The RUSH2A Study: Best-Corrected Visual Acuity, Full-Field Electroretinography Amplitudes, and Full-Field Stimulus Thresholds at Baseline

David G Birch, Peiyao Cheng, Jacque L Duncan, Allison R Ayala, Maureen G Maguire, Isabelle Audo, Janet K Cheetham, Todd A Durham, Abigail T Fahim, Frederick L Ferris 3rd, Elise Heon, Rachel M Huckfeldt, Alessandro Iannaccone, Naheed W Khan, Eleonora M Lad, Michel Michaelides, Mark E Pennesi, Katarina Stingl, Ajoy Vincent, Christina Y Weng, Foundation Fighting Blindness Consortium Investigator Group, David G Birch, Peiyao Cheng, Jacque L Duncan, Allison R Ayala, Maureen G Maguire, Isabelle Audo, Janet K Cheetham, Todd A Durham, Abigail T Fahim, Frederick L Ferris 3rd, Elise Heon, Rachel M Huckfeldt, Alessandro Iannaccone, Naheed W Khan, Eleonora M Lad, Michel Michaelides, Mark E Pennesi, Katarina Stingl, Ajoy Vincent, Christina Y Weng, Foundation Fighting Blindness Consortium Investigator Group

Abstract

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.

Keywords: Usher syndrome type 2 (USH2A); best corrected visual acuity (BCVA); electroretinography (ERG); full-field stimulus test; retinitis pigmentosa.

Conflict of interest statement

Disclosure: D.G. Birch, Biogen/Nightstarx (F), Acucela (C), ProQR (F, C), Nacuity (C), AGTC (F, C), Editas (C), 4D Therapeutics (F, C); P. Cheng None; J.L. Duncan, 4D Therapeutics (C), Acucela (F), AGTC (C), DTx Pharma, Inc. (C), Editas (C), Eloxx (C), Gyroscope (C), Biogen/Nightstarx (F, C), ProQR (C), Spark (C), SparingVision (S), Vedere Bio (S), Horama (C); A.R. Ayala None; M.G. Maguire Genentech/Roche (C), Regenera (C); I. Audo Novartis (C), SparingVision (C); J.K. Cheetham, AbbVie (I); T.A. Durham None; A.T. Fahim None; F.L. Ferris III, Bausch and Lomb (P, R), Janssen Research & Development, LLC (C) Viewpoint Therapeutics, Inc (C), Genetech (C), Norvo Nordisk (C), Apellis (C), Roche (C), SemaThera PTC Therapeutics (C), Regenera (C), Novartis (C), Eyevensys (C), Kodiak (C), 4D Molecular (C), Clear Side Biomedical (C); E. Heon None; R.M. Huckfeldt, AGTC (F), Spark (F), Biogen (F), ProQR (F), MeiraGTx (F); A. Iannaccone, Alia Therapeutics (S), ClearView Healthcare Partners (C), Teladoc Health (C), GLG Group (C), Guidepoint (C), Astellas Institute for Regenerative Medicine (C), Roivant Pharma (C), Editas (C), Rhythm Pharmaceuticals (C), IQVIA (C), Gyroscope (C), Ocugen (C), AGTC (F), AbbVie (F), Acucela (F), ProQR (F), Retinagenix (F), 4D Molecular Therapeutics (F), BridgeBio Pharma/Retinagenix (F); N.W. Khan None; E.M. Lad, Biogen/Nightstarx (C) and Novartis (C); M. Michaelides, MeiraGTx (F), Stargazer Pharma (F), Acucela (F), Astellas (F), ProQR (F), 2CTech (F); M.E. Pennesi, AbbVie/Editas (C), Spark Therapeutics (C), Wave Biosciences (C), Astellas Pharmaceuticals (C), RegenexBio (C), Iveric (C), Biogen (C), Novartis (C), Adverum (C), Gensight (F), ProQR (F), Horama (F), Eyevensys (F), Nayan (F) (I), Nacuity (F, I), Ocugen (F, I), Vedere Bio (F, I), SparingVision (F, I), AGTC (C), Sanofi (C); K. Stingl, ProQR (F); A. Vincent, ADVERUM Biotechnologies INC (C); C.Y. Weng, Allergan/AbbVie, Inc. (C), Alcon (C), Alimera Sciences (C), Regeneron (C), Novartis (C), Dutch Ophthalmic Research Center (C)

Copyright 2020 The Authors.

Figures

Figure 1.
Figure 1.
Light-adapted 3.0 flicker Electroretinography (ERG) response by clinical diagnosis. (A) Amplitude; (B) implicit time. The bottom and top of each box denote the 25th and 75th percentiles, the line inside the box denotes the median and the circle is the mean.
Figure 2.
Figure 2.
Full-field stimulus thresholds (FST) threshold results from three different participants and one normal subject. Black, blue, and red colors represent responses from white, blue, and red stimuli, respectively. (A) Cone-mediated (USH2, age 55 years old); (B) mixed (USH2, age 19 years old); (C) rod-mediated (USH2, age 61 years old); (D) normal (age 25 years old).
Figure 3.
Figure 3.
Full-field stimulus thresholds (FST) white versus blue-red by duration of disease and clinical diagnosis. Filled symbols represent USH2 participants and open symbols represent ARRP participants. Blue, red, and black symbols represent duration of disease at < 10 years, 10 to < 20 years, and ≥20 years, respectively.

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Source: PubMed

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