Congenital Cerebellar Ataxias Clinical Trial
Official title:
Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias
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.
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.
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Observational Model: Family-Based