Preclinical motor manifestations of Huntington disease

Huntington disease (HD) is an autosomal-dominant, progressive neurodegenerative condition characterized by multiple movement disorders, psychiatric disturbances, and cognitive decline. As an insidious, progressive disorder, clinical phenoconversion in HD can be quite subtle and difficult to pinpoint. In light of this ambiguity, substantial interest has developed in HD research for biomarker identification, with the intent of establishing specific changes or "stages" of disease progression. Presumably, earlier stages of dysfunction offer greater chance for intervention or modification of disease mechanisms. As such, identifying disease processes as early as possible, in a prediagnostic period if possible, has been of paramount interest. Emerging evidence suggests motor dysfunction in HD long precedes clinical diagnosis, raising questions about the initiation of HD pathology and in turn our understanding of disease progression. This chapter summarizes advances in characterizing and understanding preclinical motor manifestations in HD, including changes in eye movements, gait, and fine motor performance. Development of the most sensitive and specific outcome measures for trial design is a rapidly evolving field in HD experimental therapeutics, with exciting implications for the study and treatment of this challenging disorder.