Trimethylaminuria

The symptoms of trimethylaminuria can vary over time. The body odor is not present at birth but begins when the child begins eating foods such as eggs, liver, legumes and certain fish. Usually, symptoms start in early childhood and may get worse during puberty; in females, symptoms may also be worse near the time of menstruation, after taking oral contraceptives, and around menopause.

The FMO3 gene provides the body with instructions for making an enzyme called flavin-containing monooxygenase 3 (FMO3). The FMO3 enzyme is made in the liver and breaks down certain compounds from the diet, including trimethylamine. During digestion, bacteria in the intestines produce trimethylamine from compounds such as trimethylamine N-oxide, choline, and lecithin that are found in eggs, liver, soybeans, peas, certain fish, and other foods. Normally, the FMO3 enzyme will convert trimethylamine, the chemical that gives rotten fish its odor, to another odorless compound, trimethylamine N-oxide. This happens in the liver. Trimethylamine N-oxide is excreted in urine. However, if there are mutations (changes) in FMO3 gene, the body may not be able to make the FMO3 enzyme. If the FMO3 enzyme is missing or does not work well enough, the body cannot break down the trimethylamine to the odorless compound. This results in a buildup of trimethylamine, which is released by the body through sweat, urine, and breath, causing a fish-like body odor.

The chemical that causes the ‘fishy’ odor of trimethylaminuria is called trimethylamine (TMA). TMA is the same chemical that gives rotten fish a distinctive odor.

If an individual in a family has been diagnosed with trimethylaminuria, other members of the family are at risk to be affected as well. Family members can be tested by urine testing or genetic testing. Genetic testing can be performed after the affected family member has had genetic testing.
The way trimethylaminuria is inherited is called ‘autosomal recessive’. We all have two copies of the gene that causes trimethylaminuria, FMO3. One of these copies comes from the mother in the egg and the other copy comes from the father in the sperm. In people with trimethylaminuria, both copies of the FMO3 gene have mutations (mistakes or mispellings) and do not work the way they should. Because neither FMO3 gene is working, affected individuals have the symptoms of the disease.
Parents of a child with trimethylaminuria are usually carriers are of the condition. Carriers have one working copy of the FMO3 gene and one copy with a mutation. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) chance to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier. Because siblings of the affected individual have a 25% chance to be affected, they would benefit from testing to start diet changes early if they are affected. Siblings of the carrier parents could also be tested to find out if they are carriers. You can learn more about autosomal recessive inheritance from the Centre for Genetics Education.

Genetic counselors can help determine who in your family would benefit from testing by constructing a pedigree, or family tree. Genetic counselors can also help to coordinate testing. You can find a genetic counselor in your area by using the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors website.

Trimethylaminuria is a rare and under-diagnosed disease. However, as awareness grows, more studies will be done to try to find a cure.
One example of ongoing research is the study, Exploratory Study of Relationships Between Malodor and Urine Metabolomics, being done by Mebo Research in Florida, USA and the University of Alberta in Alberta, Canada. This study is currently recruiting participants. More information can be found at https://clinicaltrials.gov/ct2/show/NCT02683876?term=NCT02683876&rank=1.

Individuals with trimethylaminuria should be followed by a genetics team, including a genetic counselor and geneticist, who can help determine that all appropriate specialists are being seen and recommend all appropriate management as well as provide information about testing and risk to family members. A metabolic genetics clinic will include both genetics and a dietician. A dietician can help patients understand what they should and should not eat to best manage symptoms. Here are some sites that will help you find a metabolic genetics clinic near you.

Trimethylaminuria (TMAU) is a rare genetic condition that causes a distinctive fish-like body odor. The odor is described as smelling like rotting fish or rotting eggs. Trimethylaminuria can cause social and/or psychological problems because of the body odor. The odor sometimes can be more severe during puberty, with excessive sweating, and, in females, near the time of menstruation, oral contraceptive use, or menopause.

The odor associated with trimethylaminuria happens because unusually high levels of trimethylamine (TMA), which has a strong odor, are released in the urine, breath, and sweat. This is caused by mutations (changes or mistakes) in the gene FMO3. FMO3 normally tells the body to make an enzyme that metabolizes (breaks down) TMA into an odorless molecule. When the body cannot break down TMA, the body gets rid of it in urine, sweat, and other fluids.

Trimethylaminuria is diagnosed by measuring the amount of TMA present in the urine and/or by genetic testing of the FMO3 gene.

Trimethylaminuria is treated with a change in diet. Avoiding foods with high levels of TMA (or other compounds which are broken down into TMA by the body) will improve the body odor. Using acid soaps and body lotions, taking dietary supplements such as charcoal or copper-chlorophyllin tablets, intermittent antibiotics, and riboflavin supplements may also help to decrease the body odor.

The way trimethylaminuria is inherited is called "autosomal recessive." This means that to be affected, a person must have a mistake (mutation) in both copies of the FMO3 gene in each cell. The parents of a child with trimethylaminuria usually each carry one copy of the gene with a mutation. The parents are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) chance to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier. Learn more about autosomal recessive inheritance from the Centre for Genetics Education.

Doctors would usually call trimethylaminuria by its full name; some doctors might use the abbreviated from, TMAU.

Trimethylaminuria can be abbreviated TMAU.

People with trimethylaminuria are usually healthy; the main problem associated with the disease is a fishy body odor. Doctors and dietitians can help prescribe a diet that may decrease symptoms of trimethylaminuria. People with trimethylaminuria may react differently to certain medications, so your doctor should be careful prescribing medications and watch for drug reactions.

Trimethylaminuria is caused by mutations (changes) in the FMO3 gene. This gene is responsible for providing the body with instructions for making an enzyme called flavin-containing monooxygenase 3 (FMO3) that breaks down nitrogen-containing compounds from the diet, including trimethylamine (TMA). FMO3 enzyme converts trimethylamine to an odorless compound called trimethylamine N-oxide.

Trimethylaminuria is a very rare disease so doctors do not know everything there is to know about the condition, including the types of mutations (changes or variants) in the FMO3 gene that can cause the disease. Sometimes the genetic testing for trimethylaminuria identifies a ‘variant’ or ‘variant of unknown significance’.
Our genes, including FMO3, are stretches of DNA. DNA is composed of ‘letters’, four small molecules called A, T, C, and G. With genetic testing, the FMO3 gene is sequenced, meaning that each ‘letter’ of the gene is read to look for ‘misspellings’ (mutations). Sometimes these misspellings do not affect how the gene works and do not cause disease. Sometimes we know that a particular misspelling does cause problems with the way the gene works and causes disease. Other times there is a new or rare misspelling and we don’t know yet if that particular misspelling causes disease, causes a mild form of the disease, or does not cause disease. These misspellings are called ‘variants of ‘unknown significance’.

If not already performed, individuals with a ‘variant’ result would benefit from having another test for trimethylaminuria, a urine test, to determine if they may have the disease. If through this testing the patient is determined to be affected with the disease, he or she should be treated for the disease. If a patient with a ‘variant’ result does not have symptoms or tests negative on the urine test, he or she should follow the recommendation of a geneticist and possibly revisit a genetics clinic in the future to repeat urine testing. As more genetic testing is performed on patients, more information will become available for those with ‘variant’ results. A geneticist or genetic counselor may recommend a return visit in the future to review new information and what it might mean for you.

Trimethylaminuria causes a distinctive fish-like body odor. The odor is described as smelling like rotting fish or rotting eggs. Trimethylaminuria can cause social and/or psychological problems because of the body odor. This can lead to social exclusion, isolation, anxiety, depression, and low self-esteem, which can affect relationships and employment.
Certain medications may be processed differently causing drug reactions in people with trimethylaminuria. Scientists still do not know all of the roles that FMO3, the gene involved in trimethylaminuria, so there may be other symptoms we don’t know about yet. Symptoms can be temporary and mild to severe.

Genetic testing is not usually necessary to diagnose trimethylaminuria. However, genetic testing can be used in cases of uncertain or borderline results. Once an affected individual has genetic testing and their specific FMO3 gene mutations are identified, pregnancies can be tested for the mutations.

Acid soap used for treating trimethylaminuria should have a pH of 5.5 to 6.5.

If a couple is at risk of having a child with trimethylaminuria, they can consider in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD) to reduce the likelihood of having a child who is affected. This involves taking an egg from the mom and fertilizing it with sperm. The developing embryo (the combined egg and sperm) can then be tested for the genetic changes in the FMO3 gene that cause trimethylaminuria in their family. This testing is called PGD. It is important to know the exact genetic changes in the mom and dad before this is done. The doctor will then monitor the growth of the embryo and place an embryo without trimethylaminuria into the woman’s uterus. If you are interested in this option, consult your doctor and seek a fertility clinic in your area.

There is no routine newborn testing for trimethylaminuria. If a child is known to be at risk for trimethylaminuria and the specific mutations (misspellings) in the FMO3 gene (the gene associated with trimethylaminuria) are known, a child can be tested at birth. Early diagnosis is important to start diet changes that can minimize symptoms as soon as possible.

As of February 3, 2016, Mebo Research in Florida, USA and the University of Alberta in Alberta, Canada are conducting a study, Exploratory Study of Relationships Between Malodor and Urine Metabolomics. This study is not specific to trimethylaminuria but is open to any individual with self-reported odor issues. This study is currently recruiting participants. More information can be found at https://clinicaltrials.gov/ct2/show/NCT02683876?term=NCT02683876&rank=1

Trimethylaminuria can be diagnosed by a urine test and/or through genetic testing of the FMO3 gene.
The urine test involves collecting samples of urine before and after patients are given a large dose of compounds that are converted to trimethylamine. The samples are analyzed to determine the amounts of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) that are present to determine if the enzyme FMO3 can effectively convert odorous TMA to odorless TMAO when given large doses of compounds that are converted to TMA.
The genetic test involves finding mutations in each of an individual’s FMO3 genes that are known to be associated with the disease. FMO3 is the only gene that is tested. Genes are stretches of DNA. DNA is composed of ‘letter’, A, C, T, and G. With this testing, the FMO3 gene is sequenced; meaning each ‘letter’ of the gene is read to look for ‘misspellings’. If sequencing the FMO3 gene does not uncover mutations, the gene can be analyzed for large deletions or duplications of ‘letters’ of the gene. Genetic testing is not always necessary to make a diagnosis, but can help if urine test results are unclear. Identifying mutations is necessary if the patient wants to test a pregnancy for the disease.
Genetic counselors can help coordinate this testing. You can find a genetic counselor in your area by using the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors website.

The primary treatment for trimethylaminuria (TMAU) includes a change in diet to avoid foods that contain trimethylamine (TMA), choline, trimethylamine N-oxide, or lecithin. People with trimethylaminuria should avoid the following foods:

The odor associated with trimethylaminuria does not always have to be ‘fishy’. The odor is also reported as smelling like rotting fish, rotting eggs, garbage or urine. Some people have reported smelling of skunk, microwave popcorn, burnt rubber, feces, garbage or sewer.

Trimethylaminuria can be tested for by urine testing or genetic testing.
Urine testing is very reliable when testing is done correctly. If a person has changed their diet before testing, that can give a false negative result. This is why is is recommended that a person eat a specific diet before testing, such as eating saltwater fish, to avoid a false negative.
Genetic testing is a very reliable test, as long as results are interpreted accurately. The best health care professionals to interpret genetic testing are genetics professionals, such as genetic counselors.
Receiving a diagnosis of trimethylaminuria through testing is important to exclude other possible causes of odor and to start treatment.

You should talk with health care professionals, including a dietician, before starting a diet for trimethylaminuria to make sure that you are getting high enough levels of certain nutrients, particularly choline and folate. Medications and supplements can have unintended interactions, so it is important that your doctor is aware of all medications and supplements you are using.
In addition, it is important that choline is not restricted in pregnant and breast-feeding women because choline is required for nerve and brain development in fetuses and infants.

