Ó³»­´«Ã½

OBJECTIVES: To characterize the survival of individuals with pathogenic variants - including to estimate annual hazards, to judge the accuracy of previously reported retrospective survival data, and to evaluate the utility of public record searches in determining vital status.METHODS: In this single center cohort study, we gathered data on individuals who received positive antemortem genetic tests at the U.S. National Prion Disease Pathology Surveillance Center (NPDPSC). Genetic test results and autopsy status were queried from the NPDPSC database, and public record searches were conducted using online tools.RESULTS: 404 individuals received positive genetic test results. Of 206 cases symptomatic at the time of genetic testing, 188 are likely now deceased based on typical disease duration for their genetic variants. Combined autopsy and public record searches in combination confirmed 174 of these deaths, for an estimated sensitivity of 92.6%. Of 111 autopsied individuals, evidence of death was found in public record searches for 109, a sensitivity of 98.2%. Of 198 individuals who were asymptomatic at the time of testing, 32 since died of definite or possible prion disease. Among 20 of these who underwent autopsy, public record searches confirmed deaths of 18, for a sensitivity of 90%. Among 99 E200K individuals over 936 person-years of follow-up, 18 deaths were observed, significantly fewer than 27.4 expected according to life tables based on retrospective data. The age-dependent penetrance of E200K calculated from prospective data was significantly lower than that from retrospective data, with 69% penetrance by age 80 and a median age at death of 75. No significant difference was found for D178N, which appears highly penetrant, though the median age at death was numerically higher than seen in retrospective data. V210I was associated with just 2 deaths, both after age 90, consistent with minimal penetrance.DISCUSSION: These data support the accuracy of penetrance classifications for variants reported based on retrospective data, but may suggest an age of onset distribution shifted slightly later than that calculated retrospectively. Autopsy data and public death records in combination were sensitive and concordant, but additional prospective data should be gathered to support future preventive trials.CLINICAL TRIALS REGISTRATION: Not applicable.