Trimethylaminuria

Trimethylaminuria
Classification and external resources
Trimethylamine
ICD-10	E88.8
ICD-9	270.8
OMIM	602079
DiseasesDB	4835
GeneReviews	Trimethylaminuria

Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome,^[1] is a rare metabolic disorder that causes a defect in the normal production of the enzyme Flavin containing monooxygenase 3 (FMO3).^[2][3] When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly break down trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO) through a process called N-oxygenation. Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a strong fishy odor or strong body odor. The odor is not necessarily fishy, and the type of odor can vary from time to time. In that sense, the nicknames referring solely to a fishy odor are misnomers.

Contents 1 History 2 Symptoms 3 Incidence 4 Diagnosis 5 Treatment 6 Genetics 7 Popular culture 8 References

History

The first clinical case of TMAU was described in 1970.^[4]

Symptoms

Trimethylamine builds up in the body of patients with trimethylaminuria. The trimethylamine gets released in the person's sweat, urine, reproductive fluids, and breath, giving off a strong fishy or body odor. Some people with trimethylaminuria have a strong odor all the time, but most have a moderate smell that varies in intensity over time. Individuals with this condition do not have any physical symptoms, and typically appear healthy.^[5]

The condition seems to be more common in women than men, for unknown reasons. Scientists suspect that female sex hormones, such as progesterone and/or estrogen, aggravate symptoms. There are several reports that the condition worsens around puberty. In women, symptoms can worsen just before and during menstrual periods, after taking oral contraceptives, and around menopause.^[5]

This odor varies depending on many known factors, including diet, hormonal changes, stress level, amount of sweat, other odors in the space, and individual sense of smell.

Incidence

TMAU is a rare disorder that is caused by genetic and environmental factors and it can be a life-disruptive disorder. Living with TMAU can be challenging, and TMAU can adversely affect the livelihood of the people who have it, as well as their families. People, especially children, with the condition may face rejection or a lack of understanding from peers.

Diagnosis

Measurement of urine for the ratio of trimethylamine to trimethylamine oxide is the standard screening test. A blood test is available to provide genetic analysis. The prominent enzyme responsible for TMA N-oxygenation is coded by the FMO3 gene.

A similar test can be used to identify carriers of this condition - those individuals who carry one copy of a mutated gene but do not have symptoms. In this case, the person would be given a high dose of choline (one of the precursors of trimethylamine) and then have their urine tested for elevated levels of trimethylamine.

Treatment

Currently, there is no known cure or treatment for the disorder. However, some people affected by the disorder live relatively normal lives by managing their symptoms and with counseling. When the condition is suspected or known to occur in a family, genetic testing can be helpful in identifying the specific individuals who have or carry the disorder.

Ways of reducing the fishy odor may include:

• Avoiding foods such as egg yolks, legumes, red meats, fish, beans and other foods that contain choline, carnitine, nitrogen, sulfur and lecithin
• Taking low doses of antibiotics such as neomycin and metronidazole^[6] in order to reduce the amount of bacteria in the gut
• Using slightly acidic detergent with a pH between 5.5 and 6.5

Additionally, at least one study^[7] has suggested that daily intake of the supplements activated charcoal and/or copper chlorophyllin may improve the quality of life of individuals afflicted with TMAU by helping their bodies to oxidize and convert TMA to the odorless N-oxide (TMAO) metabolite. Study participants experienced subjective reduction in odor as well as objective reduction in TMA and increase in TMAO concentration measured in their urine. The study's success rates varied:

• 85% of test participants experienced complete loss of detectable "fishy" odor
• 10% experienced some reduction in detectable odor
• 5% did not experience any detectable odor reduction

Genetics

Most cases of trimethylaminuria appear to be inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. The parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene. Carriers may have mild symptoms of trimethylaminuria or experience temporary episodes of fish-like body odor.

Mutations in the FMO3 gene, which is found on the long arm of chromosome 1, cause trimethylaminuria. The FMO3 gene makes an enzyme that breaks down nitrogen-containing compounds from the diet, including trimethylamine. These compounds are produced by bacteria in the intestine as they digest proteins from eggs, meat, soy, and other foods. Normally, the FMO3 enzyme converts fishy-smelling trimethylamine into trimethylamine N-oxide which has no odor. If the enzyme is missing or its activity is reduced because of a mutation in the FMO3 gene, trimethylamine is not broken down and instead builds up in the body. As the compound is released in a person's sweat, urine, and breath, it causes the strong odor characteristic of trimethylaminuria. Researchers believe that stress and diet also play a role in triggering symptoms.

