Living with trimethylaminuria: Research awaiting the smell of success

By Warren R. Heymann, MD, FAAD
Feb. 26, 2025
Vol. 7, No. 8

I was mesmerized watching (and listening to) the PBS episode of Great Performances devoted to Rodgers and Hammerstein’s 80th anniversary. Rodgers’ melodious scores and Hammerstein’s poignant lyrics remain the ultimate standard of the musical theatre genre.

Oscar Hammerstein had a unique ability to touch your heart and head. His lyrics from “When I Marry Mr. Snow” from Carousel made me think, but not how he would have imagined.

In this song, Barbara sings to Shirley:

His name is Mister Snow
And an upstandin’ man is he
He comes home ev’ry night in his round-bottomed boat
With a net full of herring from the sea
An almost perfect beau
As refined as a girl could wish
But he spends so much time in his round-bottomed boat
That he can’t seem to lose the smell of fish

The fust time he kissed me, the whiff from his clo’es
Knocked me flat on the floor of the room;
But now that I love him, my heart’s in my nose
And fish is my fav’rite perfume

For Barbara and Mr. Snow fish odor is the centerpiece of their existence, but it is a matter of choice.

For patients with trimethylaminuria (TMAU) fish odor is an affliction that profoundly adversely affects their lives.

Although I can explain my diagnosis to people, I feel that no one truly understands how difficult and isolating an illness this is. People still pass remark about the odour and still avoid spending time with me. I find it difficult to form new relationships as a consequence of this. I feel lonely and often feel depressed. I have tried to engage in counselling but have never felt fully understood. This illness has had a devastating impact on my life as a whole, and sadly I don’t feel hopeful about treatment options. (1)

To understand what patients with body and breath malodor syndromes confront, a survey of 44 adults and 3 parents/guardians of patients with body and breath malodor syndromes was performed by Flaherty et al. Of those tested, 52% were diagnosed with TMAU. “The main problems associated with living with body/breath malodours were bullying, harassment and ostracism in either the workplace (90%) or in social settings (88%). All respondents thought their condition had disadvantaged them in their daily lives. Open-ended responses included loss of confidence, stress, exclusion, isolation, loneliness, depression and suicidal thoughts. Respondents thought their lives could be improved by greater awareness and understanding of malodour conditions by medical professionals, employers and the general public, and appreciation that the malodour was due to a medical condition and not their fault.” (2)

TMAU (aka fish odor syndrome or stale fish syndrome, OMIM 602079), is a rare metabolic disorder characterized by the abnormal accumulation and excretion of trimethylamine (TMA). The accumulation of TMA results in an offensive odor resembling that of rotting fish. TMAU is caused by homozygous or compound heterozygous mutations in the gene encoding flavin-containing monooxygenase-3 (FMO3) on chromosome 1q24. “The inheritance is autosomal recessive. TMA is a product of intestinal bacterial action. The substrates from which it is derived are choline, which, bound to lecithin, is present most abundantly in egg yolk, liver, kidney, legumes, soybeans, and peas, as well as from trimethylamine-N-oxide, a normal constituent of saltwater fishes. Normally, TMA produced in the gut is absorbed and oxidized in the liver by FMO, a microsomal mixed-function oxidase.” (3) Other metabolic syndromes, such as dimethylglycine dehydrogenase deficiency, may also cause a fish odor but will not be discussed further in this commentary. (4)

---

TMAU affects men and women, with an estimated prevalence of 1 in 200,000 to 1,000,000 individuals, possibly higher in Ashkenazi Jews. (5) TMAU may be primary or secondary. Primary TMAU occurs as a result of mutation of the FMO gene, leading to reduced hepatic metabolism of TMA to odorless trimethylamine N-oxide (TMANO), and increased levels of urinary TMA, normal or reduced levels of urinary TMANO, and an increased urinary TMA:TMANO ratio. Secondary TMAU is caused by increased TMA burden with normal hepatic metabolism, leading to increased urinary TMA and TMANO levels and a normal TMA:TMANO ratio. Fraser-Andrews et al. state, “Secondary acquired trimethylaminuria occurs as a result of an increased burden of TMA. For example, bacterial overgrowth results in increased production of TMA from its dietary precursors by gut bacteria. It may also be seen in chronic liver disease where the capacity of the FMO3 is exceeded.” (6) Other causes of secondary TMAU include portosystemic shunting, menstruation, viral hepatitis, and testosterone therapy. (5) Scimone et al. reported the case of a 37-year-old man who started antiretroviral therapy (atazanavir, abacavir, lamivudine) at age 33 for HIV infection, who developed TMAU two years later. (7)

TMAU may present at birth but often becomes noticeable during puberty. The odor emanates from the excretion of TMA through sweat, breath, urine, and other bodily secretions, and may be particularly pronounced after consuming TMA-rich foods. Halitosis may accompany TMAU. (5)

The diagnosis of TMAU may be confirmed by urinary TMA and TMANO (after a TMA challenge of fish ingestion), serum enzymatic levels of FMO3, or genetic testing specific for FMO3 mutations. (5,6).

