Trimethylaminuria - Symptoms, Causes, Treatment | NORD (2024)

Disease Overview

Trimethylaminuria is a rare disorder in which the body is not able to metabolize the chemical trimethylamine, and this causes body odor. Trimethylamine 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 foul odor can be socially and psychologically damaging in adolescents and adults.

The genetic or primary form of this disorder is inherited in an autosomal recessive pattern. The metabolic deficiency occurs because 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. Another cause of secondary trimethylaminuria is thought to be an imbalance in the types of bacteria or other microorganisms in the gut. This secondary form of the disorder is a result of an overload of trimethylamine. In this case, there is not enough enzyme to get rid of the excess trimethylamine.

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Synonyms

• fish odor syndrome
• stale fish syndrome
• TMAU

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Signs & Symptoms

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 saltwater 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 because 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.

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Causes

Primary trimethylaminuria is a rare metabolic disorder caused by changes (variants) in theFMO3gene. Humans have severalFMOgenes, but only variants inFMO3cause trimethylaminuria. For reasons that are unclear, many different variants of theFMO3gene exist.

Primary trimethylaminuria is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and 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 is 25%. The risk is the same for males and females.

Secondary trimethylaminuria occurs as the result of treatment with large doses of dietary precursors of the offending chemical or because of changes in the composition of microorganisms in the gut. Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) is insufficient to break down (metabolize) the excess trimethylamine.

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Affected populations

Trimethylaminuria is a rare metabolic disorder. Several hundred 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.

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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, based on smell, trimethylaminuria can be difficult to distinguish from other conditions that cause 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.

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Standard Therapies

Treatment
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 gene variants 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.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet atwww.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:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email:prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialregister.eu/

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Resources

RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visitwww.rareconnect.org.

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References

TEXTBOOKS
Treacy EP, Lambert DM. Trimethylaminuria. In: NORD Guide to Rare Disorders. Lippincott, Williams & Wilkins. Philadelphia, PA. 2003:503.

REVIEW ARTICLES
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.

Yamazaki H and Shimizu M. Survey of variants of human flavin-containing monooxygenase 3 (FMO3) and their drug oxidation activities. Biochem.Pharmacol. 2013; 85:1588-1593.

MacKay RJ, McEntyre CJ, Henderson C et al. Trimethylaminuria: causes and diagnosis of a socially distressing condition. Clin. Biochem. Rev. 2011;32:33-43.

Phillips IR and Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol. Sci. 2008;29:294-301.

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.

Cashman JR, Camp K, Fakharzadeh SS, et al. Biochemical and clinical aspects of the human flavin-containing monooxygenase for 3 (FMO3) related to trimethylaminuria. Curr Drug Metab. 2003;4:151-70.

Hernandez D, Addou S, Lee D, et al. Trimethylaminuria and a human FM03 mutation database. Hum. Mutat. 2003;22:209-13.

Cashman JR. Human flavin-containing monooxygenase (form 3): polymorphisms and variations in chemical metabolism. Pharmacogenetics. 2002;30:325-39.

Phillips IR, Shephard EA. Flavin-containing monooxygenases. In: Creighton TE. ed., Wiley Encyclopedia of Molecular Medicine. John Wiley and Sons, New York, NY. 2002:1297-99.

Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab. Dispos. 2001;29:517-21.

JOURNAL ARTICLES
Shimizu M, Allerston CK, Shephard EA et al. Relationship between flavin-containing mono-oxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population. 2014. Brit. J. Clin. Pharmacol. 2014;77;839-851.

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.

Busby MG, Fischer L, da Costa KA et al. Choline- and betaine-defined diets for use in clinical research and for the management of trimethylaminuria. J Am Diet Assoc. 2004;104:1836-45.

Yamazaki H, Fujieda M, Togashi M et al. Effects of the dietary supplements, activated charcoal and copper chlorophyllin, on urinary excretion of trimethylamine in Japanese trimethylaminuria patients. Life Sci. 2004;74:2739-2747.

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.

Dolphin CT, Janmohamed A, Smith RL et al. Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FMO3) gene in patients with fish-odour syndrome. Pharnmacogenetics. 2000;10:799-804.

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.

INTERNET
FMO3 mutation database. Updated Feb 26, 2024.http://databases.lovd.nl/shared/genes/FMO3Accessed April 9, 2024.

Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Updated December 18, 2018.www.genome.gov/11508983Accessed April 9, 2024.

Trimethylaminuria. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Entry No: 602079. Last Edited 04/24/2023. Available at:http://omim.org/entry/602079Accessed April 9, 2024.

Phillips IR, Shephard EA. Primary Trimethylaminuria. 2007 Oct 8 [Updated 2020 Nov 5]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.Available from: https://www.ncbi.nlm.nih.gov/books/NBK1103/ Accessed April 9, 2024.

Treacy EP. Trimethylaminuria and deficiency of flavin-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&sectionId=225085075 Accessed April 9, 2024.

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