Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05034172 |
| Other study ID # |
APHP210069 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 25, 2021 |
| Est. completion date |
August 25, 2031 |
Study information
| Verified date |
April 2024 |
| Source |
Assistance Publique - Hôpitaux de Paris |
| Contact |
Alexandra DURR, PUPH |
| Phone |
142161347 |
| Email |
alexandra.durr[@]aphp.fr |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Inherited movement disorders are rare conditions, whose cumulative prevalence are in the
order of 5-10/100,000 inhabitants, in most cases progressive and can lead to a significant
loss of autonomy after one or more decades of evolution. They include spinocerebellar ataxias
and hyperkinetic disorders (dystonias, choreas, tremor, parkinsonism and myoclonus with
variable combination of those, or more complex alteration of movements). The existence of the
National Reference Centre (CMR) for Rare Diseases (CMR Neurogenetics, devoted to ataxias and
spastic paraparesis, dystonia and rare movement disorders and CMR Huntington, devoted to
Huntington Disease) has allowed a more integrated vision of these diseases. This is
illustrated, in the same family, by the occurrence of different clinical expressions of
spinocerebellar ataxias and hyperkinetic disorders that share the same genetic background.
Conversely, different causal mutations within the same gene may have very different ages at
onset and a wide range of clinical expression, and the spectrum of new phenotypes linked to a
single gene is still expanding . Many ataxia and dystonia genes are involved in similar
pathways. There are numerous arguments supporting a share pathogenesis including synaptic
transmission and neurodevelopment .
BIOMOV project aims to :
1. establish the clinical spectrum and natural history of these diseases,
2. understand the role of genetic and familial factors on the phenotype,
3. elucidate the molecular basis of these disorders and evaluate diagnostic strategies
involving molecular tools for clinical and genetic management,
4. develop multimodal biomarkers both for physiopathological studies and for accurate
measures of disease progression,
5. develop trial ready cohorts of well characterized genetic patients,
6. test new therapies either symptomatic or based on pathophysiological mechanisms.
Description:
Inherited movement disorders are rare conditions, whose cumulative prevalence are in the
order of 5-10/100,000 inhabitants, in most cases progressive and can lead to a significant
loss of autonomy after one or more decades of evolution. They include spinocerebellar ataxias
and hyperkinetic disorders (dystonias, choreas, tremor, parkinsonism and myoclonus with
variable combination of those, or more complex alteration of movements). The existence of the
National Reference Centre (CMR) for Rare Diseases (CMR Neurogenetics, devoted to ataxias and
spastic paraparesis, dystonia and rare movement disorders and CMR Huntington, devoted to
Huntington Disease) has allowed a more integrated vision of these diseases. This is
illustrated, in the same family, by the occurrence of different clinical expressions of
spinocerebellar ataxias and hyperkinetic disorders that share the same genetic background.
Conversely, different causal mutations within the same gene may have very different ages at
onset and a wide range of clinical expression, and the spectrum of new phenotypes linked to a
single gene is still expanding .
any ataxia and dystonia genes are involved in similar pathways. There are numerous arguments
supporting a share pathogenesis including synaptic transmission and neurodevelopment .
Overall, there are a number of arguments for a shared genetic approach and biomarkers
research for these inherited movement disorders:
- Evidence from a clinico-genetic approach: A combination of several movement disorders is
often observed in the same patient with causative mutation in either genetic groups of
spinocerebellar degenerations, dystonias or choreas.
- Evidence from neuroimaging: the current concept of networks disorders underlies the
pathophysiology of these hyperkinetic movement disorders. Variable combination of
functional and/ or structural alterations of the cerebello-thalamo-cortical,
cortex-basal ganglia and corticospinal networks, and their complex interactions have
been described in ataxias ,dystonia choreas and more complex disorders.
