Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias (ATAXIC)

Study Description

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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
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 :

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.

Study Design

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

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 :	January 2012
Actual Primary Completion Date :	October 2014
Actual Study Completion Date :	October 2014

Groups and Cohorts

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Group/Cohort	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

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Biospecimen Retention:   Samples With DNA

Blood sample

Eligibility Criteria

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

All types

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

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

France
Hôpital Trousseau, Service de Génétique
Paris, France, 75012

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Principal Investigator:	Lydie Burglen, PhD	Assistance Publique

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT01488461 History of Changes
Other Study ID Numbers:	NI 08034; AOM 09178 ( Other Identifier: Assistance Publique )
First Posted:	December 8, 2011
Last Update Posted:	June 15, 2015
Last Verified:	June 2015

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Congenital cerebellar ataxias; Genetics; Gene ATCAY; Gene ABC7; Cerebellar atrophy

Additional relevant MeSH terms:

Ataxia; Cerebellar Ataxia; Spinocerebellar Ataxias; Spinocerebellar Degenerations; Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms	Cerebellar Diseases; Brain Diseases; Central Nervous System Diseases; Spinal Cord Diseases; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn