Document Detail

Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.
MedLine Citation:
PMID:  11939898     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.
I Silveira; C Miranda; L Guimarães; M-C Moreira; I Alonso; P Mendonça; A Ferro; J Pinto-Basto; J Coelho; F Ferreirinha; J Poirier; E Parreira; J Vale; C Januário; C Barbot; A Tuna; J Barros; R Koide; S Tsuji; S E Holmes; R L Margolis; L Jardim; M Pandolfo; P Coutinho; J Sequeiros
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archives of neurology     Volume:  59     ISSN:  0003-9942     ISO Abbreviation:  Arch. Neurol.     Publication Date:  2002 Apr 
Date Detail:
Created Date:  2002-04-09     Completed Date:  2002-04-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0372436     Medline TA:  Arch Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  623-9     Citation Subset:  AIM; IM    
UnIGENe, IBMC, Rua do Campo Alegre 823, 4150-180, Porto, Portugal.
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MeSH Terms
Adenine / metabolism
Cytosine / metabolism
Guanine / metabolism
Middle Aged
Nerve Tissue Proteins / genetics*,  metabolism
Polymerase Chain Reaction
Spinocerebellar Ataxias / diagnosis*,  genetics*
Trinucleotide Repeat Expansion*
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/atrophin-1; 71-30-7/Cytosine; 73-24-5/Adenine; 73-40-5/Guanine

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