Trinucleotide Repeats in 202 Families With Ataxia: A Small Expanded (CAG)n Allele at the SCA17 Locus | Genetics and Genomics | JAMA Neurology | JAMA Network
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Original Contribution
April 2002

Trinucleotide Repeats in 202 Families With Ataxia: A Small Expanded (CAG)n Allele at the SCA17 Locus

Author Affiliations

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).

Arch Neurol. 2002;59(4):623-629. doi:10.1001/archneur.59.4.623

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.