Trimethylaminuria

• Trimethylaminuria (TMAU) is an inherited metabolic disorder that is characterized by an offensive body odor that smells like rotting fish. This odor is due to the excessive excretion of a protein called trimethylamine (TMA) in the urine, sweat, and breath.
• TMAU, also known as fish odor syndrome or fish malodor syndrome, is caused by defects in a protein called flavin-containing monooxygenase 3 (FMO3). The FMO3 protein is an enzyme produced by the liver that functions mainly to break down nitrogen-containing compounds.
• TMA is consumed through the diet and is normally broken down through a process called N-oxygenation. The abnormal function of FMO3 results in the body's inability to break down TMA from food sources, especially choline-rich foods, such as milk, eggs, and peanuts. When this process does not work properly, TMA builds up and is released in the person's sweat, urine, and breath. This causes the characteristic smell associated with TMAU.
• Trimethylaminuria is a rare genetic condition with unknown incidence. This inherited disorder demonstrates how genetics can alter the way dietary substances are broken down (metabolized). However, TMAU has been diagnosed in people who have liver disease but do not have a family history of the disorder.
• While TMAU does not cause other medical problems, it can be extremely stressful for affected individuals. While some people with TMAU are not aware of their body odor, other people with the condition are very sensitive to it and may become socially withdrawn as a result. The disorder can cause generally negative effects on educational, personal, social, and career environments. TMAU has also been associated with severe depression, occasionally leading to suicidal tendencies, although evidence of this is lacking.
• While no cure exists, treatment focuses on reducing the odor release, most often through dietary restriction of foods containing choline, nitrogen, and sulfur. People with TMAU are otherwise healthy.

• 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.

• 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.

• 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.

• 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.

• 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: There is currently no cure for trimethylaminuria (TMAU), and treatment options are limited. However, with proper treatment or precautions, individuals with TMAU may be able to live normal, healthy lives. Generally, treatment is based on symptom management, although widely varying degrees of effectiveness have been reported. Depending on the type and cause of TMAU, an individual may experience mild to complete symptom relief. Getting tested for the disorder is an important first step.
• It is important for patients with TMAU to follow the treatment advice of their healthcare providers. Patients should not attempt to self-administer treatments. Medications, supplements, and dietary modifications may have unintended interactions and dietary restrictions, for example restriction of choline may result in nutritional deficits. Choline~ is essential for nerve and brain development in fetuses and infants. Therefore, pregnant and breastfeeding women should consult with their healthcare provider before restricting their dietary choline.
• Diet: The offensive odor associated with TMAU can by minimized with special diets low in trimethylamine (TMA) or its precursors. Since TMAU patients cannot metabolize TMA, limiting certain foods may reduce the buildup of TMA in the body.
• Avoiding or minimizing intake of foods such as eggs, legumes, certain meats, fish, and foods that contain choline, nitrogen, and sulfur may reduce the severity of body odor given off. Food sources of choline include soy, egg yolk, butter, banana, barley, cauliflower, corn, flax seeds, lentils, milk, oranges, potatoes, sesame seeds, tomatoes, and whole wheat bread. Affected individuals should also avoid lecithin and lecithin-containing fish oil supplements, which contain high levels of choline.
• Milk from wheat-fed cows may have significant amounts of TMA and should be avoided.
• Freshwater fish have a lower content of trimethylamine N-oxide than salt water fish and may be suitable for patients with TMAU.
• Patients should talk with their healthcare providers and/or nutritionists to design a safe and healthy diet.
• Counseling: Psychological complications or depression associated with TMAU may be treated through behavioral counseling.
• Genetic counseling may help patients and other individuals to better understand the condition.
• Aside from professional dietary advice and counseling, patients may also seek advice about other conditions that may worsen the symptoms of TMAU. These include menstruation, fever, and stress.
• Antibiotics: Antibiotics may be used to reduce odor-causing bacteria in the stomach and intestines. Neomycin, amoxicillin, and metronidazole have been used to suppress TMA production by bacteria.
• Antibiotic treatment may be useful during times associated with increased TMA production, such as during menstruation, infection, emotional upset, stress, or exercise. Neomycin appears to be the most effective in preventing the formation of TMA from choline. However, antibiotic treatment has not been effective in all cases.
• Side effects of taking antibiotics may include nausea, vomiting, stomach pain, headache, swollen tongue, or white patches inside the mouth or throat. Patients should get immediate medical attention if any signs of allergic reaction occur, including hives, fever, sore throat, severe stomach pain, diarrhea, chills, weakness, or seizure. Antibiotic treatment should be administered with caution by healthcare providers, as continued use may increase the risk of antibiotic resistance in the patient.
• Other treatments: Using soaps and other personal care products with a moderate pH between 5.5 and 6.5 may help mask body odor. This pH range helps to retain secreted TMA in a salt form, which has reduced odor and can be removed by washing.
• It has been suggested that daily intake of charcoal and/or copper chlorophyllin may minimize the odor associated with TMAU. However, the effectiveness of this treatment method may vary. Activated charcoal or copper chlorophyllin, taken by mouth, may help suppress odor-causing bacterial activity in the gut.
• Taking laxatives may help prevent odor by decreasing intestinal transit time, which reduces the amount of TMA produced in the gut. Laxatives should be used cautiously and should not be taken regularly for long periods of time.
• There is controversy regarding exercise as a treatment for body odor caused by TMAU. While some feel that exercise increases the rate at which certain compounds are broken down in the body, thus allowing sufferers to quickly excrete excess TMA, others warn that the strong body odor of TMAU is more prominent during times of excessive perspiration.

