Molecular and Clinical Correlations in Spinocerebellar Ataxia 2: A Study of 32 Families

Abstract

Spinocerebellar ataxia 2 (SCA2) is caused by the expansion of an unstable CAG repeat encoding a polyglutamine tract. One hundred and eighty four index patients with autosomal dominant cerebellar ataxia type I were screened for this mutation. We found expansion in 109 patients from 30 families of different geographical origins (15%) and in two isolated cases with no known family histories (2%). The SCA2 chromosomes contained from 34 to 57 repeats and consisted of a pure stretch of CAG, whereas all tested normal chromosomes (14-31 repeats), except one with 14 repeats, were interrupted by 1-3 repeats of CAA. As in other diseases caused by unstable mutations, a strong negative correlation was observed between the age at onset and the size of the CAG repeat (r = -0.81). The frequency of several clinical signs such as myoclonus, dystonia and myokymia increased with the number of CAG repeats whereas the frequency of others was related to disease duration. The CAG repeat was highly unstable during transmission with variations ranging from -8 to +12, and a mean increase of +2.2, but there was no significant difference according to the parental sex. This instability was confirmed by the high degree of gonadal mosaicism observed in sperm DNA of one patient.

Unexpanded and intermediate CAG polymorphisms at the SCA2 locus (ATXN2) in the Cuban population: evidence about the origin of expanded SCA2 alleles

“…4,5 Ataxic phenotype occurs when the repeat is larger than 34 CAG. 6 Triplet repeats between 32-34 fall in the gray zone for penetrance, whereas 37-75 CAG repeats are fully penetrant. 6 Only few patients having 32 and 33 CAG repeats have been reported so far, with very late onset -between 50 and 60 years of age.…”

“…6 Triplet repeats between 32-34 fall in the gray zone for penetrance, whereas 37-75 CAG repeats are fully penetrant. 6 Only few patients having 32 and 33 CAG repeats have been reported so far, with very late onset -between 50 and 60 years of age. 4,7,8 Extremely large expansions of 109, 200 and 500 CAG in infants have also been observed, [9][10][11] but are rarer.…”

A common disease haplotype segregating in spinocerebellar ataxia 2 (SCA2) pedigrees of diverse ethnic origin

“…Since the cloning of the disease gene, ataxin-2, direct testing for the mutation has greatly enhanced the investigation of families previously excluded from linkage analysis. These studies have facilitated critical analysis of the core phenotype and an assessment of the incidence of the diverse clinical features often associated with this disorder, 8,9 including correlation with the size of the expanded allele.…”

Germ-line CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2

“…2,3 The extreme expansion observed in the girl was surprising, given the fact that her father's pathogenic allele of 45 glutamine codons was interrupted by a CAA codon at position 37. Furthermore, although SCA2 primarily has been associated with pure repeats of more than 35 CAGs [13][14][15] and interrupted repeats with lengths between 34 and 49 glutamine codons with parkinsonism, 16,17 the proband in our case had a classic SCA2 phenotype. The observation that the CAG expansion in the proband's interrupted allele has happened prior to the interruption is consistent with previous results showing that the 5 0 -tract of interrupted repeats is much more prone to expansions than the 3 0 -CAG tract.…”