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.
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 soya, 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 Deficiency Syndromes” 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.
Trimethylaminuria is a rare metabolic disorder that is inherited as an autosomal recessive genetic trait (primary), or occurs as the result of treatment with large doses of dietary precursors of the offending chemical (secondary). Symptoms develop when the ability of the liver enzyme (flavin-containing monooxygenase 3) to break down (metabolize) trimethylamine is inhibited. The responsible gene, designated as FMO3, has been tracked to gene map locus 1q24.3.
Although humans have several FMO genes, changes in only one of these, FMO3, causes trimethylaminuria. For reasons that are unclear, many different changes (mutations) of the FMO3 gene exist.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1q24.3” refers to a region on the long arm of chromosome 1, within the band 24. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
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 defective 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.
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, from 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 of benefit for patients and their families.
IInformation 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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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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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.
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FMO3 mutation database: http://databases.lovd.nl/shared/genes/FMO3 (Updated August 15 2013). Accessed August 5, 2014.
Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Updated July 20, 2011. www.genome.gov/11508983 Accessed August 5, 2014.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Trimethylaminuria. Entry No: 602079. Last Edited March 21, 2012. Available at: http://omim.org/entry/602079 Accessed August 5, 2014.
Phillips IR, Shephard EA. Trimethylaminuria. 2007 Oct 8 [Updated 2011 Apr 19]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1103/ Accessed August 5, 2014.
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 http://ommbid.mhmedical.com/content.aspx?bookid=474§ionid=45374077&Resultclick=2 Accessed August 5, 2014.
Trimethylaminuria. Orphanet. Updated May 2009. www.orpha.net/static/GB/trimethylaminuria.html Accessed August 5, 2014.
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