Presymptomatic analysis of spinocerebellar ataxia type 1 (SCA1) via the expansion of the SCA1 CAG-repeat in a large pedigree displaying anticipation and parental male bias

Autosomal dominant cerebellar ataxia type 1 (ADCA1) is a clinicaland genetic heterogeneous neurodegenerative disorder which leadsto progressive cerebellar ataxia. One defective gene responsiblefor the disease was first localised to 6p (SCA1, splnocerebellarataxia type 1) and the mutation has been more recently characterised.We have analysed the CAG-repeat mutation responsible for theSCA1 phenotype in a large Spanish kindred with 41 affected members,in which positive linkage with D6S89 was previously shown. All(10) clinically affected members analysed were heterozygouswith one disease allele being between 41 to 57 CAG repeats,and the other in the normal range, from 6 to 39 repeats. Nineclinically unaffected individuals who were between the agesof 18 and 40, were found to have expansions of the CAG repeat(41 to 59), and 22 other ‘at risk’ individuals werefound to have inherited the SCA1 gene with copies of the CAGrepeat in the normal range. We have also observed that affectedfathers passed on the mutated SCA1 gene with larger increasesin the number of CAG repeats than affected mothers did. In onecase a decrease in the number of CAG repeats (51 to 50) wasdetected in the transmission from the affected mother, and intwo cases no change was observed in the transmission of a 41allele repeat by a mother. As in the other disorders in whichknowledge of the mutation has been obtained, analysis of therepeat expansion dramatically changes diagnosis of SCA1.