Genetic analysis of early onset cerebellar ataxia with retained tendon reflexes in four Tunisian families

Spinocerebellar ataxias comprise a poorly understood group of inherited deg enerative neurological diseases. Attempts to classify hereditary ataxias on the basis of the neurological features or specific clinical signs such as tendon reflex changes have proven to be unsatisfactory. Early onset cerebel lar ataxia (EOCA) is generally inherited as an autosomal-recessive trait. T hus far, we do not have accurate answers to several questions about its cla ssification. However, significant clinical heterogeneity observed in four T unisian families with typical EOCA clinical features reinforces the hypothe sis of genetic heterogeneity underlying this phenotype. We have demonstrated that three of the four families studied were not linke d to Friedreich's ataxia (FA), vitamin E deficiency ataxia (AVED), and auto somal dominant cerebellar ataxia (ADCA) loci. The fourth family showed homo zygosity for a large pathological expansion of GAA repeat in all patients, the parents being heterozygous for this mutation. We have also noted, in th e case of the family studied, that there was instability in the transmissio n of the mutation, along with a phenomenon of anticipation comparable to th at observed in dominant triplet repeat diseases. EOCA is thus clinically indistinguishable from FA, yet genetically independ ent of all known candidate genes. Genetic mapping is required for research into the causal gene and an understanding of the disease's physiopathologic mechanisms.