Primary Objective:To characterize a cohort of STXBP1-encephalopathy patients in a standardized, integrative manner, including in-depth clinical profile characterization and EEG recordings. Moreover, for a subgroup of patients, iPSC-derived induced…
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Brief title
Condition
- Neurological disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. To generate and maintain a database containing clinical profiles of patients
carrying an STXBP1 mutation, assessed in a standardized manner. The aim is to
assess whether there is a correlation between genotype (specific mutation in
STXBP1-gene) and phenotype (specific symptoms, progresion, success of
particular treatment strategies).
2. Identify any EEG biomarkers that may in the future aid diagnosis and/or
prognosis for specific patients or across the cohort of STXBP1 encephalopathy
patients. This will be investigated in an explorative manner, as well as by
quantifying the excitation/inhibition balance in order to test the hypothesis
that there is an imbalance in the brain of STXBP1-E patients.
3. To generate an in vitro cell model of human neurons with the exact genetic
make-up of STXBP1-E patients, to study the functional effects of
disease-associated STXBP1 mutations in order to gain a deeper understanding of
the pathophysiological mechanisms at the synaptic level. Cellular and molecular
laboratory technieken will be employed to measure the excitation/inhibition
balance at the cellular level as well.
Secondary outcome
Not applicable.
Background summary
STXBP1-encephalopathy is a relatively rare disorder. Patients have (usually
severe-profound) developmental delay, intellectual disability, and in the
majority of cases epileptic seizures or spasms starting at a very young age.
The hypothesis is that STXBP1-E mutations cause haploinsufficiency of the
protein STXBP1/MUNC18-1. MUNC18-1 is essential for neurotransmission between
nerve cells in the brain. One hypothesis is that haploinsufficiency causes an
imbalance between excitatory and inhibitory drive in the brain's circuitry.
Previous studies in our lab have indicated that there may be a differential
effect of lacking half of the usual MUNC18-1 protein levels between excitatory
and inhibitory neurons, however, whether this is the case in human patients
remains elusive.
Thus far, most scientific studies have reported on a single, or a few,
patients. The aim of this study is to characterize a larger cohort of STXBP1-E
patients in a standardized manner, characterizing a 'clinical profile', brain
activity using EEG, and cellular phenotypes. Generating a cellular model of
STXBP1-E including the genetic background of patients will allow investigations
into the cellular and molecular consequences of STXBP1 mutations and may in the
future also be used for screening of therapeutic strategies.
Study objective
Primary Objective:
To characterize a cohort of STXBP1-encephalopathy patients in a standardized,
integrative manner, including in-depth clinical profile characterization and
EEG recordings. Moreover, for a subgroup of patients, iPSC-derived induced
neurons will be generated to create an in vitro model of STXBP1 encephalopathy
in human neurons, which will be used to gain a deeper understanding of the
cellular and molecular effects of STXBP1 mutations.
Study design
Observational study.
Study burden and risks
The risk associated with medical history, interview/physical examination and
EEG recordings is negligible, since these are non-invasive techniques. It is
possible that an 'accidental finding' will occur. In that case, the primary
physician of the participating patient will be informed.
Skin biopsies are associated with some minimal risk of bleeding or irritation.
This procedure will be carried out by a clinician and local anaesthetics will
be used to minimize patient discomfort. It is possible to participate in the
study without the skin biopsy procedure, since biopsies will only be taken from
a subgroup of patients.
The total duration of the procedures will be one day, and one additional day
during the 'follow-up'. During the 'Clinic' day, there will be opportunity to
meet other patient (families) and researchers involved in STXBP1 research. If
desired, the procedures can also be planned on a separate day (with shorter
total duration).
Boelelaan 1085
Amsterdam 1081 HV
NL
Boelelaan 1085
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
Identified mutation in the STXBP1-gene
Exclusion criteria
Severe language barrier that is likely to hinder the procedure of informed consent.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL66152.029.18 |