SUMMARY Individuals with Smith-Magenis Syndrome (SMS) commonly experience excessive weight gain which leads to obesity, and current clinical trials are underway to treat obesity in this population. The exact causes exacerbating weight gain in this population are not known, as not all patients suffer from obesity. In addition to cognitive impairments, adults and children with SMS also suffer from anxiety, behavioral disturbances, and sleep disorder. How each of these comorbidities contribute to the presence or absence of food-related behaviors, such as preoccupation with food, emotional outbursts around food availability, and sneaking/hiding food, in SMS is unknown. Our previous data show that there is a discrepancy between measures of satiety in currently available questionnaires and the need for caregivers to lock away food. These findings indicate that the current measures do not adequately assess the satiety and food-related behavior concerns for the SMS population. Since these questionnaires were not created for the SMS population, it is likely they are missing important features necessary to fully measure the food-related behavioral phenotype in SMS. Without an accurate measurement of food-related behaviors in this population, strong clinical trials searching for an impact on obesity and its comorbidities in the SMS population will lack important clinical outcomes. In this proposal, we aim to clinically validate a clinical measure of food-related behaviors specific to the SMS population for use in clinical trials targeted to address obesity, hyperphagia, and food-related concerns. Approach: The FDA has previously modified an existing questionnaire for Prader-Willi Syndrome (the Hyperphagia Questionnaire) for use in a clinical trial (HQ-CT) using focus groups and expert review. We will use a similar approach. We will use focus groups of caregivers of individuals with SMS to understand how environmental controls around food and behavior alter answers on the Food-Related Problems Questionnaire (FRPQ) and the Hyperphagia Questionnaire for Clinical Trials (HQ-CT), currently used as primary endpoint measures for Prader-Willi Syndrome clinical trials. Additionally, we will seek to uncover other important food- related behaviors that may not be captured on these measures. Using this information, combined with our expertise in SMS and obesity, we will create a modified measure for food-related behaviors targeted to the SMS population: the SMS-FRBQ. We will then perform subsequent testing and validation for use in future clinical trials. Translation and validation of the SMS-FRBQ in Spanish will expand opportunities for patient enrollment. Summary: Successful completion of this project will result in a measure of food-related behaviors specific to the SMS population (SMS-FRBQ) which is necessary to adequately assess the efficacy and impact of therapeutic intervention trials aimed at treating weight gain or its contributing factors in this complex rare...