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USH2A: self-reported functional vision measured in associated retinal degeneration by the Michigan Retinal Degeneration Questionnaire (MRDQ).

Researchers for the Foundation Fighting Blindness (FFB) Clinical Consortium Investigator Group, based in Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, has published an analysis on self-reported functional vision (FV) measurements by the Michigan Retinal Degeneration Questionnaire (MRDQ), applied to Usher Syndrome Type 2 (USH2) and autosomal recessive non-syndromic retinitis pigmentosa (ARRP) participants. The MRDQ tool appeared to correlate well with visual function tests and the researchers, funded and supported by FFB, commented that, “MRDQ adds a new dimension of understanding on vision-related functioning and establishes this PRO (patient-reported outcome) tool as an informative measure in evaluating USH2A outcomes”. Usher is a rare disorder and patient-reported outcomes are a valuable tool for patient supports and for measuring qualitative and quantitative endpoints for clinical trial assessments.

In this study, the MRDQ sought to correlate the questionnaire scores with visual functional measures, such as best-corrected visual acuity (BCVA), full-field stimulus testing (FST), and visual fields (from static perimetry and microperimetry), and structural measures such as spectral domain optical coherence tomography (SD-OCT)-derived ellipsoid zone (EZ) area and central subfield thickness (CST) data. Pending clinical trials may be highly useful when combining both primary and secondary endpoints with highly phenotypic variabilities, such as Usher Syndrome Type 2 (USH2).  Usher syndrome is a rare disease arising from mutations in at least 9 genes that can cause different types of the disorder, including: MY07A, USH1C, CDH23, PCHD15, USH1G, USH2A, GPR98, WHRN and CLRN1.  Three subtypes of Usher (I, II and III) can be classified by the severity of the phenotype and genotype. Patients with Usher II, causing from USH2A, may present a combination of retinitis pigmentosa (RP) and congenital hearing impairment, with a delayed onset and slowly progressive pathology. The Global Retinal Inherited Disease (GRID) dataset (Prog Retin Eye Res. 2022 Jul:89:101029, doi: 10.1016/j.preteyeres.2021.10102), the USH2A gene is the second most common pathogenic variant in IRDs at 14.6%, following only behind ABCA4 (24.8%). USH2A gene translates a protein called usherin found in basement membranes in the inner ear and in the retina that plays an important role in cell development and maintenance.  Pathogenic variants in the USH2A gene can cause Usher Syndrome Type 2 (USH2) and non-syndromic autosomal recessive retinitis pigmentosa (ARRP), both of which involve progressive rod photoreceptor loss and subsequent cone degeneration.  The USH2A gene spans an estimated 800kb of DNA on chromosome 1q41 and the usherin coding sequence comprises 72 exons with 15.6kb.  This size of the coding sequence is challenging in the context of attempting to deliver a gene augmentation strategy with current viral gene capacity.

According to the current researchers, the MRDQ is a validated and psychometrically calibrated PRO instrument designed using the FDA guidelines to measure vision functioning in patients with rod-cone dystrophy, cone/cone-rod dystrophy, or macular dystrophy.  However, their paper commented that “in contrast to other more prevalent eye diseases, patients with IRDs have greater phenotypic variability as well as unique FV (functional vision) limitations”. The MRDQ uses domains of FV that segregate according to retinal function (e.g. color, contrast, and photopic peripheral) unlike other PRO instruments that segregate into social function domains (e.g. visual motor or visual processing). In the MRDQ, each domain produces a level of disability ranging from −3 to +3 theta, with a higher score indicating greater disability, that is, severity in difficulties and limitations.  The 59-item MRDQ was verbally administered to participants in RUSH2A ≥ 18 years at the 48-month visit by site staff (referenced as “The Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A)”, registered on (NCT03146078)). It was completed in person or remotely any time within the 48-month visit window (208 ± 4 weeks). MRDQ domains and 59-items are listed in the initial publication (Invest Ophthalmol Vis Sci. (IOVS) 2024;65(6):5).  In summary results, 58% were female participants and the median disease duration was 13 years. In particular, “MRDQ domains were sensitive to differences between subgroups of clinical diagnosis, age, disease duration, and FST Blue-Red mediation. MRDQ domains correlated with static perimetry, microperimetry, full-field stimulus testing, and best-corrected visual acuity (BCVA)”.