Human Molecular Genetics, Vol 7, 165-170, Copyright © 1998 by Oxford University Press
G David, A Durr, G Stevanin, G Cancel, N Abbas, A Benomar, S Belal, AS Lebre, M Abada-Bendib, D Grid, M Holmberg, M Yahyaoui, F Hentati, T Chkili, Y Agid and A Brice
Spinocerebellar ataxia 7 (SCA7) is caused by the expansion of an unstable
CAG repeat in the first exon of the SCA7 gene. We have analyzed the SCA7
mutation in 19 families and one isolated case of various geographical
origins, presenting with autosomal dominant cerebellar ataxia with
progressive macular dystrophy. The SCA7 CAG repeat was expanded in 77
patients and in 11 at-risk individuals, with alleles containing from 37 to
130 repeats, demonstrating that SCA7 is genetically homogeneous. Repeats on
normal alleles contained from 7 to 35 CAGs. There was a strong negative
correlation (r = -0.84) between the age at onset and the size of the CAG
repeat expansion in SCA7 patients. Larger expansions were associated with
earlier onset, a more severe and rapid clinical course, and a higher
frequency of decreased vision, ophthalmoplegia, extensor plantar response
and scoliosis. The frequency of other clinical signs such as dysphagia and
sphincter disturbances increased with disease duration. The mutation was
highly unstable during transmission, with a mean increase of 10 +/- 16 CAG
repeats, which was significantly greater in paternal (15 +/- 20) than in
maternal (5 +/- 5) transmissions. This correlated well with the marked
anticipation (19 +/- 13 years) observed in the families. Gonadal mosaicism,
observed in the sperm of a patient, was particularly important, with
expanded alleles ranging from 42 to >155 CAG repeats. The degree of
instability during transmission, resulting mostly in expansions, is greater
than in the seven other neurodegenerative disorders caused by polyglutamine
expansions.
ARTICLES
Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7)
INSERM U289 and Federation de Neurologie, Hopital de la Salpetriere, 47 bd. de l'Hopital, 75651 Paris Cedex 13, France.
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