Clinical trial NCT01488461: Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias
Official title: Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Congenital Cerebellar Ataxias
Early-onset Cerebellar Ataxias
Keywords: Congenital cerebellar ataxias
Genetics
Gene ATCAY
Gene ABC7
Cerebellar atrophy
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2011-12-08
Enrollment: 165
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: FAMILY_BASED
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All types

Brief summary: Congenital ataxias (CA) are rare, non progressive diseases, characterized by psychomotor retardation, hypotonia followed by ataxia. The presence of the "molar tooth" on MRI allowed to define Joubert syndrome, a peculiar form of CA. Apart from this group, CA are mostly associated with cerebellar atrophy or hypoplasia without molar tooth on MRI. CA are a clinically as well as genetically heterogeneous group of diseases. Early-onset ataxias are progressive but may be difficult to distinguish from CA in the first years of the disease. To date, few genes responsible for CA have been identified: ABC7 (X-linked CA associated with sideroblastic anemia), SLC9A6 (X-linked CA associated with severe mental retardation, autism and epilepsy), GPR56 (CA associated with polymicrogyria), ATCAY (pure CA in Cayman isolate); the involvement of the ATCAY and ABC7 genes has never been assessed in a large cohort of CA patients.

Primary objective:

To assess the frequency of mutations of the ATCAY and ABC7 genes in patients affected with non Joubert congenital or early-onset ataxia.

Secondary objective:

To identify new loci and/or genes responsible for CA To further describe the clinical phenotype of the CA and to assess the frequency of the various clinical types (pure CA/CA associated with spasticity/ syndromic CA, congenital/early-onset CA, sporadic/familial CA).

To describe the clinical phenotype of CA related to mutations in one of analysed genes.

Detailed description: All patients will be examined by a geneticist or a neuropediatric. All clinical data will be collected.

Strategy of the molecular study :

1. for all multiplex and consanguineous families a linkage analysis (loci ATCAY and ABC7 and others AC known genes) will be performed.
2. For all sporadic patients as well as linked multiplex and consanguineous families : sequencing of all coding exons of the gene ATCAY and others AC known genes.
3. For all sporadic male patients and linked families : sequencing of all coding exons of the gene ABC7.
4. For all patients with suggestive features : sequencing of all coding exons of the gene GPR56, VLDLR, NHE6 or other candidate gene.
5. In consanguineous families : linkage analysis using SNP-array and analysis of candidate genes present in the regions of extended homozygosity
6. linkage analysis in dominant families and analysis of candidate genes in the linked regions.
7. If a new AC locus is identified (using linkage or CGH array), this gene will be sequenced in all patients.

Eligibility criteria: Inclusion Criteria:

* Patient, child or adult, affected with a congenital or early-onset ataxia defined by:
* Neurological symptoms observed before age of 2 years.
* Non progressive cerebellar ataxia observed at the time of examination. Karyotype done or in progress

Exclusion Criteria:

* Metabolic disease
* Specific MRI malformations suggesting a peculiar entity : molar tooth (joubert syndrome), superior vermis dysplasia with cleft (Oligophrenin)
* Muscle weakness and elevated creatine phosphokinase (CPK)
* Clearly progressive ataxia.
* Absence of signature of the informed consent.
* Absence of affiliation to social security

Primary outcomes:
measure: Percentage of the patients with a mutation in one of the analysed genes.
timeFrame: 1 day
Secondary outcomes:
measure: Percentage of patients with severe/moderate/mild/absent intellectual deficiency
timeFrame: 1 day
measure: Percentage of patients with/without epilepsy/spasticity/extraneurological features and nature and frequency of MRI anomalies
timeFrame: 1 day
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Trousseau, Service de Génétique
Study officials:
affiliation: Assistance Publique
name: Lydie Burglen, PhD
role: PRINCIPAL_INVESTIGATOR
References: