Inherited HTT CAG repeat length does not have a major impact on Huntington disease duration

To the Editor: We read with interest the recent paper “Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease” by Langbehn et al.,¹ who performed analysis of disease duration (i.e., the time from onset to death) of Huntington disease (HD [MIM: 143100]) and observed that duration is significantly associated with both CAG repeat length and age at onset. After examining a survival model corrected for age at onset, they concluded that adult-onset HD proceeds more aggressively to death with longer CAG length.¹ While we do not disagree with their method of analysis or the resultant observations, we would offer a different interpretation of their data with different biological implications. We have previously shown that both age at onset and age at death of HD are highly correlated with the inherited length of the disease-causing expanded CAG repeat in HTT.² We also reported that disease duration is similar across repeat lengths in the adult onset CAG size range (which represents the vast majority of HD-affected individuals) and becomes shorter only for the rarer long repeats typically associated with very early onset.² We offered potential alternative explanations for the lack of an effect of inherited CAG repeat length on duration in the adult onset-associated size range, including (1) death ensues from onset but results from a pathogenic cascade that, once triggered, no longer depends on inherited CAG length or (2) death results from a CAG length-dependent process distinct from that which leads to onset.

On the assumption that death ensues consequentially from onset, Langbehn et al.,¹ test the effect of inherited CAG repeat length on disease duration by using survival analysis. An initial survival model (Model 1) that includes only CAG repeat size and sex is largely consistent with our findings, as it detects only a weak effect of CAG length on duration. However, from a second model (Model 2) that considers both CAG and age at onset, Langbehn et al.¹ find a highly significant effect of both the CAG repeat size and age at onset terms on duration. Thus, individuals with the same age at onset (and therefore equally aggressive disease) subsequently have shorter duration (i.e., more aggressive disease) if they have a longer CAG repeat. The authors conclude that adult-onset HD progresses more aggressively to death as a result of longer CAG length, but this interpretation does not take a critically important component into account.

Two components influence age at onset: inherited CAG repeat length and non-CAG factors. The non-CAG factors have been quantified as residual age at onset, i.e., the difference between an individual’s observed age at onset and the age at onset expected from their inherited CAG repeat length (determined as the mean age at onset for all those with the same CAG length). The existence of significant effects due to non-CAG factors has been directly demonstrated by successful genome-wide association (GWA) studies that have identified genetic modifiers of HD age at onset.^3,4 When Langbehn et al.¹ fix age at onset to examine survival curves and then attribute differences in duration to CAG repeat length, they do not take into account the non-CAG factors that influence age at onset. In our view, these non-CAG modifying factors, not the CAG repeat, are primarily responsible for the observed effect on duration. For example, across the HD population, an inherited repeat of 45 CAGs is associated with a mean age at onset of ∼40 years. A group of HD individuals with age at onset 40 consists of: (1) individuals with 45 CAGs and no net influence of non-CAG factors (i.e., these individuals display the age at onset expected based on their actual CAG repeat size), (2) individuals with CAG repeat size <45 and non-CAG factors with a net onset-hastening influence (i.e., displaying earlier onset than expected from their actual CAG repeat size), and (3) individuals with CAG repeat size >45 and non-CAG factors with a net onset-delaying influence (i.e., displaying later onset than expected from their actual CAG repeat size). Consequently, the comparison of survival curves at fixed age at onset performed by Langbehn et al.,¹ which leads to their conclusion concerning the effect of longer CAG lengths on duration, cannot in fact distinguish between effects of the CAG repeat size on duration and effects of the non-CAG factors on duration.

The way to distinguish which of these two components is most responsible for the effect on duration is to compare individuals with different CAG lengths in the absence of any net effect of the non-CAG factors. As noted above, at any given age at onset, those individuals with a CAG length that predicts that particular age at onset (i.e., those with no residual age at onset) display no net influence of non-CAG factors. For example, in our HD modifier GWA dataset, inherited CAG repeats of 41, 43, 45, and 47 are associated with mean ages at onset of 55.7, 47.3, 40.1, and 35.3, respectively.⁴ Consequently, rather than comparing survival curves at a fixed age at onset, one must compare survival curves associated with different CAG lengths at the mean age at onset associated with each CAG length. In our previous publication, the mean duration after the mean age at onset associated with each different adult-onset CAG repeat was very similar at ∼15 years.² This indicated a lack of effect of CAG repeat length on duration despite a large effect on age at onset over the same size range. This comparison leads to the conclusion that it is the non-CAG factors that are responsible for the differences in survival observed at fixed age at onset in the age range representing the majority of adult-onset HD-affected individuals. Unfortunately, we cannot perform this comparison directly with the data in Langbehn et al.¹ because this study does not report the required details of the relationship between CAG repeat and age at onset. Our interpretation of the data is that there may be a weak effect of CAG length on disease duration in the adult age range, but the strong effect detected in Model 2 is due to the non-CAG factors that influence onset not to CAG length. Thus, the potential alternative explanations for the lack of a major effect of inherited CAG repeat length on disease duration in the adult-onset-associated size range remain on the table, including (1) a process that leads from onset to death that is not strongly dependent on inherited CAG repeat size or (2) parallel unconnected CAG repeat-driven processes that result separately in onset and death, respectively.

Our investigations of HD genetics and genetic modifiers have supported a two-component model of HD pathogenesis in which somatic expansion of the CAG repeat to a critical threshold then triggers cellular damage mechanisms.^4,5 In this regard, the phenotypic deterioration seen in HD may not proceed as a series of obligate mechanistically connected sequential steps that lead from onset to death. Indeed, somatic CAG expansion could proceed at different rates, exhibit different critical thresholds, and trigger different damage mechanisms in different cell types. As an example of the latter, in a mouse model of spinocerebellar ataxia 1 (SCA1 [MIM: 164400]), a related CAG expansion disorder, the mechanism that drives cell death in cerebellum does not operate in the brainstem despite disease pathology in both regions.^6,7 Similarly, we have recently provided evidence in human HD that the emergence of phenotypes in the motor and cognitive domains is influenced differentially by genetic modifiers, suggesting parallel processes that have impact on different neuronal circuits.⁸ Consequently, it is important to note that the apparent lack of a strong impact of inherited CAG repeat length on disease duration that emerges from our prior publications and from our interpretation of the Langbehn et al.¹ data does not preclude an important role for CAG-repeat-mediated processes after onset. Rather, it suggests that some phenotypes, such as death, may result from CAG-repeat-mediated processes that impact different cell types than those responsible for the clinical measures used to define onset or disease in early manifest individuals.