Trimethylaminuria is a metabolic disorder that occurs when the body is unable to break down certain nitrogen-containing compounds such as trimethylamine. Trimethylamine, which has a fishy odor, is produced in the intestines when certain types of food (i.e. eggs, liver, legumes, fish and some vegetables) are digested. As trimethylamine begins to accumulate in the body, it is released in the sweat, urine, reproductive fluids, and breath. This leads to the characteristic odor of trimethylaminuria. Affected individuals do not have other health problems related to the condition, but the unpleasant odor can result in social and psychological problems. Trimethylaminuria seems to be more common in women. Researchers think this may be due to higher hormone levels aggravating symptoms of the disorder.

Trimethylaminuria is often caused by changes (mutations) in the FMO3 gene and is inherited in an autosomal recessive manner. Although there is no cure, trimethylaminuria can often be managed by reducing the amount of trimethylamine in the body. For example, affected people can modify their diet to avoid foods with high levels of trimethylamine.

Trimethylaminuria is a disorder in which the body is unable to break down trimethylamine, a chemical compound that has a pungent odor. Trimethylamine has been described as smelling like rotten or decaying fish. As this compound builds up in the body, it causes affected people to give off a strong fishy odor in their sweat, urine, and breath. The intensity of the odor may vary over time. The odor can interfere with many aspects of daily life, affecting a person's relationships, social life, and career. Some people with trimethylaminuria experience depression and social isolation as a result of this condition.

Trimethylaminuria is a metabolic condition in which an individual is not able to convert trimethylamine into a compound called trimethylamine N-oxide. Trimethylaminuria, has been around for centuries, but has only gained scientific recognition and support in the past 30 years.

What is Trimethylamine?

Trimethylamine is the compound that gives fish the fishy odor. Trimethylamine N-oxide does not smell.

What are the symptoms of trimethylamineuria?

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 odor. Some people with trimethylaminuria have a strong odor all the time, but most have a moderate smell that varies in intensity over time. Other than the strong fishy odor, individuals with this condition typically appear healthy.

The condition seems to be more common in women than men, but scientists don't know why. 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.

What causes trimethylaminuria?

People with trimethylaminuria have an impaired version of the enzyme flavin-containing monooxygenase 3 (FMO3). This is the enzyme that converts trimethylamine to to trimethylamine N-oxide. FMO3 is produced by the liver and is a member of a family of similar enzymes responsible for metabolizing compounds that contain nitrogen, sulfur, or phosphorous. The enzyme is coded for by the FMO3 gene. Trimethylaminuria may be caused by a variety of genetic changes to the FMO3 gene. Not all of the functions of the FMO3 enzyme are known, so physicians don't know what other symptoms besides odor may be associated with trimethylaminuria.

Is trimethylaminuria inherited?

Yes. Trimethylaminuria is usually inherited in an autosomal recessive fashion, which means that two non-functioning FMO3 genes are usually needed for a person to have symptoms. Both parents of an individual with trimethylaminuria are "carriers" of the condition, in other words, they both carry one copy of an altered gene for FMO3. Since this condition usually requires two altered genes to cause symptoms, typically neither parent of an individual with trimethylaminuria has any symptoms. Sometimes, "carriers" of one copy of an FMO3 mutation may have mild symptoms of trimethylaminuria or have temporary episodes of fish-like odor. Due to the variability of symptoms people with trimethylaminuria experience, researchers think that different genetic mutations in FMO3 can influence the symptoms of the disease, affecting time of onset and how strong the odor is. They also suspect that stress and diet play a role in triggering symptoms.

How is trimethylaminuria diagnosed?

A urine test is used to diagnose trimethylaminuria. The person's urine is tested to look for higher levels of trimethylamine. Testing can be done by giving choline by mouth followed by urine collection a certain number of times over a 24 hour period. Urine testing should be performed on two separate occasions when the individual is on a non-restricted diet. The test measures the ratio of trimethylamine to trimethylamine N-oxide present in the urine.

A carrier of this condition can be identified by the "TMA challenge" or a "TMA load" test. This involves giving an individual a 600 dmg pill of trimethylamine (TMA). Carriers of trimethylaminuria excrete 20-30 percent of total trimethylamine as the free unmetabolized amine and the rest as trimethylamine N-oxide. Non-carriers excrete less than 13% of the dose as trimethylamine. Gene testing called gene sequencing can be used to look for mutations in the FMO3 gene. Gene testing is currently available only through research laboratories.

