Characterizing Rate of progression in USHer syndrome type 2 (CRUSH) study

Usher syndrome is the most common form of congenital deafblindness. Patients
with Usher syndrome are hearing impaired or profoundly deaf from birth and 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.
This leads in the majority of patients to severe visual impairment or blindness
around the 50th-60th year of life. There are no treatment options for the
retinal degeneration. The hearing impairment is treated with hearing aids and
later cochlear implantation.
Usher syndrome is an autosomal recessively inherited disorder and is known to
be genetically heterogeneous. Currently, 10 Usher syndrome genes have been
identified. Research nowadays is, however, shifting from gene identification
and functional analysis of encoded Usher syndrome proteins towards development
of (genetic) therapies to treat Usher syndrome-related blindness. For Usher
syndrome type 1b, the first phase I/II clinical studies already started using
UshStat®.[1] As the retinal symptoms manifest during the first or second decade
of life, there is a window of opportunity to stop the progression before onset
of symptoms or in an early stage of the disease.
Usher syndrome leads to reduced mobility and social isolation. In addition,
studies in the United States indicate that healthcare costs for patients with
Usher syndrome are $7,000 higher per person per year than for the average
population. In the Netherlands, there are an estimated 850 individuals with
Usher syndrome.

To measure the effect of a (genetic) therapy, it is crucial to know the
detailed natural course of the clinical deterioration over time. Several
genetic therapy studies for other disorders are currently delayed because the
natural history has not been studied in detail previously. It is therefore
essential to start natural history studies as early as possible.
Our previous phenotype studies of the past decades were retrospectively
performed and are not suitable and extensive enough to reconstruct a thorough
view on the natural course of clinical deterioration in Usher syndrome. A novel
prospective study that very thoroughly examines visual deterioration in Usher
syndrome over time is therefore essential to establish the natural course of
visual deterioration.
By performing detailed visual examinations that are repeated at regular
intervals and by combining the acquired data, we will be able to capture the
gradual decline. This study will not only provide us with knowledge on the
natural history of clinicaldeterioration in Usher syndrome type 2, but more
importantly also helps us to determine 1. the necessary type of (combined)
examinations, 2. the sample size and 3. length of studies (in years) that are
essential to evaluate (future) genetic therapy in Usher syndrome type 2
A sophisticated database that is suitable for (inter)national collaboration
will be developed to store data anonymously. The data collection mainly focuses
on evaluation of visual function and to a lesser degree also on auditory and
vestibular function. In our previous studies on the auditory phenotype a lot of
variability in hearing impairment was observed. This variability cannot be
explained by genetic factors only. We aim to identify the additional
etiological factors by adding questionnaires and psychophysical audiometric
tests. In addition, the vestibular phenotype was never thoroughly evaluated in
Usher syndrome type 2 patients and is therefore an interesting additional
research topic that is included in this study. Finally, we also want to
evaluate the impact of the disease on quality of life and psychosocial and
general well-being by using validated questionnaires.

Main objective: To map the natural course of the visual and hearing
deterioration in Usher Syndrome type 2 for upcoming genetic therapy studies.

Secondary Objective 1): To determine a. the necessary type of (combined)
examinations, b. the sample size and c. length of studies (in years) essential
to evaluate future genetic therapy in Usher syndrome.
Secondary objective 2): To counsel patients with Usher syndrome type 2 with
detailed information on the prognosis of Usher syndrome type 2.
Secondary Objective 3): We aim 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 patients.

Longitudinal, prospective natural history study of Usher syndrome patients with
a one-year follow up for a total of four years. As, to date, no treatments are
available for Usher syndrome patients, they have not been followed up on a
regular basis, and therefore detailed information on disease progression is
lacking. This observational study will provide reliable data on the natural
history of Usher syndrome.

Participants do not benefit, risks are considered negligible and procedures are
non-invasive.

Most of the study procedures are considered part of standard care. There are no
known risks beyond those involved in standard clinical care. The risks and
discomforts that may be involved in the usual care of the patients during the
period of time of prospective data collection:

- Visual acuity testing, (micro)perimetry, ERG and questionnaires require time
and concentration of the patient, which might cause frustration, but no lasting
adverse effects are associated with these non-invasive tests.
- Dilating eye drops will be used prior to fundus photography, OCT, FAF, ERG,
FST, and microperimetry. Dilating eye drops cause a blurry vision for a few
hours, and may sting, cause light-sensitivity, or an allergic reaction. There
is a very small risk of inducing a narrow-angle glaucoma attack from the pupil
dilation. Since all participants will have had prior pupil dilation usually on
multiple occasions, the odds of the event in these patients are even smaller.
If glaucoma occurs, treatment is available. Participants are instructed to
contact our department in the extremely unlikely event of eye drop-induced
glaucoma.
- IOP measurement and ERG: In rare instances, the cornea may be scratched
during measurement of intra-ocular pressure or use of a contact lens electrode.
An abrasion like this may be painful, but it heals quickly with no lasting
effects. In the event that a participant experiences a corneal abrasion,
antibiotic ointment will be administered and an eye patch may be placed over
the eye.
- The audiometric tests require time and concentration of the patient, which
might cause frustration and tiredness, but also no lasting adverse effects are
associated with these non-invasive tests.
- The caloric measurement and rotational chair tests (part of vestibular exam)
can cause minor dizziness and discomfort, which will be of short duration. The
other vestibular tests do not cause these complaints.