Multicentric Longitudinal Prospective Study in a European Cohort of MYO7A Patients: Disease Course and Implications for Gene Therapy.

PURPOSE . We investigated the natural history of retinal dystrophy owing to variants in the MYO7A gene. M ETHODS . Fifty-three patients (mean age, 33.6 +/- 16.7 years) with Usher syndrome owing to biallelic, mostly pathogenic, variants in MYO7A underwent baseline and two annual follow-up visits. Best-corrected visual acuity (BCVA), semiautomatic kinetic visual field, full-field electroretinogram, color fundus imaging, microperimetry, spectral-domain optical coherence tomography, and fundus autofluorescence were assessed. RESULTS . At baseline, all patients presented with decreased BCVA (66.4 +/- 17.9 Early Treatment Diabetic Retinopathy score and 59.5 +/- 21.7 Early Treatment Diabetic Retinopathy score, in the better- and worse-seeing eyes, respectively), restricted semiautomatic kinetic visual field (III4e area, 3365.8 +/- 4142.1 degrees 2 ; 4176.4 +/- 4400.3 degrees 2 ) and decreased macular sensitivity (9.7 +/- 9.9 dB; 9.0 +/- 10.2 dB). Spectral-domain optical coherence tomography revealed reduced central macular thickness (259.6 +/- 63.0 pm; 250.7 +/- 63.3 pm) and narrowed ellipsoid zone band width (2807.5 +/- 2374.6 pm; 2615.5 +/- 2370.4 pm). Longitudinal analyses (50 patients) showed a significant decrease of BCVA in better-seeing eyes, whereas no changes were observed in worse-seeing eyes for any parameter. BCVA, semiautomatic kinetic visual field (III4e and V4e) and macular sensitivity were related significantly to age at baseline. Hyperautofluorescent foveal patch (16 eyes [31.4%]) and abnormal central hypoautofluorescence (9 eyes [17.6%]) were significantly associated with worse morphological and functional read-outs compared with the 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, confirming the slow disease progression. More important, this study emphasizes the key role of fundus autofluorescence patterns in retinal impairment staging and advocates its adoption as an objective biomarker in patient selection for future gene therapy clinical trials.