UNCLONED EXPANDED CAG CTG REPEAT SEQUENCES IN AUTOSOMAL-DOMINANT CEREBELLAR-ATAXIA (ADCA) DETECTED BY THE REPEAT EXPANSION DETECTION (RED) METHOD/

In some neurodegenerative diseases, genetic anticipation correlates wi th expansions of the CAG/CTG repeat sequence above the normal range th rough the generations of a pedigree. Among these neurodegenerative dis eases are late onset autosomal dominant cerebellar ataxias (ADCA). ADC A are genetically heterogeneous disorders with different cloned genes for spinocerebellar ataxia type 1 (SCA1), type 2 (SCA2), type 3 or Mac hado-Joseph disease (SCA3/MJD), and type 6 (SCA6). Another related dom inant ataxia, dentatorubral-pallidoluysian atrophy (DRPLA), also shows CAG/CTG repeat expansions. Genetic anticipation has been reported for all of them except for the recently cloned SCA6 gene. Other, as yet u ndetected SCA genes may show the same features. We have used the repea t expansion detection (RED) method to detect repeat expansions directl y in DNA samples from ADCA patients not resulting from known genes. Ou r sample consists of 19 affected index cases, corresponding to 52.8% o f our ADCA families without CAG/CTG repeat expansions in the SCA1, SCA 2, SCA3/MJD, SCA6, or DRPLA genes. Eighty-nine percent of the index ca ses had expansions of a CAG/CTG sequence greater than 40 repeats by RE D, while these were observed in only 26.9% of 78 healthy subjects from the general population (p<0.0001). The distribution of RED fragments in controls and ADCA patients also shows significant differences with the Mann-Whitney U test (U=376.5, p=0.0007). Moreover, there was a sig nificant inverse correlation between the size of expansion and the age of onset (r=-0.54, p=0.018). These results show CAG/CTG repeat expans ions of over 40 repeats in our sample of ADCA families not resulting f rom known SCA genes.