Trimethylaminuria

Etiology

Primary Trimethylaminuria

Primary trimethylaminuria occurs secondary to a genetic mutation of the FMO3 gene, located on chromosome 1q24.3. Various FMO3 mutations result in decreased enzyme activity, impaired substrate binding, or disrupted protein structure.[4] Primary TMAU is predominately inherited in an autosomal recessive manner; both copies of FMO3 need to be mutated for TMAU to manifest. However, some rare cases of TMAU may exhibit partial enzyme deficiency due to heterozygosity, compound heterozygosity, or regulatory mutational variants affecting FMO3 expression.[5]

Failure to metabolize TMA results in its accumulation; it is subsequently excreted via urine, sweat, breath, and other body secretions. The excess excretion is what causes the fishy odor.[6] 

In rare instances, an inborn error of metabolism resulting from a deficiency of the enzyme dimethylglycine dehydrogenase leads to a 100-fold serum and 20-fold urine increase of N,N-dimethylglycine (DMG); these patients also exhibit a fishy odor.[7] 

Secondary Trimethylaminuria

Secondary trimethylaminuria also results in excessive accumulation of TMA. Patients with secondary TMAU have functional enzymes that become overwhelmed due to excess dietary intake of the precursors to the offending chemical. These dietary precursors include choline in eggs, beans, and peas and carnitine in red meats and fish. Some individuals use carnitine as a performance-enhancing supplement.[8][6] Choline is used in the treatment of Alzheimer disease and Huntington disease.

Colonic anaerobic bacteria produce TMA from dietary precursors such as choline, carnitine, and lecithin, which are absorbed into the enterohepatic circulation by simple diffusion.[9] Symptoms of TMAU can develop when the liver enzyme flavin-containing monooxygenase 3 becomes overwhelmed.

Other potential causes of secondary trimethylaminuria are liver failure, portosystemic shunting, menstruation, viral hepatitis, and testosterone therapy.[10]

Epidemiology

The global prevalence of TMAU is estimated at 1 in 200,000 to 1 in 1,000,000 individuals.[11] However, due to the lack of awareness and low diagnosis rates, the true prevalence may be higher, particularly in specific populations. It has been reported that individuals of Ashkenazi Jewish descent may have a higher incidence of TMAU. The carrier rate among individuals of New Guinean origin is 11%.[12] 

TMAU affects both males and females; there may be differences in symptom severity. Some studies have suggested that females may experience more severe symptoms due to hormonal fluctuations during menstruation and pregnancy.[13] While TMAU can present at any age, symptoms often become more noticeable during puberty when hormonal changes occur.[14]

Pathophysiology

Primary TMAU is caused by a dysfunction or deficiency of the flavin-containing monooxygenase 3 (FMO3) enzyme due to mutations in FMO3.[15] The FMO3 enzyme plays a crucial role in the metabolism of TMA, a compound with a fishy odor.

The FMO3 enzyme is primarily expressed in the liver and functions as a monooxygenase enzyme. The principal function of the FMO3 enzyme is to oxidize and convert TMA into trimethylamine N-oxide (TMAO), which is odorless and nontoxic.[16] The dysfunctional or deficient FMO3 enzyme in patients with primary TMAU impairs TMA conversion, resulting in an increased TMA:TMAO ratio.[17][18] The accumulated TMA is passively absorbed into the bloodstream and is released through various excretory routes, including sweat, breath, and urine, giving rise to the distinctive fishy odor associated with TMAU.[19]

The gut microbiota produces TMA by metabolizing certain nitrogen-containing compounds, such as choline and carnitine, in certain foods. In individuals with TMAU, the excessive production of TMA by colonic bacteria further contributes to the accumulation of TMA in the body.[9]

History and Physical

The characteristic presenting features of TMAU are a fishy body odor, halitosis, and malodorous urine. The persistent and often unpredictable nature of the odor associated with TMAU can have significant psychological and social implications.[20] Individuals with TMAU may experience embarrassment, low self-esteem, social isolation, and a negative impact on their overall quality of life. Depression is reported in many individuals with trimethylaminuria.[2]

The hallmark symptom of TMAU is the presence of a persistent and unpleasant body odor similar to rotting fish. This odor may begin at birth or nearer to puberty.[21] Not everyone can smell TMA; some patients have reported being unaware of the smell. The odor arises from the excretion of TMA through sweat, breath, urine, and other bodily secretions.[22] The intensity of the odor can fluctuate and may be influenced by factors such as diet, stress, hormonal changes, and medications. The odor may be described as fishy, musty, or ammonia-like, and it may be particularly pronounced after consuming TMA-rich foods.[23]

In addition to body odor, individuals with TMAU may also experience halitosis or bad breath, resulting from TMA excretion through the breath, leading to an unpleasant smell.[24]

The urine may have a distinct smell reminiscent of rotten fish or ammonia.

Evaluation

Diagnosing TMAU requires clinical evaluation and biochemical and genetic testing. Biochemical laboratory testing may require several steps.

