Trimethylaminuria
Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome,[1] is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3).[2][3] When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert the fishy-smelling chemical trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation.
Trimethylaminuria
Primary trimethylaminuria
Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a fishy odor. Primary trimethylaminuria is caused by genetic mutations that affect the FMO3 function of the liver. Symptoms matching TMAU can also occur when there is no genetic cause, yet excessive TMA is excreted - this has been described as secondary trimethylaminuria (TMAU2).
Trimethylamine enters the body via the consumption of certain foods and supplements:
TMA in the gut is absorbed through the intestinal lining and enters the bloodstream, where it is processed by the liver. A healthy liver produces an abundance of the enzyme FMO3, which neutralises the TMA by oxidising it to an odourless TMAO. If FMO3 enzyme production is compromised, or there is too much TMA for the amount of enzyme, then TMA will continue to circulate in the bloodstream until enough enzyme is produced. While TMA is in the bloodstream, it is filtered out via the kidneys (95% over 24 hours[9]) to the bladder, and slowly exits the body in bodily fluids; urine, sweat, saliva, reproductive fluids and breath. TMA has no known interactions with any known internal or organ function.
Although lecithin, creatinine and betaine are technically precursors to TMA, pilot studies have shown no significant effect on the production of excess TMA/TMAO in urinary analysis at normal dietary levels of consumption.[5] When taken in large quantities (12g/day) betaine has been known to cause fish odor symptoms,[10] meaning that there is some conversion of betaine to TMA if supplements are taken regularly.
Symptoms and signs[edit]
Trimethylamine is most noticeable in urine, as it is captured, concentrated and released in intervals. Fishy smelling urine is a primary identifying symptom in infant children (Trimethylaminuria literally meaning "trimethylamine in urine").
Trimethylamine is also released in the person's sweat, reproductive fluids, and breath, and can give off a fishy odor when the concentration of trimethylamine is high enough to be detected. The intensity of the smell is directly correlated with the concentration of trimethylamine in the bloodstream.
People with TMAU may have an intermittent fish-like body odor, depending on diet and the severity of their FM03 mutation. In a study by Wise PM,[11] of 115 positively identified TMAU subjects, after a choline challenge load test (intentionally ingesting a TMA precursor) only 10% expressed a smell at a social distance. When in a fasted state (12 hours) 0% had a smell detectable at a social distance and only 5% had some minor malodour at an intimate distance. These findings suggested that those that produced an odour had a more severe form of FMO3 impairment.
Smell events are often sporadic and episodic in nature (based on diet over the previous 24 hours), making it often difficult to diagnose by smell alone. Some people with trimethylaminuria report having a strong odor all the time, but there has not been any evidence apart from self reported symptoms that this is the case.
Individuals with this condition do not have any physical symptoms, and they typically appear healthy.[12]
The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that such female sex hormones as progesterone and estrogen aggravate the condition. According to several reports, the condition worsens around puberty. In women, symptoms may worsen just before and during menstrual periods, after taking oral contraceptives, and around menopause.[12]
Measurement of urine for the ratio of trimethylamine to trimethylamine N-oxide is the standard screening test. A blood test is available to provide genetic analysis. The prominent enzyme responsible for TMA N-oxygenation is coded by the FMO3 gene.
