Papers by Silvia Piacentini
Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly... more Objective: Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs. Methods: We modeled natural log-transformed age at onset as a function of CAG repeat lengths of expanded and normal alleles and their interaction by linear regression. Results: An apparently significant effect of interaction on age at motor onset among 4,068 subjects was dependent on a single outlier data point. A rigorous statistical analysis with a well-behaved dataset that conformed to the fundamental assumptions of linear regression (e.g., constant variance and normally distributed error) revealed significance only for the expanded CAG repeat, with no effect of the normal CAG repeat. Ten subjects with 2 expanded alleles showed an age at motor onset consistent with the length of the larger expanded allele. Conclusions: Normal allele CAG length, interaction between expanded and normal alleles, and presence of a second expanded allele do not influence age at onset of motor manifestations, indicating that the rate of HD pathogenesis leading to motor diagnosis is determined by a completely dominant action of the longest expanded allele and as yet unidentified genetic or environmental factors. Neurology ® 2012;78:690–695 GLOSSARY HD Huntington disease. Huntington disease (HD) is a neurodegenerative disorder with motor impairment, cognitive decline, and psychiatric manifestations 1,2 caused by an expanded CAG trinucleotide repeat (35 CAGs) in the gene encoding huntingtin. The expansion shows a very strong negative correlation with age at onset of motor signs. 3–7 Although the dominant inheritance pattern of HD indicates that one expanded allele is sufficient to trigger the disorder, polymorphism of the normal allele CAG repeat (i.e., the number of consecutive CAGs in the nonexpanded allele; 36 CAGs) has been suggested in some but not all studies to influence the timing of onset of disease manifestations. 6 –9 Recently, an interaction of the expanded and normal allele was reported in a large study to modify age at onset based upon motor signs, cognitive change, and behavioral manifestations. 10 Counterintuitively, longer normal alleles (e.g., 30 CAGs) seemingly delayed age at onset of subjects with longer expanded CAG alleles (e.g., 50 CAGs). 10 This finding would have important implications for the precise molecular mechanism that initiates HD pathogenesis, as it would suggest that individual huntingtin molecules might physically interact, with a resultant alteration of the pathogenic potential of the expanded repeat. Similarly, if the normal allele can modify HD pathogenesis, it would provide a potential Authors' affiliations are provided at the end of the article. Coinvestigators and Contributors are listed on the Neurology Web site at www.neurology.org.
Journal of Neurology, Neurosurgery & Psychiatry, 2012
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Papers by Silvia Piacentini