Hearing Loss and Vestibular Function in Usher Syndrome Type 2A

Background

Usher syndrome type 2A (USH2a) is caused by pathogenic variants in the USH2A gene and is the most common form of Usher syndrome. Clinically, it presents with a moderate-to-severe congenital sensorineural hearing loss combined with progressive retinitis pigmentosa that typically becomes symptomatic in adolescence. Unlike Usher type 1, the vestibular system is generally considered intact in USH2a — but how intact, and over how long?

These are not idle questions. As gene therapy approaches for retinal disease advance and cochlear implantation becomes more routine in this population, we increasingly need robust natural history data: how fast does the hearing loss actually progress, what happens to speech understanding, and should we be looking at the vestibular system more systematically?

The CRUSH study (a prospective, longitudinal natural history study at Radboudumc, see e.g., Radboudumc - Usher Syndrome Research; and CRUSH Database - Usher Syndrome Knowledge Portal) was designed to answer exactly these questions. Our paper (Wijn et al., 2025), led by Dirk Wijn and with contributions from Mirthe Fehrmann, Sybren Robijn, Hedwig Velde, Jeroen Smits, and others, reports on 4 years of structured follow-up in 33 USH2a patients and 2 patients with USH2A-associated non-syndromic retinitis pigmentosa (nsRP).

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Hearing Loss Progression

The headline finding for pure-tone audiometry is a statistically significant decline of 2.3 dB in PTA 0.5–4 kHz over 4 years (P = 0.017). This is a modest but real signal and importantly, one that exceeds what we would expect from presbycusis alone. The progression was most pronounced at the mid-to-high frequencies (see fig 2), consistent with the cochlear regions most vulnerable in USH2A-related pathology.

What makes this clinically useful is that these are prospectively collected measurements from a single center, using standardized protocols across all time points. Cross-sectional comparisons in genetics clinics often underestimate progression because of population heterogeneity; a within-subject longitudinal design is far more sensitive and meaningful for counseling individual patients.

One finding worth highlighting in conversations with patients: speech reception thresholds (SRT) remained relatively stable despite the decline in pure-tone thresholds. This means patients will notice slightly deteriorating audiograms at routine visits, but their functional communication ability, as captured by speech testing, holds up better than the pure-tone picture might suggest. This distinction matters enormously for patient-facing counseling, and for timing decisions around cochlear implantation.

The two nsRP patients (same USH2A pathogenic variants, no clinical RP) had normal hearing, which is a useful datapoint for genetic counseling in family members with isolated retinal disease.

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Vestibular Phenotype: Mostly Intact Semicircular Canals, but Subtle Otolith Dysfunction

The vestibular results are, in some ways, the most interesting part of the study, and the part most likely to change clinical practice.

As expected for USH2a, semicircular canal function was largely preserved: video head impulse testing (vHIT), velocity step tests, and caloric reflex tests were all within normal limits in more than 90% of patients. Patient-reported balance problems on the Dizziness Handicap Inventory (DHI) were also absent or minor.

This is reassuring — but the otolith picture is different.

• Cervical VEMPs (cVEMP) — assessing saccular function — were abnormal in 34% of patients
• Ocular VEMPs (oVEMP) — assessing utricular function — were abnormal in 75% of patients

These findings indicate subclinical otolith organ dysfunction in a substantial proportion of USH2a patients who report no balance complaints and have intact canal function. This dissociation between patient-reported symptoms and objective test findings is clinically important: if we rely only on symptoms or vHIT results, we will miss a significant proportion of patients with vestibular pathology.

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What This Means in Practice

1. Annual audiological follow-up is warranted. A 2.3 dB decline over 4 years in the speech frequency range is small but real, and the mid-to-high frequency progression is consistent with cochlear base involvement. Stable SRT is reassuring but should not replace pure-tone tracking, both are essential when CI timing is under consideration.

2. Cochlear implant timing deserves proactive discussion. In USH2a, progressive hearing loss and progressive vision loss are on parallel trajectories. Cochlear implantation is optimally performed while audiovisual learning and integration are still available. The longitudinal hearing data from CRUSH now provide a firmer empirical basis for those timing conversations.

3. VEMPs belong in the USH2a assessment protocol. The high prevalence of abnormal oVEMPs (75%) in the absence of subjective balance problems argues for routine VEMP testing in USH2a — not because patients complain, but because the underlying organ is silently compromised. This may have relevance for fall risk in the context of concurrent visual field loss, and is relevant if CI fitting approaches that rely on vestibular input are under consideration.

4. Distinguish the nsRP phenotype. Patients with USH2A-associated nsRP carry the same variants without clinical RP, and had normal hearing in this sample. For genetic counseling in such families, this reassurance about hearing, with the caveat that systematic follow-up is still indicated, is clinically useful.

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1. Wijn, D. H., Fehrmann, M. L. A., Robijn, S. M. M., Velde, H. M., Smits, J. J., van Wijk, E., Beynon, A. J., Cals, F. L. J., Hoyng, C. B., Yzer, S., Lanting, C. P., & Pennings, R. J. E. (2025). From Sound to Stability: Lessons Learned From the CRUSH Study on Hearing Loss Progression and Vestibular Phenotype in Usher Syndrome Type 2A. Otology & Neurotology, 10.1097/MAO.0000000000004851. https://doi.org/10.1097/MAO.0000000000004851