In this study we aim to further characterize E/I balance (at different translational levels), and its relation to metabolic- and immune processes, clinical profiles, behavior and cognition
ID
Source
Brief title
Condition
- Chromosomal abnormalities, gene alterations and gene variants
- Developmental disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Per participant:
1. Neurophysiological profile, including relative and absolute power spectra,
mean frequencies, functional excitation/inhibition (fE/I) ratio, measured on
different translational levels (clinical EEG measurement and patient-derived
IPSC-based models)
2. Metabolic profile (based on medical history, physical examination, blood
measures, urine sample, X-hand)
3. Immunlogical profile (based on medical history, physical examination, blood
measures)
4. Outcomes of neurocognitive and behavioral measures: Vineland adaptive
behavior scale (3rd edition), WISC-V or WPPSI-IV, and PAROM (or alternative
tools, depending on the developmental age of the participant)
5. Knowledge on participant-specific medications which are in vitro effective
to restore the neuronal E/I balance
Secondary outcome
not applicable
Background summary
Neurodevelopmental disorders (NDDs), including intellectual disability (ID),
autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder
(ADHD), are complex and the etiology of these disorders is barely understood.
Monogenetic NDDs (mNDDs) are a subclass of the NDDs, caused by rare gene
mutations in 1 out of the >1000 NDD genes known today. The with mNDD associated
life-long medical, psychiatric, and developmental vulnerability results in
tremendous suffering for patients and their relatives. Until now, no effective
treatments are available for ID and ASD, and none of the NDDs can yet be cured.
Pathophysiology of mNDDs is multifactorial and include the genetic defects, and
dysregulation of molecular/synaptic, metabolic and immune processes. Genetic
mutations and dysregulation of molecular/synaptic, metabolic and immune
processes, disturb the E/I homeostasis. Moreover, E/I balance dysregulation in
mNDDs is an underlying cause of disrupted brain functioning, altered social
behavior, cognitive impairment, increased seizure susceptibility and
information processing disorder. As E/I balance can be considered as
translational framework in many forms of mNDDs, intervening in the E/I balance
dysregulation might lead to the development of targeted treatments, to correct
either the precipitating defect (metabolic and/or immune dysfunction) and/or
the E/I balance regulation itself.
Study objective
In this study we aim to further characterize E/I balance (at different
translational levels), and its relation to metabolic- and immune processes,
clinical profiles, behavior and cognition
Study design
Multi-center Prospective Observational study with minimally invasive
measurements.
Study burden and risks
Participants will receive characterization of clinical, laboratory and
neurocognitive profiles and they receive their individual research results,
which may be of help in more targeted medical guidance. Second, participants
will contribute to syndrome-specific knowledge, and the results obtained
through this study may guide in better counseling, screening and understanding
of these disorders in the future. Ultimately, this knowledge results in the
availability of evidence-based precision medicine for the participants, the
included mNDDs, and mNDDs with comparable clinical profiles. Moreover,
participants in this study may be invited to take part in future follow-up
studies, in which medication is tested in vitro and in n=1 (individualized)
clinical trials, providing novel perspectives.
Minimal risks of the study for individual participants are:
- Blood drawing: hematoma and pain at the site of venapuncture
- Blood collection and EEG measurement might cause psychological stress and
anxiety in patients which will be reduced by careful explanations of the
procedure and the assistance of social childcare workers in calming procedures
if needed. Because we only make an EEG in resting state and during auditive
Evoked Related Potentials, there is no risk for provoking epilepsy.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
- Written informed consent to participate in this study
- Molecularly confirmed pathogenic defect in one of the following genes: EHMT1,
SETD1A, KMT2A, KMT2C, KMT2D, KDM3B, KDM6B, DNMT3A, (Chromatinopathies) or
STXBP1, SYT1, SNAP25, RIMS1 (SNAREopathies)
- Age >=5 or <=17 years old
Exclusion criteria
- No molecular confirmed diagnosis of a defect in one of the following genes:
EHMT1, SETD1A, KMT2A, KMT2C, KMT2D, KDM3B, KDM6B, DNMT3A (Chromatinopathies) or
STXBP1, SYT1, SNAP25, RIMS1 (SNAREopathies).
- Additional or larger genetic defects that influence the gene of
interest related phenotype
- Age <=4 or >=18 years old
- Extremely or very preterm birth (<32 weeks of pregnancy)
- Presence of serious, unstable illnesses (including gastro-intestinal,
respiratory, cardiovascular, endocrinologic, metabolic)
- Presence of severe psychiatric disease (e.g., current major depression or
psychosis)
- Inability to visit the outpatient clinic of Radboudumc or N=You Amsterdam UMC
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 | NL81570.091.22 |