Phenotypic and Genotypic Studies in Congenital and Early Onset Ataxias

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.

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