Not everyone with trimethylaminuria is able to smell his or her own odor. Some people report they can only smell the odor when it is very strong.

Trimethylaminuria is probably under-diagnosed since people with mild odor may not seek treatment, so it is hard to know how often affected people will have symptoms. In people diagnosed with trimethylaminuria, the severity can range from mild to severe. The severity depends on environmental factors, like what a person eats, and the specific mutations (changes) present in FMO3, the gene associated with the disease. Some mutations may have a mild effect on the enzyme and lead to a mild form of the disease while other mutations stop the enzyme from working at all and cause more severe symptoms.

At this time, there is no cure for trimethylaminuria and enzyme replacement therapy is not possible. The best approach is to follow diet as well as other management recommendations and possibly become involved in research studies.

People with trimethylaminuria should be followed by a genetics team, including a genetic counselor and geneticist, who can help determine that all appropriate specialists are being seen and recommend all appropriate management as well as provide information about testing and risk to family members. A metabolic genetics clinic will include both genetics and a dietician. A dietician can help patients understand what they should and should not eat to best manage symptoms.
The patient ‘s primary care physician should be knowledgeable about the disease in order to prescribe antibiotics appropriately as well as understand avoid using medications that are processed by the FMO3 enzyme. Physicians can also help their patients locate acidic soaps and lotions, copper-chlorphyllin tablets and riboflavin supplements.
Physicians should also be aware of the social and psychological problems that can be associated with the strong body odor and make referrals to mental health professionals as needed.

Not all foods are broken down into trimethylamine (TMA), so there will be many foods that you can eat without any restrictions. A dietician is the best person to help someone affected with trimethylaminuria understand what they should and should not eat to make sure that they get enough levels of certain nutrients, particularly choline and folate.
Pregnant and breast-feeding women should consult with a dietician since the diet for trimethylaminuria usually involves low choline, a compound which is a needed for nerve and brain development in fetuses and infants.

If you are following a trimethylaminuria diet, you will need to adjust your diet before becoming pregnant. The diet for trimethylaminuria includes eating less choline, but choline is required for normal nerve and brain development in fetuses and infants. During pregnancy and breast feeding, a woman should NOT restrict choline as this will interfere with the baby’s development. Before pregnancy, a woman with trimethylaminuria should speak with a dietician to find out what changes she will need to make to her diet.
During pregnancy, women can speak with their doctors about other treatment options, including temporarily taking antibiotics to reduce the amount of TMA that is produced in the intestines by decreasing the number of TMA-producing bacteria in the intestines.

Large scientific studies are needed to find out how well any treatment works. As of 2016, no such study has been done to find out how well the diet for trimethylaminuria works to reduce odor. No single treatment plan has the same effect on everyone. For some people, the diet is very effective, while for others it is not. It is important to work with your doctor and dietician to determine the best plan for you.

Trimethylaminuria (TMAU) is rare. There have been over 100 people reported with the disorder; however, the exact frequency is not known. It may be under-diagnosed since people with very mild symptoms may not know they have it.

The way trimethylaminuria is inherited is called ‘autosomal recessive’. We all have two copies of the gene that causes trimethylaminuria, FMO3. One of these copies comes from the mother in the egg and the other copy comes from the father in the sperm. In people with trimethylaminuria, both copies of the FMO3 gene have mutations (mistakes or mispellings) and do not work the way they should. Because neither FMO3 gene is working, affected individuals have the symptoms of the disease.
Parents of a child with trimethylaminuria are usually carriers are of the condition. Carriers have one working copy of the FMO3 gene and one copy with a mutation. Carriers of trimethylaminuria are usually unaffected but may have mild symptoms under some circumstances. Carriers have a 50% chance of passing on a mutated copy of FMO3 to each child.
If two carriers have a child and each parent passes on their mutated copy of FMO3, that child will be affected. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) chance to have the condition, a 50% (1 in 2) chance to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier. Learn more about autosomal recessive inheritance from the Centre for Genetics Education.

