Patient experience informing outcomes and research in rare disease: Citrin deficiency as a case study

The rapid expansion of therapies for rare diseases, including urea cycle disorders (UCDs), has intensified the need for endpoints that reflect meaningful benefit to patients. In rare inborn metabolic disorders, conventional clinical assessments and fragmented natural history data may not fully capture the daily disease burden. Citrin deficiency (CD) exemplifies this challenge: despite heterogeneous, age-dependent phenotypes, a "silent" or "adaptive" period is often described as largely asymptomatic based on clinical and biochemical measures. We present a patient-organization-led, patient-centered qualitative survey as a complementary approach to uncover "hidden" disease burden in a rare metabolic and urea cycle disorder. In an in-depth survey of seven adult CD patients, findings identified gaps between clinical descriptions and patient-reported disease burden. Fatigue and symptoms triggered by high carbohydrate intake emerged as key impacts on quality of life (QoL) among all surveyed patients. Other symptoms included under-recognized gastrointestinal (GI) issues, poor appetite, and psychological impacts. These findings contrasted with existing literature and questioned the concept of an asymptomatic adaptive phase. Although limited by the cohort size (n = 7), the current study illustrates how this approach can identify patient-important domains that standard clinical frameworks may under-capture. We propose that these domains should inform the development of fit-for-purpose patient-reported outcome measures (PROMs) and be integrated with relevant biochemical or molecular markers as endpoints for therapeutic studies and inform better research priorities and clinical management. More broadly, patient-organization-led qualitative surveying offers a scalable strategy to align translational efforts with outcomes that matter to patients across rare diseases.