Trimethylaminuria (2024)

Continuing Education Activity

Trimethylaminuria (TMAU) is a rare metabolic disorder resulting in the accumulation of trimethylamine. Primary TMAU is an autosomal recessive genetic condition that results in the deficiency or dysfunction of the hepatic enzyme flavin monooxygenase 3. Trimethylamine is a foul-smelling metabolite excreted in body fluids causing affected individuals to exude a fishy odor. While not a life-threatening condition in and of itself, TMAU can have significant psychological and social implications. Proper diagnosis and implementation of appropriate management strategies can help improve symptoms and overall quality of life for patients with TMAU. This activity reviews the pathogenesis, pathophysiologic mechanisms, clinical features, diagnostic testing, and management strategies of TMAU and highlights the integral role of the interprofessional team in treating patients with this rare condition.

Objectives:

• Identify the risk factors for trimethylaminuria in patients presenting with malodor.

• Correlate the pathogenic and pathophysiologic mechanisms of trimethylaminuria with the clinical signs and symptoms of the disease.

• Apply diagnostic testing protocols in the evaluation of patients with suspected trimethylaminuria.

• Develop and effectively implement interprofessional treatment strategies to improve patient outcomes for those affected by trimethylaminuria.

Access free multiple choice questions on this topic.

Introduction

Trimethylaminuria (TMAU), also known as fish odor syndrome or stale fish syndrome, is a rare metabolic disorder characterized by the abnormal accumulation and excretion of trimethylamine (TMA).The accumulation of TMA results in a strong, offensive odor resembling that of rotting fish.[1]

The underlying pathogenesis of TMAU is usually a deficient ordysfunctionalhepatic enzyme, flavin-containing monooxygenase 3 (FMO3). This enzyme metabolizes TMA into an odorless compound, trimethylamine N-oxide (TMAO).[2]

TMA has a strong fishy smell and is a pheromone in different organisms.[2]A case reportdescribed this condition in 1970, but it is believed that trimethylaminuria had been in existence long before then.[3]

Etiology

Primary Trimethylaminuria

Primary trimethylaminuria occurs secondary toa genetic mutation of the FMO3 gene, located on chromosome 1q24.3. Various FMO3mutations 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 FMO3need to bemutated for TMAU to manifest. However, some rare cases of TMAU may exhibit partial enzyme deficiency due toheterozygosity, compound heterozygosity, or regulatory mutational variants affecting FMO3 expression.[5]

Failure to metabolizeTMA 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 metabolismresulting 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 produceTMA from dietary precursorssuch ascholine, carnitine, and lecithin, which are absorbed into the enterohepatic circulation by simple diffusion.[9]Symptoms of TMAU can develop when theliver 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 ofTMAU 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 ofTMAU. The carrier rate among individuals of New Guinean origin is11%.[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 TMAUis 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 theliver and functions as a monooxygenase enzyme. The principal function of the FMO3 enzymeis to oxidize and convert TMA into trimethylamine N-oxide (TMAO), which is odorless and nontoxic.[16] The dysfunctional or deficient FMO3 enzyme inpatients 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 ofTMAU 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. Thisodor may begin at birth or nearer to puberty.[21]Not everyone can smell TMA; somepatients have reported being unaware of the smell. The odor arisesfrom 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, resultingfrom TMAexcretion through the breath, leading to an unpleasant smell.[24]

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

Evaluation

DiagnosingTMAUrequires 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 FMO3mutations. 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 ofTMAU 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 canproduce symptom management. A specific questionnaire for patients with TMAU has been developed to evaluate treatment efficacy; the toolincludes questionsabout 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.

Dietarymodificationsto reduce the intake of TMA precursorsare 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]

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 charcoalcan 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 studyrevealed 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]

vagin*l disorders, such as bacterial vaginosis or trichom*oniasis, can cause a fishy odor similar to that of TMAU. These isolated vagin*l conditions can be identified through careful examination, including genitourinary examination, pH testing, and microscopic evaluation of vagin*l 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 asinfrequent 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. Regularappointments 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.

