Clinical characteristics.

Primary trimethylaminuria is characterized by a fishy odor resembling that of rotten or decaying fish that results from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids. No physical symptoms are associated with trimethylaminuria. Affected individuals appear normal and healthy; however, the unpleasant odor often results in social and psychological problems. Symptoms are usually present from birth and may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around the time of menopause.

Diagnosis/testing.

The diagnosis of primary trimethylaminuria is established in a proband who:

• Excretes (under normal dietary conditions) in the urine more than 10% of total trimethylamine (TMA) as the free amine; and
• Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in FMO3 on molecular genetic testing.

Management.

Treatment of manifestations:

Dietary restriction of:

• Trimethylamine (present in milk obtained from wheat-fed cows) and its precursors including choline (present in eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas [Brussels sprouts, broccoli, cabbage, cauliflower]), lecithin and lecithin-containing fish oil supplements;
• Trimethylamine N-oxide (present in seafood [fish, cephalopods, and crustaceans]);
• Inhibitors of FMO3 enzyme activity such as indoles (found in brassicas).

Note: Planning and monitoring of diet to ensure that the daily intake of choline and folate meets recommendations for age and sex; no restriction of dietary choline during pregnancy and lactation.

Use of:

• Acid soaps and body lotions to remove secreted trimethylamine by washing;
• Activated charcoal and copper chlorophyllin to sequester trimethylamine produced in the gut;
• Antibiotics (metronidazole, amoxicillin, and neomycin) to suppress production of trimethylamine by reducing bacteria in the gut;
• Riboflavin supplements to enhance residual FMO3 enzyme activity.

Agents/circumstances to avoid: Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity (seafoods: fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products; food supplements and "health" foods that contain high doses of choline and lecithin; drugs metabolized by the enzyme FMO3; circumstances that promote sweating (e.g., exercise, stress, emotional upsets).

Evaluation of relatives at risk: Biochemical testing of sibs to identify those who are affected and will benefit from management to reduce production of trimethylamine.

Genetic counseling.

Primary trimethylaminuria is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one FMO3 pathogenic variant based on family history). If both parents are known to be heterozygous for an FMO3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the FMO3 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Primary trimethylaminuria should be suspected in individuals with the following clinical findings and family history.

Body odor resembling that of rotten or decaying fish. Unoxidized trimethylamine (TMA) excreted in the urine, breath, sweat, and reproductive fluids is highly volatile and has a pungent ammoniac odor reminiscent of rotting fish [Mitchell & Smith 2001, Mitchell 2005, Mackay et al 2011].

Note: Diagnosis of primary trimethylaminuria cannot be based on the examiner’s sense of smell due to the following:

• The presence of the odor is often episodic and thus may not be noticeable when the person is examined.
• The human nose is normally very sensitive to trimethylamine, with some individuals being able to detect concentrations as low as 1 part in 10⁹; however, olfactory testing is subjective and some people are unable to detect the smell of trimethylamine.
• The odor may be caused by compounds other than trimethylamine.

Urinary excretion of trimethylamine (TMA). Individuals complaining of or exhibiting a fishy odor should be tested for urinary excretion of TMA, ideally on two separate occasions [Mitchell & Smith 2001, Mitchell 2005]. Although testing can be done under normal dietary conditions, it may help to consume a meal rich in choline (e.g., 2 eggs + 400 g "baked" [haricot] or soya beans) prior to testing.

Note: Because unaffected women may have transient trimethylaminuria at the onset of and during menstruation [Shimizu et al 2007], women should not be tested during this time frame.