Note
: Currently, there is insufficient evidence available on the safety and effectiveness of integrative therapies for preventing or treating trimethylaminuria. The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies or preventive measures.

A

Strong scientific evidence

• Music therapy
  : Music has been referred to as an ancient tool of healing. Many different forms of music intervention have been used to reduce depression and anxiety in a variety of medical conditions and medical procedures. There is evidence that music therapy may increase responsiveness to antidepressant medication. In elderly adults with depression, a home-based program of music therapy may have long-lasting effects. In depressed adult women, music therapy may lead to reductions in heart rate, respiratory rate, blood pressure, and depressed mood.
• St. John's wort
  : Extracts of St. John's wort (Hypericum perforatum) have been recommended traditionally for a wide range of medical conditions, with the most common modern-day use being the treatment of depression. St. John's wort has been extensively studied in Europe over the last two decades, with more recent research in the United States. Short-term studies (one to three months) suggest that St. John's wort is more effective than placebo (sugar pill), and equally effective as tricyclic antidepressants (TCAs) in the treatment of mild-to-moderate depression. Comparisons to the more commonly prescribed selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac®) or sertraline (Zoloft®), are more limited. However, other data suggest that St. John's wort may be just as effective as SSRIs with fewer side effects. Safety concerns exist as with most conventional and integrative therapies. Studies of St. John's wort for severe depression have not provided clear evidence of effectiveness.
• In published studies, St. John's wort has generally been well tolerated at recommended doses for up to one to three months. The most common adverse effects include gastrointestinal upset, skin reactions, fatigue/sedation, restlessness or anxiety, sexual dysfunction (including impotence), dizziness, headache, and dry mouth. St. John's wort should not be used if pregnant or breastfeeding, unless otherwise directed by a doctor.
• Avoid if allergic or hypersensitive to plants in the Hypericaceae
  family. Rare allergic skin reactions like itchy rash have been reported. Avoid with HIV/AIDS drugs (protease inhibitors) like indinavir (Crixivan®), or non-nucleoside reverse transcriptase inhibitors, like nevirapine (Viramune®). Avoid with immunosuppressant drugs (like cyclosporine, tacrolimus or myophenic acid). Avoid with organ transplants, suicidal symptoms, or before surgery. Use cautiously with a history of thyroid disorders. Use cautiously with drugs that are broken down by the liver, with monoamine oxidase inhibitors (MAOI) or selective serotonin reuptake inhibitors (SSRIS), digoxin, or birth control pills. Use cautiously with diabetes or with a history of mania, hypomania (as in bipolar disorder), or affective illness.

