Multicentric longitudinal prospective study in Usher Syndrome due to MYO7A mutations: disease course and implications for gene therapy

Abstract

Purpose : To investigate the natural history of retinitis pigmentosa due to variants in the MYO7A gene in order to search for possible genotype – phenotype correlations and biomarkers because of upcoming gene therapy trials.

Methods : Fifty-three patients (mean age 33.6 ± 16.7 years) with Usher syndrome due to MYO7A biallelic pathogenic variants and with visual acuity ≥ 20/640 in at least one eye underwent baseline and two annual follow-up visits, assessing best-corrected visual acuity (BCVA), semiautomatic kinetic visual field (SKVF), full-field electroretinogram (ffERG), color fundus imaging, microperimetry (MP), spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF).

Results : At baseline, all subjects presented with decreased BCVA (66.4 ± 17.9 ETDRS score; 59.5 ± 21.7 ETDRS score in the better- and worse-seeing eyes, respectively), restricted SKVF (III4e area: 3365.8 ± 4142.1°2; 4176.4 ± 4400.3°2), and reduced macular sensitivity (MS) (9.7 ± 9.9 dB; 9.0 ± 10.2 dB). SD-OCT scans revealed a slightly reduced central macular thickness and a narrowed ellipsoid zone (EZ) band width. Longitudinal analysis demonstrated a statistically significant decrease of BCVA in the better-seeing eyes (p-value: <0.001), whereas no significant changes were observed in the worse-seeing eyes for any parameter. We found that BCVA, SKVF area (III4e and V4e), and MS were significantly related to patients’ age at baseline (p-value: <0.01). The analysis of the most frequent FAF patterns in the best-seeing eyes showed that hyperautofluorescent foveal patch (16 eyes, 31.4%) and abnormal central hypoautofluorescence (9 eyes, 17.6%) were significantly (p-value: <0.05) associated with worse morphological and functional read-outs (i.e., BCVA, SKVF, MS, EZ band width) when compared to hyperautofluorescent ring pattern (22 eyes, 43.1%).

Conclusions : Our European multicentric study offers the first prospective longitudinal analysis in one of the largest cohorts of MYO7A patients described to date and confirmed the slow disease progression, in line with the findings of previously published cross-sectional and retrospective studies. More importantly, this study emphasizes the key role of FAF patterns in the staging of retinal impairment in MYO7A patients and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.