Clinical Diagnosis

Trimethylaminuria may present with a body odor resembling that of rotten or decaying fish [Mitchell & Smith 2001, Mitchell 2005, Mackay et al 2011].

Diagnosis of trimethylaminuria has been discussed in detail [Cashman et al 2003] and "best-practice" diagnostic guidelines have been summarized [Chalmers et al 2006; see ].

Diagnosis based on the sense of smell of the examiner is complicated by 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.

Testing

Metabolism of trimethylamine is primarily via N-oxygenation, catalyzed by the enzyme flavin-containing monooxygenase 3 (FMO3) [Lang et al 1998, Cashman et al 2003, Phillips et al 2007].

Biochemical testing. Trimethylaminuria is characterized by excretion of excessive amounts of unoxidized trimethylamine in the urine, breath, sweat, and reproductive fluids. Trimethylamine is extremely volatile and has a pungent ammoniacal odor reminiscent of rotting fish [Mitchell 2005, Mackay et al 2011].

Diagnosis of trimethylaminuria is based on 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: more than 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 about 15 to 20 mg/day, appears to represent a threshold for the presence of the fishy body odor associated with the disorder [Mitchell & Smith 2001].

Note: (1) Some forms of trimethylaminuria are transient or episodic [Mitchell & Smith 2001, Mitchell 2005]; to distinguish them from the primary inherited form, biochemical testing should be performed on two separate occasions. (2) Choline challenge. It may also help to carry out the biochemical testing after an oral challenge of choline bitartrate (2.5 to 15g, depending on age) [Chalmers et al 2006]. Although this level of choline challenge is generally well tolerated, one individual developed an adverse reaction, with fever and vomiting [Chalmers et al 2006]. (3) Because unaffected women may have a short episode of trimethylaminuria at the onset of and during menstruation [Shimizu et al 2007], females should not be tested during this time frame.

The methods of detecting TMA and TMA N-oxide in urine currently available involve sophisticated equipment and require skilled and experienced personnel:

• Head-space gas chromatography (GC) or GC-mass spectrometry [Mills et al 1999]. Disadvantages: GC techniques are time consuming, TMA N-oxide must be chemically reduced to TMA before analysis, and both TMA and TMA produced by reduction of TMA N-oxide must be extracted from urine.
• Mass spectroscopy (MS)^* including fast atom bombardment MS (FAB-MS) [Mamer et al 1999], electrospray ionization tandem MS (ESI-MS/MS) [Johnson 2008], direct infusion electrospray quadruple time-of-flight MS [Mamer et al 2010], or matrix-assisted laser desorption/ionization time-of-flight MS (MALDI-TOFMS) [Hsu et al 2007]
• Proton nuclear magnetic resonance (NMR) spectroscopy^* [Maschke et al 1997, Murphy et al 2000, Podadera et al 2005, Lee et al 2006]

* MS and proton NMR have the advantage of being able to detect TMA and TMA N-oxide simultaneously with great sensitivity. NMR has the further advantage of requiring no prior extraction or separation of metabolites and thus measurement can be done directly on urine samples.

Heterozygotes

• Under normal dietary conditions heterozygotes (carriers) and unaffected individuals excrete less than 10% of total TMA as the unmetabolized free amine and thus cannot be distinguished [Cashman et al 2003].
• TMA challenge. Carriers can be detected using a "TMA load" test in which 600 mg of TMA is given orally in a gelatin capsule. After the TMA load test, carriers excrete 20%-30% of total TMA as the free unmetabolized amine, whereas unaffected individuals excrete less than 13% of total TMA as the free unmetabolized amine [Mitchell & Smith 2001].

Testing Strategy

To confirm/establish the diagnosis in a proband. Individuals complaining of or exhibiting a fishy odor should be tested for urinary excretion of TMA, ideally on two separate occasions. Testing can be done under normal dietary conditions or following a choline challenge.

Note: The choline challenge described in Testing can help confirm TMA in affected individuals. The choline challenge does not distinguish between carriers and unaffected individuals.

If an individual excretes more than 10% of total TMA as the free amine under normal dietary conditions, sequence analysis should be offered.

• If an individual is found to be homozygous or compound heterozygous for known loss-of-function mutations of FMO3, the diagnosis is confirmed.
• If novel mutations are found, it is important to establish that:
  • The mutations are not relatively common in the general population, i.e., polymorphic variants;
  • They cosegregate with the disorder in the family;
  • They abolish (or substantially reduce) the ability of FMO3 to catalyze N-oxygenation of TMA, as assessed by assaying heterologously expressed mutant protein.

Carrier testing for at-risk relatives. Carriers can be distinguished from unaffected individuals with the TMA challenge described in Testing, Heterozygotes or by molecular genetic testing which requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in FMO3.

