Molecular and clinical study of 18 families with ADCA type II: Evidence for genetic heterogeneity and De Novo mutation

The SCA7 mutation has: been found in 54 patients and 7 at-risk subjects fro m 17 families who have autosomal dominant cerebellar ataxia (ADCA) II with progressive pigmentary maculopathy. In one isolated case, haplotype reconst ruction through three generations confirmed a de novo mutation owing to pat ernal meiotic instability. Different disease-associated haplotypes segregat ed among the SCA7-positive kindreds, which indicated a multiple origin of t he mutation. One family with the clinical phenotype of ADCA type II did not have the CAG expansion that indicated locus heterogeneity. The distributio n of the repeat size in 944 independent normal chromosomes from controls; u naffected at-risk subjects, and one affected individual fell into two range s. The majority of the alleles were in the first range of 7-19 CAG repeats. A second range could be. identified with 28-35 repeats, and we provide evi dence that these repeats represent intermediate alleles that are prone to f urther expansion. The repeat size df the pathological allele, the widest re ported for all GAG-repeat disorders, ranged from 37 to similar to 220. The repeat size showed significant negative correlation with both. age at onset and age at death. Analysis of the clinical features in the patients with S CA7 confirmed that the most frequently associated features are pigmentary m aculopathy, pyramidal tract involvement, and slow saccades. The subjects wi th <49 repeats tended to have a less complicated neurological phenotype and a longer disease duration, whereas the converse applied to subjects with g reater than or equal to 49 repeats. The degree of instability during meioti c transmission was greater than in all other GAG-repeat disorders and was p articularly striking in paternal transmission, in which a median increase i n repeat size of 6 and an interquartile range of 12 were observed, versus a median increase of 3 and interquartile range of 3.5 in maternal transmissi on.