ATAXIC: Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT01488461

Collaborator

(none)

165

Enrollment

Location

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Congenital Cerebellar Ataxias Early-onset Cerebellar Ataxias	Genetic: blood sample

Detailed Description

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

Strategy of the molecular study :

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

Study Design

Study Type:

Observational

Actual Enrollment :

165 participants

Observational Model:

Family-Based

Official Title:

Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias

Study Start Date :

Jan 1, 2012

Actual Primary Completion Date :

Oct 1, 2014

Actual Study Completion Date :

Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
patients ataxic	Genetic: blood sample Blood sample will be analysed in order to check presence or not of mutation in ABC7, SLC9A6, GPR56, ATCAY.

Arm

Intervention/Treatment

patients ataxic

Genetic: blood sample

Blood sample will be analysed in order to check presence or not of mutation in ABC7, SLC9A6, GPR56, ATCAY.

Outcome Measures

Primary Outcome Measures

Percentage of the patients with a mutation in one of the analysed genes. [1 day]

Secondary Outcome Measures

Percentage of patients with severe/moderate/mild/absent intellectual deficiency [1 day]
Percentage of patients with/without epilepsy/spasticity/extraneurological features and nature and frequency of MRI anomalies [1 day]

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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