How is trimethylaminuria treated?

There is currently no cure for trimethylaminuria. However, it is possible for people with this condition to live normal, healthy lives. The following are some ways a person with trimethylaminuria can lower symptoms of odor:

• Avoiding foods containing trimethylamine and its precursors (choline, lecithin and trimethylamine N-oxide).

• Trimethylamine is present in high levels in milk obtained from wheat-fed cows

• Choline is present in high amounts in:

  • Eggs

  • Liver

  • Kidney

  • Peas

  • Beans

  • Peanuts

  • Soy products

  • Brassicas (brussel sprouts, broccoli, cabbage, and cauliflower)

  • Lecithin and lecithin-containing fish oil supplements

• Trimethylamine N-oxide is present in seafood (fish, cephalopods, crustaceans). Freshwater fish have lower levels of trimethylamine N-oxide.

• Taking low doses of antibiotics to reduce the amount of bacteria in the gut. This suppresses the production of trimethylamine.

• Taking laxatives can decrease intestinal transit time and reduce the amount of trimethylamine produced in the gut.

• Taking supplements to decrease the concentration of free trimethylamine in the urine.

• Activated charcoal taken at a dose of 750mg twice daily for ten days. Copper chlorophyllin taken at a dose of 60mg three times a day after meals for three weeks.

• Using soaps with a moderate pH, between 5.5 and 6.5. Trimethylamine is a strong base (pH 9.8), thus soaps with pH closer to that of normal skin help retain the secreted trimethylamine in a less volatile form that can be removed by washing.

• Taking riboflavin (vitamin B2) supplements to enhance any residual FMO3 enzyme activity. Recommended intake is 30-40mg taken 3-5 times per day with food.

• Avoiding factors that promote sweating, such as exercise, stress, and emotional upsets.

It is important that a person who has trimethylamuinuria follow the treatment advice of their health care provider. They should not attempt to self-administer

Unfortunately at this time, enzyme replacement therapy with the enzyme FMO3, which when absent, is believed to cause the condition, is not an option in the management of trimethylaminuria.

Variants (also known as mutations) in the FMO3 gene cause trimethylaminuria. This gene provides instructions for making an enzyme that breaks down nitrogen-containing compounds from the diet, including trimethylamine. This compound is produced by bacteria in the intestine during the digestion of eggs, liver, legumes (such as soybeans and peas), certain kinds of fish, and other foods. Normally, the FMO3 enzyme converts strong-smelling trimethylamine into another molecule that has no odor. If the enzyme is missing or its activity is reduced because of a variant in the FMO3 gene, trimethylamine is not processed properly and can build up in the body. As excess trimethylamine is released in a person's sweat, urine, and breath, it causes the odor characteristic of trimethylaminuria. Researchers believe that stress and diet also play a role in triggering symptoms.

Although FMO3 gene variants account for most cases of trimethylaminuria, the condition can also be caused by other factors. The strong body odor may result from an excess of certain chemical compounds in the diet or from an abnormal increase in bacteria that produce trimethylamine in the digestive system. A few cases of the disorder have been identified in adults with liver or kidney disease. Temporary symptoms of this condition have been reported in a small number of premature infants and in some healthy women at the start of menstruation.

Normal Function

The FMO3 gene provides instructions for making an enzyme that is part of a larger enzyme family called flavin-containing dimethylaniline monooxygenases (FMOs). These enzymes break down compounds that contain nitrogen, sulfur, or phosphorus. The FMO3 enzyme, which is made chiefly in the liver, is responsible for breaking down nitrogen-containing compounds derived from the diet.

One of these compounds is trimethylamine, which is the molecule that gives fish their fishy smell. Trimethylamine is produced as bacteria in the intestine help digest certain proteins obtained from eggs, liver, legumes (such as soybeans and peas), certain kinds of fish, and other foods. The FMO3 enzyme normally converts fishy-smelling trimethylamine into another compound, trimethylamine-N-oxide, which has no odor. Trimethylamine-N-oxide is then excreted from the body in urine.

Researchers believe that the FMO3 enzyme also plays a role in processing some types of drugs. For example, this enzyme is likely needed to break down the anticancer drug tamoxifen, the anti-inflammatory medication benzydamine, the antifungal drug ketoconazole, and certain medications used to treat depression (antidepressants).

