Baseline characteristics of patients with Usher Syndrome due to MYO7A mutations enrolled in a prospective natural history study

Purpose : Natural history data of Usher Syndrome (USH) due to MYO7A mutations are scarce. In view of future gene therapy studies, we assessed the natural course and investigated potential clinical endpoints in patients with USH due to MYO7A mutations. Methods : a multicenter prospective longitudinal (two-year) natural history study was designed within Ushther project (www.ushther.eu/). Patients aged 8 years or older with USH due to MYO7A mutations and a visual acuity ≥ 20/640 in at least one eye were recruited. We assessed: best-corrected visual acuity (BCVA, ETDRS), kinetic Visual field (VF, Octopus 900), spectral domain optical coherence tomography (OCT), microperimetry (MP, MAIA), and full-field electroretinogram (ERG). Regression analysis on baseline data was performed to estimate progression with age. Results : Forty-four patients aged 9-72 years (34.7 ± 16.1 years) were enrolled at the 3 centers. At baseline, patients showed a reduced BCVA (0.47 ± 0.30 logMAR in RE; 0.43 ± 0.32 logMAR in LE) and a constricted visual field (using V4e stimulus size: 5,436°2 ± 878°2 in RE; 5,722°2 ± 903°2 in LE). Moreover, MP showed a reduced macular sensitivity (8.2 ± 1.7 dB in RE; 8.2 ± 1.7 in LE). From preliminary analysis of OCT scans, we observed a disrupted Ellipsoid Zone (EZ) band with a mean width of 1,880 ± 329 µm in RE and of 1,842 ± 307 µm in LE. ERG responses were below noise level in all patients but five who showed markedly reduced responses in a rod-cone pattern. Cross-sectional analysis showed a decline with age of the BCVA (at a mean annual rate of 0.015 logMAR/year equivalent to about 1 EDTRS letter / year; P<0.001), of VF (3.8%/year; P<0.001) and of macular sensitivity (-3.8%/year; P=0.003). We observed a less pronounced (P=0.099) decline of the EZ band width (-1.7%/year). NGS analysis revealed 20 novel variants in MYO7A out of the 45 identified mutations. Missense mutations (16) were the most frequent, followed by nonsense (13). Other truncating mutations include: frameshift (8), splice variants (6) and two deletions. Conclusions : Based on our cross-sectional data, BCVA and VF appear good outcome measures to assess progression with age in patients with USH due to MYO7A mutations. Follow-up data will be required to assess consistency of the data and further explore the role of MP and OCT, particularly, to evaluate a window of opportunity for innovative therapies.