OBJECTIVES/SPECIFIC AIMS: This study (1) investigated the presence and severity of autonomic nervous system (ANS) dysfunction in patients with pre-symptomatic Huntington Disease (HD) and (2) determined if pharmacologic manipulation of the ANS could modify the progression of HD. METHODS/STUDY POPULATION: Using a unique data set of children at-risk for HD (the Kids-HD study), markers of autonomic function (resting heart rate [rHR], blood pressure [BP], and core body temperature [CBT]) were compared between pre-symptomatic, gene-expanded children (psGE) and healthy developing children using mixed models analyses controlling for sex, age, and body mass index. Included participants had to be < 18 years old and be at least 10 years from their predicted motor diagnosis of HD. Using the Enroll-HD database, inverse-propensity score weighted, Cox Regression analyses investigated the effects of beta-blockers on the timing of motor diagnosis of presymptomatic, adult patients with HD. RESULTS/ANTICIPATED RESULTS: Compared to healthy controls, the psGE participants had significantly (p<0.05) higher mean rHR, systolic BP percentile, and CBT compared to the healthy controls (elevated by 4.01 bpm 0.19°C, and 5.96 percentile points, respectively, in the psGE group). Participants from Enroll-HD who were using a beta-blocker prior to motor diagnosis (n=65) demonstrated a significantly lower annualized risk of motor diagnosis [HR=0.56, p=0.03], compared to other participants with HD (n=1972). DISCUSSION/SIGNIFICANCE OF IMPACT: Sympathetic nervous system activity is elevated in patients with HD decades prior to their predicted motor diagnosis. Furthermore, modulation of the sympathetic nervous system with beta-blockers significantly lowers the annualized risk of motor diagnosis of HD.