Search

Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7 mutation in 19 families and one isolated case of various geographical origins, presenting with autosomal dominant cerebellar ataxia with progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77 patients and in 11 at-risk individuals, with alleles containing from 37 to 130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on normal alleles contained from 7 to 35 CAGs. There was a strong negative correlation (r = -0.84) between the age at onset and the size of the CAG repeat expansion in SCA7 patients. Larger expansions were associated with earlier onset, a more severe and rapid clinical course, and a higher frequency of decreased vision, ophthalmoplegia, extensor plantar response and scoliosis. The frequency of other clinical signs such as dysphagia and sphincter disturbances increased with disease duration. The mutation was highly unstable during transmission, with a mean increase of 10 +/- 16 CAG repeats, which was significantly greater in paternal (15 +/- 20) than in maternal (5 +/- 5) transmissions. This correlated well with the marked anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism, observed in the sperm of a patient, was particularly important, with expanded alleles ranging from 42 to >155 CAG repeats. The degree of instability during transmission, resulting mostly in expansions, is greater than in the seven other neurodegenerative disorders caused by polyglutamine expansions.

Spinocerebellar ataxia 2 (SCA2) is caused by the ex-pansion of an unstable CAG repeat encoding a poly-glutamine tract. One hundred and eighty four indexpatients with autosomal dominant cerebellar ataxiatype I were screened for this mutation. We found ex-pansion in 109 patients from 30 families of differentgeographical origins (15%) and in two isolated caseswith no known family histories (2%). The SCA2chromosomes contained from 34 to 57 repeats andconsisted of a pure stretch of CAG, whereas all testednormal chromosomes (14–31 repeats), except one with14 repeats, were interrupted by 1–3 repeats of CAA. Asin other diseases caused by unstable mutations, astrong negative correlation was observed between theage at onset and the size of the CAG repeat ( r = –0.81).The frequency of several clinical signs such as myo-clonus, dystonia and myokymia increased with thenumber of CAG repeats whereas the frequency ofothers was related to disease duration. The CAG repeatwas highly unstable during transmission with vari-ations ranging from –8 to +12, and a mean increase of+2.2, but there was no significant difference accordingto the parental sex. This instability was confirmed bythe high degree of gonadal mosaicism observed insperm DNA of one patient.INTRODUCTIONAutosomal dominant cerebellar ataxias (ADCAs) are a clinicallyheterogeneous group of neurodegenerative disorders. Type IADCA, characterized by the variable association of cerebellarataxia with supranuclear ophthalmoplegia, optic atrophy, extra-pyramidal signs, dementia and amyotrophy (1,2), is geneticallyheterogeneous. Five different loci have been mapped: SCA1 on6p ( 3), SCA2 on 12q ( 4), SCA3/MJD (Machado–Joseph disease)on 14q ( 5,6), SCA4 on 16q ( 7) and SCA5 on 11cen ( 8). SCA1 ( 9)and SCA3/MJD ( 10) were the first to be identified. The mutationis the expansion of an unstable CAG repeat encoding apolyglutamine tract. Recently, Trottier et al. (11), using amonoclonal antibody which specifically recognizes proteins withpolyglutamine expansions, detected an abnormal 150 kDa proteinin SCA2 patients, suggesting that this disorder was caused bytranslated CAG expansions. Very recently, three independentgroups (12–14) identified the SCA2 gene which carries anexpanded CAG repeat in its coding sequence in patients,confirming this hypothesis. The gene encodes a 1312 amino acidprotein of unknown function (12,14).