phenotypic and genotypic studies in congenital and early onset ataxias

Conditions: Congenital Cerebellar Ataxias; Early-onset Cerebellar Ataxias

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.

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

Keywords: congenital cerebellar ataxias genetics gene atcay gene abc7 cerebellar atrophy