Document Detail

Improvement in the molecular diagnosis of Machado-Joseph disease.
MedLine Citation:
PMID:  11708990     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Direct detection of the gene mutation allows for the confirmation of the clinical diagnosis of Machado-Joseph disease (MJD), the most frequent cause of autosomal dominant spinocerebellar ataxia worldwide. OBJECTIVE: To address the main difficulties in our national MJD predictive testing program. The first was the emergence of intermediate alleles, for which it is not yet possible to determine whether they will cause disease. The second was the issue of homoallelism, ie, homozygosity for 2 normal alleles with exactly the same (CAG)(n) length, which occurs in about 10% of all test results. METHODS: A large pedigree with 1 affected patient carrying a 71 and a 51 CAG repeat and 2 asymptomatic relatives carrying the 51 CAG repeat and normal-size alleles underwent clinical and molecular studies. Intragenic haplotypes for these alleles were determined. A representative sample of the healthy population in the region was obtained to assess the distribution of the normal (CAG)(n) length. We established the genotype for 4 intragenic polymorphisms in the gene for MJD (MJD1) in 21 homoallelic individuals, to distinguish their 2 normal chromosomes. In addition, we developed a new Southern blot method to completely exclude cases of nonamplification of expanded alleles in the homoallelic individuals. RESULTS: The study of the family in which the 51 CAG repeat was found suggests that the allele is apparently not associated with disease. These intermediate alleles were not present in a large sample of the healthy population from the same region. Intragenic polymorphisms allowed distinction of the 2 different normal alleles in all cases of homoallelism. The absence of an expanded allele was also confirmed by Southern blot. CONCLUSIONS: We propose an improved protocol for molecular testing for MJD. These strategies, developed to overcome the practical difficulties mostly in the presymptomatic and prenatal diagnosis of MJD, should prove useful for other polyglutamine-related disorders.
P Maciel; M C Costa; A Ferro; M Rousseau; C S Santos; C Gaspar; J Barros; G A Rouleau; P Coutinho; J Sequeiros
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Archives of neurology     Volume:  58     ISSN:  0003-9942     ISO Abbreviation:  Arch. Neurol.     Publication Date:  2001 Nov 
Date Detail:
Created Date:  2001-11-15     Completed Date:  2001-12-07     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0372436     Medline TA:  Arch Neurol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1821-7     Citation Subset:  AIM; IM    
UnIGENe, IBMC, Universidade do Porto, 4150-180 Porto, Portugal.
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MeSH Terms
Base Sequence
Genetic Testing / methods*
Machado-Joseph Disease / diagnosis*,  genetics*
Middle Aged
Molecular Sequence Data
Nerve Tissue Proteins / genetics*
Nuclear Proteins
Polymorphism, Genetic / genetics
Repressor Proteins
Trinucleotide Repeat Expansion
Reg. No./Substance:
0/Nerve Tissue Proteins; 0/Nuclear Proteins; 0/Repressor Proteins; EC 3.4.22.-/ATXN3 protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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