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Trimethylaminuria

What is Trimethylaminuria?

Trimethylaminuria (TMAU) is a rare metabolic disorder characterized by a strong body odor that resembles the smell of rotting fish.  Trimethylamine (TMA) is a chemical with a strong odor that is produced in the body. TMA is produced by all individuals by the bacteria that naturally reside in the large intestine from certain dietary precursor molecules. These gut bacteria are healthy and essential to the overall health of the individual. Unlike unaffected individuals, those affected by TMAU lack the ability to break down TMA to non-odorous molecules. As a result of the presence of high amounts of TMA in bodily secretions such as sweat, urine, and the air that is breathed out, affected individuals may experience a strong body odor that is characteristic of TMA. 

Enzymes are proteins that speed up chemical reactions in the body. The high amount of TMA in this condition occurs because the enzyme that is responsible for the breakdown of TMA does not have the capacity to break down the amounts that are present in the body. TMAU may occur as primary genetic, secondary, transient childhood, transient menstrual, or dietary conditions.

 

 

Synonyms

  • Fish-odor syndrome
  • Fish malodor syndrome
  • TMAU
  • Stale fish syndrome

Trimethylaminuria (TMAU) is a rare metabolic disorder characterized by a strong body odor that resembles the smell of rotting fish.  Trimethylamine (TMA) is a chemical with a strong odor that is produced in the body. TMA is produced by all individuals by the bacteria that naturally reside in the large intestine from certain dietary precursor molecules. These gut bacteria are healthy and essential to the overall health of the individual. Unlike unaffected individuals, those affected by TMAU lack the ability to break down TMA to non-odorous molecules. As a result of the presence of high amounts of TMA in bodily secretions such as sweat, urine, and the air that is breathed out, affected individuals may experience a strong body odor that is characteristic of TMA. 

Enzymes are proteins that speed up chemical reactions in the body. The high amount of TMA in this condition occurs because the enzyme that is responsible for the breakdown of TMA does not have the capacity to break down the amounts that are present in the body. TMAU may occur as primary genetic, secondary, transient childhood, transient menstrual, or dietary conditions.

 

Acknowledgement of Trimethylaminuria has not been added yet.

TMAU has been described in over two hundred cases but it is thought to be more common. The true prevalence is unknown as it is believed that undiagnosed TMAU is relatively common in individuals with disorders of malodor production for which the cause is unknown.

Name Abbreviation
Fish-odor syndrome Fish-odor syndrome
Fish malodor syndrome Fish malodor syndrome
TMAU TMAU
Stale fish syndrome Stale fish syndrome

TMA is produced from dietary precursors by gut bacteria. Precursors are molecules that are subsequently modified to form other molecules. TMA precursors are present in foods such as egg yolk, liver, kidney, peas, soybean, legumes, shellfish, and salt-water fish. Once produced, TMA is broken down in the liver into non-odorous products by an enzyme called flavin-containing monooxygenase (FMO3). In individuals affected by TMAU, there is an imbalance between the amount of TMA that needs to be broken down and the capacity of FMO3 to facilitate this breakdown. As a result, the excess TMA builds up and is eliminated from the body through bodily secretions such as urine and sweat as well as breath. 

In most cases, TMAU is present as a primary genetic form due to a defect in FMO3, the gene responsible for encoding the FMO3 enzyme. TMAU occurs in individuals who have inherited a defective FMO3 from both their parents, resulting in an autosomal recessive mode of inheritance. However, a milder form of this condition might be present in individuals with one healthy and one defective gene. As a result of this defect, the encoded enzyme may be insufficient or ineffective in facilitating the breakdown of TMA. The primary form is present at birth but may only become apparent as the child begins to eat foods that contain the precursor molecules. 

Secondary TMAU appears in adults with no history of the condition themselves or in family members. Secondary TMAU is very rare and the exact cause is unknown. There is some evidence suggesting that disorders of the liver may contribute to the development of secondary TMAU. Specifically, viral hepatitis, a liver infection caused by viruses, seems to be linked to the secondary form of this condition. 

Transient childhood TMAU appears in infants that are born prematurely and are given supplements that contain TMA precursors. The fish odor disappears once the supplement is removed from the infant’s diet and fails to develop again once the supplement is re-introduced after a few months. It is believed that transient childhood TMAU occurs because the responsible enzyme matures throughout childhood and is less active in affected infants. Other cases of transient childhood TMAU have been associated with the presence of only one defective FMO3 gene. 

Transient menstrual TMAU develops in affected women at the onset of menstruation. During this time, the odor intensifies in affected individuals or may temporarily appear in otherwise healthy women. This is likely due to the inhibition of the FMO3 enzyme by the hormonal changes that occur during the menstrual cycle.

Precursor overload may also lead to TMAU. In such cases, TMAU emerges after administration of certain Alzheimer’s disease and Huntington’s disease medications that contain a TMA precursor. These individuals might have healthy FMO3 levels and activity and TMAU only occurs due to an increased amount of TMA precursor intake.

 

The primary symptom of TMAU is the body odor that resembles the smell of rotting fish. The affected individuals appear healthy and have no other physical symptoms. In primary TMAU, the symptoms are present at birth but may intensify before menstruation in affected females or during puberty. The intensity of the smell widely varies among individuals and it may be barely noticeable in some.

Diagnosis of TMA is made based on a combination of clinical, biochemical, and genetic testing. A history of rotting fish body odor is suggestive of TMAU. Urine samples can be tested for the presence of TMA as affected individuals have higher urinary TMA levels. Genetic testing can help confirm the diagnosis although not all cases are associated with genetic causes.

Healthy individuals have a low amount of TMA in their urine as TMA is broken down in the liver before its urinary excretion. TMA levels are elevated in affected individuals as TMA cannot be sufficiently broken down. Thus, a urine sample can be used to measure the amount of TMA that has not been broken down by the liver. A high amount of urinary TMA suggests TMAU. Urinary testing can be performed without changing the individual’s dietary intake but more commonly it is performed after substrate loading. In these cases, the individual is asked to eat foods that are rich in TMA precursors before a urine sample is obtained. Genetic testing is particularly helpful in the diagnosis of transient or milder versions of TMAU.

Affected individuals can benefit from frequent changing of their clothes and bathing with acid soaps that reduce the odor of TMA in sweat. In addition, dietary restriction of TMA precursors may be helpful. However, caution must be taken to meet dietary recommendations as some of these precursors are essential to the body. Avoiding saltwater fish is often recommended as the primary dietary management. Furthermore, some vegetables such as Brussel sprouts and cauliflower are known to inhibit the activity of FMO3 and decrease the breakdown of TMA. Limiting the intake of such vegetables can also prove beneficial.

Short-term treatment with certain antimicrobials that reduce the bacteria present in the large intestine can also be helpful. Vitamin B2 supplements can also enhance the activity of FMO3 and reduce the symptoms.

 

TMAU does not pose much medical concern as it typically does not affect the body in a significant way and affected individuals have no other physical signs and symptoms besides the foul odor.  However, the quality of life may be affected as TMAU presents challenges in an individual’s personal and professional relationships.

Certain circumstances can intensify the malodor such as exercise, menstruation, fever, and stress. Information about such factors can help the individual plan and manage their condition better.

Mackay R, McEntyre C, Henderson C, Lever M, George P. Trimethylaminuria: causes and diagnosis of a socially distressing condition. Clinical Biochemistry Review. 2011;32(1):33–43.

Phillips I, Shephard E. Primary Trimethylaminuria. 2007. In: Adam M, Ardinger H, Pagon R, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1103/

D'Angelo R, Scimone C, Esposito T, Bruschetta D, Rinaldi C, Ruggeri A, Sidoti A. Fish odor syndrome (trimethylaminuria) supporting the possible FMO3 down expression in childhood: a case report. Journal of medical case reports. 2014; 8: 328. doi:10.1186/1752-1947-8-328

Sabir N, Jones E, Padmakumar B. Trimethylaminuria. BMJ Case Reports. 2016; 2016:bcr2015213742. doi:10.1136/bcr-2015-213742

Mitchell S, Smith R. Trimethylaminuria: The Fish Malodor Syndrome. Drug Metabolism and Disposition. 2001; 29 (4):517-521. 

Chalmers R, Bain M, Michelakakis H, Zschocke J. Iles R. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. Journal of Inherited Metabolic Disease. 2006; 29:162. https://doi.org/10.1007/s10545-006-0158-6

Messenger J, Clark S, Massick S, Bechtel M. A review of trimethylaminuria: (fish odor syndrome). Journal of Clinical Aesthetic Dermatology. 2013;6(11):45–48.

Welcome to RareShare Created by biotechguy
Last updated 31 Mar 2012, 03:13 AM

Posted by tekdiva
31 Mar 2012, 03:13 AM

Hi David! I see that it has been over 3 years since you posted this. I really want to know more about TMAU and how to get tested... I am almost positive that I have this and have had it for at least 15 years. I believe my parents also had it and "fear" for my daughter...

Posted by biotechguy
2 Jan 2009, 01:30 AM

Hi, My name is David Isserman and I am one of the co-founders of RareShare. I just wanted to quickly welcome you all to the Site. If you ever have any questions about RareShare or suggestions on improving the Site, please feel free to contact me at david@rareshare.org. David

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Last updated 14 Apr 2009, 10:14 PM

Posted by kemetian
14 Apr 2009, 10:14 PM

if anyone is in the california,,,sacramento area and you would like support email me and you can drop by one of our support groups kemetian43@yahoo.com

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