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Trinucleotide Repeats in 202 Families With Ataxia
A Small Expanded (CAG)n Allele at the SCA17 Locus
I. Silveira, PhD;
C. Miranda, MSc;
L. Guimarães, BSc;
M.-C. Moreira, MSc;
I. Alonso, BSc;
P. Mendonça, BSc;
A. Ferro, BSc;
J. Pinto-Basto, MD;
J. Coelho, BSc;
F. Ferreirinha, BSc;
J. Poirier, BSc;
E. Parreira, MD;
J. Vale, MD, PhD;
C. Januário, MD;
C. Barbot, MD;
A. Tuna, MD;
J. Barros, MD;
R. Koide, MD;
S. Tsuji, MD, PhD;
S. E. Holmes, PhD;
R. L. Margolis, MD;
L. Jardim, MD, PhD;
M. Pandolfo, MD;
P. Coutinho, MD, PhD;
J. Sequeiros, MD, PhD
Arch Neurol. 2002;59:623-629.
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.
From UnIGENe, Instituto de Biologia Molecular e Celular (Drs Silveira,
Pinto-Basto, and Sequeiros, Messrs Miranda, Mendonça, and Coelho, and
Mss Guimarães, Moreira, Alonso, Ferro, and Ferreirinha) and Laboratório
de Genética Médica, Instituto de Ciências Biomédicas
Abel Salazar, Universidade do Porto (Dr Sequeiros, Mr Miranda, and Mss Guimarães,
Moreira, Alonso, Ferro, and Ferreirinha), Serviço de Neuropediatria,
Hospital Maria Pia (Dr Barbot), and Serviço de Neurologia, Hospital
Geral de Santo António (Drs Tuna and Barros), Porto, Serviço
de Neurologia, Hospital Fernando Fonseca, Amadora (Dr Parreira), Serviço
de Neurologia, Hospital Egas Moniz, Lisbon (Dr Vale), Serviço de Neurologia,
Hospital Universidade Coimbra, Coimbra (Dr Januário), and Serviço
de Neurologia, Hospital São Sebastião, Feira (Dr Coutinho),
Portugal; Centre Hospitalier de l'Université de Montréal, Hôpital
Notre-Dame, Montréal, Quebec (Dr Pandolfo, Mr Miranda, and Ms Poirier);
Serviço de Genética Médica, Hospital Clínicas,
Porto Alegre, Brazil (Dr Jardim); Department of Neurology, Brain Research
Institute, Niigata University, Niigata, Japan (Drs Tsuji and Koide); and Johns
Hopkins University School of Medicine, Baltimore, Md (Drs Holmes and Margolis).
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