Natural Disease Course in Usher Syndrome Patients Harboring USH2A Variant p.Cys870* in Exon 13, Amenable to Exon Skipping Therapy

The aim of the study was to determine the rate of retinal degeneration in patients with c.2610C>A (p.Cys870*) in USH2A exon 13, amenable to exon skipping therapy. There were nine patients from seven families, three of whom were male (two were homozygous). Seven patients had follow-up data (median of 11 years). Analysis included best corrected visual acuity (BCVA, decimal Snellen), visual field (Goldmann perimetry target II/4), fundus autofluorescence (FAF), optical coherence tomography (OCT), and microperimetry (MP). The median age at the onset of nyctalopia was 20 years (range, 8-35 years of age). At the first exam, at a median age of 42 years, the median BCVA was 0.5 (0.2-1.0), and the median visual field diameter was 23° (5°-114°). Imaging showed a hyperautofluorescent ring delineating preserved foveal photoreceptors in 78% (7/9) of patients, while 22% (2/9) had a hyperautofluorescent patch or atrophy, reflecting advanced disease. Survival analysis predicted that 50% of patients reach legal blindness based on a visual field diameter < 20° at the age of 52 (95% CI, 45-59) and legal blindness based on a BCVA ≤ 0. 1 (20/200) at the age of 55 (95% CI, 46-66). Visual field constriction occurred at the median rate of radial 1.5 deg/year, and hyperautofluorescent ring constriction occurred at the median rate of 34 μm/year. A non-null second allele was found in two patients: p.Thr4315Pro and p.Arg303His; the patient with p.Arg303His had a milder disease. The rates of progression will be useful in the design and execution of clinical trials.