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Last updated: 8/15/2024
Years published: 1994, 1995, 1999, 2005, 2011, 2014, 2017, 2020, 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Elizabeth Shephard, PhD, Professor of Molecular Biology, Department of Structural and Molecular Biology, University College London and Ian Phillips, PhD, Emeritus Professor of Molecular Biology, School of Biological and Behavioral Sciences, Queen Mary University of London, for assistance in the preparation of this report.
Trimethylaminuria (TMAU) is a rare disorder in which the body is not able to metabolize the chemical trimethylamine, and this causes body odor. Trimethylamine has a characteristic rotten fish smell.
When the normal metabolic process of trimethylamine fails, trimethylamine accumulates in the body and its odor is detected in the personโs sweat, urine and breath. The foul odor can be socially and psychologically damaging in adolescents and adults.
Trimethylaminuria can be primary or secondary.
The genetic or primary form of this disorder is caused by changes (variants) in the FMO3 gene and results in a deficiency of the FMO3 enzyme which is necessary for the trimethylamine metabolism. Enzymes are natureโs catalysts and act to speed up biochemical processes. Without the FMO3 enzyme, foods containing carnitine, choline and/or trimethylamine N-oxide are processed to trimethylamine but no further, leading to trimethylamine accumulation and, therefore, causing a strong fishy odor.
A secondary form of trimethylaminuria (trimethylaminuria, not caused by genetic FMO3 deficiency), can be classified as acquired trimethylaminuria which emerges during adult life because of some medical conditions, transient (childhood trimethylaminuria or associated with menstruation) and due to precursor overload, such as resulting from the side effects of treatment with large doses of the amino-acid derivative L-carnitine (levocarnitine) or choline.
Treatment depends on the symptoms and may include avoiding certain foods or antibiotic administration, certain supplements and special body soaps.
The fish-odor smell is the obvious symptom; otherwise, affected individuals appear normal and healthy.
As trimethylamine builds up in the body, it causes affected individuals to emit a strong fishy odor in their sweat, urine and breath.
In people with primary trimethylaminuria, symptoms are often present from birth. In secondary trimethylaminuria symptoms develop later.
The condition may worsen during puberty. In women, symptoms are most severe just before and during menstruation, after taking oral contraceptives and around menopause.
Primary trimethylaminuria is a rare metabolic disorder caused by changes (variants) in the FMO3 gene. Humans have several FMO genes, but only variants in FMO3 cause trimethylaminuria.
The FMO3 gene provides instructions for making an enzyme known as FMO3 that is part of a larger enzyme family called flavin-containing dimethylaniline monooxygenases (FMOs). These enzymes break down compounds that contain nitrogen, sulfur, or phosphorus.
The enzyme FMO3, which is mostly produced in the liver, oversees decomposing nitrogen-containing substances that come from food.
Trimethylamine, the chemical that gives fish their distinct smell, is one of these substances. As bacteria in the gut aid in the digestion of specific proteins found in foods such as eggs, liver, legumes (including soybeans and peas), some types of fish and other legumes, trimethylamine is formed. Normally, the fishy-smelling trimethylamine is changed into the odorless trimethylamine-N-oxide by the FMO3 enzyme. Afterwards, trimethylamine-N-oxide is eliminated from the body in urine. Variants in the FMO3 gene may impair the enzyme function.
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 TMAU occurs when the body accumulates too much TMA, even though the enzymes responsible for breaking it down usually work well. This overload can happen when a person consumes a lot of certain foods or due to other factors that affect how TMA is processed. Foods that can cause TMA buildup can occur after eating foods that are high in substances like choline, carnitine and lecithin, which gut bacteria break down into TMA:
When these foods or supplements are consumed in large quantities, the liver enzyme responsible for breaking down TMA can become overwhelmed, leading to symptoms of TMAU.
Other factors besides diet that can contribute to secondary TMAU, include:
Secondary TMAU can also be categorized into different types depending on the cause:
Trimethylaminuria is a rare disorder. 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.
Although the first case of TMAU was documented around 1970, as of 2020, only a few hundred cases have been reported in the medical literature. A study on the prevalence of TMAU found that about 1% of the white British population are carriers of a disease-causing FMO3 gene variant. In contrast, studies in other ethnic groups such as the New Guinean population, revealed a higher carrier rate of 11%. Carriers have one FMO3 gene variant, but usually do not show any symptoms of TMAU unless they are exposed to an overload of TMA precursors.
TMAU affects males and females, but there may be differences in how severe the symptoms are. Some studies suggest that females might experience more severe symptoms because of hormonal changes during their menstrual cycle and pregnancy. TMAU can appear at any age, but the symptoms often become more noticeable during puberty when the body goes through hormonal changes.
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. In people with deficient or dysfunctional FMO3 activity, urinary trimethylaminuria (TMA) levels will be elevated following the administration of the large doses of TMA.
Genetic testing identifying FMO3 gene variants can confirm the diagnosis of primary trimethylaminuria. Genetic testing can also distinguish between primary genetic trimethylaminuria, which will result in severe symptoms, and secondary, non-genetic forms of the disorder.
In people with mild cases, symptoms are relieved when foods containing choline and lecithin are restricted. Some people with 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.
Some people have gene variants that do not completely abolish FMO3 activity, and for these people, 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 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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
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/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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 โ 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
Awosika AO, Anastasopoulou C. Trimethylaminuria. [Updated 2023 Jul 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK594255/ Accessed August 15, 2024.
FMO3 mutation database. Updated Feb 26, 2024. http://databases.lovd.nl/shared/genes/FMO3 Accessed April 9, 2024.
Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Updated December 18, 2018. www.genome.gov/11508983 Accessed 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/602079 Accessed 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. GeneReviewsยฎ [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§ionId=225085075 Accessed April 9, 2024.
Carrier. National Human Genome Research Institute. August 14, 2024. https://www.genome.gov/genetics-glossary/Carrier Accessed August 15, 2024.
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