Deterrence and Patient Education

Patient education plays a vital role in TMAU management by empowering individuals with knowledge about their condition and providing them with strategies to cope with its challenges.Several patient education modalities may be employed when caring for patients with TMAU.

Individualized one-on-one counseling sessions with healthcare professionals, such as geneticists, metabolic specialists, or registered dietitians, can provide tailored information about TMAU. These sessions allow for a personalized approach, addressing the specific needs, concerns, and questions of the individual. Individual counseling can cover dietary modifications, hygiene practices, treatment options, and coping strategies.[34]

Group education sessions or support groups can bring together individuals with TMAU to share experiences, learn from one another, and receive information from healthcare professionals. These sessions foster a sense of community, reduce feelings of isolation, and provide a platform for mutual support and encouragement.

The development of mobile applications specifically designed for individuals with TMAU can provide on-the-go access to educational resources, diet trackers, hygiene reminders, and community forums. These interactive applications allow individuals to track their symptoms, monitor their dietary intake, and receive personalized recommendations.

Enhancing Healthcare Team Outcomes

Interprofessional management ofTMAU involves a collaborative approach among various healthcare professionals to address the complex challenges associated with this condition. The interprofessional team typically includes primary care practitioners, geneticists, dietitians, psychologists or counselors, and nurses. Together, they aim to provide comprehensive care, education, and support to the patient.[20]

Geneticists play a crucial role in confirming the diagnosis ofTMAU through genetic testing. They can identify specific mutations in FMO3and provide genetic counseling to affected individuals and their families.

Primary carepractitioners and specialists, such as metabolic disorder specialists, collaborate tomonitor symptoms,evaluate treatment effectiveness, address concerns, and make necessary adjustments to the management plan.

Dietitians or nutritionists are vital in guiding individuals withTMAUto adopt a low-choline diet. They provide personalized dietary recommendations to minimize the intake of choline-rich foods, which are precursors toTMA production.

Psychologists, counselors, and social workers provide invaluable psychosocial support to individuals with TMAUby addressingemotional challenges, social stigma, and self-esteem and body image issues. Counseling sessions may focus on coping strategies, stress management techniques, and building resilience. Support groups or online communities can also facilitate connections with others facing similar challenges.

By leveraging the expertise and collaboration of multiple healthcare professionals, the interprofessional management ofTMAU aims to provide comprehensive care that addresses the medical, dietary, psychological, and social aspects of the condition. This approach ensures a holistic and patient-centered approach, improving outcomes and quality of life for individuals living with TMAU.

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

References

1.

Loo RL, Chan Q, Nicholson JK, Holmes E. Balancing the Equation: A Natural History of Trimethylamine and Trimethylamine-N-oxide. J Proteome Res. 2022 Mar 04;21(3):560-589. [PubMed: 35142516]

2.

Messenger J, Clark S, Massick S, Bechtel M. A review of trimethylaminuria: (fish odor syndrome). J Clin Aesthet Dermatol. 2013 Nov;6(11):45-8. [PMC free article: PMC3848652] [PubMed: 24307925]

3.

Humbert JA, Hammond KB, Hathaway WE. Trimethylaminuria: the fish-odour syndrome. Lancet. 1970 Oct 10;2(7676):770-1. [PubMed: 4195988]

4.

Antoñanzas J, Querol-Cisneros E, Alkorta-Aranburu G, Patiño-García A, España A. Primary trimethylaminuria syndrome: more than an unpleasant odor. Int J Dermatol. 2023 Mar;62(3):e176-e178. [PubMed: 35975805]

5.

Makiguchi M, Shimizu M, Yokota Y, Shimamura E, Hishinuma E, Saito S, Hiratsuka M, Yamazaki H. Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources. Drug Metab Dispos. 2023 Jul;51(7):884-891. [PubMed: 37041084]

6.