Elevation of urinary TMA levels suggests impaired metabolism and can indicate TMAU.[25] To perform this test, a urine sample is collected and analyzed for TMA using specialized laboratory techniques. Patients with results suggestive of TMAU may undergo a TMA challenge or TMA load test. A TMA challenge test begins with administering a large dose of TMA, which can be administered by eating a 300 g portion of marine fish. A random urine collection within 2 to 12 hours after the TMA load is sampled and the levels of TMA and TMAO are quantified.[16] In patients with deficient or dysfunctional FMO3 activity, urinary TMA levels will be elevated following the challenge.[26]

The enzymatic activity of FMO3 may be quantified directly using blood samples.[27] Reduced or absent FMO3 enzymatic activity supports the diagnosis of TMAU.

Patients with TMAU may undergo genetic testing to identify specific FMO3 mutations. Genetic testing is performed using blood or saliva to detect specific genetic variants associated with TMAU. Genetic testing can confirm the diagnosis, identify the specific genetic mutation, and help determine the inheritance pattern of the disorder.[16]

Treatment / Management

The management of TMAU focuses on minimizing the symptoms and improving the quality of life for affected individuals.[6] While there is currently no cure for TMAU, various approaches can produce symptom management. A specific questionnaire for patients with TMAU has been developed to evaluate treatment efficacy; the tool includes questions about different aspects of health to address all disease consequences.[28] The treatment options for TMAU include dietary modification, antibiotic therapy, activated charcoal administration, modifications to personal hygiene, and psychological support.(B2)

Dietary modifications to reduce the intake of TMA precursors are often recommended. Foods rich in choline, carnitine, and TMAO should be limited or avoided. This may include reducing or eliminating the consumption of certain types of fish, red meats, liver, eggs, legumes, and specific vegetables. Working with a registered dietitian specializing in metabolic disorders can be beneficial in developing an appropriate dietary plan.[29](B3)

In some cases, low-dose antibiotics may be prescribed to reduce the population of TMA-producing bacteria in the gut. Antibiotics like neomycin and metronidazole have been used with varying degrees of success.[30] However, long-term antibiotic use should be carefully monitored due to potential side effects and the risk of antibiotic resistance.

Activated charcoal can absorb and reduce TMA levels in the gut. It may be used as a supplement to help minimize TMA production and absorption. However, its effectiveness can vary among individuals.

Copper chlorophyllin, a chlorophyll derivative, has been used as a supplement to help reduce body odor. Copper chlorophyllin is believed to neutralize odor-causing compounds; its effectiveness in managing TMAU symptoms is still being investigated, and individual responses may vary.

Maintaining good personal hygiene practices, including regular bathing or showering using odor-reducing soaps or washes, can help minimize the odor associated with TMAU.

Trimethylaminuria can have a significant impact on self-esteem and mental well-being. Seeking support from mental health professionals, joining support groups, and engaging in counseling can be valuable in managing the emotional and psychological aspects of living with TMAU.[20] 

A recent study revealed that the endovascular closure treatment resolved TMAU in patients with congenital portosystemic shunts when performed between birth and age 21.[31][32]

Differential Diagnosis

When evaluating a patient with suspected TMAU, it is essential to consider other genetic, systemic, or precise conditions that may present with similar symptoms or overlapping biochemical abnormalities.[33]

Vaginal disorders, such as bacterial vaginosis or trichomoniasis, can cause a fishy odor similar to that of TMAU. These isolated vaginal conditions can be identified through careful examination, including genitourinary examination, pH testing, and microscopic evaluation of vaginal secretions. Nucleic acid amplification testing is also available.

Certain foods, such as seafood, can cause transient body odor that resembles TMAU. However, this type of dietary-related odor is temporary and dissipates once the food is eliminated from the diet. Obtaining a detailed dietary history and evaluating the relationship between food intake and the onset of symptoms can help differentiate between dietary-induced odor and TMAU.

Liver or kidney dysfunction can lead to changes in body odor. Hepatic diseases, such as cirrhosis or hepatic enzyme deficiencies, can result in a fishy or ammonia-like body odor.

Various metabolic disorders can manifest abnormal body odors. For instance, isovaleric acidemia, a rare genetic disorder, can cause a distinctive "sweaty feet" odor. Other metabolic disorders associated with characteristic odors include maple syrup urine disease and phenylketonuria (PKU). Comprehensive metabolic screening tests and targeted investigations can aid in ruling out these conditions.

Hormonal fluctuations, particularly during puberty, menstruation, or pregnancy, can influence body odor. Changes in sweat composition and secretion during these periods can sometimes lead to a fishy odor. Assessing the relationship between hormonal changes and the onset of symptoms can help differentiate hormonal-induced body odor from trimethylaminuria.

Poor personal hygiene practices, such as infrequent bathing or inadequate use of hygiene products, can lead to body odor.

Prognosis

TMAU is a chronic condition, and while there is currently no cure, it is not life-threatening. With proper management and support, many individuals with TMAU can lead fulfilling lives. Regular appointments with healthcare professionals specializing in metabolic disorders, adherence to treatment plans, and maintaining a healthy lifestyle can help individuals manage symptoms and optimize their prognosis. 

Complications

The characteristic fishy odor associated with TMAU can lead to significant social and psychological distress. Individuals with TMAU may experience embarrassment, social isolation, and low self-esteem due to the persistent and often unpredictable nature of the odor.[16] They may also be at risk of anxiety and depression due to social stigma.[2] These psychological and emotional challenges can profoundly impact relationships, employment opportunities, and overall quality of life.