General: Trimethylaminuria (TMAU) is inherited as a mutation of a specific gene through an autosomal recessive pattern. The mutated gene responsible for TMAU is called flavin-containing monooxygenase 3 (FMO3). This means that the mutated FMO3 gene is inherited on a non-sex chromosome and two copies of the mutation, one from each parent, are needed to cause TMAU. Any person with at least one copy of the mutation may pass it on to their children. Carriers, who only have one copy of the mutated FMO3 gene, may still experience a milder version of TMAU symptoms.
The FMO3 gene, found on chromosome 1, contains the instructions for making an enzyme that the body needs to break down a substance called trimethylamine (TMA). Normally, TMA is produced by bacteria in the intestines during digestion of proteins from eggs, meat, soy, legumes, certain types of fish, and other foods. The enzyme produced by FMO3 converts TMA into an odorless substance called trimethylamine N-oxide. Patients with TMAU do not have this enzyme, and as a result, TMA builds up in the body, causing symptoms of TMAU as it is released through the sweat, urine, and breath.
Type of mutation: Due to the variability of symptoms that people with TMAU experience, researchers believe that different types of genetic mutations in FMO3 may influence the symptoms of the disease. The type of mutation may affect time of onset and the strength of the odor. There are between 40 and 50 different types of mutations associated with TMAU. Although FMO3 mutations account for most known cases of TMAU, some cases are caused by other factors.
Hormones: In females, researchers suspect that female sex hormones, such as progesterone and/or estrogen, may worsen symptoms of TMAU. The research is unclear about why this occurs. Some believe that FMO3 enzyme activity is decreased in response to steroid hormones, including progesterone and estrogen.
Diet: A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria that normally break down TMA in the digestive system.
Liver or kidney damage: A few cases of the disorder have been identified in adults with liver damage caused by hepatitis. TMAU has also been reported in adults with kidney disease.
Stress: Researchers also believe that stress may play a role in triggering symptoms.
General: Trimethylaminuria (TMAU) was previously diagnosed based on clinical symptoms and urine analysis alone. Research has led to the development of genetic testing, which can identify mutations in the FMO3 gene associated with symptoms of TMAU and other diagnostic tests that lead to more conclusive diagnoses.
Tests for trimethylamine (TMA) content: Screening for TMAU is done through a urine sample to measure amino acid content. Since people with TMAU cannot break down trimethylamine (TMA) and because choline is one compound that makes up TMA, the test is performed by administering a high dose of choline. Testing can be done by giving choline by mouth followed by urine collection over a 24-hour period. The test measures the ratio of TMA to trimethylamine N-oxide, the chemical product of TMA metabolism, in the urine. TMAU may be diagnosed based on high levels of TMA in the urine.
A more conclusive test that measures elevated levels of TMA in the body is performed by analyzing amino acid content in a liver sample.
TMA challenge test: Another diagnostic test that has been developed is called the TMA challenge or a TMA load test. This test may be used to identify a carrier of a mutation of the flavin-containing monooxygenase 3 (FMO3) gene, which codes for the main enzyme that breaks down TMA. Carriers of FMO3 mutations are those individuals who have inherited one copy of a mutated gene but may show only mild or no symptoms of TMAU.
The TMA challenge involves giving an individual an oral dose of TMA. Genetic carriers of TMAU excrete between 20% and 30% of the total TMA in its unmetabolized form and the rest as trimethylamine N-oxide, the metabolized form. Non-carriers excrete less than 13% of the dose as TMA.
Genetic testing: Genetic testing is available to diagnose TMAU or identify carriers of FMO3 mutations. TMAU diagnosis is typically confirmed through a blood test, which can provide genetic analysis of an individual who is symptomatic. A positive diagnosis is generally based on mutations in the FMO3 gene, accompanied by high levels of TMA in the blood.
Development of genetic testing can provide conclusive evidence of TMAU. However, it may be difficult to diagnose other forms of TMAU, especially those cases resulting from multiple mutations or those with non-genetic causes.
signs and symptoms
Common symptoms of trimethylaminuria (TMAU) include offensive body odor, increased heartbeat, and high blood pressure.
TMAU causes a fishy body odor that is released in the person's sweat, urine, and breath. This odor is generally more prominent after consumption of foods containing choline, nitrogen, or sulfur, since these foods contain compounds that cannot be broken down (metabolized) by people with TMAU.
The odor generally varies in odor and strength and is thought to depend on several factors. These include diet, hormonal changes, other odors in the surrounding environment, and on the sense of smell and odor perception of other people.
The scent given off by people with TMAU has also been compared to a variety of other odors that are generally considered unpleasant. These include cigarette smoke, garbage, feces, urine, sulfur, and rotten eggs.
Some people with TMAU give off a strong odor all the time, but most have a moderate smell that varies in intensity over time.
Individuals with this condition do not generally have any physical symptoms and typically appear to be otherwise healthy.
Psychological and social problems: While most individuals with trimethylaminuria (TMAU) appear physically healthy, the characteristic body odor that accompanies this disorder may cause negative psychological and social consequences.
The most serious complications of TMAU appear to be reactions to the excessive amounts of trimethylamine (TMA) released in the sweat, breath, urine, and other bodily secretions, causing the individual to give off a powerful and offensive body odor. This condition may negatively affect personal, educational, and professional lives of affected individuals.
Some individuals become socially withdrawn and isolated and may go on to develop depression. The condition can be particularly acute and severe for young children and adolescents who may be subject to ridicule and loss of self-esteem.
General: Trimethylaminuria (TMAU) is considered a rare disorder, with only about 200 cases reported worldwide. Affected individuals appear healthy and risk factors other than family history remain unclear. Increased awareness of this metabolic problem in recent years makes its prevalence unclear, as many previous cases may have gone undiagnosed.
Family history: Most cases of TMAU are inherited, so people with a family history of the disorder have an increased risk of developing TMAU.
The disorder appears to be inherited in an autosomal recessive pattern. Autosomally inherited disorders are caused by gene mutations, or abnormalities, on the any of the 22 non-sex chromosomes. In the case of TMAU, the genetic mutation affects a gene called FMO3, which contains the genetic instructions for making the flavin-containing monooxygenase 3 (FMO3) protein.
People inherit two copies of each autosomal gene, one from each parent. Recessive inheritance means that both copies of a gene must be defective to cause disease. Individuals that have only one defective gene may not develop the disease, but are considered carriers. Carriers may pass the abnormal gene to their children. Carriers of an FMO3 mutation may experience mild symptoms of TMAU or temporary episodes of fish-like body odor.
Children born to parents who are both carriers of the autosomal recessive gene have a one in four chance of inheriting two copies of the abnormal gene (one from each parent) and developing the disease. These children also have a 50% chance of inheriting just one abnormal gene, which would make them a carrier.
Liver or kidney damage: A few cases of TMAU have been reported in adults with liver or kidney disease but no family history of the disorder.
Diet: Some people may give off a fish-like body odor if their diet contains an excess of certain proteins or if there is an increase in bacteria that normally produce TMA in the digestive system.
Individuals who experience temporary TMAU symptoms may reduce their risks of developing a permanent metabolic disorder by eating healthy foods that are low in choline, sulfur, or nitrogen content, and by exercising regularly.
Gender: The disorder appears to occur more frequently in females, and symptoms may be more severe just before and during menstruation, after taking birth control pills, and around the time of menopause.