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Improvement in the Molecular Diagnosis of Machado-Joseph Disease
Patrícia Maciel, PhD;
Maria do Carmo Costa, BSc;
Anabela Ferro, BSc;
Marylène Rousseau, BSc;
Cláudia Sofia Santos, BSc;
Claudia Gaspar, PhD;
José Barros, MD;
Guy A. Rouleau, MD, PhD;
Paula Coutinho, MD, PhD;
Jorge Sequeiros, MD, PhD
Arch Neurol. 2001;58:1821-1827.
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.
From the UnIGENe, Instituto de Biologia
Molecular e Celular (Drs Maciel, Gaspar, and Sequeiros and Mss Costa,
Ferro, and Santos), and the Deptartamento Estudos de
Populações, Instituto de Ciências Biomédicas de
Abel Salazar (Dr Sequeiros), Universidade do Porto, and Serviço
de Neurologia, Hospital de St António (Dr Barros), Porto,
Portugal; Instituto Superior de Ciências da Saúde-Norte,
Paredes, Portugal (Dr Maciel); Centre for Research in Neuroscience,
McGill University and the Montreal General Hospital Research Institute,
Montreal, Québec (Ms Rousseau and
Drs Gaspar and Rouleau); and
Serviço de Neurologia, Hospital de St Sebastião, Santa
Maria da Feira, Portugal (Dr Coutinho).
Corresponding author: Patrícia Maciel, PhD, UnIGENe,
IBMC, Universidade do Porto, 4150-180 Porto, Portugal.
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