Schmidt and Leroux reviewed therapeutic options for TMAU. Existing treatment strategies are classified into the following groups: precursor intake limitation (notably foods rich in choline and carnitine), protonation of TMA (frequent washing with low pH soaps), targeting of the gut metabolism (antibiotics such as metronidazole, probiotics, activated charcoal, laxatives), and targeting of the enzyme FMO3 (potentially enzyme replacement or gene therapy). (8) Axillary microwave destruction of the sweat glands proved beneficial in a case of TMAU. (9) Patients may benefit from a multidisciplinary team of dieticians, mental health professionals, and support groups. (5)

Point to Remember: Both primary and secondary trimethylaminuria can be socially debilitating. While dietary manipulation remains the cornerstone of treatment, our understanding of the disease may allow enzyme replacement or gene therapy for a brighter future.

Our expert’s viewpoint

Claire Quigley, MB BCh BAO, MRCPI
Department of Dermatology
Tallaght University Hospital
Dublin, Ireland

Trimethylaminuria (TMAU) is a rare metabolic disorder characterized by the abnormal excretion and accumulation of trimethylamine (TMA). TMA has a foul odour said to resemble that of rotting fish. Choline, L-Carnitine and Trimethylamine-oxidase (TMAO) (odourless) are ingested through dietary sources such as meat, eggs and legumes. They are broken down by gut microbiota to form TMA. TMA then typically undergoes oxidation by flavin-containing monooxygenase 3 (FMO3) gene to be broken down into the odourless TMAO and excreted. Problems arise when there is either a genetic deficiency in FMO3 (Primary TMAU) or metabolic circumstances overpower available FMO3 (Secondary TMAU) leading to an accumulation of TMA which is then excreted in bodily fluid such a sweat, urine, and tears. Suspected patients should be assessed using a simple urine test analyzing the TMA:TMAO ratio, if this is positive, a genetic test can be done to assess for primary vs secondary TMAU. Genetic testing may also help predict the inheritance pattern of this disorder.

The foul odour emitted from excretions containing TMA from the affected person can result in a significant psychosocial burden. Odour emission is often unpredictable and persistent and can lead to embarrassment, low-self-esteem, social isolation, anxiety, and depression. The treatment options for TMAU include dietary modification, antibiotic therapy, activated charcoal administration, modifications to personal hygiene, and psychological support. Patients should be referred to a metabolic multi-disciplinary team to ensure they have adequate support. Although broad and varied, current treatment options are not wholly effective and unfortunately, despite best efforts, patients still suffer the psychosocial burden and stigmatization of this illness. Elimination diets, while offering the most help, are often extreme and challenging to maintain. Dieticians with special interest and experience in metabolic disorders are necessary to help maintain consistency and compliance with the diet. Although not life threatening, the social and psychological challenges of TMAU can profoundly impact a person’s life and so input with psychology, peer support groups, and health care professions specifically trained and aware of these challenges is vital to provide appropriate support to patients managing this chronic illness.

1. Quigley C, Loftus C, Clowry J, Irvine AD. Living with a rare disease: a patient perspective of life with trimethylaminuria. Clin Exp Dermatol. 2024 Apr 23;49(5):530-531. doi: 10.1093/ced/llae003. PMID: 38180074.

2. Flaherty CC, Phillips IR, Janmohamed A, Shephard EA. Living with trimethylaminuria and body and breath malodour: personal perspectives. BMC Public Health. 2024 Jan 18;24(1):222. doi: 10.1186/s12889-024-17685-w. PMID: 38238734; PMCID: PMC10797923.

3. https://omim.org/entry/602079 (accessed July 7, 2024)

4. Binzak BA, Wevers RA, Moolenaar SH, Lee YM, Hwu WL, Poggi-Bach J, Engelke UF, Hoard HM, Vockley JG, Vockley J. Cloning of dimethylglycine dehydrogenase and a new human inborn error of metabolism, dimethylglycine dehydrogenase deficiency. Am J Hum Genet. 2001 Apr;68(4):839-47. doi: 10.1086/319520. Epub 2001 Feb 28. PMID: 11231903; PMCID: PMC1275637.

5. Awosika AO, Anastasopoulou C. Trimethylaminuria. 2023 Jul 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 37603646.

6. Fraser-Andrews EA, Manning NJ, Ashton GH, Eldridge P, McGrath J, Menagé Hdu P. Fish odour syndrome with features of both primary and secondary trimethylaminuria. Clin Exp Dermatol. 2003 Mar;28(2):203-5. doi: 10.1046/j.1365-2230.2003.01230.x. PMID: 12653714.

7. Scimone C, Alibrandi S, Donato L, Giofrè SV, Rao G, Sidoti A, D'Angelo R. Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin. J Clin Pharm Ther. 2021 Apr;46(2):304-309. doi: 10.1111/jcpt.13315. Epub 2020 Nov 28. PMID: 33247860.

8. Schmidt AC, Leroux JC. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today. 2020 Sep;25(9):1710-1717. doi: 10.1016/j.drudis.2020.06.026. Epub 2020 Jun 29. PMID: 32615074.

9. Patel F, Tu YM, Fernandes S, Chapas A. A case of axillary bromhidrosis secondary to trimethylaminuria successfully treated with microwave-based therapy. JAAD Case Rep. 2019 Oct 7;5(10):915-917. doi: 10.1016/j.jdcr.2019.07.018. PMID: 31646163; PMCID: PMC6804454.

---