Fig. 2.

Potential relationship of CAG tract expansion and clinical Huntington’s disease events. The premanifest period of the disease may reflect the presence of a proportion of disease-relevant cells with sufficient somatic expansion to induce neuronal dysfunction, but too few to manifest overt clinical symptoms. Premanifest HD includes a presymptomatic period where no signs or symptoms are present, and prodromal HD, characterised by the onset of subtle signs and symptoms, which may be the result of the HTT CAG length expanding beyond an unknown pathogenic threshold in increasing numbers of disease-relevant cells. Manifest HD— characterised by chorea and gradual worsening of motor and cognitive difficulties— may then arise once a significant number of disease-relevant cells have passed this threshold. Somatic expansion in susceptible cell populations is likely to be occurring throughout the premanifest and prodromal stages of disease as indicated by the hypothetical dashed line, although the actual trajectory of this expansion will depend on the inherited repeat length and is likely to differ in different cell types. Therefore, the relationship between the trajectory of somatic expansion and clinical phenotypes is currently hypothetical. Figure adapted from Ross et al. [45] and Bates et al. [3] and created using BioRender.com.