False positives can occur in the following conditions, where elevated TMA can be present in the urine without any underlying TMAU:
A similar foul-smelling odor of the urine has also been associated with colonization of the urinary tract with a bacterium called Aerococcus urinae, especially in children.[18]
Olfactory reference syndrome is a condition where there is a persistent false belief and preoccupation with the idea of emitting an abnormal body odor. According to McNiven[19] at a Canadian genetics clinic, 83% of referrals for genetic testing for TMAU were deemed likely to instead have ORS. Findings found that the use of “fecal/sewage” as a description, and the use of multiple descriptors of the smell, and 'incorrect' locations of smell origin effectively differentiated ORS from TMAU. In the literature on body odour identification, emphasis is frequently placed on multiple consultations to reduce the risk of misdiagnosis, and also asking the individual to have a reliable confidant accompany them to the consultation who can confirm the reality of the reported symptom. ORS patients are unable to provide such confidants as they have no objective odor.[20][21]
A fecal smell (fecal body odour) is often a self reported symptom associated with TMAU,[19] however there is no recorded evidence of fecal body odour present in any study related to TMAU. Cashman JR[22] found that 53% of TMAU and 59% of non-TMAU subjects suffered from regular halitosis, dental plaque on the back of the tongue, which produced on average "200-600 ppb of sulfurous/fecal smelling volatile sulfur compounds (i.e., VSC: hydrogen sulfide; methylmercaptan; dimethylsulfide) with each exhalation, creating a ‘malodorous cloud’ in their vicinity”. It is possible that other causes such as halitosis, haemorrhoids, bromhidrosis, ORS or in severe cases, a bowel obstruction leading to fecal vomiting may be the cause of fecal smells.
There is the possibility that someone may suffer from both Trimethylaminuria and ORS-like paranoia, due to the potential lack of ability to smell the odour oneself and the worry that it generates. It is recommended to organise reliable confidants, colleagues, friends or relatives ("odor buddies"[23]) to work with the sufferer to discretely inform them if they are presenting an odour.
Affected individuals experience shame and embarrassment, fail to maintain relationships, avoid contact with people who comment on their condition, and are obsessive about masking the odour with hygiene products and even smoking. The malodorous aspect can have serious and destructive effects on schooling, personal life, career and relationships, resulting in social isolation, low self-esteem, depression, paranoid behaviour, and suicide. Delayed diagnosis, body odour and the lack of cure may lead to psychosocial issues. When the condition is suspected or known to occur in a family, genetic testing can be helpful in identifying the specific individuals who have or carry the disorder.[24]
The metabolic and clinical manifestations of TMAU are generally regarded as benign, as there is no associated organ dysfunction. This designation, and the fact that the condition is often unrecognised by doctors, misdiagnosed and can have important ramifications including missed or delayed diagnosis.[24]
There is no known permanent cure for primary trimethylaminuria, but symptoms can in most cases be managed via diet,[25] and sometimes by certain supplements (as below).
Diet and supplement use should be overseen by medical professionals and nutritionists, as dietary restrictions can have other serious adverse health effects. Choline in particular is an essential nutrient required for proper neural formation in foetal and childhood development, if pregnant or breast-feeding a low choline diet should be avoided.
Ways of reducing the fishy odor may include:
Additionally, at least one study[32] has suggested that daily intake of the supplements activated charcoal and copper chlorophyllin may temporarily improve the quality of life of individuals afflicted with TMAU by helping their bodies to oxidize and convert TMA to the odorless N-oxide (TMAO) metabolite. Study participants experienced subjective reduction in odor as well as objective reduction in TMA and increase in TMAO concentration measured in their urine. The study found that:
History[edit]
The first clinical case of TMAU was described in 1970.[43] Her mother related that her child, a 6 year old girl, had intermittently had a peculiar "fishy" odour. Analysis of her urine showed an elevated level of trimethylamine, and that a chemically pure free base sample of trimethylamine smelled similar to the patient's fishy odor. They tested her condition by giving her more trimethylamine, which substantially increased her odour (which it did not in control subjects).
Notable media[edit]
In 2014, singer/songwriter Cassie Graves was first featured in the Daily Mail, the Daily Mirror, and The Metro UK newspapers in both print and Online,[44] giving an interview about her experiences with Trimethylaminuria. The article was later repurposed in media across the globe, most notably by HuffPost.[45]
In 2016, Graves was then featured in Princess Productions' Medical Mysteries on UK's Channel 5, which went on a journey to find an official diagnosis for the condition, and again sparked a global media interest in the condition.
The 2010 novel Boxer, Beetle by Ned Beauman features a character with trimethylaminuria.
The 2023 film The Holdovers, directed by Alexander Payne, features a character with trimethylaminuria, although the condition was first described in the year in which the movie takes place.