Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases

Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansi ons encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA ) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 spo radic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2 , 15% SCA3, 6% SCAI, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutat ion in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and s hare a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 17 to 29 for SCA2, 67 to 77 for SCA3, and 3 8 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 r epeats. The highest CAG repeat variation in meiotic transmission of expande d alleles was detected in SCA7, this being of +67 units in one paternal tra nsmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal In SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG re peats, whereas normal alleles were interrupted by 1-2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1-3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was id entified as a recessive form due to GAA-repeat expansions in the Friedreich 's ataxia gene.