B

Good scientific evidence

• Dehydroepiandoseterone (DHEA)
  : DHEA is a hormone made in the human body that serves as precursor to male and female sex hormones (androgens and estrogens). The majority of clinical trials investigating the effect of DHEA on depression support its use for this purpose under the guidance of a healthcare provider. Further research is needed to confirm these results. Few side effects are reported when DHEA supplements are taken by mouth in recommended doses. Side effects may include fatigue, nasal congestion, headache, acne, or rapid/irregular heartbeats. In women, the most common side effects are abnormal menses, emotional changes, headache, and insomnia. Individuals with a history of abnormal heart rhythms, blood clots or hypercoagulability, and those with a history of liver disease, should avoid DHEA supplements. Caution is advised when taking DHEA supplements, as numerous drug interactions are possible. DHEA is not recommended during pregnancy or breastfeeding.
• Psychotherapy
  : Psychotherapy is an interactive process between a person and a qualified mental health professional (psychiatrist, psychologist, clinical social worker, licensed counselor, or other trained practitioner). A broad range of psychotherapies have been shown to be effective for the treatment of depression, including behavior therapy, cognitive-behavioral therapy, and interpersonal therapy. Brief dynamic therapy, marital therapy, and family therapy may work best, depending on the patient's problems and circumstances. Psychotherapy, in combination with prescription medicine, may help treat depression as a complication of trimethylaminuria.
• Yoga
  : Yoga is an ancient system of relaxation, exercise, and healing with origins in Indian philosophy. Several human studies support the use of yoga for depression in both children and adults. Although this early research is promising, better studies are needed.
• It should be noted that there is controversy regarding exercise, including yoga, as a treatment method for people with TMAU. While some feel that exercising will increase the rate at which certain compounds are metabolized in the body, thus allowing sufferers to faster excrete as much excess TMA as possible, others warn that symptoms (strong body odor) of TMAU may be more prominent during times of excessive perspiration.

C

Unclear or conflicting scientific evidence

• Copper
  : Copper is a mineral that occurs naturally in many foods, including vegetables, legumes, nuts, grains, fruits, shellfish, avocado, beef, and animal organs (liver and kidneys). Preliminary evidence suggests that the use of copper chlorophyllin results in a reduced urinary free trimethylamine (TMA) concentration and normalization of trimethylamine N-oxide (TMAO). Further research is required in this field before recommendations can be made.
• Avoid if allergic/hypersensitive to copper. Avoid use of copper supplements during the early phase of recovery from diarrhea. Avoid with hypercupremia or genetic disorders affecting copper metabolism (such as Wilson's disease, Indian childhood cirrhosis, or idiopathic copper toxicosis). Avoid with HIV/AIDS. Use cautiously with water containing copper concentrations greater than six milligrams per liter. Use cautiously with anemia, arthralgias, or myalgias. Use cautiously if taking oral contraceptives. Use cautiously if at risk for selenium deficiency. The Recommended Dietary Allowance (RDA) is 1,000 micrograms for pregnant women. The Recommended Dietary Allowance (RDA) is 1,300 micrograms for breastfeeding women.
• Riboflavin (Vitamin B2)
  : Riboflavin is a water-soluble vitamin that is involved in many processes in the body, including normal cell function, growth, and energy production. Adequate nutrient supplementation with riboflavin may be required for the maintenance of adequate cognitive function. Treatment with B-vitamins, including riboflavin, has been reported to improve depression scores in patients taking tricyclic antidepressants. This may be related to tricyclic-caused depletion of riboflavin levels.
• Supplements of riboflavin, a precursor of the FAD prosthetic group of FMOs, may help maximize residual FMO3 enzyme activity in patients with trimethylaminuria, allowing further breakdown of trimethylamine. Children given riboflavin should be monitored closely because excessive amounts may cause gastrointestinal distress.
• Avoid if allergic or hypersensitive to riboflavin. Since the amount of riboflavin a human can absorb is limited, riboflavin is generally considered safe. Riboflavin is generally regarded as being safe during pregnancy and breastfeeding. The U.S. Recommended Dietary Allowance (RDA) for riboflavin in pregnant women is higher than for non-pregnant women, and is 1.4 milligrams daily (1.6 milligrams for breastfeeding women).

• For inherited cases of trimethylaminuria (TMAU), there is currently no known effective method of prevention of the disorder. However, there are treatments an individual may follow to reduce the severity of their symptoms. These may include dietary restrictions or low-dose antibiotics. Patients with TMAU should take their medications exactly as prescribed and/or strictly follow their diets in order to reduce symptoms.
• Although preventing metabolic disorders is generally difficult, individuals can be tested to determine if they are carriers of the disease. Although carriers do not experience symptoms of the disease, they may pass the disease to their children. Anyone with a family history of TMAU or who experiences symptoms of the disorder should be tested.
• 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. It should be noted that although exercise is a healthy preventive measure for many metabolic disorders, there is controversy regarding exercise during symptomatic episodes in TMAU patients.