Trimethylaminuria: FMO3 mutations that cause malodorous body odor

Often referred to as ‘fish odor disease’, trimethylaminuria causes a strong odor in sweat, urine, and breath. While it may be easy to make jokes about, trimethylaminuria can have a serious impact on a person’s social and mental well-being, especially during childhood.

This article explores the FMO3 gene, which encodes the enzyme that breaks down trimethylamine. I’ll explain how to check your 23andMe or AncestryDNA data and then end with a few lifehacks that may help with managing the enzyme deficiency.

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FMO3 gene mutations cause trimethylaminuria (TMAU):

Trimethylaminuria is a metabolic disorder caused by high levels of trimethylamine, which has a distinctive odor.

Trimethylamine (TMA) forms in the intestines from various nutritional substrates when intestinal bacteria break down choline, carnitine, betaine, and ergothioneine. TMA then absorbs into the bloodstream from the intestines.[ref]

Foods with TMA -> gut bacteria -> TMAO conversion

Foods high in the precursors for trimethylamine (TMA) include:[ref]

  • eggs
  • liver
  • kidney
  • peas
  • beans
  • peanuts
  • Brussels sprouts, broccoli, cabbage, cauliflower
  • lecithin
  • soy products
  • some mushrooms (ergothioneine)

Gut bacteria act upon the foods containing the TMA precursors to produce trimethylamine. After TMA is absorbed in the intestines, the FMO3 enzyme converts it into TMAO (trimethylamine-N-oxide).[ref]

TMAO (trimethylamine-N-oxide) is the oxidized form of trimethylamine (TMA). Several problems linked to it include lipid homeostasis, diabetes, and heart health.

The drawback of high TMAO: A number of studies link higher plasma TMAO levels to an increased relative risk of thrombosis (heart attack, stroke). Platelets become a little bit more sticky – more easily activated to clump together – when levels of TMAO are high.[ref]

Too little FMO3 causes the opposite problem. Trimethylaminuria (a.k.a. fish odor disease) results from not enough trimethylamine (TMA) converting into TMAO.

Balance is critical here… you don’t want too much TMAO because of heart disease, but you also don’t want too much TMA due to the odor.

People with trimethylaminuria (TMAU) have genetic mutations in the FMO3 gene that lead to decreased enzyme function, resulting in trimethylamine (TMA) remaining in the bloodstream. The TMA has a bad (sometimes fishy) smell that can exude from the body.

Thus, we need just the right amount of TMA to TMAO conversion.

What are the signs and symptoms of trimethylaminuria?

The diagnosis of trimethylaminuria (TMAU) is based on a distinctive odor and high urinary TMA levels in comparison to TMAO.

The amount of TMA will vary over the course of the day, depending on what a person eats (e.g., choline or other TMA precursors). Thus, measuring the ratio is a better way to know how much TMA is being converted to TMAO. In general, a ratio of (TMAO/(TMAO + TMA)) is below 0.8 in people with mutations in the FMO3 gene.[ref]

The odor caused by TMAU smells like…

Most research studies refer to the body odor in trimethylaminuria (TMAU) as a ‘fishy odor’ or ‘rotten fish’, but patients with TMAU sometimes describe the odor in different ways. To some people, it could smell like garbage, urine, or rotting eggs. Plus, the presence of the odor can vary based on diet and gut microbiome composition.

A study of people with particularly malodorous BO found that about a third of them had TMAU.[ref]

Is trimethylaminuria always genetic?

Primary trimethylaminuria (TMAU) occurs due to a mutation that causes the FMO3 gene not to function well. Two copies of FMO3 mutations are generally needed to cause trimethylaminuria. Sometimes, though, a stronger odor is noticed in people with one copy of a mutation, depending on diet and the gut microbiome.

But…the cause of trimethylaminuria may not always be genetic.

While primary TMAU is a genetic disease caused by mutations in the FMO3 gene, a transient form is also possible.

The FMO3 enzyme is produced mainly in the liver. Adults can acquire TMAU if they have liver cirrhosis or viral hepatitis, which impairs liver function.

