Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare
metabolic disorder
A metabolic disorder is a disorder that negatively alters the body's processing and distribution of macronutrients, such as proteins, fats, and carbohydrates. Metabolic disorders can happen when abnormal chemical reactions in the body alter the ...
that causes a defect in the normal production of an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
named
flavin-containing monooxygenase 3 (FMO3). 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
Trimethylamine (TMA) is an organic compound with the formula N(CH3)3. It is a trimethylated derivative of ammonia. TMA is widely used in industry. At higher concentrations it has an ammonia-like odor, and can cause necrosis of mucous membranes ...
(TMA) from precursor compounds in food digestion into
trimethylamine oxide (TMAO), through a process called
''N''-oxidation.
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).
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 (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, 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.
The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that such female sex hormones as
progesterone
Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
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
In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
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 may have mild symptoms of trimethylaminuria or experience temporary episodes of fish-like body odor.
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in the ''FMO3''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
, which is found on the long arm of
chromosome 1, cause trimethylaminuria. The ''FMO3'' gene makes an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that breaks down
nitrogen
Nitrogen is a chemical element; it has Symbol (chemistry), symbol N and atomic number 7. Nitrogen is a Nonmetal (chemistry), nonmetal and the lightest member of pnictogen, group 15 of the periodic table, often called the Pnictogen, pnictogens. ...
-containing compounds from the diet, including trimethylamine. These compounds are produced by bacteria in the intestine as they digest proteins from
eggs,
meat
Meat is animal Tissue (biology), tissue, often muscle, that is eaten as food. Humans have hunted and farmed other animals for meat since prehistory. The Neolithic Revolution allowed the domestication of vertebrates, including chickens, sheep, ...
,
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
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a ''nonsense codon'', or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. No ...
, and
missense mutations are three of the most common. Nonsense and missense mutations cause the most severe
phenotypes
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological properti ...
.
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 (predominately seafood; saltwater fish, shellfish, seaweed and kelp). TMAO is converted by bacteria in the
lower gastrointestinal tract (gut) into TMA.
* When a food substance, supplement or medicine that contains a TMA precursor (
choline or
carnitine
Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...
) is ingested. Some precursor is absorbed into the bloodstream in the small intestine before reaching the gut (the RDI of choline is 450–550 mg per day, which is absorbed this way), 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 (±13%) 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. While TMA is in the bloodstream, it is filtered out via the kidneys (95% over 24 hours
) 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
Lecithin ( ; from the Ancient Greek "yolk") is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues which are amphiphilic – they attract both water and fatty substances (and so ar ...
,
creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
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 (12g/day) 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 positive
A false positive is an error in binary classification in which a test result incorrectly indicates the presence of a condition (such as a disease when the disease is not present), while a false negative is the opposite error, where the test resu ...
s can occur in the following conditions, where elevated TMA can be present in the urine without any underlying TMAU:
*
Urinary tract infection
A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra (urethritis) while upper urinary tract infections affect the kidney (pyel ...
*
Bacterial vaginosis
Bacterial vaginosis (BV) is an infection of the vagina caused by excessive growth of bacteria. Common symptoms include increased vaginal discharge that often smells like fish. The discharge is usually white or gray in color. Burning with urina ...
*
Cervical cancer
Cervical cancer is a cancer arising from the cervix or in any layer of the wall of the cervix. It is due to the abnormal growth of cells that can invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later sympt ...
* Advanced liver or kidney disease
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
Olfactory reference syndrome (ORS) is a psychiatric condition in which there is a persistent false belief and preoccupation with the idea of emitting abnormal body odors which the patient thinks are foul and offensive to other individuals. People ...
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
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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 (i.e., VSC:
hydrogen sulfide
Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is toxic, corrosive, and flammable. Trace amounts in ambient atmosphere have a characteristic foul odor of rotten eggs. Swedish chemist ...
; methylmercaptan; dimethylsulfide) 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
Bowel obstruction, also known as intestinal obstruction, is a mechanical or Ileus, functional obstruction of the Gastrointestinal tract#Lower gastrointestinal tract, intestines which prevents the normal movement of the products of digestion. Ei ...
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") 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.
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.
Treatment
There is no known permanent cure for primary trimethylaminuria, but symptoms can in most cases be managed via diet,
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:
* Avoiding all seafood, including fish, shellfish, kelp, and seaweed. Sea life contains TMAO, which is used as an
osmolyte to counter hydrostatic pressure underwater.
* Reducing the consumption of foods and supplements that contain
carnitine
Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into mitochondria to be oxidized for f ...
, such as red meat (beef, lamb and pork), liver, and offal. A study performed by Wang Z
found that when comparing diets where the main protein source was red meat, white meat and non-meat protein sources, consumption of red meat increased the production of TMAO, whereas white meat and non-meat protein diets generated only low to negligible amounts TMAO. This study indicates that red meat is a major driver of TMA production by altering the balance of microbiota in the stomach due to the carnitine found in red meat. A further study by Crimarco A
found that a 8 week plant based diet significantly reduced TMAO production, and further, that after switching the diet to include animal based protein, TMAO production was less than the participants who had only been given an animal protein based diet. The findings suggest that the microbiome in the gut is modified by a plant based diet, and for a time a person will lack the bacteria required to convert choline and carnitine into TMA at the same rate of an animal protein based diet.