Urinary excretion of TMA is measured as one of the following:

• Percent of total trimethylamine (TMA) (i.e., free TMA plus the non-odorous metabolite TMA N-oxide) excreted in the urine as unmetabolized free TMA [Cashman et al 2003, Mackay et al 2011]
  • Severe trimethylaminuria: >40% of total TMA excreted as unmetabolized free TMA
  • Mild trimethylaminuria: 10%-39% of total TMA excreted as unmetabolized free TMA
  • Unaffected: 0%-9% of total TMA excreted as unmetabolized free TMA
• Concentration of unmetabolized TMA in the urine. A urinary concentration of free TMA of 10 µg/mL (18-20 µmol/mmol creatinine) or higher, correlating with a urinary output of TMA of ~15-20 mg/day, appears to represent a threshold for the presence of the fishy body odor associated with the disorder [Mitchell & Smith 2001].
  Note: Currently available specific methods of detecting TMA and TMA N-oxide in urine involve sophisticated equipment and require skilled, experienced personnel. The methods used in mass spectrometry [Li et al 2017] and proton NMR [Murphy et al 2000] can detect TMA and TMA N-oxide simultaneously with great sensitivity. NMR has the additional advantage of requiring no prior extraction or separation of metabolites, making measurement possible directly on urine samples.

Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of primary trimethylaminuria is established in a proband who:

• Excretes (under normal dietary conditions) in urine more than 10% of total trimethylamine (TMA) as the free amine; and
• Has biallelic (homozygous or compound heterozygous), known loss-of-function pathogenic variants in FMO3 identified on molecular genetic testing (see Table 1).
  Note: Identification of biallelic FMO3 variants of uncertain significance (or identification of one known FMO3 pathogenic variant and one FMO3 variant of uncertain significance) does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing and genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of primary trimethylaminuria has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Primary trimethylaminuria is characterized by fishy odor resulting from excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids [Mitchell & Smith 2001, Mitchell 2005, Mackay et al 2011].

No physical symptoms are associated with primary trimethylaminuria; affected individuals appear normal and healthy. However, the unpleasant odor characteristic of the disorder often results in social and psychological problems [Mitchell & Smith 2001] and can have serious effects on personal and working lives. These may include the following:

• 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. Individuals with primary trimethylaminuria exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine [Mayatepek et al 2004]. Although affected individuals would be expected to exhibit altered metabolism of drugs that are acted upon by FMO3 [Phillips & Shephard 2017], there are no published reports of such effects.

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

For individuals with primary trimethylaminuria, symptoms are usually present from birth. The condition may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and around menopause.

Treatment and dietary management may alleviate symptoms in some, but not all individuals.

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.

Genotype-Phenotype Correlations

On a normal diet, individuals with biallelic loss-of-function FMO3 pathogenic variants secrete more than 40% of total TMA as the free unmetabolized amine and consequently have a fishy odor.

Several pathogenic nonsense or missense variants that abolish or severely impair the ability of the FMO3 enzyme to catalyze N-oxygenation of TMA have been identified [Phillips et al 2007, Yamazaki & Shimizu 2013]. In general, the more severe the reduction in FMO3 enzyme activity, the more severe the manifestations and the less the response to treatment.

Some nonsynonymous variants, when present in cis configuration (e.g., p.Glu158Lys and p.Glu308Gly) result in moderately decreased enzyme activity [Phillips & Shephard 2020]. In the homozygous state (i.e., p.Glu158Lys and p.Glu308Gly present in cis configuration on both chromosomes), they may cause mild or transient primary trimethylaminuria, particularly in infants and young children [Zschocke & Mayatepek 2000], who have low expression of FMO3 [Koukouritaki et al 2002].

Although the rare variant p.Val187Ala alone does not affect enzyme activity, a combination of this variant in cis configuration with p.Glu158Lys severely affects enzyme activity and contributes to severe trimethylaminuria [Motika et al 2009].

Nomenclature

Primary trimethylaminuria has been described as fish-odor syndrome, fish malodor syndrome, and stale fish syndrome.

Prevalence

The incidence of heterozygotes (carriers) in the white British population is 0.5% to 1.0%. It is higher in other populations studied: 1.7% in Jordan, 3.8% in Ecuador, and 11.0% in New Guinea [Mitchell et al 1997].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with primary trimethylaminuria, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Determine the urinary ratio of trimethylamine (TMA) N-oxide to total TMA on a normal diet. The general rule is that the lower the ratio the more severe the disorder:
  • Ratios of 70%-89% are classified as mild.
  • Ratios lower than 70% are classified as severe.
• Assess social issues associated with body odor. These may include harassment, bullying, discrimination, negative self-image, social isolation, and relationship problems [Lateef & Marshall-Lucette 2017, Roddy et al 2020]. An assessment tool for evaluation of social and mental health effects of the disorder has been proposed [Rutkowski et al 2019].
• Consult with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of primary trimethylaminuria in order to facilitate medical and personal decision making.

