Spinocerebellar ataxias in 114 Brazilian families: clinical and molecular findings

To the Editor: Dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases that affect the cerebellum, brain stem, and spinocerebellar tracts. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17 and dentatorubral pallidoluysian atrophy (DRPLA) are caused by CAG trinucleotide repeat expansions (1). SCA8 has a CTG expansion in the causative gene. SCA10 has been found to represent a large expansion of a pentanucleotide (ATTCT) repeat (2). The frequency of each SCA varies between regions and ethnic groups. Machado–Joseph disease (MJD/SCA3) is the most common SCA among populations with Portuguese and Azorean background and populations in Japan and Germany (3–10). SCA2 is common in Cuba, India, Korea, and Italy (11– 14). SCA10 has been only described in the New World (15–19). Our aim was to determine the frequency of the SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA17 and DRPLA among SCA families who have the same geographic origin, namely southern Brazil (Rio Grande do Sul). Clinical, epidemiological, and molecular features are also described herein. Cases were recruited based on the following inclusion criteria: (1) ataxia, often associated with other neurological signs; and (2) inheritance as an autosomal dominant trait. Neurological examination followed a standard examination already published (19). Presence and gradation of several neurological findings were evaluated as numeric ordinal variables. Peripheral blood was collected, and genomic DNA was isolated from peripheral blood leukocytes, using the salting-out technique, as previously described (20). Molecular analyses of the repeat loci were performed by molecular tests specific to each ataxia by PCR amplification. Southern blot was performed to SCA10 locus. Patients were stratified according to their molecular diagnosis. Clinical variables were then compared between these groups. Comparisons were performed using analysis of variance (ANOVA), when the variable was parametric, or the Kruskal–Wallis test (KW test), when the variable was nonparametric. A Bonferroni procedure was done, in order to correct for multiple testing. This study was approved by the ethics committee of the institution where it was conducted; informed consent forms were filled out by all patients. A total of 114 families with autosomal dominant trait were investigated during an 8-year period (up to 2004). Diagnosis, ethnicity, and main clinical features are presented in Tables 1 and 2. SCA3 was the most prevalent, comprising 84.2% of all SCAs. The other SCAs were far less common and represented from one to five pedigrees each. The number of clinically examined patients with the diverse molecular diagnoses was variable. Due to this, some statistical comparisons could not be done: SCA1 and SCA10 patients were excluded from comparisons. Neurological findings that showed statistical differences among groups were (1) nystagmus, less frequent in cases with SCA2 and SCA7 than in the general sample; (2) limb ataxia, more severe in SCA6 patients; and (3) pyramidal findings and optic atrophy, more common in SCA7 patients than in other groups (p , 0.0025, 0.0025, 0.041 and 0.0411, respectively; KW test). Most of the present families were of mixed ancestry but Portuguese surnames prevailed. In our region, the main Portuguese ancestry was Azorean in origin, dating from circa 1750 (7). The Amerindians are another important ancestry. The composition of mitochondrial Amerindian markers in urban Brazilian populations is high and varies between 22% and 54% (26). This finding shows the importance of this Brazilian ancestry. So far, SCA10 has only been described in American families (15–18, 27). The finding of two SCA10 kindreds is in line with the hypothesis that this mutation is somehow restricted to patients with an Amerindian ancestry. Although some of the present families have already been described (7, 18, 19, 28), they had never been compared. We made these comparisons