title: The number of CAG repeats within the normal allele does not influence the age of onset in Huntington's disease.
abstract: Huntington's disease (HD) is caused by the expansion of the number of CAG repeats on the chromosome 4p16.3, which results in elongated glutamine tract of huntingtin. The purpose of this work was to examine the interaction between the normal and mutant alleles of this gene and their effect on the clinical onset of HD. We hypothesized that in patients with identical number of CAG repeats within the mutant allele, the age of onset of HD is influenced by the number of CAG repeats within the normal allele. We analyzed the relations between the number of CAG repeats within the normal and mutant alleles, the age at HD onset, and the character of initial symptoms in 468 patients with clinically expressed HD. Although the Cox regression coefficient of 0.15 was significant (P < 0.0001), the regression model explained only 28% of the variance of the age at onset related to the effect of the number of CAG repeats within normal allele. Within the groups of patients with the same number of CAG repeats of the mutant allele, number of CAG repeats of the normal allele was found uncorrelated to the age at onset. Furthermore, when analyzing subgroups of patients with the same allelic composition on both alleles, we failed to observe any correlation with the age at the onset. Our analysis gives no corroboration to the idea of a normal allele having a share in the modification of the age at HD onset. We believe that with the current state of knowledge it is not possible to devise a mathematical model for HD onset prediction because too many entirely unknown modifying factors are still involved.
authors.affiliation: Department of Neurology, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic. jiri.klempir@seznam.cz
authors.forename: Jiří
authors.initials: J
authors.lastname: Klempíř
authors.forename: Jana
authors.initials: J
authors.lastname: Zidovská
authors.forename: Jan
authors.initials: J
authors.lastname: Stochl
authors.forename: Věra Kebrdlová
authors.initials: VK
authors.lastname: Ing
authors.forename: Tereza
authors.initials: T
authors.lastname: Uhrová
authors.forename: Jan
authors.initials: J
authors.lastname: Roth
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D018153:Czech Republic; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D016016:Proportional Hazards Models; D018911:Trinucleotide Repeats / Q000235:genetics*; D055815:Young Adult
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins