Trimethylaminuria
Encyclopedia
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 the enzyme
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 break down trimethylamine
(TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO) through a process called N-oxygenation. Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a strong fishy odor
or strong body odor
. The odor is not necessarily fishy, and the type of odor can vary from time to time. In that sense, the nicknames referring solely to a fishy odor are misnomers.
The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that female sex hormones, such as progesterone
and/or estrogen, aggravate symptoms. There are several reports that the condition worsens around puberty. In women, symptoms can worsen just before and during menstrual periods, after taking oral contraceptives, and around menopause.
This odor varies depending on many known factors, including diet, hormonal changes, stress level, amount of sweat, other odors in the space, and individual sense of smell.
or a lack of understanding from peers.
A similar test can be used to identify carriers of this condition - those individuals who carry one copy of a mutated gene but do not have symptoms. In this case, the person would be given a high dose of choline (one of the precursors of trimethylamine) and then have their urine tested for elevated levels of trimethylamine.
Ways of reducing the fishy odor may include:
Additionally, at least one study has suggested that daily intake of the supplements activated charcoal and/or copper chlorophyllin
may 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's success rates varied:
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 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
s 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 mutation
s, nonsense mutations, and missense mutations are three of the most common. Nonsense and missense mutations cause the most severe phenotypes.
Although FMO3 mutations account for most known cases of trimethylaminuria, some cases are caused by other factors. A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria in the digestive system. A few cases of the disorder have been identified in adults with liver
damage caused by hepatitis
.
The evolution of the FMO3 gene has recently been studied, including the evolution of some mutations associated with TMAU.
by Ned Beauman features a leading character with trimethylaminuria.
Inborn error of metabolism
Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances into others...
that causes a defect in the normal production of the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
Flavin containing monooxygenase 3
Flavin containing monooxygenase 3
Dimethylaniline monooxygenase [N-oxide-forming] 3 is an enzyme that in humans is encoded by the FMO3 gene.-External Links:* -Further reading:...
(FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly break down trimethylamine
Trimethylamine
Trimethylamine is an organic compound with the formula N3. This colorless, hygroscopic, and flammable tertiary amine has a strong "fishy" odor in low concentrations and an ammonia-like odor at higher concentrations...
(TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO) through a process called N-oxygenation. Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a strong fishy odor
Trimethylamine N-oxide
Trimethylamine N-oxide, also known by several other names and acronyms, is the organic compound with the formula 3NO. This colorless solid is usually encountered as the dihydrate. It is an oxidation product of trimethylamine and a common metabolite in animals. It is an osmolyte found in saltwater...
or strong body odor
Body odor
Body odor or body odour, sometimes colloquially abbreviated as B.O., is the smell of bacteria growing on the body. The bacteria multiply rapidly in the presence of sweat, but sweat itself is almost completely odorless to humans....
. The odor is not necessarily fishy, and the type of odor can vary from time to time. In that sense, the nicknames referring solely to a fishy odor are misnomers.
Symptoms
Trimethylamine builds up in the body of patients with trimethylaminuria. The trimethylamine gets released in the person's sweat, urine, reproductive fluids, and breath, giving off a strong fishy or body odor. Some people with trimethylaminuria have a strong odor all the time, but most have a moderate smell that varies in intensity over time. Individuals with this condition do not have any physical symptoms, and typically appear healthy.The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that female sex hormones, such as progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and/or estrogen, aggravate symptoms. There are several reports that the condition worsens around puberty. In women, symptoms can worsen just before and during menstrual periods, after taking oral contraceptives, and around menopause.
This odor varies depending on many known factors, including diet, hormonal changes, stress level, amount of sweat, other odors in the space, and individual sense of smell.
Incidence
TMAU is a rare disorder that is caused by genetic and environmental factors and it can be a life-disruptive disorder. Living with TMAU can be challenging, and TMAU can adversely affect the livelihood of the people who have it, as well as their families. People, especially children, with the condition may face rejectionRejection
The word "rejection" was first used in 1415. The original meaning was "to throw" or "to throw back".Rejection may mean:* Social rejection, in psychology, an interpersonal situation that occurs when a person or group of people exclude an individual from a social relationship* Transplant rejection,...
or a lack of understanding from peers.
