refle Drs. he term “disease” is generally applied to a constellation of abnormal symptoms and the pathology that underlies them. Both of these features place the emphasis on the ate stage of what can be a long disease process, particularly in ate-onset neurodegenerative disorders. In the most common eurodegenerative disorders, the etiology involves multiple preipitating factors; so this late stage of the disease process then ecomes the necessary focus of research into disease mechaism, because there is no ready way to identify earlier steps midst the noise of etiologic and interpersonal variation. Howver, in a genetic disorder, like Huntington’s disease (HD), the ene defect provides a discrete starting point for investigating the echanism from its earliest stages, before those clinical features hat are thought of as diagnostic of the disorder (1). Ind D, all individuals have the same type of genetic mutation, an xpanded polyglutamine-encoding CAG trinucleotide repeat in he huntingtin gene. This genetic insult is present in the individal from conception, and consequently, the disease process can e thought of as beginning at that time. To define the full extent f the disease process then requires investigation of differences haracteristic of HD mutation carriers that occur at any stage in ife. The two articles in this issue by Duff et al. (2) and by Vass t al. (3) represent examples of this approach applied specif o psychiatric measures. They demonstrate clearly that abnormalties occur in HD mutation carriers compared with non-mutation arriers many years before onset of diagnostic symptoms. In Duff t al., a large sample of prediagnosed HD mutation carriers howed significant evidence of subtle psychiatric symptoms, ncluding depression, anxiety, and obsessive compulsiveness, ompared with non-HD mutation carriers born to an HD parent. assos et al. found a specific increase in extroverted hostility in smaller study of Greek subjects. Both investigations were made ossible by the ability to determine with certainty, with a olecular test, which individuals would later develop HD pahology and diagnostic symptoms. Thus, although the subtle sychiatric differences cannot themselves be considered diagostic of HD, they do reveal that the HD mutation makes a ifference before the appearance of those symptoms that are iagnostic. These articles add to the growing evidence of an active isease process in the brains of HD mutation carriers more than 0 years before diagnosis (4 – 8). The findings might ngoing modulation of neuronal function or connectivity by the D mutation, increasing neuronal dysfunction due to mutant untingtin or the outright loss of particular neurons. In any vent, these articles reinforce the notion that there are differnces between HD mutation carriers and non-HD mutation