Beyond Malodor: A Multinational Patient-Reported Study of the Diagnostic, Psychosocial, and Cognitive Burden of Trimethylaminuria

Background Trimethylaminuria (TMAU) is a rare metabolic disorder characterized by malodor resulting from impaired metabolism of trimethylamine, but its broader impact on patients lives remains insufficiently characterized. This study aimed to assess the diagnostic, psychosocial, educational, occupational, and treatment-related burden of TMAU across a multinational patient population and to explore cognitive manifestations identified during the study. Methods We conducted a multinational, cross-sectional, patient-reported survey using an anonymous online questionnaire. Of 450 submissions, 401 participants provided valid authorization for analysis. The survey assessed demographic characteristics, symptom and diagnostic experiences, educational and occupational consequences, psychosocial burden, and perceptions of current management. Cognitive complaints emerging during the initial study prompted a follow-up survey focused on cognitive symptoms and their functional impact, completed by 306 participants from the original cohort. The association between cognitive symptom frequency and severity was assessed using Spearman rank correlation. Results Participants represented more than 40 countries, and 61.1% were female. A substantial diagnostic gap was observed, with 65.8% reporting no official diagnosis or clear medical explanation of probable TMAU. Social and psychological consequences were prominent, including physical rejection or social exclusion (78.8%), bullying or derogatory treatment (61.1%), and substantial disruption of educational and occupational participation. Most participants (84.3%) considered currently available treatment options insufficient. In the cognitive follow-up survey, 68.0% reported cognitive difficulties at least several times per week, 58.8% reported moderate or severe symptoms, and 66.7% reported at least moderate interference with daily activities, work, or studies. Greater cognitive symptom frequency was significantly associated with greater severity (Spearman coefficient = 0.451, p < 0.001). Conclusions TMAU is associated with a multidimensional patient-reported burden extending beyond malodor to psychosocial, educational, occupational, and previously underrecognized cognitive manifestations. These findings support earlier recognition, multidisciplinary care, and development of mechanism-based therapies evaluated using patient-centered outcomes that include daily functioning, cognitive symptoms, and quality of life.