision in dim ambient light. Approximately half of all RHO mutations result in a Class B phenotype where mutant rods are retained in some retinal regions but show severe degeneration in other regions. We determined the natural history of dysfunction and degeneration of retained rods by serially evaluating patients. Even when followed for more than 20 years, rod function and structure at some retinal locations could remain unchanged. Other locations showed loss of both vision and photoreceptors but the rate of rod vision loss was greater than the rate of photoreceptor degeneration. This unexpected divergence in rates with disease progression implied the development of a rod function deficit beyond loss of cells. The divergence of progression rates was also detectable over a short interval of 2 years near the health-disease transition in the superior retina. A model of structure-function relationship supported the existence of a large rod function deficit which was also most prominent near regions of health-disease transition. Our studies support the realistic therapeutic goal of improved night vision for retinal regions specifically preselected for rod function deficit in patients. Vision is initiated with the absorption of photons by opsin molecules located in the outer segment antenna of retinal photoreceptor cells. Resulting hyperpolarization of the photoreceptor plasma membrane activates inter-neuronal signaling pathways which reach the visual cortex culminating in perception. Any number of defects along the complex visual pathway can give rise to loss of vision. Monogenic defects causing inherited retinal diseases (IRDs) act primarily at retinal photoreceptors and provide an opportunity to understand detailed mechanism of vision loss. One of the most common IRDs is due to mutations in Rhodopsin (RHO) associated with autosomal dominant retinitis pigmentosa (adRP) 1-4. RHO encodes the opsin molecules expressed only in rod photoreceptors which provide night vision. Thus, the primary consequence of the molecular defect in RHO-adRP is abnormal night vision. Day vision mediated by cone photoreceptors are often affected secondarily through non-cell-autonomous mechanisms. There are currently no approved treatments for RHO-adRP, but promising therapeutic approaches directed to the rod photoreceptors include knock-down-and-replace gene therapy 5 , anti-sense oligonucleotides 6 , and modification of proteasomal activity 7. The human RHO-adRP disease phenotype is well represented by only two classes of mutations 8-13 despite the hypothesized existence of a variety of pathomechanisms in vitro 14,15. Patients with Class A phenotype have severe, early and retina-wide loss of rod photoreceptors with residual visual function originating only from cone cells. In Class B RHO phenotypes on the other hand, loss of rods is limited to certain retinal regions, or sectors, but rods (and cones) are retained in neighboring regi...