Finding suitable clinical endpoints for ARID1B-related intellectual disability

De novo truncating mutations in AT rich interactive domain 1B (ARID1B) are
found in about 1% of patients with intellectual disability (ID). Recently, an
ARID1B mouse model showed a reduction of inhibitory gabaergic interneurons, and
that stimulation of the GABA system by clonazepam in these mice reverses their
cognitive and behavioural phenotype. Although it would be of interest to
eventually test clonazepam in ARID1B patients, there are currently few suitable
clinical endpoints to determine treatment effects in these patients. The LUMC
has an internationally recognized expertise centre for patients with ARID1B
mutation and has access to an international cohort of about 150 patients. In
the Netherlands, there are currently 35 known ARID1B patients. This puts LUMC
in a unique position to perform research in this rare patient group. CHDR has a
lot of experience conducting central nervous system (CNS) tests using the
Neurocart® system. The Neurocart® consists of a battery of non-invasive tests
that cover all functional domains of the CNS. It provides rapid retesting of
both subjective and objective measures. Furthermore, the CHDR home-monitoring
platform allows for the registration of physical activity, including heart rate
and sleep in an at home-setting. This study aims to identify relevant endpoints
for the detection of drug effects in children with ARID1B.

- To determine between-subject and within-subject variability of the study
endpoints.
- To determine the differences between subjects and healthy controls regarding
the study endpoints.
- To identify suitable endpoints for future clinical trials in patients with
ARID1B-related intellectual disability.

Observational, non-interventional case-control study to investigate possible
endpoints to be used in future clinical trials.

This is a non-interventional study. The study assessments have been chosen
because they are considered to be non-invasive and are relatively easy to
perform. In an earlier study where the Neurocart® was used to perform
measurements in children aged 8-13, tolerability was excellent and all the
participants said to like the study *quite much* or *very much*. EEG electrodes
were considered to be *non-annoying* by 66% of subjects and 66% of subjects
would participate again in a similar study (3). Modifications to the Neurocart®
will be made to make the environment as child-friendly as possible, for example
with the use of a chair extender and a safe ramp to enable the completion of
certain tests.
The actual burden for subjects consists of the time spend behind the
Neurocart®, which is not longer than a typical outpatient clinic visit in the
expertise centre of the LUMC. Study subjects will have no direct benefit from
study participation. The value of this research is in gaining insights into the
neurocognitive phenotype of ARID1B syndrome and develop possible endpoints for
future clinical trials. Such knowledge is an important step in the research for
therapeutic interventions. The proposed research can be considered
group-related because it is only feasible by including patients themselves.