Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04923854 |
| Other study ID # |
APHP191023 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2021 |
| Est. completion date |
July 1, 2027 |
Study information
| Verified date |
May 2021 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
Anna MARUANI, MD |
| Phone |
+331 40 03 22 60 |
| Email |
anna.maruani[@]aphp.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Autism Spectrum Disorders (ASD) are a heterogeneous group of severe developmental
abnormalities of the nervous system characterized by deficits in social interaction and
verbal and nonverbal communication affecting approximately 1% of the general population.
In 5-40% of cases, genetic factors are identified as the cause of these disorders.
Despite this unique definition and the advancement of techniques, ASD is still a clinically
and genetically heterogeneous condition, as several hundred genes have been identified to
date.
Primary Objective and Endpoint Primary Objective:
Exploration of phenotypic heterogeneity in patients with ASD.
Primary endpoint:
- Routine Care Clinical Investigation Criteria.
- Scores on assessment scales,
Description:
Autism Spectrum Disorders (ASD) are a heterogeneous and severe developmental abnormalities of
the nervous system characterized by deficits affecting social interactions and verbal and
nonverbal communication (DSM-5, 2013), affecting approximately 1% of the general population
(Brugha, 2012). In 5-40% of cases, genetic factors are identified as the cause of these
disorders, prevalence depending on the technique used (Exome and/or SNPs Array) and the
associated intellectual deficit. In the majority of cases, the etiology remains unknown. The
familial aggregation of ASDs and the significant excess of concordant monozygotic twins over
dizygotic twins demonstrate the strong involvement of genetic factors in autism. Studies of
microdeletions/microduplications (copy number variants) or by Whole Exome Sequencing and
Whole Genome Sequencing (Single Nucleotide Variants) show the involvement of many genes in
the predisposition to autism. However, ASD remains a clinically and genetically heterogeneous
disorder, since several hundred genes have been identified to date.
The main objective of our project is to allow the retrospective and prospective collection of
data on the phenotypic and genetic characterization of ASD patients in a structured way in
order to allow the development of a new dynamic in terms of research. The identification of
genetic factors (Delorme et al, Nature Medicine, 2013) and biological pathways involved in
the emergence of autistic symptoms (Bourgeron, Nature Neuroscience 2015) is fundamental. The
identification of biological pathways is an indispensable step for the development of new
therapeutic strategies. In addition, a major challenge of this study is to better understand
the phenotype/genotype relationships in ASD. This requires the constitution of a large cohort
of patients taking into account their multimodal, extensive and precise exploration of
clinical, neuroanatomical (MRI, EEG) and biological phenotypes and to correlate them with
genetic data.
The work carried out by our teams and collaborators has led to the identification of numerous
genes associated with ASD and involved in synaptic formation and regulation: NLGN3-4 (Jamain
et al, Nature Genetics 2003), SHANK1-3 (Durand el al Nature Genetics 2007, Sato et al Am J
Hum Genet 2013, Leblond et al Plos Genetics 2013, 2014), CNTN-6 (Mercati et al Mol Psychiatry
2016) and CNTNAP4 (Karayannis, Nature, 2014) (for review Toro et al, TIGS 2012; Delorme et
al, Nature Medicine ,2013; Bourgeron, Nature Neuroscience 2015). This work was combined with
extensive phenotypic explorations of patients and their relatives. It has allowed us to
specify the neuroanatomical characteristics of the patients (Lefebvre et al. Biol Psychiatry
2014) and their genetic substrate (Toro et al, Mol Psychiatry 2015), but also the underlying
cognitive processes (Dumas et al, PNAS, 2014; Zalla et al. Cortex 2014, 2015; Grezes et al
Hum Brain Mapp, 2014). More recently, we have shown the existence of abnormalities in the
regulation of the melatonin synthesis pathway (Pagan et al, TransPsychiatry 2014; Pagan et
al, J pineal Res 2015) or immunological abnormalities (in particular HLA anomalies (Bennabi
et al, 2018)
Description of the population to be studied and rationale for its choice
We wish to explore the heterogeneity of autism spectrum disorders in a population received in
routine care in our evaluation units. These are patients followed in the Child and Adolescent
Psychiatry Department at the Robert Debré Hospital in Paris, who meet the diagnostic criteria
of ASD according to DSM-5, aged 0 to 17 years.
Description of the element(s) on which the research focuses
The main objective of our project is to explore the phenotypic heterogeneity of ASD. The
collection of data from the routine clinical evaluation of a large number of subjects will
allow for a better phenotypic and genetic characterization of patients in a structured manner
to allow for the development of a new dynamic in terms of research. We wish to carry out a
non-interventional, mono-centric study based on data from the evaluation of patients in
clinical practice.
To allow this work we must favour:
1. the collection of phenotypic data of the patients evaluated in our service, including
- Clinical phenotypes: standardized evaluation of phenotypes in clinical practice,
according to current recommendations
- Neuroanatomical phenotypes: brain imaging (MRI), electrophysiology EEG,
Eye-Tracking,
- Biological phenotypes: serological, genetic of patients hospitalized in our
department;
2. the linking of these data via a database regrouping this information (or allowing them
to be grouped);
3. the development of a new dynamic in terms of translational research concerning ASD.
The creation of this cohort, based on data from the evaluation done in clinical practice,
will help identify biological pathways involved in autism, the development of new therapeutic
strategies for patients and a more personalized medicine.
Justification of the duration of the research.
The total duration of the research will be 6 years (5 years of inclusion and a maximum of 12
months of patient observation), renewable by possible extension of the study.
This duration will allow the collection of data from the evaluation of approximately 300
patients per year (i.e. 1500 patients over the next 5 years). This study duration is
essential to collect a sufficient number of patients to have enough statistical power for the
study. Also the extensive phenotypic and genetic exploration requires - in order to be able
to cross-reference the data and establish relevant subgroups - to have large samples of
subjects.