Schmidt AC, Leroux JC. Treatments of trimethylaminuria: where we are and where we might be heading. Drug Discov Today. 2020 Sep;25(9):1710-1717. [PubMed: 32615074]

7.

Binzak BA, Vockley JG, Jenkins RB, Vockley J. Structure and analysis of the human dimethylglycine dehydrogenase gene. Mol Genet Metab. 2000 Mar;69(3):181-7. [PubMed: 10767172]

8.

Fraser-Andrews EA, Manning NJ, Ashton GH, Eldridge P, McGrath J, Menagé Hdu P. Fish odour syndrome with features of both primary and secondary trimethylaminuria. Clin Exp Dermatol. 2003 Mar;28(2):203-5. [PubMed: 12653714]

9.

Fennema D, Phillips IR, Shephard EA. Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease. Drug Metab Dispos. 2016 Nov;44(11):1839-1850. [PMC free article: PMC5074467] [PubMed: 27190056]

10.

Donato L, Alibrandi S, Scimone C, Castagnetti A, Rao G, Sidoti A, D'Angelo R. Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU. J Pers Med. 2021 Jan 31;11(2) [PMC free article: PMC7912098] [PubMed: 33572540]

11.

Wise PM, Eades J, Tjoa S, Fennessey PV, Preti G. Individuals reporting idiopathic malodor production: demographics and incidence of trimethylaminuria. Am J Med. 2011 Nov;124(11):1058-63. [PubMed: 21851918]

12.

Mitchell SC, Zhang AQ, Barrett T, Ayesh R, Smith RL. Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations. Pharmacogenetics. 1997 Feb;7(1):45-50. [PubMed: 9110361]

13.

Shimizu M, Cashman JR, Yamazaki H. Transient trimethylaminuria related to menstruation. BMC Med Genet. 2007 Jan 27;8:2. [PMC free article: PMC1790885] [PubMed: 17257434]

14.

Doyle S, O'Byrne JJ, Nesbitt M, Murphy DN, Abidin Z, Byrne N, Pastores G, Kirk R, Treacy EP. The genetic and biochemical basis of trimethylaminuria in an Irish cohort. JIMD Rep. 2019 May;47(1):35-40. [PMC free article: PMC6498825] [PubMed: 31240165]

15.

Shimizu M, Yamamoto A, Makiguchi M, Shimamura E, Yokota Y, Harano M, Yamazaki H. A family study of compound variants of flavin-containing monooxygenase 3 (FMO3) in Japanese subjects found by urinary phenotyping for trimethylaminuria. Drug Metab Pharmaco*kinet. 2023 Jun;50:100490. [PubMed: 36889044]

16.

Mackay RJ, McEntyre CJ, Henderson C, Lever M, George PM. Trimethylaminuria: causes and diagnosis of a socially distressing condition. Clin Biochem Rev. 2011 Feb;32(1):33-43. [PMC free article: PMC3052392] [PubMed: 21451776]

17.

Murphy HC, Dolphin CT, Janmohamed A, Holmes HC, Michelakakis H, Shephard EA, Chalmers RA, Phillips IR, Iles RA. A novel mutation in the flavin-containing monooxygenase 3 gene, FM03, that causes fish-odour syndrome: activity of the mutant enzyme assessed by proton NMR spectroscopy. Pharmacogenetics. 2000 Jul;10(5):439-51. [PubMed: 10898113]

18.

Hernangómez Vázquez S, González González C, Lancho Monreal EM, Alonso Cristobo ME, Mallol Poyato MJ, García-Vao Bel CM. [Trimethylaminuria: three different mutations in a single family]. Nutr Hosp. 2019 Apr 10;36(2):492-495. [PubMed: 30864455]

19.

Krueger ES, Lloyd TS, Tessem JS. The Accumulation and Molecular Effects of Trimethylamine N-Oxide on Metabolic Tissues: It's Not All Bad. Nutrients. 2021 Aug 21;13(8) [PMC free article: PMC8400152] [PubMed: 34445033]

20.