MEBO Research is a public charity based in Florida, USA, with a mission to initiate research in certain conditions, particularly those that cause malodor, and to promote awareness about these conditions. You can donate to MEBO Research at: http://meboresearch.org/donate/

Trimethylaminuria is diagnosed by a urine test. Genetic testing is also available, though usually not necessary to make a diagnosis.
The urine test can be done in two different ways. The first two steps involve eating a diet low in choline and trimethylamine (TMA) for three days. After this, one or more samples of urine are collected (20 mL volumes stored at -20C). Next, patients are either given a meal containing marine fish, such as cod, or oral choline dissolved in water or orange juice, then all urine is collected for the next 48 or 72 hours. The samples are analyzed to determine the amounts of TMA and trimethylamine N-oxide (TMAO) that are present to determine if the enzyme FMO3 is working properly.
In people with primary trimethylaminuria (with mutations in FMO3) there will be too much TMA compared to TMAO in the urine. In people with secondary trimethylaminuria (without mutations in FMO3), there will be increased TMA in the urine, but the ratio of TMA to TMAO will be normal.
The urine test can also identify people who are carriers, which means they have one copy of the FMO3 gene with a mutation and one without, but only if the procedure described above is followed.
The urine test results of a patient with a urinary tract infection can look similar to trimethylaminuria, so after a positive result, urinary tract infections should be excluded.
The genetic test involves looking for mutations (changes or mispellings) in the FMO3 gene that are known to cause with the disease. FMO3 is the only gene that is tested. Genes are stretches of DNA. DNA is composed of four ‘letters’, A, C, T, and G. With this testing, the FMO3 gene is sequenced, meaning that each ‘letter’ of the gene is read to look for ‘misspellings’ (mutations). If sequencing the FMO3 genes does not uncover mutations, the gene can be analyzed for large deletions or duplications of a bigger portion of the gene. Genetic testing is not always necessary to make a diagnosis, but can help if urine test results are unclear. Identifying mutations is necessary if the patient wants to test a pregnancy for the disease.
Genetic counselors can help coordinate this testing. You can find a genetic counselor in your area by using the "Find a Genetic Counselor" tool on the National Society of Genetic Counselors website.

To find information about clinical research on trimethylaminuria, watch clinicaltrials.gov. Once on the website, search for studies using a variety of key terms, including trimethylaminuria as well as related terms, such as malodor. Keeping in contact with support groups can help you stay on top of the latest clinical trials and drugs. Support groups include RareConnect and the TMAU UK Support Group.

MEBO Research is a public charity based in Florida, USA, with a mission to initiate research in rare conditions, particularly those that cause malodor and to promote awareness about these conditions. MEBO Research includes a community outreach program to assist those affected. http://meboresearch.org
A person with trimethylaminuria can be seen by a doctor called a "medical geneticist" or "metabolic physician." These specialists are familiar with treating rare metabolic conditions. A metabolic genetics clinic will also have a dietician available to help manage the dietary changes. Here are some sites that will help you find a metabolic genetics clinic near you.

Trimethylaminuria is a very rare disease. It is unlikely that there is a local support group for the disorder. However, online support groups, such as RareConnect, can connect you virtually with a community of other affected individuals and could potentially lead to in-person meetings.

Individuals who have been given a diagnosis of trimethylaminuria due to a genetic mutation in their FMO3 gene will always have the disease because we are not able to change our genes. However, symptoms will improve for many people with treatment.

Both males and females are just as likely to inherit or pass on the disease. The symptoms may be worse in females, especially during the time just before and during menstruation, after taking oral contraceptives and around menopause.

Eating foods or taking supplements that contain trimethylamine (TMA), choline, or lecithin can make the body odor worse. People with trimethylaminuria should follow a special diet, avoiding foods such as milk from wheat-fed cows, certain seafood, eggs, offal, legumes, brassicas (brussels sprouts, broccoli, cabbage, cauliflower) and soya products. Choline should NOT be restricted in infants, young children, and pregnant or breast-feeding women as choline is important in nerve and brain development. A dietitian can help you adjust your diet while maintaining adequate nutrition.
Some drugs are also metabolized (broken down) by FMO3, the enzyme affected in trimethylaminuria, and should be avoided. These include antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac. Exercise and stress can lead to excessive sweating and exacerbate the body odor.