Treatment of Manifestations

Strategies for the treatment of primary trimethylaminuria summarized in this section are reviewed by Schmidt & Leroux [2020].

Restriction of dietary trimethylamine and its precursors. In some instances the disorder can be successfully managed by dietary restriction of precursors of trimethylamine. This is particularly true of "mild" or moderate forms of primary trimethylaminuria. Affected individuals respond differently to different forms of dietary restriction; thus, urinary excretion of trimethylamine and trimethylamine N-oxide should be monitored to identify the most effective dietary regimen for an individual.

Dietary regimens should be planned and monitored to ensure that the daily intake of choline and folate meet recommendations for the age and sex of the individual [National Academies Collection 1998]. For adults, adequate daily intake of choline is 550 mg for males and 425 mg for females.

• Choline is one of the most important dietary sources of trimethylamine. Dietary choline is absorbed through the small intestine; however, when the absorptive capacity of the small intestine is overloaded, gut bacteria metabolize choline into trimethylamine, which is readily absorbed into the blood stream.
  Foods rich in choline include eggs, liver, kidney, peas, beans, peanuts, soya products, and brassicas (Brussels sprouts, broccoli, cabbage, cauliflower) as well as rapeseed products such as oil and flour.
  Nutritionally balanced, choline-restricted diets suitable for the treatment of trimethylaminuria have been developed [Busby et al 2004].
  Because choline is essential in the fetus and in young infants for nerve and brain development, it should not be over-restricted in infants, children, and pregnant or lactating women. Large amounts of choline are transferred to the fetus via the placenta and to the newborn infant via the mother's milk, thus potentially depleting maternal choline reserves. Dietary restriction of choline increases the requirement for folate, a methyl donor.
• Trimethylamine N-oxide. Affected individuals should avoid eating seafood (fish, cephalopods, and crustaceans) because of its high content of trimethylamine N-oxide, which is reduced to trimethylamine in the human gut. Babies with trimethylaminuria who are breastfed after their mothers have eaten seafood may develop a fishy odor.
  Note: Freshwater fish have a lower content of trimethylamine N-oxide and thus are not a problem.
• Other. Milk obtained from wheat-fed cows may have significant amounts of trimethylamine and thus should be avoided.
  Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
  In addition to being a source of trimethylamine precursors, brassicas (Brussels sprouts, broccoli, cabbage, and cauliflower) contain indoles, which may inhibit FMO3 enzyme activity and thus increase urinary excretion of trimethylamine [Cashman et al 1999]. Intake of such vegetables should be restricted.

Use of acid soaps and body lotions. Trimethylamine is a strong base (pKa 9.8). Thus, at pH 6.0, less than 0.02% of trimethylamine exists as the volatile free base. The use of soaps and body lotions with a pH close to that of normal skin (pH 5.5-6.5) helps retain secreted trimethylamine in a less volatile salt form that can be removed by washing.

Sequestering of trimethylamine produced in the gut. When taken as dietary supplements, activated charcoal (750 mg 2x/day for 10 days) and copper chlorophyllin (60 mg 3x/day after meals for 3 weeks) decrease the concentration of free trimethylamine in the urine [Yamazaki et al 2004].

Suppression of intestinal production of trimethylamine. A short course of antibiotics to modulate or reduce the activity of gut microflora, and thus suppress the production of trimethylamine, is effective in some cases [Chalmers et al 2006]. Such treatment may be useful when dietary restriction needs to be relaxed (e.g., for important social occasions), or when trimethylamine production appears to increase (e.g., during menstruation, infection, emotional upset, stress, or exercise). Three antibiotics with different target organisms have been used: metronidazole, amoxicillin, and neomycin. Neomycin appears to be the most effective in preventing formation of trimethylamine from choline [Chalmers et al 2006].

