What are the other Names for this Condition? (Also known as/Synonyms)

• Fish Malodor Syndrome
• Stale Fish Syndrome
• TMAU (Trimethylaminuria)

What is Trimethylaminuria? (Definition/Background Information)

• 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

(Source: Trimethylaminuria; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Trimethylaminuria? (Age and Sex Distribution)

• Trimethylaminuria is a rare congenital disorder. The presentation of symptoms typically increases at around puberty
• Although both genders may be affected, the condition is more prevalent in females 
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Trimethylaminuria? (Predisposing Factors)

• A positive family history may be an important risk factor, since Trimethylaminuria is an inherited condition
• Ingestion of foods that are rich in trimethylamine may be a risk factor for developing the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Trimethylaminuria? (Etiology)

• Most cases of Trimethylaminuria are caused by changes (mutations) in the FMO3 gene. This gene provides the body with instructions to make an enzyme that is responsible for breaking down certain nitrogen-containing compounds such as trimethylamine
  • A mutation in this gene prevents the enzyme from functioning properly, so it is unable to break down compounds like trimethylamine
  • As trimethylamine begins to build up in the body, it is released in a person's sweat, urine, and breath. Trimethylamine has a fishy odor, and this leads to the characteristic features of Trimethylaminuria
• In some instances, Trimethylaminuria may occur in those who do not have changes in both copies of the FMO3 gene. In such cases, the condition may be caused by having high levels of trimethylamine due to the presence of more trimethylamine-producing bacteria in the gut
• High levels of trimethylamine can also be caused by a diet high in foods that create trimethylamine as they are metabolized (broken down)
• Trimethylaminuria is usually inherited in an autosomal recessive manner

(Source: Trimethylaminuria; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive mode of inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Trimethylaminuria?

In some cases, individuals with one defective copy of the FMO3 gene may exhibit mild symptoms of Trimethylaminuria. The signs and symptoms of Trimethylaminuria may include:

• Fishy odor in body fluids and breath
• Anemia
• Depressivity
• Hypertension
• Neutropenia
• Recurrent pneumonia
• Splenomegaly
• Tachycardia

(Source: Trimethylaminuria; Orphanet, National Institute of Health and Medical Research (INSERM), Paris.)

How is Trimethylaminuria Diagnosed?

A diagnosis of Trimethylaminuria is based on the following:

• A physical examination
• The presence of characteristic signs and symptoms
• An evaluation of family and personal medical history
• Urine test to measure the level of trimethylamine in the urine (this test may be conducted following oral ingestion of choline)
• Molecular genetic testing for FMO3 gene mutation(s), to check for or confirm Trimethylaminuria

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Trimethylaminuria?

The complications of Trimethylaminuria may include:

• Social embarrassment
• Anxiety
• Low self-esteem
• Depression

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Trimethylaminuria Treated?

Although there is permanent treatment or cure for Trimethylaminuria, the following are some methods may help 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.

(Source: Trimethylaminuria; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How can Trimethylaminuria be Prevented?

Trimethylaminuria may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders
• Regular medical screening at periodic intervals with tests and physical examinations are recommended

What is the Prognosis of Trimethylaminuria? (Outcomes/Resolutions)

In general, the long-term outlook (prognosis) for people with Trimethylaminuria is good.

• Affected individuals 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

(Source: Trimethylaminuria; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Trimethylaminuria:

• It has been reported that the fishy odor may be very intense in women just prior to or post-menstruation
• Additionally, exercise, stress, and emotional upsets, may increase the intensity of fishy smell

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/