Transient TMAU can occur during menstruation or when consuming high amounts of choline (TMA precursor).

People with a combination of several FMO3 common genetic variants are more likely to have transient TMAU.[ref]

What else does the FMO3 enzyme do?

The FMO3 gene encodes an enzyme that is important in several reactions in the body (including the breakdown of TMAO).

Nicotine metabolism: Nicotine is mainly metabolized in the body using the CYP2A6 enzyme. But the FMO3 enzyme can also play a role in nicotine metabolism, especially in people who have genetic variants that cause low CYP2A6 activity. Additionally, people with genetic variants that slow the FMO3 enzyme function have an altered response to nicotine.[ref] (Check your CYP2A6 genetic variants.)

Drug metabolism: Certain drugs, including tamoxifen and cimetidine, are metabolized using the FMO3 enzyme. Serious interactions can occur with FMO3 mutations and busulfan, which is used in stem cell transplants.[ref][ref]

FMO3 Genotype Report:

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Common variants that decrease FMO3 enzyme function:

Carrying several copies of common FMO3 variants that decrease FMO3 function could cause mild, transient malodor, likely depending on choline in the diet and the gut microbiome.[ref]

Check your genetic data for rs2266782 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased FMO3 function[ref][ref][ref][ref]; increased risk of hypertension, especially in smokers[ref]
  • A/G: somewhat decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs2266782 is .

Check your genetic data for rs2266780 (23andMe v4, v5; AncestryDNA):

  • G/G: somewhat decreased FMO3 function[ref][ref][ref]
  • A/G: somewhat decreased FMO3 function
  • A/A: typical FMO3 function

Members: Your genotype for rs2266780 is .

Check your genetic data for rs909530 (23andMe v4 only):

  • T/T: somewhat decreased FMO3 function[ref][ref] (probably mild)
  • C/T: somewhat decreased FMO3 function
  • C/C: typical FMO3 function

Members: Your genotype for rs909530 is .

Check your genetic data for rs1736557 (23andMe v4, v5; AncestryDNA):

  • A/A: decreased FMO3 function[ref]; may add to trimethylaminuria combined with other FMO3 variants[ref][ref]
  • A/G: decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs1736557 is .

More severe impact on FMO3 enzyme function (rare mutations):

Traditionally, TMAU is referred to as an autosomal recessive disease, requiring two copies of a rare mutation in the FMO3 gene. Sometimes, though, a person who carries one copy of an FMO3 mutation will have transient trimethylaminuria, usually depending on diet. Additionally, a combination of a rare mutation along with several of the more common variants (above) may also result in trimethylaminuria.[ref]

Check your genetic data for rs72549332 (AncestryDNA):

  • A/A: trimethylaminuria possible in conjunction with a second mutation[ref]
  • A/G: decreased FMO3 function
  • G/G: typical

Members: Your genotype for rs72549332 is .

Check your genetic data for rs72549326 (AncestryDNA):

  • T/T: trimethylaminuria possible[ref]
  • C/T: decreased FMO3 function
  • C/C: typical

Members: Your genotype for rs72549326 is .

Check your genetic data for rs72549322 (AncestryDNA):

  • G/G: trimethylaminuria possible in conjunction with a second mutation[ref]
  • A/G: decreased FMO3 function
  • A/A: typical

Members: Your genotype for rs72549322 is .

Check your genetic data for rs61753344 (23andMe v4, v5: AncestryDNA):

  • T/T: decreased FMO3 function[ref]
  • G/T: decreased FMO3 function
  • G/G: typical FMO3 function

Members: Your genotype for rs61753344 is .

Check your genetic data for rs3832024 (23andMe v5):

  • DD or -/-: decreased FMO3 function[ref]
  • DI or -/TG: decreased FMO3 function
  • II or TG/TG: typical FMO3 function

Members: Your genotype for rs3832024 is .

Lifehacks for trimethylaminuria:

Below are some research-based diet and supplement recommendations that work for some people with TMAU. Talk with your doctor, of course, if you have been diagnosed with TMAU, to find out what is right for you.

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and also an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.

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