Age at onset variance analysis in spinocerebellar ataxias: a study in a Dutch-French cohort.

Bart P. C. van de Warrenburg, Harrie Hendriks, Alexandra Dürr, Martin C. A. van Zuijlen, Giovanni Stevanin, Agnès Camuzat, Richard J. Sinke, Alexis Brice, Berry P. H. Kremer
Ann Neurol.. 2005-03-03; 57(4): 505-512
DOI: 10.1002/ana.20424

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1. Ann Neurol. 2005 Apr;57(4):505-12.

Age at onset variance analysis in spinocerebellar ataxias: a study in a
Dutch-French cohort.

van de Warrenburg BP(1), Hendriks H, Dürr A, van Zuijlen MC, Stevanin G, Camuzat
A, Sinke RJ, Brice A, Kremer BP.

Author information:
(1)Department of Neurology, University Medical Center Nijmegen, The Netherlands.

In dominant spinocerebellar ataxias (SCAs), the issue of whether non-CAG
dependent factors contribute to onset age remains unsettled. Data on SCA
genotype, onset age, normal/expanded CAG repeat length, sex of the patient and
transmitting parent, and family details were available from 802 patients. Based
on the model [log(10) (age at onset) = k – b CAG(exp) + epsilon], we examined
changes in adjusted R(2) and residual standard error following incorporation of
the other factors in this model. The expanded repeat explained 44.3 to 74.9% of
onset age variance, although this was less than 50% in SCA3 and SCA6, implicating
a large effect of non-CAG factors. The relation between onset age and CAG repeat
was similar for SCA1, 3, 6, and 7, but different for SCA2, pointing to different
polyglutamine effects in SCA2. For SCA2 and SCA3, 17.1 and 45.5% of onset age
variance, respectively, were explained by currently (unidentified) familial
factors. We found a significant contribution of the nonexpanded allele in SCA1
and SCA6. Besides polyglutamine motif (determined by the expanded CAG repeat
length), we identified the following age at onset modifiers: protein context in
SCA2; familial factors in SCA2 and SCA3; and the nonexpanded CAG repeat in SCA1
and SCA6.

DOI: 10.1002/ana.20424
PMID: 15747371 [Indexed for MEDLINE]

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