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Trimethylaminuria

What is trimethylaminuria?

Trimethylaminuria is also known as ‘fish (mal)odour syndrome’ because of the characteristic fishy body odour.

Trimethylamine is a volatile aliphatic molecule, best known as the smell of rotting fish. Marine fish are high in trimethylamine N-oxide which is converted to trimethylamine by bacteria. Bacteria in the bowel produce the malodourous trimethylamine from trimethylamine N-oxide or choline. Normally it is converted to the odourless trimethylamine N-oxide by an enzyme in the liver, known as trimethylamine oxidase or flavin-containing mono-oxygenase 3 (FMO3). Humans are unusually sensitive to the smell of trimethylamine and are able to detect as low a level as 0.9ppm.

In trimethylaminuria, this malodourous molecule is excreted in sweat, urine, breath, saliva, vaginal and other body secretions. It is one of the causes of bromhidrosis (malodorous sweat).

Who gets trimethylaminuria?

Primary trimethylaminuria is a rare autosomal recessive genetic disease (MIM 602079), meaning the affected person has inherited two copies of the defective gene, one from each parent. Two defective copies of the gene result in a failure to produce sufficient active FMO3 enzyme. The parents are generally unaware of carrying the gene except in rare circumstances when they may develop the body odour transiently. It has been estimated that 1% of the general population in the UK carry one defective copy of the gene, ranging up to 11% in Papua New Guinea. The gene has been identified and many different mutations detected in sufferers. Some mutations cause a reduction in FMO3 enzyme activity and others result in complete loss of enzyme activity. This form of trimethylaminuria usually presents in childhood after the child has been weaned onto foods high in choline or trimethylamine N-oxide. There is a female predominance in diagnosed cases and carriers.

Secondary trimethylaminuria occurs when the liver FMO3 enzyme is either overwhelmed or underactive for some reason. The enzyme may be overwhelmed by an excessive dietary intake of trimethylamine precursors or when there is bacterial overgrowth in the bowel resulting in increased production of trimethylamine. The enzyme then cannot cope with the increased level of trimethylamine absorbed from the bowel, and some trimethylamine leaks into the general circulation causing the characteristic smell. The enzyme may be underactive in liver and kidney disease, during menstruation or in the presence of inhibitors such as those derived from eating Brussel sprouts, oral thiourea or topical hydroquinone. It is likely that in many instances, secondary trimethylaminuria occurs in cases with an inherent reduction in enzyme activity such as in a carrier for the defective gene (a heterozygote).

A transient form has been described in childhood. Investigations confirm the elevated level of trimethylamine in the urine, but the actual conversion of trimethylamine to trimethylamine N-oxide is borderline normal. It resolves spontaneously after months or years and the levels and conversion are then normal. It is thought to be due to overproduction of trimethylamine in the bowel, although no abnormality could be demonstrated. It is important to distinguish this form from primary trimethylaminuria by measuring both the trimethylamine and trimethylamine N-oxide levels in urine.

Trimethylamine is also the cause of the fishy smell associated with bacterial vaginosis.

Clinical features

The only feature of this condition is the bad body smell (including halitosis – bad breath), of which the sufferer may be completely unaware. Sufferers are otherwise physically well with normal mental and general development.

The smell may fluctuate and triggers for an increase in odour include:

  1. menstruation, with a worsening just before and during a menstrual period. Studies of normal subjects show a reduced enzyme activity of 60-70% at this time. Thus it appears sex hormones affect the ability to metabolise trimethylamine.
  2. use of the oral contraceptive pill
  3. excessive stress or emotional upset
  4. exercise
  5. infection, especially with fever
  6. dietary intake of high choline or trimethylamine N-oxide-containing foods.

However, this offensive body odour causes major social issues resulting in psychological distress and some develop an obsession about personal cleanliness. Children have difficulties at school with ridicule, rejection and teasing about personal hygiene. Many severe cases leave school early because of this, resulting in educational disadvantage. In adult life, similar problems may occur in the workplace, affecting career prospects, and cause difficulties with interpersonal relationships. This may result in feelings of shame, embarrassment, low self-esteem and social isolation. Frustration, anxiety, depression, paranoia, drug addiction (cigarettes, alcohol and illicit drugs) and attempted suicide are common outcomes, particularly for those severely affected. This is a condition with wide-ranging social and psychological effects.

How is the diagnosis made?

The diagnosis should be considered in patients presenting because of body odour, especially if described as fishy. In one study in the UK of 187 patients presenting due to body odour, 17 were described as fishy. Eleven of the 17 had trimethylaminura, but none of the others were affected with this condition.

The diagnosis is confirmed on 24-hour urine collection while on a normal diet, and an 8-hour urine collection after either a marine fish meal (for children) or 600mg oral trimethylamine load (adults). Both trimethylamine and trimethylamine N-oxide should be measured. The trimethylamine challenge will detect both carriers and sufferers, as both will have a reduced conversion to trimethylamine N-oxide. Normal subjects will convert more than 80% of the trimethylamine to the N-oxide form, carriers convert less than 80% and sufferers less than 25% after the oral challenge. In menstruating females, the timing of the test is important as it may be a transient problem.

The genetic mutation can be characterised, although this is generally for research purposes currently.

Treatment

Counselling sufferers is a most important part of treatment as it acknowledges their medical condition and explains the cause.

Dietary modification is the basis of treatment as avoidance of trimethylamine precursors reduces the body odour:

  1. Marine (sea- or salt-water) fish, including cephalopods and crustaceans, must be avoided completely as they have the highest concentration of the precursor trimethylamine N-oxide. Freshwater fish can be eaten.
  2. Foods identified to be high in choline include egg yolks, soyabeans, peas, beans, peanuts and other legumes, liver, kidney and other offal, and brassicas such as rapeseed (canola). It is possible that the choline in egg yolks is in a form that is not converted to trimethylamine by bowel bacteria. Foods in this category may be eaten in reduced amount by some sufferers.
  3. The role of lecithins, carnitine and other betaines remains unresolved. Red meat is high in carnitine and some sufferers may need to restrict their intake.

Washing with low pH (pH5.5-6.5) soaps and shampoos removes traces of trimethylamine from the skin and hair.

Some sufferers respond well to courses of neomycin, amoxicillin or metronidazole as these alter the bowel bacteria, reducing the production of trimethylamine. This will be particularly helpful in secondary trimethylaminuria due to bacterial overload and can be used in primary trimethylaminuria for important social situations or when dietary restriction cannot be maintained. To reduce the risk of antibiotic-resistance, antibiotics should only be used intermittently or alternated every 2 weeks.

Oral copper-chlorophyllin may also give temporary improvement by altering the bowel bacteria.

In severe cases of primary trimethylaminuria, the metabolism of some drugs may theoretically be affected as these may be processed by the same FMO3 enzyme. Drugs that may be affected include nicotine (in cigarettes), codeine, cimetidine, ketoconazole, sulindac, itopride and tamoxifen. This may result in an exaggerated clinical effect or increased incidence of adverse drug events.

Hydroquinone used topically as a depigmenting agent has been reported to trigger the fish odour in those using the drug in large amount for a long time. As it is an anti-oxidase, it may inhibit the oxidation of trimethylamine to trimethylamine N-oxide, especially in carriers.

Draft 24 February 2010

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Author: Dr Delwyn Dyall-Smith FACD, Dermatologist.

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