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Molecular Genetics of Hereditary Spinocerebellar Ataxia
Mutation Analysis of Spinocerebellar Ataxia Genes and CAG/CTG Repeat Expansion Detection in 225 Italian Families
Alfredo Brusco, PhD;
Cinzia Gellera, PhD;
Claudia Cagnoli, BSc;
Alessandro Saluto, BSc;
Alessia Castucci, BSc;
Chiara Michielotto, BSc;
Vincenza Fetoni, MD;
Caterina Mariotti, MD;
Nicola Migone, MD;
Stefano Di Donato, MD;
Franco Taroni, MD
Arch Neurol. 2004;61:727-733.
Background Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia [SCA] 1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 [FGF14]-SCA, and dentatorubral-pallidoluysian atrophy [DRPLA]). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, FGF14, and DRPLA), and in all but the recently identified SCA14, SCA17, PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat.
Objectives To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.
Patients Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait.
Results We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/CTG 1 [ERDA1] or CTG repeat on chromosome 18q21.1 [CTG18.1]). In 1 patient, the expansion was assigned to the DRPLA gene.
Conclusions The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.
From the Dipartimento di Genetica, Biologia e Biochimica, Università di Torino and Unitá Operativa Genetica Medica, Ospedale San Giovanni Battista di Torino, Torino, Italy (Drs Brusco, Cagnoli, Saluto, and Migone and Ms Michielotto); and UO Biochimica e Genetica, Istituto Nazionale Neurologico Carlo Besta (Drs Gellera, Mariotti, Di Donato, and Taroni and Ms Castucci), and UO Neurologia, Ospedale Predabissi, Melegnano (Dr Fetoni), Milano, Italy.
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