Diagnosis
Measurement of urine for the ratio of trimethylamine to trimethylamine 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.A similar test can be used to identify carriers of this condition - those individuals who carry one copy of a mutated gene but do not have symptoms. In this case, the person would be given a high dose of choline (one of the precursors of trimethylamine) and then have their urine tested for elevated levels of trimethylamine.
Treatment
Currently, there is no known cure or treatment for the disorder. However, some people affected by the disorder live relatively normal lives by managing their symptoms and with counseling. 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.Ways of reducing the fishy odor may include:
- Avoiding foods such as egg yolks, legumes, red meats, fish, beans and other foods that contain cholineCholineCholine is a water-soluble essential nutrient. It is usually grouped within the B-complex vitamins. Choline generally refers to the various quaternary ammonium salts containing the N,N,N-trimethylethanolammonium cation....
, carnitineCarnitineCarnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
, nitrogenNitrogenNitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
, sulfurSulfurSulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...
and lecithinLecithinLecithin is a generic term to designate any group of yellow-brownish fatty substances occurring in animal and plant tissues, and in egg yolk, composed of phosphoric acid, choline, fatty acids, glycerol, glycolipids, triglycerides, and phospholipids .The word lecithin was originally coined in 1847 by... - Taking low doses of antibiotics such as neomycinNeomycinNeomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...
and metronidazoleMetronidazoleMetronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
in order to reduce the amount of bacteria in the gut - Using slightly acidic detergent with a pH between 5.5 and 6.5
Additionally, at least one study has suggested that daily intake of the supplements activated charcoal and/or copper chlorophyllin
Chlorophyllin
Chlorophyllin refers to any one of a group of closely related water-soluble salts that are semi-synthetic derivatives of chlorophyll, differing in the identity of the cations associated with the anion. Its most common form is a sodium/copper derivative used as a food additive and in alternative...
may 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's success rates varied:
- 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
Genetics
Mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the FMO3 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
, which is found on the long arm of chromosome 1, cause trimethylaminuria. The FMO3 gene makes an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that breaks down nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...
-containing compounds from the diet, including trimethylamine. These compounds are produced by bacteria in the intestine as they digest proteins from eggs
Egg (food)
Eggs are laid by females of many different species, including birds, reptiles, amphibians, and fish, and have probably been eaten by mankind for millennia. Bird and reptile eggs consist of a protective eggshell, albumen , and vitellus , contained within various thin membranes...
, meat
Meat
Meat is animal flesh that is used as food. Most often, this means the skeletal muscle and associated fat and other tissues, but it may also describe other edible tissues such as organs and offal...
, soy, and other foods. Normally, the FMO3 enzyme converts fishy-smelling trimethylamine into trimethylamine N-oxide
Trimethylamine N-oxide
Trimethylamine N-oxide, also known by several other names and acronyms, is the organic compound with the formula 3NO. This colorless solid is usually encountered as the dihydrate. It is an oxidation product of trimethylamine and a common metabolite in animals. It is an osmolyte found in saltwater...
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 mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s, nonsense mutations, and missense mutations are three of the most common. Nonsense and missense mutations cause the most severe phenotypes.
Although FMO3 mutations account for most known cases of trimethylaminuria, some cases are caused by other factors. A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria in the digestive system. A few cases of the disorder have been identified in adults with liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
damage caused by hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
.
The evolution of the FMO3 gene has recently been studied, including the evolution of some mutations associated with TMAU.
Popular culture
The novel Boxer, BeetleBoxer Beetle
Boxer, Beetle is a novel by British author Ned Beauman. It was first published by Sceptre on 5 August 2010. The novel was shortlisted for the Guardian Best First Book Award in 2010. - Overview :...
by Ned Beauman features a leading character with trimethylaminuria.