- Genetic diagnosis: deciphering diagnosis with wide range of phenotypes Even in times of
next generation sequencing covering exomes and genomes, diagnosing spinocerebellar
degenerations, dystonia and other hyperkinetic disorders remains a challenge as: i) the
causative gene remains to be identified for a substantial share those disorders; the
pathogenicity of variants of unknown significance in known and potential novel disease
genes often requires time-consuming functional analyses not available on a routine
basis; ii) in many countries, including France, access to diagnostic whole exome and
whole genome sequencing is still limited; iii) the proportions of abnormal expansions
not seen in exome studies are frequent in spinocerebellar degenerations and need a
technological development to identify them. Analysis of familial forms revealed a great
heterogeneity of the phenotype within the same family in terms of age at onset, severity
and clinical presentation. Moreover, this phenotypic variability is not explained only
by the genetic heterogeneity but also by the underlying frequent exonic or intronic
expansions of triplet or more complex repeats, and more recently by the discovery of
genetic modifiers ; iv) for dystonia and hyperkinetic disorders, some of those disorders
also include nonmovement disorders neurological (e.g. intellectual deficiencies,
hypotonia at birth, immature motor control, deafness, visual defects) and
non-neurological (dysmorphological features) symptoms and the movement disorders panels
do not always include the genes involved in developmental disorders; v) among the
dominantly inherited forms such as Huntington disease, the access to genetic testing
procedures allows early preventive therapeutic interventions in premanifest individuals.
There is a lack of clinical evaluation to tackle the efficiency of treatment and the
need for biomarker development.
- Natural history and prognosis: need for quantitative, reproducible markers, sensitive to
evolution Biomarkers search is ongoing in those pathologies. They are valuable in
assisting diagnosis, have prognostic value, quantify disease progression and serve as
outcome parameters in clinical trials.
These elements demonstrate the need to develop quantitative tools that are easy to use,
reproducible and sensitive to disease progression in order to accurately determine the
natural history of the disease. This lack of systematic knowledge impedes diagnosis, patient
counselling and therapy development.
Overall: Identification of the underlying gene and its pathogenic changes or variant(s)
contributes to precise diagnosis, genetic counselling and follow-up. Advances in molecular
genetics have highlighted the genotypic complexity, justifying the need for rigorous clinical
and para-clinical evaluation to establish relevant phenotype-genotype correlations. In
dystonia and in spinocerebellar degenerations attempts have been made to classify the genes
involved.
Molecular genetic analysis will make it possible to specify the correlations between
phenotype and genotype in order to propose rational molecular diagnostic strategies based on
the frequency and nature of mutations, taking into account the phenotype. Genetic analyses
will have an impact in terms of public health since they will serve as a basis for guiding
requests for molecular analyses in these pathologies. In addition, recent advances in
therapeutic trials will need the careful selection of participants, mostly based on
biomarkers, for successful testing of new therapeutical agents. Therefore, it seems essential
that this cohort of patients be supplemented by a collection of biological material for
genetic research.
BIOMOV project aims to : 1) establish the clinical spectrum and natural history of these
diseases, 2) understand the role of genetic and familial factors on the phenotype, 3)
elucidate the molecular basis of these disorders and evaluate diagnostic strategies involving
molecular tools for clinical and genetic management, 4) develop multimodal biomarkers both
for physiopathological studies and for accurate measures of disease progression, 5) develop
trial ready cohorts of well characterized genetic patients, 6) test new therapies either
symptomatic or based on pathophysiological mechanisms.
It is crucial to be able to establish a large cohort of patients whose genotype will be
specified. Follow-up of patients at different stages of the disease will make it possible to
collect the natural history of the disease in a descriptive manner, with prospects for
patient management, since the prognosis in terms of loss of autonomy or disability will be
better specified. However, the main interest of the proposed clinical follow-up is to be able
to quantitatively describe the progression of the main neurological diseases. These data are
absolutely essential for the future implementation of therapeutic trials. The number of
patients likely to be recruited and followed up a unique resource for such a project
