The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease.

Am J Hum Genet
Authors
Keywords
Abstract

Huntington disease (HD) is caused by an expanded HTT CAG repeat that leads in a length-dependent, completely dominant manner to onset of a characteristic movement disorder. HD also displays early mortality, so we tested whether the expanded CAG repeat exerts a dominant influence on age at death and on the duration of clinical disease. We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation's length. It is also unaffected by a strong genetic modifier of HD motor onset. These findings suggest two parsimonious alternatives. (1) HD pathogenesis is driven by mutant huntingtin, but before or near motor onset, sufficient CAG-driven damage occurs to permit CAG-independent processes and then lead to eventual death. In this scenario, some pathological changes and their clinical correlates could still worsen in a CAG-driven manner after disease onset, but these CAG-related progressive changes do not themselves determine duration. Alternatively, (2) HD pathogenesis is driven by mutant huntingtin acting in a CAG-dependent manner with different time courses in multiple cell types, and the cellular targets that lead to motor onset and death are different and independent. In this scenario, processes driven by HTT CAG length lead directly to death but not via the striatal pathology associated with motor manifestations. Each scenario has important ramifications for the design and testing of potential therapeutics, especially those aimed at preventing or delaying characteristic motor manifestations.

Year of Publication
2016
Journal
Am J Hum Genet
Volume
98
Issue
2
Pages
287-98
Date Published
2016 Feb 04
ISSN
1537-6605
URL
DOI
10.1016/j.ajhg.2015.12.018
PubMed ID
26849111
PubMed Central ID
PMC4746370
Links
Grant list
U01 NS082079 / NS / NINDS NIH HHS / United States
R01 NS091161 / NS / NINDS NIH HHS / United States
P50 NS016367 / NS / NINDS NIH HHS / United States
R01NS091161 / NS / NINDS NIH HHS / United States
NS16367 / NS / NINDS NIH HHS / United States
U01NS082079 / NS / NINDS NIH HHS / United States