Fish Odour Syndrome and Trimethylaminuria

Author: Gabriele Lerda
Date: 19/02/2013



The Fish odour syndrome is characterised by a strong body odour of rotting fish due to poor hygiene, gingivitis, bacterial vaginosis and urinary tract infections. Other causes of odour body can occur as a result from an excess of proteins in the diet, or from an increase in bacteria that normally produce trimethylamine in the GI tract. This condition may also be caused by advanced kidney or liver disease or by a rare inherited metabolic disorder known as Trimethylaminuria.
In case of Trimethylaminuria the constant and unpleasant odour can result in a variety of psychological problems that go from social exclusion to suicidal tendencies.


The odour of fish is caused by an abnormal excretion of a tertiary aliphatic amine, trimethylamine (TMA), in the breath, urine, saliva and vaginal secretions. This amine is very volatile at ambient temperatures, it smells of rotting fish and is readily detected by human nose at very low concentrations (<1 ppm). Trimethylamine has a 100-fold greater olfactory potency than the oxide (TMAO).

In GI tract, dietary TMAO ingested in foods rich in choline and carnitine such as marine fish, red meat, egg yolk, beans and peas, is reduced to TMA by the colonic microflora and absorbed by passive diffusion across the cell membranes. It enters the enterohepatic circulation and is removed by the liver. In normal liver cells, TMA is oxygenated back to the odourless TMAO by the microsomal flavin-containing monooxygenase FMO3. TMAO so formed is very water soluble and in the normal subject is excreted mainly in the urine.

The flavin-containing monooxygenase (FMO) is a family of enzymes that like the cytochrome P450 (CYP) superfamily evolved to metabolize xenobiotics. FMO and CYP are between 50 and 60 kDa, located in the endoplasmic reticulum and are present in highest amounts in liver with significant amounts also present in other portals of entry for xenobiotics or in excretory organs (nasal, lung, GI, skin, kidney). There are no identified mechanism-based inhibitors of FMO. FMOs, like CYPs, exhibit tissue- and developmental-dependent expression, but are not inducible by xenobiotics as are the CYPs. (articolo 1) FMO3, both mRNA and protein, mutations of which cause trimethylaminuria, is first identified in 30% of foetal livers in the first trimester of pregnancy, disappears in the second and third trimesters, but identified again by 21 post-natal days
irrespective of gestation. This gradually increases to 8% of adult levels at about nine months age, 20% by 11 years, and even by 18 years the level of FMO3 is still significantly below adult levels. There is therefore a remarkable switch of enzyme form from FMO1 in foetal liver, to FMO3 as well as FMO5 in adult liver. The majority of pathogenic mutations described are missense mutations. Nonsense mutations, small deletions (1 or 2 bp) resulting in frameshift mutations and one large deletion (12.2 kb) have also been reported. Mechanisms regulating FMO3 transcription are of particular interest because of the temporal and tissue-specific nature of expression. In one study, important transcriptional regulatory domains were identified within the promoter, containing
NFY, USF1 and YY1 constitutive expression elements, plus Pbx2/Hox and NF-E2 elements which may contribute to developmental and tissue-specific expression.
In a later study of sequences further upstream, a C/EBPβ element was located.

Individuals affected by Trimethylaminuria have a reduced capacity to metabolize trimethylamine into trimethylamine N-oxide. Excessive amounts of the volatile molecule are therefore excreted in the body fluids, which give off a strong fishy smell.
Excess trimethylamine results from a mismatch between the ability of the enzyme FMO3 to catalyze the N-oxygenation of trimethylamine and the amount of substrate.

Reasons for the pathologies and diagnosis

Two types of trimethylaminuria exist, resulting from one of the following:

Decrease in the amount or activity of the enzyme FMO3, resulting from either genetic factors (mutations in FMO3), physiologic factors (hormone levels), or environmental factors (presence of inhibitory chemicals). This type of trimethylaminuria is characterized by a high urinary TMA/TMA N-oxide ratio.
Substrate overload of FMO3 enzyme activity resulting from either an excess of dietary precursors of TMA or variations in gut flora, causing increased release of TMA. This type of trimethylaminuria is characterized by a high concentration of TMA in the urine, but a normal urinary TMA/TMA N-oxide ratio.

The primary syndrome (primary genetic Trimethylaminuria) is inherited in an autosomal recessive manner. The defective enzyme is flavin-containing monooxygenase 3, the gene for which (FMO3) is located in chromosome region 1q23–25. Several different mutations of the FMO3 gene have been reported to cause fish odour syndrome.
The decreased enzyme capacity to form non-odorous trimethylamine N-oxide can be also a result by hormonal modulation or liver damage (transient trimethylaminuria).

The rotten fish odour is usually present from childhood and is exacerbated during puberty. In women, the offensive odour may be enhanced by oral contraceptives or may increase just before and during menstruation as a result of hormonal inhibition of the oxidation of trimethylamine.

The biochemical diagnosis is established by measuring the ratio of trimethylamine N-oxide to trimethylamine in the urine. Among people without trimethylaminuria, more than 97% of excretion occurs as trimethylamine N-oxide. In patients with the condition, the ratio is reduced.
The incidence of heterozygous carriers of the allele for trimethylaminuria has been studied in relatively few populations, trimethylaminuria is considered a rare genetic disorder.
Patients with trimethylaminuria have no physical abnormality. However, the unpleasant odour can result in a variety of psychosocial problems:

• In childhood, being shunned, ridiculed, or bullied at school, leading to aggressive or disruptive behavior and poor educational performance
• A sense of shame or embarrassment, leading to low self-esteem and reluctance to seek medical help
• Avoidance of contact with people, leading to social isolation, loneliness, frustration, and depression
• Difficulties in initiating or maintaining relationships
• In extreme cases, paranoid behavior, desperation, and suicidal tendencies

The enzyme FMO3 is also involved in the metabolism of various therapeutic drugs. Affected individuals exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine.
Benzydamine metabolism in vivo is impaired in patients with deficiency of flavin-containing monooxygenase 3 2004.

Dysfunctional metabolism of endogenous amines such as tyramine that are substrates of the enzyme FMO3 may contribute to the depression seen in some persons.

Treatment involves counselling and dietary adjustments including avoidance of choline-rich produce (eggs, liver, peas, soybeans and sea fish), which reduces the excretion of trimethylamine and may reduce the odour. Occasionally, a short course of metronidazole, neomycin and lactulose can suppress production of trimethylamine by reducing the activity of gut microflora. Soaps with a pH value 5.5–6.5 have been reported to reduce the odour dramatically in some patients. They act by retaining secreted trimethylamine (a strong base) in a less volatile salt form.

Other. Historical references to individuals who appear to have had trimethylaminuria include the description of Satyavati, a young woman who smelled of rotting fish, in the Mahabharata, the Indian epic of the Bharata Dynasty compiled in about AD 400, and Trinculo's description of Caliban ("he smells like a fish") in Shakespeare's The Tempest.

“What have we here? A man or a fish? Dead or alive?
A fish; he smells like a fish; a very ancient and fish-like
smell; a kind of not of the newest Poor John”
William Shakespeare, The Tempest II. ii.26-29.

Fish odour syndrome 2011
Transient trimethylaminuria related to menstruation 2007
Fish odour syndrome 1999

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