Clinical and genetic association studies reveal within-individual variability as an integral part of Huntington disease

Abstract

AbstractHuntington disease (HD) is one of the most common repeat expansion disorders. Clinically, HD patients exhibit considerable visit-to-visit variability in symptoms and signs independent of measuring method or rater, yet neither the precise nature nor the determinants of this clinical variability are known. Leveraging detailed genetic and longitudinal clinical data from large cohorts of HD patients, this work1)establishes within-individual variability in disease expression as an integral part of HD semiology, demonstrating that it increases with disease duration, mutation size, younger age-at-onset, and lower body weight,2)provides a mathematical framework linking higher phenotypic variability to increased predictive entropy, revealing a fundamental relation between within-individual variability and energy expenditure, and3)identifies novel genetic modifiers of both within-individual variability and age-at-onset in HD. Thus, accounting for within-individual variability in HD could facilitate the discovery of pathogenic mechanisms and outcomes directly relevant to the development of disease modifying therapies.