Clinical phenotype and progression of Usher syndrome related to mutations in MYO7A or USH2A

Abstract

Purpose : To compare the clinical phenotype and natural history of retinitis pigmentosa (RP) in a large Italian cohort of patients affected by Usher syndrome (USH) carrying mutations in MYO7A and USH2A, the most common USH type 1 (USH1) and type 2 (USH2) genes, respectively.

Methods : 88 patients with a clinical diagnosis of either USH1 (26 patients) or USH2 (62 patients) were genetically screened. 48 subjects had disease-causing mutations: 10 patients in MYO7A, 33 in USH2A, and 5 in other USH genes (CDH23, PDZD7 and CDH23/USH2A). Clinical examination included best-corrected visual acuity (BCVA), fundus examination, Goldmann visual field (GVF), electroretinogram (ERG), audio-vestibular assessment. In order to assess onset of visual, audio-vestibular disfunction, standardized questionnaires were submitted to the patients or their parents. Finally, longitudinal analysis was performed over a median follow-up time of 3.5 years. Repeated-measure longitudinal regression analysis was performed on log-transformed values to estimate the mean rate of change. The study was approved by the local Ethics Committee, and performed in compliance with the declaration of Helsinki and international guidelines. All the patients provided a written informed consent.

Results : The comparison between MYO7A and USH2A patients showed an earlier onset of hearing impairment, vestibular dysfunction and also of RP and visual symptoms (night blindness) in MYO7A patients compared to those of USH2A. Moreover, the MYO7A patients started to walk in older age than USH2A. BCVA and GVF decreased faster in MYO7A than in USH2A patients (mean annual exponential rates for BCVA: -3.92% vs -3.44%, p= 0.025 and for GVF: -8.52% vs -4.97%, p= 0.005), whereas there was no significant difference between the two groups of patients for ERG amplitudes (8.06% vs 2.76%, p= 0.172). Finally, based on BCVA and GVF, MYO7A patients reached legal blindness at a median age of 37 years, compared to the 52 years of USH2A subjects.

Conclusions : Our data showed that MYO7A patients presented an earlier disease onset and a more severe visual impairment than USH2A patients. For the first time in literature, the current longitudinal analysis demonstrated a faster progression of retinal disease in MYO7A patients rather than in USH2A patients. Finally, this information could be helpful for the clinical classification of the disease and for the design of gene therapy clinical trials

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.