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Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterised by the association of cerebellar ataxia and, in most patients, progressive macular degeneration leading to loss of autonomy and blindness. The patients die after 5-30 years of evolution. The cause of the disease has been identified as a (CAG)n repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized alleles carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence which results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a wide variety of countries and ethnic groups. In a large number of SCA7 families (n = 41) of different origins, we have determined the haplotypes segregating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G3145TG/A3145TG). Four different haplotypes were found for centromeric markers (G3145TG/A3145TG-D3S1287-D3S3635) in the majority of the kindreds from four different geographic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Europe and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent regional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on intermediate alleles have been observed, suggesting the existence of different pools of at-risk chromosomes in this population.

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).

Expansion of trinucleotide CAG repeats coding for polyglutamine has been implicated in five neurodegenerative disorders, including spinocerebellar ataxia (SCA) 1 and SCA3 or Machado-Joseph disease (SCA3/MJD), two forms of type I autosomal dominant cerebellar ataxias (ADCA). Using the 1C2 antibody which specifically recognizes large polyglutamine tracts, particularly those that are expanded, we recently reported the detection of proteins with pathological glutamine expansions in lymphoblasts from another form of ADCA type I, SCA2, as well as from patients presenting with the distinct phenotype of ADCA type II. We now have screened a large series of patients with ADCA or isolated cases with cerebellar ataxia, for the presence of proteins with polyglutamine expansions. A 150 kDa SCA2 protein was detected in 16 out of 40 families with ADCA type I. This corresponds to 24% of all ADCA type I families, which is much more frequent than SCA1 in this series of patients (13%). The signal intensity of the SCA2 protein was negatively correlated to age at onset, as expected for an expanded and unstable trinucleotide repeat mutation. The disease segregated with markers closely linked to the SCA2 locus in all identified SCA2 families. In addition, a specific 130 kDa protein, which segregated with the disease, was detected in lymphoblasts of patients from nine families with ADCA type II. It was also visualized in the cerebral cortex of one of the patients, demonstrating its translation in the nervous system. Finally, no new disease-related proteins containing expanded polyglutamine tracts could be detected in lymphoblasts from the remaining patients with ADCA or isolated cases with cerebellar ataxia.