Genetic diagnosis of individuals at risk of CADASIL: prospect for future therapeutic development

CADASIL is the most frequent hereditary cerebral small vessel disease worldwide. The disease is responsible for a slow and progressive accumulation of cerebral ischemic insults that lead to disabling cognitive and motor symptoms at late age. Although there is currently no cure for this condition, future therapies may concern subjects only at early stage of the disease. This will raise the question of the participation of asymptomatic carriers of pathogenic NOTCH3 gene mutation in future clinical trials, which will presuppose acceptance of presymptomatic genetic diagnosis. In this study, we questioned the population at risk of CADASIL who had not undergone a diagnostic procedure yet. Based on a questionnaire survey carried out by an independent team of sociologists, we analyzed what underlies the choice of people at risk to undergo or not to undergo a genetic test, and what could constitute the tipping point that could lead people who were initially not interested in their diagnosis to have recourse to it. Our results suggest that, far from being a simple, unequivocal path, the decision-making process leading to the choice of diagnosis is initially slowed down by the need to distance oneself from the disease so that it doesn't take over one's life, and then evolves under the influence of a complex tangle between advancing age, the presence of early symptoms, and the personal relationship with uncertainty. It cannot be ruled out that the real and imminent prospect of therapy may also modify responses to this type of survey.