Diagnostic criteria for Huntington's disease based on natural history.

Huntington's disease (HD) is currently diagnosed based on the presence of motor signs indicating 99% "diagnostic confidence" for HD. Recent advances in the understanding of HD natural history and neurobiology indicate that disease-related brain changes begin at least 12 to 15 years before the formal diagnosis based on motor onset. Furthermore, subtle motor dysfunction, cognitive changes, and behavioral alterations are often seen before diagnosis made according to the current criteria. As disease-modifying treatments are developed, likely beginning therapy early will be desirable. We therefore suggest that expanded diagnostic criteria for HD should be adapted to better reflect the natural history of the disease, to enable the conduct of clinical trials in premanifest subjects targeting prevention of neurodegeneration, and to facilitate earlier symptomatic treatment. We propose a new set of criteria for HD diagnostic categories in the International Classification of Diseases that reflect our current understanding of HD natural history and pathogenesis. Based on defined criteria, for example, the Diagnostic Confidence Level and the Total Functional Capacity scales of the Unified Huntington's Disease Rating Scale, HD should be divided in the categories "genetically confirmed" with the subcategories "presymptomatic," "prodromal," and "manifest" and "not genetically confirmed" subdivided into "clinically at risk," "clinically prodromal," and "clinically manifest."