Information on the following diseases can be found in the Related Disorders section of this report:

• None

The fish-odor smell is the obvious symptom, but other signs may be expressed, such as hypertension and abnormal rapid breathing (tachycardia).

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 trimethylamine-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, 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).

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 to 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 1q23-q25.

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 1q23-q25" refers to a region on the long arm of chromosome 1, between bands 21 and 25. 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 to have 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 to both carry the same abnormal gene, which increases the risk to have 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.

Diagnosis
The presence of the rotten-fish odor is diagnostic, especially in severe cases. For mild cases, and to detect possible carriers of trimethylaminuria, urine analysis after the administration of large doses of trimethylamine or choline is used. Genetic testing is available to confirm a diagnosis.

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-oxide into trimethylamine. If the disorder is acquired due to L-carnitine, symptoms disappear with reduction of dosage.

Genetic counseling may be of benefit 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: prpl@cc.nih.gov

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

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Trimethylaminuria. Entry Number; 602079: Last Edit Date; 2/3/1999.

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

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

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.

Philips 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.

Krueger SK, Williams DE, Yueh MF, et al. Genetic polymorphisms of flavin-containing mono-oxygenase (FMO). Drug Metab Rev. 2002;34:523-32.

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

JOURNAL ARTICLES
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.

Zhang j, Tran Q, Lattard V, et al. deleterious mutations in the flavin-containing monooxygenase 3 (FMO3) gene causing trimethylaminuria. Pharmacogentics. 2003;13:495-500.

Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos. 2001;29
(4 Pt 2):517-21.

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. Pharnmacogentics. 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.

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. Missense mutation in flavin-containing monooxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17:491-94.

FROM THE INTERNET
Learning About Trimethylaminuria. National Human Genome Research Institute (NHGRI). Last Reviewed: October 2004. 4pp.
www.genome.gov/11508983

Trimethylaminuria. Genetics Home Reference. Published: May 13,2005. 3pp.
http://ght.nlm.nih.gov/condition=trimethylaminuria

Trimethylaminuria. Orphanet. Update:15/05/2005. 1p.
www.orpha.net/static/GB/trimethylaminuria.html