Hearing Loss as a Prognostic Indicator of Visual Function in USH2A-associated Retinal Degeneration.

Abstract

Purpose : Mutations in Usherin 2A (USH2A) cause Usher syndrome (USH), which manifests as retinitis pigmentosa (RP) with neurosensory hearing loss, or autosomal recessive non-syndromic RP (NSRP). However, few studies have characterized natural disease phenotype for patients with USH2A-associated retinal degenerations. Thus, we performed a cross-sectional analysis comparing electroretinography (ERG) data, retinal structure, and distribution of severe mutations between NSRP and USH patients harboring compound heterozygous or homozygous mutations in USH2A.

Methods : A total of 15 RP patients with two pathogenic mutations in USH2A were included, specifically eight USH patients and seven age-matched NSRP patients. Patients were diagnosed with USH if subjective hearing loss was present or NSRP if hearing loss was denied. To evaluate visual function prognosis, 30 Hz-flicker ERG was compared between groups. Ellipsoid zone (EZ) line length on SD-OCT and autofluorescent (AF) ring diameters on fundus AF imaging were compared. To determine the distribution of alleles containing severe mutations between each group, logistic regression models were utilized.

Results : NSRP patients had higher mean 30 Hz-flicker amplitudes of 21.1 ± 8.0 µV (mean ± SE) compared to USH patients, who had a mean of 2.1 ± 0.5 µV (p = 0.02). Of USH patients, 75% (6/8) had at least one severe mutation, defined as a frameshift or nonsense mutation, compared to 29% (2/7) of NSRP patients (p=0.13). The proportion of total alleles containing a severe mutation was 50% in the USH group compared to 14% of NSRP patients, with an odds ratio of 6.0 (confidence intervals: 1.1, 32) (p=0.04). There was no statistically significant difference in EZ-line length or AF ring diameters between groups.

Conclusions : NSRP patients had superior visual function prognoses as predicted by 30 Hz-flicker ERG and a higher proportion of alleles with severe mutations in this cohort. Our data suggests USH manifests as a more severe phenotype compared to NSRP patients with mutations in the same Usherin gene. A genetic threshold in which mutation burden relates to visual and auditory phenotype may exist. Larger cohort studies that compare visual function and audiometry of USH2A patients with their genotype are necessary to address this hypothesis. The presence or absence of hearing loss in USH2A patients may allow specialists to provide a more accurate prognosis.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.