Characterizing Rate of Progression in USHer Syndrome (CRUSH) Study

Mutations in USH2A give rise to two phenotypes: Usher syndrome type 2a (USH2A) and nonsyndromic RP (USH2A associated nsRP). Usher syndrome is the most common form of congenital deafblindness. Patients with Usher syndrome are hearing impaired or profoundly deaf from birth and this can be rehabilitated with hearing aids or a cochlear implant. Furthermore, these patients develop retinitis pigmentosa (RP), a slowly progressive type of retinal degeneration that usually starts in the first or second decade of life. In both USH2A and nsRP patients the disease leads to severe visual impairment and eventually blindness around the 50th-70th year of life. There are no treatment options for the retinal degeneration. We do not know if they also suffer from balance complaints.

Currently, genetic therapy for Usher syndrome type 2 and USH2A associated nsRP is in development. But to measure the effect of a (genetic) therapy, it is crucial to know the detailed natural course of the visual and hearing deterioration over time. Several genetic therapy studies for other disorders are currently delayed, because the natural history of the disease has not been studied in detail previously.

The main objective is to map the natural course of the visual and hearing deterioration in Usher Syndrome 2 and USH2A associated nsRP for upcoming genetic therapy studies. Secondary objectives are: 1) To determine the necessary type of (combined) examinations, the sample size and length of studies (in years) essential to evaluate future genetic therapy in Usher syndrome. 2) To improve counselling of patients with Usher syndrome type 2 and USH2A associated nsRP with detailed information on the prognosis. 3) To identify additional etiological factors that explain variability in hearing impairment by adding questionnaires and psychophysical audiometric tests; and to assess the vestibular phenotype in Usher syndrome type 2 and USH2A associated nsRP patients.

This is a longitudinal, prospective natural history study. The study population consists of healthy human volunteers, 16 - 55 yr old with a confirmed genetic diagnosis of Usher Syndrome type 2 or and USH2A associated nsRP.

The main study endpoint is the natural course of the visual and hearing deterioration in Usher Syndrome type 2 and USH2A associated nsRP, over a time span of 4 years.

There are no risks associated with participation.


Eligibility Criteria:
Inclusion Criteria:

* Clinically diagnosed with rod-cone degeneration and at least two; pathogenic or likely pathogenic mutations in one of the Usher type 2 genes;
* Willing and able to complete the informed consent process;
* Ability to return for all study visits over 48 months;
* Age ≥ 16 years.

Both eyes must meet all of the following:

* Clinical diagnosis of a rod-cone degeneration;
* Clear ocular media and adequate pupil dilation to permit good quality photographic imaging;
* Ability to perform kinetic and static perimetry reliably;
* Baseline visual acuity ETDRS letter score of 54 or more \[approximate Snellen equivalent 20/80 or better\];
* Stable fixation;
* Clinically determined \[on Octopus 900 Pro\] kinetic visual field III4e area 7,5°, or more in the study eye.

Exclusion Criteria:

* Mutations in genes that cause autosomal dominant RP, X-linked RP, or presence of biallelic mutations in autosomal recessive RP/retinal dystrophy genes other than Usher genes;
* Expected to enter experimental treatment trial at any time during this study History of more than 1 year of cumulative treatment, at any time, with an agent associated with pigmentary retinopathy (including hydroxychloroquine, chloroquine, thioridazine, and deferoxamine).

If either eye has any of the following, the patient is not eligible:

* Current vitreous hemorrhage;
* Current or any history of rhegmatogenous retinal detachment;
* Current or any history of (e.g., prior to cataract or refractive surgery) spherical equivalent of the refractive error worse than -8 Diopters of myopia;
* History of intraocular surgery (e.g., cataract surgery, vitrectomy, penetrating keratoplasty, or LASIK) within the last 3 months;
* Current or any history of confirmed diagnosis of glaucoma (e.g., based on glaucoma visual field, nerve changes, or glaucoma filtering surgery);
* Current or any history of retinal vascular occlusion or proliferative diabetic retinopathy;
* Expected to have cataract removal surgery during the study;
* History or current evidence of ocular disease that, in the opinion of the investigator, may confound assessment of visual function;
* History of treatment for retinitis pigmentosa that could affect the progression of retinal degeneration (including participation in a clinical trial within the last year or a retained drug delivery device).

If either ear has any of the following, the patient is not eligible:

* The audiometric PTA(1-2-4kHz) for the best hearing ear should not exceed 75dB HL;
* Patients with bilateral cochlear implants cannot participate in the study;
* A planned, second, cochlear implantation during the study.