I think the paper would be more accurately framed as a study of the TMAU community, rather than of people with confirmed TMAU. Recruitment included people who self-reported TMAU as well as those with a clinical diagnosis or a medical explanation consistent with the condition, and the paper states that many participants lacked biochemical or genetic confirmation. This is still valuable, because it captures the very real psychosocial and functional burden experienced within TMAU-oriented patient communities, but it limits how confidently those findings can be attributed specifically to TMAU itself.

A title that reflects this distinction would make the conclusions more defensible without diminishing the study’s value. For example: “Beyond Malodor: A Multinational Patient-Reported Study of the Diagnostic, Psychosocial, and Cognitive Burden Within the TMAU Community” or “…Among People With Confirmed, Suspected, or Self-Reported TMAU.” That wording better matches the actual sample and avoids implying that all reported outcomes represent manifestations of biochemically confirmed TMAU.

The wording really needs to make it clear that the majority of people who answered this survey do not necessarily have TMAU and the social and psychological issues may well be unrelated to TMAU itself - especially any biochemical element involving TMA. Especially when the results are all lumped together without finer grained breakdowns of diagnoses.

In regards to citation 16 - Bouchemal et al. (2019), the main point of the article is extremely relevant but overlooked.

Bouchemal is cited here primarily in support of biochemical/genetic evaluation and the need to distinguish confirmed TMAU from other causes of malodor. However, the clinical findings of that study are also highly relevant to interpretation of the psychosocial results in the present cohort and ORS mistaken for TMAU.

In Bouchemal et al., the two participants who most clearly met the biochemical and genetic criteria for recessively inherited TMAU were children. Their malodor was confirmed by both parents and clinicians, urinary TMA was elevated, and they carried compound-heterozygous FMO3 variants. Nevertheless, both attended normal schools, had no reported psychological problems, and the authors described the level of complaint and discomfort as low for the children and their families.

The contrast with the 11 adult participants in the same study was striking. All complained of malodor, but clinicians could not confirm an unpleasant odor in any of them, and urinary TMA levels were within the normal control range in all adults. All 11 had a history of psychiatric conditions, including depressive symptoms in six. Ten of the 11 believed they had malodor partly because they interpreted remarks or behaviour of other people as evidence of it—for example, interpreting someone leaving the room as being caused by their odor. The reported complaint and functional impact was extremely high in this adult group than in the two metabolically confirmed children. All were implied to have Olfactory Reference Syndrome.

Clearly, a series containing only two confirmed children cannot establish that genuine TMAU generally has little psychosocial impact. Age, family support, disease severity and other factors could readily explain their comparatively favourable outcome. Nor do the adult findings prove that every person with an unconfirmed odor complaint has olfactory reference disorder (ORD/ORS). Bouchemal et al. themselves nevertheless emphasize the importance of psychiatric differential diagnosis, and describe ORS as an important consideration in people presenting with subjective malodor.

Much of the manuscript's main contribution is the very high reported psychological and functional burden attributed to TMAU, yet the current cohort combines confirmed, clinically suspected and self-identified cases, and a large majority lack an official diagnosis or clear medical explanation. The Bouchemal findings demonstrate why this distinction may materially affect interpretation: in their small specialist cohort, the greatest psychosocial burden occurred in adults whose metabolic TMAU diagnosis was not established, whereas the two participants with the clearest objective TMAU findings happened to report comparatively little psychosocial impairment.

It would strengthen the manuscript if the authors discussed this aspect of reference 16 explicitly. Ideally, the paper should compare psychosocial outcomes by diagnostic certainty, for example, biochemically/genetically confirmed TMAU, clinician-diagnosed/probable TMAU, untested self-identified cases, and participants with previous negative testing. Additionally, seperating out diagnosed and "clear medical explanation and probable TMAU" should also be done.

It would be much more compelling result if the psychological results of the differently diagnosed cohorts were shown.