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Updated: Jun 25, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Relationship between CAG repeat length and brain volume in premanifest and early Huntington's disease
Susie M D Henley1, Edward J Wild, Nicola Z Hobbs
1Dementia Research Centre, Institute of Neurology, University College, London, UK. shenley@drc.ion.ucl.ac.uk
Insights
Huntington's disease (HD) is linked to CAG repeat length, which correlates with brain atrophy in specific regions. Longer CAG repeats are associated with reduced brain volume in both striatal and extra-striatal areas.
Area of Science:
- Neuroscience
- Genetics
- Neurology
Background:
- Huntington's disease (HD) is a genetic neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene.
- The relationship between CAG repeat length and disease progression, including brain volume changes, remains incompletely understood.
- Conflicting findings exist regarding repeat length's predictive power for disease onset and severity in adults.
Purpose of the Study:
- To investigate the association between CAG repeat length and brain volume in individuals with Huntington's disease.
- To examine group differences in brain volume between premanifest HD gene carriers, early HD patients, and controls.
- To explore the extent to which CAG repeat length predicts regional brain atrophy.
Main Methods:
- Utilized voxel-based morphometry (VBM) to analyze whole-brain grey matter volume.
- Studied a cohort of pre- and post-motor onset HD gene carriers (n=61) and 20 controls.
- Correlated CAG repeat length with brain volume, controlling for age, and performed group comparisons.
Main Results:
- Increased CAG repeat length was significantly associated with reduced brain volume in the caudate nucleus, putamen, insula, parahippocampal gyrus, anterior cingulate, and occipital lobe.
- Early HD subjects showed significant grey matter volume reduction in widespread cortical and subcortical areas compared to controls.
- No significant brain volume differences were observed between premanifest HD gene carriers and controls.
Conclusions:
- Expanded CAG repeat length in Huntington's disease is associated with atrophy in both striatal and extra-striatal brain regions.
- These findings suggest that CAG repeat length influences widespread brain degeneration beyond the traditionally affected striatum.
- The results have implications for monitoring disease progression and evaluating the efficacy of disease-modifying therapies in HD.
Abstract:
Huntington's disease (HD) is caused by an expanded CAG repeat on the gene encoding for the protein huntingtin. There are conflicting findings about the extent to which repeat length predicts signs of the disease or severity of disease progression in adults. This study examined the relationship between CAG repeat length and brain volume in a large cohort of pre- and post-motor onset HD gene carriers, using voxel-based morphometry (VBM), an approach which allowed us to investigate the whole brain without defining a priori regions of interest. We also used VBM to examine group differences between 20 controls, 21 premanifest, and 40 early HD subjects. In the 61 mutation-positive subjects higher CAG repeat length was significantly associated with reduced volume of the body of the caudate nucleus bilaterally, left putamen, right insula, right parahippocampal gyrus, right anterior cingulate, and right occipital lobe, after correcting for age. The group contrasts showed significant reduction in grey matter volume in the early HD group relative to controls in widespread cortical as well as subcortical areas but there was no evidence of difference between controls and premanifest subjects. Overall we have demonstrated that increased CAG repeat length is associated with atrophy in extra-striatal as well as striatal regions, which has implications for the monitoring of disease-modifying therapies in the condition.
