Overlap between age-at-onset and disease-progression determinants in Huntington disease

Abstract

Objective: A fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.

Methods: Using observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.

Results: A total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat-dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.

Conclusion: Our findings imply that targeting of CAG repeat-dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.

Figure 1. Association between the rate of clinical progression and HTT CAG repeat size and residual age at onset

To further explore and visualize the data, we first divided the patient cohort in 3 different groups based on either CAG repeat size (A, C, E, and G) or residual age at onset (B, D, F, and H). Next, for each clinical measure and each category of CAG repeat size or residual age at onset, we applied a separate linear mixed-effects model to estimate the mean trajectory of change in clinical scores in time for different categories of HTT CAG repeat size or residual age at onset. The rate of deterioration on the Unified Huntington’s Disease Rating Scale total functional capacity (A) total motor score (C), a cognitive summary score (E), and body mass index (BMI) (G) increased significantly with a larger expanded HTT CAG repeat size. Conversely, the rate of functional (B), motor (D), and cognitive decline (F) was slower in those patients who had an age at onset later than that expected based on their expanded HTT CAG repeat size compared to those with an age at onset at or earlier than expected based on their expanded HTT CAG repeat size. However, residual age at onset had no influence on the rate of weight loss (H). The straight lines represent the mean predicted scores while the dashed areas around the regression lines denote the 95% confidence intervals of the mean. The 3 categories of expected age at onset, i.e., “earlier,” “expected,” and “later,” were defined based on tertiles of residual age at onset as minimum (−16.4) to ≤−2.3, >−2.3 to ≤2.9, and >2.9 to maximum (21.8) years, respectively.

Figure 2. Variance in clinical progression explained by age at onset determinants in HD

A substantial proportion of variation in clinical deterioration as assessed by the Unified Huntington’s Disease Rating Scale total functional capacity, total motor score, and a cognitive summary score could be attributed to the same factors that determine age at onset in HD, with expanded HTT CAG repeat size being by far the most important determinant of disease progression as well. However, there was only a small degree of overlap between the determinants of age at onset and weight loss in HD. Bar height indicates the mean magnitude of the coefficient of determination (R²) per category, while the error bars indicate the associated bootstrapped 95% bias-corrected and accelerated confidence intervals of this statistic (see text and table 1 for details). BMI = body mass index; HD = Huntington disease.