Trimethylaminuria


Trimethylaminuria, also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3. When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert the rotting fish smelling chemical trimethylamine from precursor compounds in food digestion into trimethylamine oxide, through a process called N-oxidation.
Trimethylamine can temprorarily build up in the bloodstream and is released in the person's urine, sweat, and breath, giving off a rotten fish 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.

Symptoms and signs

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.
Trimethylamine is also released in a person's sweat, reproductive fluids, and breath, and can give off a rotten fish 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 rotten fish-like body odor, depending on diet and the severity of their FM03 mutation. In a 2011 study by Wise and colleagues of 115 positively identified TMAU subjects, after a choline challenge load test, only 10% expressed a smell at a social distance. In a fasted state, 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 who produced an odour had a more severe form of FMO3 impairment.
Smell events are often sporadic and episodic in nature, 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.
For unknown reasons, the condition seems more common in women than in men. 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.

Genetics

Most cases of trimethylaminuria appear to be inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. The parents of an individual with an autosomal recessive disorder are both carriers of one copy of the altered gene. Carriers are asymptomatic and are not at risk of developing the disorder.
Mutations in the FMO3 gene, which is found on the long arm of chromosome 1, cause trimethylaminuria. The FMO3 gene makes an enzyme that breaks down nitrogen-containing compounds from the diet, including trimethylamine. These compounds are produced by bacteria in the intestine as they digest proteins from eggs, meat, soy, and other foods. Normally, the FMO3 enzyme converts fishy-smelling trimethylamine into trimethylamine N-oxide which has no odor. If the enzyme is missing or its activity is reduced because of a mutation in the FMO3 gene, trimethylamine is not broken down and instead builds up in the body. As the compound is released in a person's sweat, urine, and breath, it causes the strong odor characteristic of trimethylaminuria. Researchers believe that stress and diet also play a role in triggering symptoms.
There are more than 40 known mutations associated with TMAU. Loss-of-function mutations, nonsense mutations, and missense mutations are three of the most common. Nonsense and missense mutations cause the most severe phenotypes.
In 2007 the evolution of the FMO3 gene was studied, including the evolution of some mutations associated with TMAU.

Metabolic pathway

Trimethylamine enters the body via the consumption of certain foods and supplements:
  • When food is consumed that contains TMA and/or TMAO. TMAO is converted by bacteria in the lower gastrointestinal tract into TMA.
  • When a food substance, supplement or medicine that contains a TMA precursor is ingested. Some precursor is absorbed into the bloodstream in the small intestine before reaching the gut, however there is a limit to the transport capacity of the intestine, and not all precursor is exposed to the process. Unabsorbed precursor ends up in the gut. Certain bacteria in the gut can convert those precursors to TMA, the proportion of precursor converted to TMA is related to the amount of specific bacteria in the gut but on average 63% of excess choline, and 31% of carnitine are converted to TMA.
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.
Regradless of FMO3 capacity, while TMA is in the bloodstream it is filtered out via the kidneys 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. When taken in large quantities betaine has been known to cause fish odor symptoms, meaning that there is some conversion of betaine to TMA if supplements are taken regularly.

Diagnosis

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.
Consumption of certain Brassica vegetables, in particular brussels sprouts, due to dietary indoles reducing FMO3 activity - research found that a diet including 300g of brussels sprouts per day for 3 weeks temporarily reduced FMO3 capability from 90%+ to ~70%. No odour was reported on any of the participants. This may result in minor secondary TMAU result.
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 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.
Unrelated fecal smells are an often misinterpreted self reported symptom associated with TMAU, Cashman JR found that 53% of TMAU and 59% of non-TMAU subjects suffered from regular halitosis, caused by dental plaque on the back of the tongue, which produced on average "200-600 ppb of sulfurous/fecal smelling volatile sulfur compounds with each exhalation, creating a 'malodorous cloud' in their vicinity". It is possible that other causes such as halitosis, haemorrhoids, regular 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 to work with the sufferer to discreetly 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.
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.