* If not pregnant or breastfeeding, reducing the consumption of foods and supplements containing
choline - fish, red meat, white meat, offal, egg yolks,
legumes
Legumes are plants in the pea family Fabaceae (or Leguminosae), or the fruit or seeds of such plants. When used as a dry grain for human consumption, the seeds are also called pulses. Legumes are grown agriculturally, primarily for human consu ...
, beans, whey products, milk, and other foods that contain high levels of choline. Choline is an essential nutrient so complete elimination of choline is unadvised. As above, white meat (chicken, turkey) and plant based products may be fine to consume if red meat is predominantly avoided. Note, while raw ingredients like soybeans have a relatively high choline content, some processed products like soy sauce, soy milk and tofu have low choline content, due to dilution of ingredients, small serving size, or removal as a byproduct during the manufacturing process. It's best to check the choline content
of food and the portion size for a better understanding of how much choline is being consumed.
* Vitamin B2 at 50 mg per day in combination with diet resolved smell issues for 2 children with TMAU.
B2 was found to increase residual FMO3 performance in the liver, meaning more TMA is neutralised.
* Taking low doses of antibiotics such as
neomycin
Neomycin, also known as framycetin, is an aminoglycoside antibiotic that displays bactericidal activity against Gram-negative aerobic bacilli and some anaerobic bacilli where resistance has not yet arisen. It is generally not effective against ...
and
metronidazole
Metronidazole, sold under the brand name Flagyl and Metrogyl among others, is an antibiotic and antiprotozoal medication. It is used either alone or with other antibiotics to treat pelvic inflammatory disease, endocarditis, and bacterial vagino ...
in order to reduce the amount of bacteria in the gut, although this is not recommended as a long term solution due to antibiotic resistance and other side effects.
* Using slightly acidic detergent and body washes with a pH between 5.5 and 6.5
Additionally, at least one study
has suggested that daily intake of the supplements
activated charcoal
"Activated" is a song by English singer Cher Lloyd. It was released on 22 July 2016 through Vixen Records. The song was made available to stream exclusively on ''Rolling Stone'' a day before to release (on 21 July 2016).
Background
In an inter ...
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:
* 85% of test participants experienced complete loss of detectable "fishy" odor
* 10% experienced some reduction in detectable odor
* 5% did not experience any detectable odor reduction
Secondary trimethylaminuria
Although ''FMO3'' mutations account for most known cases of trimethylaminuria, some cases are caused by other factors.
A fish-like body odor can result from extreme excess consumption of TMA precursors such as choline, carnitine and betaine (usually unobtainable via regular dietary intake, it requires high levels of supplement intake). 900mg of trimethylamine, 8g-20g of choline,
3g of carnitine or 20g betatine has been known to cause temporary TMAU-like fish odour symptoms. These symptoms only last until supplement intake has ceased. Note, the RDI for choline is 450-550mg and most typical diets fall below this value, so an excessive amount of precursor is required.
Two cases of the disorder have been identified in adults with
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
damage caused by
hepatitis
Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
. It is unknown if these cases were temporary or not as the individuals did not return for subsequent testing.
In the case where someone is experiencing liver failure or kidney failure,
TMA is sometimes an element present as part of
fetor hepaticus, the "breath of the dead".
TMAU2 and gut dysbiosis
Between the years of 1997 and 2017, Sheffield Children's Hospital in England diagnosed several hundred people with TMAU2, and suggested the majority to be caused by
dysbiosis in the gut. There is no reference to scientific research confirming gut dysbiosis alone can cause TMAU2, and this type of diagnosis was not produced at other testing sites. Cases were claimed to be successfully cured with antibiotics and dietary changes as above. In 2017 a new gas chromatography machine and testing procedure was introduced, which has far fewer false positive results, and very few (if any) TMAU2 results.
While the balance of gut bacteria does play a part in the amount of TMA being produced from precursors in the gut (antibiotic treatment temporarily stops odour), gut bacteria in general convert a significant proportion of dietary TMA precursors already. For example, on average 63% of excess choline, and 31% of carnitine (+-13%) are converted to TMA
by an average gut profile - even if dysbiosis raised these values to 100%, it would still not meet the thresholds as above for precursor overload on a regular diet. TMAU2 by gut dysbiosis is currently a hypothetical
condition requiring further research.
History
The first clinical case of TMAU was described in 1970.
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).
Society and culture
In 2014, singer/songwriter Cassie Graves was first featured in the
Daily Mail
The ''Daily Mail'' is a British daily Middle-market newspaper, middle-market Tabloid journalism, tabloid conservative newspaper founded in 1896 and published in London. , it has the List of newspapers in the United Kingdom by circulation, h ...
, the
Daily Mirror
The ''Daily Mirror'' is a British national daily Tabloid journalism, tabloid newspaper. Founded in 1903, it is part of Mirror Group Newspapers (MGN), which is owned by parent company Reach plc. From 1985 to 1987, and from 1997 to 2002, the tit ...
, and The
Metro UK newspapers in both print and Online, giving an interview about her experiences with Trimethylaminuria. The article was later repurposed in media across the globe, most notably by
HuffPost
''HuffPost'' (''The Huffington Post'' until 2017, itself often abbreviated as ''HPo'') is an American progressive news website, with localized and international editions. The site offers news, satire, blogs, and original content, and covers p ...
.
References
External links
''This article incorporates public domain text fro
The U.S. National Library of Medicinean
The National Human Genome Research Institute'
{{Amino acid metabolic pathology
Inborn errors of metabolism
Autosomal recessive disorders
Rare diseases