Enhancement of residual FMO3 enzyme activity. Supplements of riboflavin, a precursor of the FAD prosthetic group of FMOs, may help maximize residual FMO3 enzyme activity [Manning et al 2012]. Recommended intake is 30-40 mg 3-5x/day with food. Children given riboflavin should be monitored closely because excessive amounts may cause gastrointestinal distress.

Counseling. Affected individuals and their families benefit from counseling. Realization that the problem is the result of a recognized medical condition may help. As well as receiving dietary advice, affected individuals should be advised that the condition may be exacerbated during menstruation and by factors that promote sweating, such as fever, exercise, stress, and emotional upsets.

Assessment of efficacy of treatment. A tool for patient self-assessment of the effect of treatment on social and mental health aspects of the disorder has been proposed [Rutkowski et al 2019].

Agents/Circumstances to Avoid

The following should be avoided:

• Foods with a high content of precursors of trimethylamine or inhibitors of FMO3 enzyme activity, including seafood (fish, cephalopods, and crustaceans), eggs, offal, legumes, brassicas, and soya products. Avoid or eat in moderation.
• Food supplements and "health" foods that contain high doses of the trimethylamine precursors choline and lecithin
• Drugs that are metabolized by the FMO3 enzyme; for example, the antipsychotic clozapine; the monoamine oxidase B inhibitor deprenyl; the anti-histamine ranitidine; the anti-estrogen tamoxifen; and the nonsteroidal anti-inflammatories benzydamine and sulindac [Phillips & Shephard 2017]. These compete for residual FMO3 activity. As well as exacerbating the condition, reduced metabolism of the drug may cause adverse effects.
• Factors that promote sweating (e.g., exercise, stress, emotional upsets)

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Choline, which is essential for nerve and brain development in the fetus, should not be over-restricted in pregnant women with primary trimethylaminuria.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Primary trimethylaminuria is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one FMO3 pathogenic variant based on family history).
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an FMO3 pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• If both parents are known to be heterozygous for an FMO3 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with primary trimethylaminuria are obligate heterozygotes (carriers) for a pathogenic variant in FMO3.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an FMO3 pathogenic variant.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the FMO3 pathogenic variants in the family.

Biochemical genetic testing. Under normal dietary conditions heterozygotes (carriers) and unaffected individuals excrete less than 10% of total trimethylamine (TMA) as the unmetabolized free amine and thus cannot be distinguished [Cashman et al 2003]; carriers are best identified by molecular genetic testing.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the FMO3 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for primary trimethylaminuria are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Metabolism of trimethylamine is primarily via N-oxygenation, catalyzed by the enzyme flavin-containing monooxygenase 3 (FMO3) [Dolphin et al 1997, Lang et al 1998].

Trimethylamine is derived from dietary precursors, such as choline and trimethylamine N-oxide, via the action of bacteria in the gut [Mitchell 2005, Mackay et al 2011, Fennema et al 2016]. It is normally metabolized in the liver by the enzyme FMO3 to produce trimethylamine N-oxide, which is non-volatile and non-odorous [Fennema et al 2016]. 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.

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

• Decrease in the amount or activity of the enzyme FMO3, resulting from genetic factors (mutation of 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 two types of trimethylaminuria are intimately interrelated: a combination of genetic, physiologic, and environmental factors may interact to give rise to the disorder. For instance, a substrate load that is handled by one individual may represent a substrate overload for a person whose FMO3 enzyme activity is decreased.

Mechanism of disease causation. Loss of function

Revision History

• 5 November 2020 (bp) Comprehensive update posted live
• 1 October 2015 (me) Comprehensive update posted live
• 19 April 2011 (me) Comprehensive update posted live
• 18 March 2008 (cd) Revision: sequence analysis available clinically
• 8 October 2007 (me) Review posted live
• 30 July 2007 (eas) Original submission

Published Guidelines / Consensus Statements

• Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006. [PubMed: 16601883]

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