Trimethylaminuria is sometimes called TMAU, fish odor syndrome, fish malodor syndrome, stale fish syndrome, or TMAuria.

There are no organ-specific treatments for trimethylaminuria. is treated with a change in diet. Avoiding foods with high levels of TMA (or other compounds which are broken down into TMA by the body) will improve the body odor. Using acid soaps and body lotions, taking dietary supplements such as charcoal or copper-chlorophyllin tablets, intermittent antibiotics, and riboflavin supplements may also help to decrease the body odor. Individuals affected by trimethylaminuria may benefit from counseling as many suffer low self-esteem, social exclusion and isolation because of their odor, leading to anxiety and depression.

Trimethylaminuria is characterized by a fish-like body odor. The odor can resemble rotting fish, rotting eggs, garbage, or urine. The odor comes from extra trimethylaminure in the urine, sweat, and breath.

MEBO Research is a public charity based in Florida, USA, with a mission to initiate research in rare conditions, particularly those that cause malodor and to promote awareness about these conditions. MEBO Research includes a community outreach program to assist those affected. Learn more at: http://meboresearch.org
RareConnect houses websites for a variety of rare conditions, including trimethylaminuria. This site contains information about trimethylaminuria as well as discussion boards for members to connect. Learn more at: https://www.rareconnect.org/en/community/trimethylaminuria/forum

The TMAU UK Support Group also includes discussion forums and information at: http://tmau.org.uk

Primary trimethylaminuria caused by mutations (changes) in the FMO3 gene that stop the enyzme from processing the strong smelling trimethylamine (TMA) into an odorless compound is always genetic; there are other conditions which cause a similar odor that are not genetic which are often called secondary trimethylaminuria.

Secondary trimethylaminuria can be caused by having too much TMA in the body from diet or medication (including choline, which is processed by the body into TMA) or from an overgrowth of bacteria (which produce TMA in the gut). It can also happen with other diseases which interfere with the FMO3 enzyme (such as hepatitis) or that affect the way the body gets rid of TMA (such as kidney disease). Transient trimethylaminuria associated with menstruation can occur in women just before and during menstruation.

The main type of trimethylaminuria is called primary trimethylaminuria. Primary trimethylaminuria is caused by mutations (changes or mistakes) in a gene called FMO3. FMO3 normally tells the body to make an enzyme that metabolizes (breaks down) the strong-smelling trimethylamine (TMA) into an odorless molecule. When the body cannot break down TMA, the body gets rid of it in urine, sweat, and other fluids, causing a fish-like body odor.

Secondary trimethylaminuria can occur if too much trimethylamine is present in the body. Causes of secondary trimethylaminuria include getting too much TMA or choline (which the body breaks down into TMA) from food, too much bacteria in the intestines (bacteria produce trimethylamine), liver or kidney disease, cervical cancer, or a urinary tract infection. Premature infants and healthy women at the start of menstruation can also show temporary symptoms.

There are other conditions which can cause a fishy body odor similar to primary trimethylaminuria (the genetic form of this condition in which mutations (changes) in the FMO3 gene stop the enyzme from processing the strong smelling trimethylamine (TMA) into an odorless compound); these conditions are often called secondary trimethylaminuria.

Secondary trimethylaminuria can be caused by having too much TMA in the body from diet or medication (including choline, which is processed by the body into TMA) or from an overgrowth of bacteria (which produce TMA in the gut). It can also happen with other diseases which interfere with the FMO3 enzyme (such as hepatitis) or that affect the way the body gets rid of TMA (such as kidney disease). Transient trimethylaminuria associated with menstruation can occur in women just before and during menstruation. Body odor can also be caused by urinary tract infections, bacterial vaginosis, cervical cancer, poor hygiene, and a similar rare condition called dimethylglycinuria.