Fig.6.

HD pathogenesis consists of two sequential components: somatic CAG expansion that results in cellular damage after a threshold length is reached. To illustrate the concept of a two component model of HD pathogenesis, which likely also applies to at least some other repeat disorders, hypothetical plots are shown for somatic expansion in the average target cell for two different starting alleles, uninterrupted CAG repeats of 45 units (orange), in the fully penetrant size range, and 38 units (blue), in the partially penetrant size range. Depicted are plots in the absence of a modifier (solid line) and in the presence of a strong onset-delaying modifier (dashed line), a weak onset-hastening modifier (dash-dotted line) or a strong onset-hastening modifier (dotted line). Somatic expansion the CAG repeat causes it to cross a threshold length (denoted by the dashed purple line) and trigger damaging consequences once in the range shaded as light purple. The CAG repeat inherited as 45 units crosses the threshold line at an early age that can be shifted earlier or later by modifiers of somatic CAG expansion while somatic expansion of the 38 CAG repeat crosses the threshold only late in life, except that in the presence of the strong onset-delaying modifier, the somatic CAG length in the average cell never exceeds the critical threshold to trigger damage during the lifetime of the subject.