The FMO3 enzyme may also be involved in processing nicotine, an addictive chemical found in tobacco. Normal variations (polymorphisms) in the FMO3 gene may affect the enzyme's ability to break down these substances. Researchers are working to determine whether FMO3 polymorphisms can help explain why people respond differently to certain drugs.

Health Conditions Related to Genetic Changes

Trimethylaminuria

More than 40 variants (also known as mutations) in the FMO3 gene have been identified in people with trimethylaminuria. Some of these variants lead to the production of a small, nonfunctional version of the FMO3 enzyme. Other variants change single building blocks (amino acids) used to build the enzyme, which alters its shape and disrupts its function. Without enough functional FMO3 enzyme, the body is unable to convert trimethylamine into trimethylamine-N-oxide effectively. As a result, trimethylamine builds up in the body and is released in an affected person's sweat, urine, and breath. The excretion of this compound is responsible for the strong body odor characteristic of trimethylaminuria. Studies suggest that diet and stress also play a role in determining the intensity of the fish-like odor.

Other Names for This Gene

• Dimethylaniline monooxygenase [N-oxide-forming] 3
• Dimethylaniline oxidase 3
• FMO3_HUMAN
• FMOII

Genomic Location

Trimethylaminuria is characterized primarily by a fishy odor that occurs when excess trimethylamine is released in the person's sweat, urine, reproductive fluids, and breath. Although some affected people may have a constant strong odor, most have a moderate odor that can vary in intensity. Factors that promote sweating, such as exercise, stress, and emotional upsets, may worsen the odor. In females, symptoms may be more severe right before and during menstruation, after taking oral contraceptives, or around the time of menopause.

Affected people typically do not have any additional signs and symptoms and appear healthy. However, the odor can interfere with many aspects of daily life, leading to social and psychological problems.

Trimethylaminuria is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition, but in some cases carriers of trimethylaminuria may have mild symptoms or have temporary episodes of fish-like odor. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

A diagnosis of trimethylaminuria is often suspected based on the presence of characteristic signs and symptoms. A urine test and genetic testing can then be ordered to confirm the diagnosis. The urine test measures the level of trimethylamine in the urine, as affected individuals would be expected to have high trimethylamine urine levels. This test may be done after a person is given a dose of choline by mouth.

Genetic testing is available for FMO3, the gene known to cause trimethylaminuria. Carrier testing for at-risk relatives and prenatal testing are possible if the disease-causing mutations in the family are known.

Although there is no cure for trimethylaminuria, the following are some ways to reduce symptoms of odor:

• Avoidance of foods that contain trimethylamine and its precursors (choline, lecithin, and trimethylamine N-oxide). Trimethylamine is present in high levels in milk obtained from wheat-fed cows. Choline is present in high amounts in: eggs, liver, kidney, peas, beans, peanuts, soy products, brussels sprouts, broccoli, cabbage, and cauliflower. Trimethylamine N-oxide is present in seafood
• Low doses of antibiotics. This decreases the amount of trimethylamine that is made by bacteria in the intestines
• Laxatives can decrease the amount of time food remains in the intestines and therefore reduce the amount of trimethylamine made
• Nutritional supplements (activated charcoal and copper chlorophyllin) can decrease the concentration of trimethylamine in the urine
• Soaps with a moderate pH (between 5.5 and 6.5) can help remove the secreted trimethylamine from the skin
• Riboflavin (vitamin B2) supplements can enhance any existing FMO3 enzyme activity (which breaks down trimethylamine)
• Avoidance of exercise, stress, emotional upsets, and other factors that can promote sweating

People with trimethylaminuria may also find the following to be helpful:

• Behavioral counseling to help with depression and other psychological symptoms
• Genetic counseling to better understand how they developed trimethylaminuria and the risks of passing the condition on to their children

NOTE: People should follow the treatment advice of their healthcare provider and should not attempt to self-administer these treatment approaches. Medications and supplements can have unintended interactions, and dietary restrictions can result in nutritional deficits.

In general, the long-term outlook (prognosis) for people with trimethylaminuria is good. Affected people have a normal life expectancy and aside from the fishy odor, the condition is typically not associated with other health problems.

Although some cases (especially those that are mild or moderate) can be successfully managed with a restricted diet, the odor can interfere with aspects of daily life. Consequently, many people affected by this condition struggle with depression and other psychological problems.