There are more than 40 known mutations associated with TMAU.^[8][9] Loss-of-function mutations, nonsense mutations, and missense mutations are three of the most common. Nonsense and missense mutations cause the most severe phenotypes.

Although FMO3 mutations account for most known cases of trimethylaminuria, some cases are caused by other factors. A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria in the digestive system. A few cases of the disorder have been identified in adults with liver damage caused by hepatitis.

The evolution of the FMO3 gene has recently been studied, including the evolution of some mutations associated with TMAU.^[10]

Popular culture

The novel Boxer, Beetle by Ned Beauman features a leading character with trimethylaminuria.

Gordon Crisp of Freaks and Geeks has trimethylaminuria.

Though it is never stated outright, it is possible that the minor character Reek in George R. Martin's A Song Of Ice and Fire has this condition, given his symptoms.

References

This article incorporates public domain text from The U.S. National Library of Medicine and The National Human Genome Research Institute

Inborn error of amino acid metabolism (E70–E72, 270) K→acetyl-CoA Lysine/straight chain Glutaric acidemia type 1 · type 2 · Hyperlysinemia · Pipecolic acidemia · Saccharopinuria Leucine Maple syrup urine disease · Isovaleric acidemia · 3-Methylcrotonyl-CoA carboxylase deficiency · 3-hydroxy-3-methylglutaryl-CoA lyase deficiency · 3-Methylglutaconic aciduria 1 Tryptophan Hypertryptophanemia G G→pyruvate→citrate Glycine Sarcosinemia · D-Glyceric acidemia · Glutathione synthetase deficiency Glycine→Creatine: GAMT deficiency · Glycine encephalopathy G→glutamate→ α-ketoglutarate Histidine Carnosinemia · Histidinemia · Urocanic aciduria Proline Hyperprolinemia · Prolidase deficiency Glutamate/glutamine SSADHD G→propionyl-CoA→ succinyl-CoA Valine Maple syrup urine disease · Hypervalinemia · Isobutyryl-CoA dehydrogenase deficiency Isoleucine Maple syrup urine disease · Beta-ketothiolase deficiency · 2-Methylbutyryl-CoA dehydrogenase deficiency Methionine Hypermethioninemia · Homocystinuria · Cystathioninuria General BC/OA Propionic acidemia · Methylmalonic acidemia · Methylmalonyl-CoA mutase deficiency G→fumarate Phenylalanine/tyrosine Phenylketonuria Tetrahydrobiopterin deficiency · 6-Pyruvoyltetrahydropterin synthase deficiency Tyrosinemia Type II tyrosinemia · Type III tyrosinemia/Hawkinsinuria · Alkaptonuria/Ochronosis · Type I tyrosinemia Tyrosine→Melanin Albinism: Ocular albinism (1) · Oculocutaneous albinism (Hermansky–Pudlak syndrome) · Waardenburg syndrome Tyrosine→Norepinephrine Dopamine beta hydroxylase deficiency · reverse: Brunner syndrome G→oxaloacetate Urea cycle/Hyperammonemia (arginine, aspartate) N-Acetylglutamate synthase deficiency · Carbamoyl phosphate synthetase I deficiency · Ornithine transcarbamylase deficiency/translocase deficiency · Citrullinemia · Argininosuccinic aciduria · Argininemia Transport/ IE of RTT Solute carrier family: Cystinuria · Hartnup disease · Lysinuric protein intolerance · Iminoglycinuria Fanconi syndrome: Oculocerebrorenal syndrome · Cystinosis Other Trimethylaminuria · 2-Hydroxyglutaric aciduria · Fumarase deficiency M: MET mt, k, c/g/r/p/y/i, f/h/s/l/o/e, a/u, n, m k, cgrp/y/i, f/h/s/l/o/e, au, n, m, epon m(A16/C10),i(k, c/g/r/p/y/i, f/h/s/o/e, a/u, n, m)