Autosomal dominant cerebellar ataxias comprise a wide spectrum of diseases with different clinical/neuropathological profiles. At least 30 responsible loci (SCA) have been mapped. Nucleotide repeat expansions have been identified as responsible for the disease in 9 genes including those caused by polyglutamine-coding (CAG) repeat expansions in the SCA1-3,6,7 and 17 genes and rare forms caused by non-coding repeats in the SCA8,10 and 12 genes. More recently, conventional mutations were reported in SPTBN2/SCA5, TTBK2/SCA11, KCNC3/SCA13, PRKCG/SCA14, ITPR1/SCA15/16, FGF14/SCA27, AFG3L2/SCA28 as well as in the puratrophin gene. The relative prevalence of the SCA genes and their associated phenotype was investigated in 826 index patients from families with a dominant transmission of the disease collected from 1990 to 2008 in the Pitié-Salpêtrière university-hospital in Paris or through clinical national networks using standardized clinical charts. The most frequently mutated genes were SCA3 (20.4%), SCA2 (9.7%), SCA1 (7.7%), SCA7 (5.7%) and SCA6 (1.8%). Missense mutations in SCA14 (1.8%), SCA28 (1.6%), SCA13 (1.2%) and SCA5 (0.8%) were less frequent. We found SCA17 (0.2%) and SCA12 (0.2%) to be very rare, while no cases of SCA10,27 or puratrophin were identified. In subclinical selections, heterozygous deletions in SCA15/16 (4/76) and a non-sense mutation in SCA11 (1/77) were also detected. Genotype-phenotype correlations showed that CAG repeat expansion diseases shared a rapidly progressive and severe disease course with onset in the thirties. On the contrary, the clinical picture associated with conventional mutations in the recently identified genes was milder despite the frequent presence of marked cerebellar atrophy on MRI.
Conventional mutations are associated with a different phenotype than polyglutamine expansions in spinocerebellar ataxias
CAGNOLI, CLAUDIA;BRUSCO, Alfredo;
2009-01-01
Abstract
Autosomal dominant cerebellar ataxias comprise a wide spectrum of diseases with different clinical/neuropathological profiles. At least 30 responsible loci (SCA) have been mapped. Nucleotide repeat expansions have been identified as responsible for the disease in 9 genes including those caused by polyglutamine-coding (CAG) repeat expansions in the SCA1-3,6,7 and 17 genes and rare forms caused by non-coding repeats in the SCA8,10 and 12 genes. More recently, conventional mutations were reported in SPTBN2/SCA5, TTBK2/SCA11, KCNC3/SCA13, PRKCG/SCA14, ITPR1/SCA15/16, FGF14/SCA27, AFG3L2/SCA28 as well as in the puratrophin gene. The relative prevalence of the SCA genes and their associated phenotype was investigated in 826 index patients from families with a dominant transmission of the disease collected from 1990 to 2008 in the Pitié-Salpêtrière university-hospital in Paris or through clinical national networks using standardized clinical charts. The most frequently mutated genes were SCA3 (20.4%), SCA2 (9.7%), SCA1 (7.7%), SCA7 (5.7%) and SCA6 (1.8%). Missense mutations in SCA14 (1.8%), SCA28 (1.6%), SCA13 (1.2%) and SCA5 (0.8%) were less frequent. We found SCA17 (0.2%) and SCA12 (0.2%) to be very rare, while no cases of SCA10,27 or puratrophin were identified. In subclinical selections, heterozygous deletions in SCA15/16 (4/76) and a non-sense mutation in SCA11 (1/77) were also detected. Genotype-phenotype correlations showed that CAG repeat expansion diseases shared a rapidly progressive and severe disease course with onset in the thirties. On the contrary, the clinical picture associated with conventional mutations in the recently identified genes was milder despite the frequent presence of marked cerebellar atrophy on MRI.
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