Browsing by Subject "Retinitis Pigmentosa"

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    ItemOpen Access
    Baseline Visual Field Findings in the RUSH2A Study: Associated Factors and Correlation With Other Measures of Disease Severity.
    (American journal of ophthalmology, 2020-11) Duncan, Jacque L; Liang, Wendi; Maguire, Maureen G; Audo, Isabelle; Ayala, Allison R; Birch, David G; Carroll, Joseph; Cheetham, Janet K; Esposti, Simona Degli; Durham, Todd A; Erker, Laura; Farsiu, Sina; Ferris, Frederick L; Heon, Elise; Hufnagel, Robert B; Iannaccone, Alessandro; Jaffe, Glenn J; Kay, Christine N; Michaelides, Michel; Pennesi, Mark E; Sahel, José-Alain; Foundation Fighting Blindness Consortium Investigator Group

    Purpose

    To report baseline visual fields in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) study.

    Design

    Cross-sectional study within a natural history study.

    Methods

    Setting: multicenter, international.

    Study population

    Usher syndrome type 2 (USH2) (n = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP) (n = 47) associated with biallelic disease-causing sequence variants in USH2A.

    Observation procedures

    Repeatability of full-field static perimetry (SP) and between-eye symmetry of kinetic perimetry (KP) were evaluated with intraclass correlation coefficients (ICCs). The association of demographic and clinical characteristics with total hill of vision (VTOT) was assessed with general linear models. Associations between VTOT and other functional and morphologic measures were assessed using Spearman correlation coefficients and t tests.

    Main outcome measures

    VTOT (SP) and III4e isopter area (KP).

    Results

    USH2 participants had more severe visual field loss than ARRP participants (P < .001, adjusting for disease duration, age of enrollment). Mean VTOT measures among 3 repeat tests were 32.7 ± 24.1, 31.2 ± 23.4, and 31.7 ± 23.9 decibel-steradians (intraclass correlation coefficient [ICC] = 0.96). Better VA, greater photopic ERG 30-Hz flicker amplitudes, higher mean microperimetry sensitivity, higher central subfield thickness, absence of macular cysts, and higher III4e seeing area were associated with higher VTOT (all r > .48; P < .05). Mean III4e isopter areas for left (4561 ± 4426 squared degrees) and right eyes (4215 ± 4300 squared degrees) were concordant (ICC = 0.94).

    Conclusions

    USH2 participants had more visual field loss than participants with USH2A-related ARRP, adjusting for duration of disease and age of enrollment. VTOT was repeatable and correlated with other functional and structural metrics, suggesting it may be a good summary measure of disease severity in patients with USH2A-related retinal degeneration.
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    ItemOpen Access
    Cell type-specific changes in retinal ganglion cell function induced by rod death and cone reorganization in rats.
    (Journal of neurophysiology, 2017-07) Yu, Wan-Qing; Grzywacz, Norberto M; Lee, Eun-Jin; Field, Greg D
    We have determined the impact of rod death and cone reorganization on the spatiotemporal receptive fields (RFs) and spontaneous activity of distinct retinal ganglion cell (RGC) types. We compared RGC function between healthy and retinitis pigmentosa (RP) model rats (S334ter-3) at a time when nearly all rods were lost but cones remained. This allowed us to determine the impact of rod death on cone-mediated visual signaling, a relevant time point because the diagnosis of RP frequently occurs when patients are nightblind but daytime vision persists. Following rod death, functionally distinct RGC types persisted; this indicates that parallel processing of visual input remained largely intact. However, some properties of cone-mediated responses were altered ubiquitously across RGC types, such as prolonged temporal integration and reduced spatial RF area. Other properties changed in a cell type-specific manner, such as temporal RF shape (dynamics), spontaneous activity, and direction selectivity. These observations identify the extent of functional remodeling in the retina following rod death but before cone loss. They also indicate new potential challenges to restoring normal vision by replacing lost rod photoreceptors.NEW & NOTEWORTHY This study provides novel and therapeutically relevant insights to retinal function following rod death but before cone death. To determine changes in retinal output, we used a large-scale multielectrode array to simultaneously record from hundreds of retinal ganglion cells (RGCs). These recordings of large-scale neural activity revealed that following the death of all rods, functionally distinct RGCs remain. However, the receptive field properties and spontaneous activity of these RGCs are altered in a cell type-specific manner.
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    ItemOpen Access
    Comparative study of PRPH2 D2 loop mutants reveals divergent disease mechanism in rods and cones.
    (Cellular and molecular life sciences : CMLS, 2023-07) Ikelle, Larissa; Makia, Mustafa; Lewis, Tylor; Crane, Ryan; Kakakhel, Mashal; Conley, Shannon M; Birtley, James R; Arshavsky, Vadim Y; Al-Ubaidi, Muayyad R; Naash, Muna I
    Mutations in the photoreceptor-specific tetraspanin gene peripherin-2 (PRPH2) lead to widely varying forms of retinal degeneration ranging from retinitis pigmentosa to macular dystrophy. Both inter- and intra-familial phenotypic heterogeneity has led to much interest in uncovering the complex pathogenic mechanisms of PRPH2-associated disease. Majority of disease-causing mutations in PRPH2 reside in the second intradiscal loop, wherein seven cysteines control protein folding and oligomerization. Here, we utilize knockin models to evaluate the role of three D2 loop cysteine mutants (Y141C, C213Y and C150S), alone or in combination. We elucidated how these mutations affect PRPH2 properties, including oligomerization and subcellular localization, and contribute to disease processes. Results from our structural, functional and molecular studies revealed that, in contrast to our understanding from prior investigations, rods are highly affected by PRPH2 mutations interfering with oligomerization and not merely by the haploinsufficiency associated with these mutations. On the other hand, cones are less affected by the toxicity of the mutant protein and significantly reduced protein levels, suggesting that knockdown therapeutic strategies may sustain cone functionality for a longer period. This observation provides useful data to guide and simplify the current development of effective therapeutic approaches for PRPH2-associated diseases that combine knockdown with high levels of gene supplementation needed to generate prolonged rod improvement.
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    ItemOpen Access
    The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline.
    (Translational vision science & technology, 2020-10-08) Birch, David G; Cheng, Peiyao; Duncan, Jacque L; Ayala, Allison R; Maguire, Maureen G; Audo, Isabelle; Cheetham, Janet K; Durham, Todd A; Fahim, Abigail T; Ferris, Frederick L; Heon, Elise; Huckfeldt, Rachel M; Iannaccone, Alessandro; Khan, Naheed W; Lad, Eleonora M; Michaelides, Michel; Pennesi, Mark E; Stingl, Katarina; Vincent, Ajoy; Weng, Christina Y; Foundation Fighting Blindness Consortium Investigator Group

    Purpose

    The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 (USH2A)-related Retinal Degeneration (RUSH2A) multicenter study.

    Methods

    Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models.

    Results

    In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated (P = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders (P = 0.04) and duration of visual loss (P < 0.001) also were associated with FST white stimulus.

    Conclusions

    USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression.

    Translational relevance

    Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations.