October 21, 2020
Years published: 1994, 1995, 1999, 2005, 2011, 2014, 2017, 2020
NORD gratefully acknowledges Elizabeth Shephard, PhD, Professor of Molecular Biology, Department of Structural and Molecular Biology, University College London and Ian Phillips, PhD, Visiting Professor of Molecular Biology, Department of Structural and Molecular Biology, University College London and Emeritus Professor of Molecular Biology, School of Biological and Chemical Sciences, Queen Mary University of London, for assistance in the preparation of this report.
Trimethylaminuria is a rare disorder in which the body’s metabolic processes fail to alter the chemical trimethylamine. Trimethylamine is notable for its unpleasant smell. It is the chemical that gives rotten fish a bad smell. When the normal metabolic process fails, trimethylamine accumulates in the body, and its odor is detected in the person’s sweat, urine and breath. The consequences of emitting a foul odor can be socially and psychologically damaging among adolescents and adults.
The genetic or primary form of this disorder is transmitted in an autosomal recessive pattern. The metabolic deficiency occurs as a result of a failure in the cell to make a specific protein, in this case the enzyme flavin-containing monooxygenase 3 (FMO3). Enzymes are nature’s catalysts and act to speed up biochemical processes. Without this enzyme, foods containing carnitine, choline and/or trimethylamine N-oxide are processed to trimethylamine and no further, causing a strong fishy odor.
A secondary form of trimethylaminuria may result from the side effects of treatment with large doses of the amino-acid derivative L-carnitine (levocarnitine) or choline. This secondary form of the disorder is a result of an overload of trimethylamine. In this case, there is not enough of the enzyme to get rid of the excess trimethylamine.
The fish-odor smell is the obvious symptom; otherwise affected individuals appear normal and healthy.
Trimethylamine is normally formed by bacterial action in the intestine on choline (found in foods such as soy, liver, kidneys, wheat germ, brewer’s yeast, and egg yolk), or on trimethylamine N-oxide (found in salt water fish). The trimethylamine is then carried to the liver where it is converted to trimethylamine N-oxide, a metabolic product that has no odor.
When secondary trimethylaminuria develops as a result of large oral doses of L-carnitine, choline or lecithin, the symptoms disappear as the dosage is lowered. L-carnitine is used in the treatment of carnitine-deficiency syndromes and is sometimes used by athletes who believe it enhances physical strength. (For more information on this disorder, choose “carnitine” as your search words in the Rare Disease Database). Choline is used in the treatment of Huntington disease and Alzheimer disease. Choline and lecithin are present in certain food supplements and ‘health’ foods.
Primary trimethylaminuria is a rare metabolic disorder caused by changes (mutations) in the FMO3 gene. Humans have several FMO genes, but only mutations in FMO3 cause trimethylaminuria. For reasons that are unclear, many different mutations of the FMO3 gene exist.
Primary trimethylaminuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and, therefore, have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents of both carrying the same abnormal gene, which increases the risk of having children with a recessive genetic disorder.
Secondary trimethylaminuria occurs as the result of treatment with large doses of dietary precursors of the offending chemical. Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) is insufficient to break down (metabolize) the excess trimethylamine.
Trimethylaminuria is a rare metabolic disorder. More than 100 cases have been reported in the medical literature. Some clinicians believe that the disorder is under-diagnosed since many people with mild symptoms do not seek help. However, some physicians do not recognize the symptoms of trimethylaminuria when a person with body odor seeks a diagnosis.
The presence of the rotten-fish odor is indicative, especially in severe cases. However, diagnosis based on smell is unreliable because the odor is often episodic and not everyone can detect the smell of trimethylamine. In addition, on the basis of smell, trimethylaminuria can be difficult to distinguish from other conditions that give rise to an unpleasant body odor. Diagnosis is based on urinary analysis of trimethylamine and trimethylamine N-oxide, which can distinguish between severe and mild cases. Urine analysis after the administration of large doses of trimethylamine can distinguish carriers of the condition from unaffected individuals. Genetic testing is available to distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, and secondary, non-genetic forms of the disorder.
In mild cases, symptoms are relieved when foods containing choline and lecithin are restricted. Some severe cases may require the administration of a gut-sterilizing antibiotic such as metronidazole. This treatment reduces the number of intestinal bacteria that break down choline and trimethylamine N-oxide into trimethylamine. In the case of mutations that do not completely abolish FMO3 activity, supplements of riboflavin might help maximize residual enzyme activity. Dietary supplements such as activated charcoal and copper chlorophyllin can bind trimethylamine in the gut and hence reduce the amount available for absorption. The use of slightly acidic soaps and body lotions can convert trimethylamine on the skin into a less volatile form that can be removed by washing. If the disorder is acquired due to excessive doses of L-carnitine, choline or lecithin, symptoms disappear with reduction of dosage.
Genetic counseling may be helpful for patients and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials conducted in Europe, contact:
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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Schmidt AC and Leroux J-C. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov. Today 2020; 259(9):1710-1717. https://doi.org/10.1016/j.drudis.2020.06.026
Shephard EA, Treacy EP and Phillips IR. Clinical utility gene card for: trimethylaminuria – update 2014. Eur. J. Hum. Genet. 2015;20:doi:10.1038/ejhg.2014.226.
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Chalmers RA, Bain MD, Michelakakis H, et al. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J Inherit Metab Dis. 2006;29:162-72.
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Allerston CK, Vetti, HH, Houge G et al. A novel mutation in the flavin-containing monooxygenase 3 gene (FMO3) of a Norwegian family causes trimethylaminuria. Mol. Genet. Metab. 2009;98:198-202.
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Cashman JR, Akerman BR, Forrest SM et al. Population-specific polymorphisms of the human FMO3 gene: significance for detoxication. Drug Metab Dispos. 2000;28:169-73.
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Murphy HC, Dolphin CT, Janmohamed A et al. A novel mutation in the flavin-containing monooxygenase 3 gene, FMO3, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetcis. 2000;10:439-51.
Dolphin CT, Janmohamed A, Smith RL, et al. Missense mutation in flavin-containing monooxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17:491-94.
FMO3 mutation database. Updated August 6, 2020. http://databases.lovd.nl/shared/genes/FMO3 Accessed October 20, 2020.
Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Updated December 18, 2018. www.genome.gov/11508983 Accessed October 20, 2020.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Trimethylaminuria. Entry No: 602079. Last Edited 03/24/2017. Available at: http://omim.org/entry/602079 Accessed October 20, 2020.
Phillips IR, Shephard EA. Primary Trimethylaminuria. 2007 Oct 8 [Updated 2015 Oct 1]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1103/ Accessed October 20, 2020.
Treacy EP. Trimethylaminuria and deficiency of favin-containing monooxygenase type 3 (FMO3). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 88.1. Available at: https://ommbid.mhmedical.com/content.aspx?bookId=2709§ionId=225085075 Accessed October 20, 2020.
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