Roddy D, McCarthy P, Nerney D, Mulligan-Rabbitt J, Smith E, Treacy EP. Impact of trimethylaminuria on daily psychosocial functioning. JIMD Rep. 2021 Jan;57(1):67-75. [PMC free article: PMC7802621] [PubMed: 33473342]

21.

Pardini RS, Sapien RE. Trimethylaminuria (fish odor syndrome) related to the choline concentration of infant formula. Pediatr Emerg Care. 2003 Apr;19(2):101-3. [PubMed: 12698036]

22.

Kloster I, Erichsen MM. Trimethylaminuria. Tidsskr Nor Laegeforen. 2021 Sep 28;141 [PubMed: 34597008]

23.

Haugaard LK, Lund AM, Patursson P, Christensen E. [Fish odour--could be a sign of trimethylaminuria]. Ugeskr Laeger. 2010 Nov 22;172(47):3268-9. [PubMed: 21092725]

24.

Mitchell SC. Trimethylaminuria (fish-odour syndrome) and oral malodour. Oral Dis. 2005;11 Suppl 1:10-3. [PubMed: 15752091]

25.

Bouchemal N, Ouss L, Brassier A, Barbier V, Gobin S, Hubert L, de Lonlay P, Le Moyec L. Diagnosis and phenotypic assessment of trimethylaminuria, and its treatment with riboflavin: ¹H NMR spectroscopy and genetic testing. Orphanet J Rare Dis. 2019 Sep 18;14(1):222. [PMC free article: PMC6751875] [PubMed: 31533761]

26.

Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J Inherit Metab Dis. 2006 Feb;29(1):162-72. [PubMed: 16601883]

27.

Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997 Dec;17(4):491-4. [PubMed: 9398858]

28.

Rutkowski K, Rahman Y, Halter M. Development and feasibility of the use of an assessment tool measuring treatment efficacy in patients with trimethylaminuria: A mixed methods study. J Inherit Metab Dis. 2019 Mar;42(2):362-370. [PubMed: 30734325]

29.

Li M, Al-Sarraf A, Sinclair G, Frohlich J. Fish odour syndrome. CMAJ. 2011 May 17;183(8):929-31. [PMC free article: PMC3091902] [PubMed: 21422137]

30.

Rehman HU. Fish odor syndrome. Postgrad Med J. 1999 Aug;75(886):451-2. [PMC free article: PMC1741321] [PubMed: 10646019]

31.

Ponce-Dorrego MD, Hernández-Cabrero T, Garzón-Moll G. Endovascular Treatment of Congenital Portosystemic Shunt: A Single-Center Prospective Study. Pediatr Gastroenterol Hepatol Nutr. 2022 Mar;25(2):147-162. [PMC free article: PMC8958053] [PubMed: 35360378]

32.

Ponce-Dorrego MD, Garzón-Moll G. Endovascular Closure Resolves Trimethylaminuria Caused by Congenital Portosystemic Shunts. Pediatr Gastroenterol Hepatol Nutr. 2019 Nov;22(6):588-593. [PMC free article: PMC6856509] [PubMed: 31777726]

33.

Hur E, Gungor O, Bozkurt D, Bozgul S, Dusunur F, Caliskan H, Berdeli A, Akcicek F, Basci A, Duman S. Trimethylaminuria (fish malodour syndrome) in chronic renal failure. Hippokratia. 2012 Jan;16(1):83-5. [PMC free article: PMC3738402] [PubMed: 23930066]

34.

Khan SA, Shagufta K. A rare case of fish odor syndrome presenting as depression. Indian J Psychiatry. 2014 Apr;56(2):185-7. [PMC free article: PMC4040069] [PubMed: 24891709]

Disclosure: Ayoola Awosika declares no relevant financial relationships with ineligible companies.

Disclosure: Catherine Anastasopoulou declares no relevant financial relationships with ineligible companies.