Effect of Body Weight on Age at Onset in Huntington Disease

Abstract

ObjectiveWeight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.MethodsUsing data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.ResultsInverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = −0.44 years per unit increase in BMI, confidence interval: −1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.ConclusionsAlthough maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

Microarray profiling of hypothalamic gene expression changes in Huntington’s disease mouse models

“…In addition to prior studies on high caloric diets and the use of transgenic mice to induce weight gain [29-34]; increases in body weight in HD appear to be insufficient to significantly modify disease features in animal models. In line with this, van der Burg and colleagues followed up on results from the original BMI and disease progression study [25] and reported that there is no causal relation between BMI and age of onset in clinical HD [35]. Hence, there is a need for elucidating specific mechanisms underlying HD metabolic changes and how it modifies disease features in HD.…”

A Novel Huntington’s Disease Assessment Platform to Support Future Drug Discovery and Development

“…However, clinical cases demonstrated that body weight loss is not necessarily the results of the disease itself but rather an insidious consequence of a generally reduced metabolism [ 63 ]. Clinically, HD patients usually suffer from swallowing problems and they are more likely to choke, resulting in lower body mass index than healthy individuals [ 64 ]. In order to assess the aspect of HD-related body weight loss in zQ175 Δneo mice, we also measured the food consumption on a weekly basis.…”

Movement Disorders and the Gut: A Review

“…Studies have demonstrated that the degree of weight loss may correlate with an individual's CAG repeat length, with longer expansions associated with more profound weight loss. 72 Although a person's BMI does not appear to predict age of onset of manifest HD, 73 it may dictate the speed of progression, with lower BMI at disease onset portending more rapid decline in function. 74 The actual cause for weight loss in HD is not entirely understood.…”