Natural History

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

The 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]. It is normally metabolized in the liver by the enzyme FMO3 to produce trimethylamine N-oxide, which is non-volatile and non-odorous [Cashman et al 2003, Phillips et al 2007]. 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 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 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.

No physical symptoms are associated with 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. Affected individuals exhibit abnormal metabolism of the nonsteroidal anti-inflammatory benzydamine [Mayatepek et al 2004]. Anecdotal evidence suggests that the metabolism of other drugs that are substrates of the enzyme FMO3 may also be affected.

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

For individuals with primary genetic 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, probably because of a decrease in expression of FMO3 in response to steroid hormones.

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 who are homozygous or compound heterozygous for loss-of-function FMO3 mutations secrete more than 40% of total TMA as the free unmetabolized amine and consequently have a fishy odor.

Several nonsense or missense mutations that essentially abolish the ability of the FMO3 enzyme to catalyze N-oxygenation of TMA have been identified [Hernandez et al 2003, Phillips et al 2007]. In general, the greater the effect of the mutation on the FMO3 enzyme activity the more severe the symptoms and the less responsive to treatment.

More common normal variants have little or no effect on enzyme activity; however, combinations of common variants (e.g., p.Glu158Lys and p.Glu308Gly) in cis configuration (i.e., on the same chromosome) may cause "mild" trimethylaminuria, resulting in the excretion of 10%-39% of total TMA as the free unmetabolized amine [Zschocke et al 1999].

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

Nomenclature

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

Prevalence

The incidence of heterozygous carriers in the white British population is 0.5% to 1.0%. It is higher in other ethnic groups studied: 1.7% in Jordanian, 3.8% in Ecuadorian, and 11.0% in New Guinea [Mitchell et al 1997].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with trimethylaminuria, it is recommended that the urinary ratio of TMA N-oxide to total TMA on a normal diet be determined:

• Ratios of 70%-89% are classified as mild.
• Ratios lower than 70% are classified as severe.

The general rule is that the lower the ratio the more severe the disorder.

Treatment of Manifestations

Strategies for the treatment of trimethylaminuria summarized below are covered in detail in Cashman et al [2003] and in "best-practice" guidelines [Chalmers et al 2006; see ].

Restriction of dietary trimethylamine and its precursors. In some cases the disorder can be successfully managed by dietary restriction of precursors of trimethylamine. This is particularly true of "mild" or moderate forms of the disorder. 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.

• Choline. One of the most important dietary sources of trimethylamine is choline. 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].
  
  Affected individuals should avoid lecithin (an important dietary source of choline) and lecithin-containing fish oil supplements.
• 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.
  
  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 [Fraser-Andrews et al 2003, 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].

Laxatives, such as lactulose, to decrease intestinal transit time may also reduce the amount of trimethylamine produced in the gut.

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. Recommended intake is 30-40 mg, three to five times per 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.

Prevention of Primary Manifestations

See Treatment of Manifestations.

Prevention of Secondary Complications

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.

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 [Institute of Medicine, National Academy of Sciences USA 1998; Cashman et al 2003]. For adults, adequate daily intake of choline is 550 mg for males and 425 mg for females.

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 et al 2007]. 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, such as exercise, stress, and emotional upsets

Evaluation of Relatives at Risk

Biochemical testing of sibs is appropriate to identify those who are affected and will benefit from early treatment of manifestations. If the causative mutations in the family have been identified, at-risk relatives can be offered molecular genetic testing.

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

Therapies Under Investigation

Search ClinicalTrials.gov 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

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 and therefore carry one mutant allele.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, each sib of an affected individual has 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 an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with trimethylaminuria are obligate heterozygotes (carriers) for a disease-causing mutation.

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

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is available once the mutations have been identified in the family.

Biochemical genetic testing. Carrier status can be clarified using biochemical testing by analyzing the concentration and ratio of trimethylamine and trimethylamine N-oxide in urine after an oral challenge of trimethylamine (600 mg).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning.

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as trimethylaminuria that do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Published Guidelines/Consensus Statements

1. Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. 2006. Available online. Accessed 4-12-11. [PubMed: 16601883]

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Suggested Reading

1. Phillips IR, Shephard EA. Flavin-containing monoxygenases: mutations, disease and drug response. Trends Pharmacol Sci. 2008;29:294–301. [PubMed: 18423897]
2. Treacy EP. Trimethylaminuria and deficiency of flavin-containing monooxygenase type 3 (FMO3). In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 88.1. Available online. Accessed 4-12-11.

Revision History

• 19 April 2011 (me) Comprehensive update posted live
• 18 March 2008 (cd) Revision: sequence analysis available clinically
• 8 October 2007 (me) Review posted to live Web site
• 30 July 2007 (eas) Original submission