Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7).
1. Hum Mol Genet. 1998 Feb;7(2):165-70.
Molecular and clinical correlations in autosomal dominant cerebellar ataxia with
progressive macular dystrophy (SCA7).
David G(1), Dürr A, Stevanin G, Cancel G, Abbas N, Benomar A, Belal S, Lebre AS,
Abada-Bendib M, Grid D, Holmberg M, Yahyaoui M, Hentati F, Chkili T, Agid Y,
(1)INSERM U289 and Fédération de Neurologie, Hôpital de la Salpêtrière, 47 bd. de
l’Hôpital, 75651 Paris Cedex 13, France.
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.
PMID: 9425222 [Indexed for MEDLINE]