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TRIMETHYLAMINURIA


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Trimethylaminuria (TMAU) is given its own page since it is currently the only recognized and accepted 'systemic' body odor condition by the medical community. It was detected in 1970 by a group of doctors in Colorado who tested a child with other health issues. The child was also said to have a 'fishy odor' at times. They performed a urine test and discovered high levels of trimethylamine (TMA). The University of Colorado, Denver, still has TMAU testing available today. Very few other labs currently offer TMAU testing. In the US, HBRI in San Diego and the Arkansas Children's Hospital are known to do TMAU testing, as well as a thorough 'body odor' examination at Monell Chemical Senses Center in Philadelphia. A full list of known international TMAU labs can be seen in the list at the bottom of this page.

Primary Trimethylaminuria (commonly known as TMAU1) is one type of 'FMO3 deficiency'. It is a genetic metabolic disorder currently taught as being inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (carriers) and therefore, carry one mutant allele. Heterozygotes (carriers) are supposedly asymptomatic (not affected). Mild or intermittent symptoms can sometimes occur in carriers of FMO3 mutations. This deficiency of FMO3 enzyme results in an inefficient FMO3 function with a failure to metabolize the chemical Trimethylamine(TMA), which smells of rotting fish. Frequently, major FMO3 substrates include sulfur-, nitrogen-, selinium- and phosphorous-containing chemicals may also not be properly metabolized by the FMO3 enzymes, and thus produce an odor different from fish.

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. It is generally regarded that there are 2 types of Primary TMAU : the severe type, and mild type. 

The severe type is the textbook genetic type of TMAU, where the person has 2 mutant copies of FMO3 that is very low-functioning. It is now accepted that milder forms exist, and these will usually involve variants or polymorph FMO3 copies, which are usually much more higher functioning, but still below normal. The current estimate of severe TMAU is not greater than around 1 in 5000, which in the USA could mean a 'severe TMAU' estimate of around 60,000. Presumably the number of 'mild' cases would be much higher. Primary trimethylaminuria can be generally assumed to be a result of 'FMO3 deficiency', although there are cases where FMO3 variants can metabolize certain types of FMO3 substrates but not others.

Trimethylamine (TMA) is a chemical created in the intestines by a few bacteria during the digestive process of foods containing choline. TMA is a chemical found in fish, sharks and rays, molluscs, and crustaceans, and is the main odorant that is characteristic of degrading seafood. 

TMA is normally transported to the liver to be metabolized into non-odorous Trimethylamine-n-oxide (TMAO) by the flavin-containing monooxygenase 3 (FMO3) metabolic enzyme produced in the liver.  Both TMAO and TMA are normally excreted in the urine.  However, when there is a deficiency of the FMO3 enzyme due to an autosomal recessive condition resulting in an FMO3 mutation, TMA is then not oxidized, and thus remains in an odorous state.  Over time, this chemical compound may stay in the body longer building up and causing the excretion of a strong and offensive odor to leave the body through every single pore, breath, urine, and reproductive fluids.

 Secondary Trimethylaminura (TMAU2) is an acquired form of TMAU usually  involving an overproduction of TMA by gut flora in a patient with normal FMO3 function (i.e. does not have an FMO3 deficiency). Experts believe that TMAU2 from overproduction of TMA by bacterial overgrowth in the gut can be experienced for many years, but if the correct antibiotic therapy is applied, it can be cured by eradication of the bacteria responsible, though the bacterial overgrowth tends to return. Secondary TMAU, or TMAU2, has been recognized for many years, particularly in the UK, although much of the TMAU interest has been in the inherited metabolic disorder FMO3 deficiency, TMAU1.

Both TMAU1 and TMAU2 can be controlled with periodic antibiotic therapy as well as dietary choline restriction of eggs, liver, beans, carnitine (meat), and TMAO rich foods (seafood). Choline and TMAO are broken down by gut bacteria into TMA, which creates a favorable environment for the bacteria to grow in. The odor effects of TMA may also be reduced by activated charcoal or copper chlorophyllin tablets to adsorb the TMA in the gut, which is later eliminated in the feces. The alkaline pH of TMA in the sweat can be neutralized with the use of pH skin cleansers and creams.

Psycho-social consequences : Socially offensive metabolic odor significantly interferes in the affected person's social life, such as in school, work, or personal relationship.  This social crisis usually results in profound psycho-social side effects, as portrayed in our community written Our journey: overcome the stigma of the invisible monster. written by sufferers as a fund-raising tool for MEBO Research, as well as the two books, When Bathing Is Not Enough, by Alice Mata, and Carry Wilson's autobiography, The Foul Body Odor that Amost Killed Me. Since this condition tends to initially become more symptomatic in adolescence, the affected person is for the most part rejected by his or her classmates and peers, and usually in a very cruel manner resulting is social isolation.In adulthood, most are harassed in the workplace for the same reason, and are usually the first to be terminated from employment as a result, frequently independent of work performance.  These social conditions produce profound psychological injury resulting in severe symptoms of depression and anxiety that prevent the affected person from being a productive member in society.  Many ultimately have resorted to dependency on social benefits, such as unemployment compensation and/or Social Security Disability benefits.  


According to some experts, 40% of persons affected with body odor conditions report they have remained housebound for at least a week at a time out of fear of offending others.  Two-thirds have contemplated suicide, and a third have attempted it.  The vast majority suffer from depression or some other mental disorder, and sometimes substance abuse, since most develop a very lonely lifestyle without relief in sight at a very young age, and are struck by the overwhelming distress that comes with being socially ostracized.  Erroneously, due to total lack of social awareness and understanding of this condition, most in society perceive it as an offensive lack of personal hygiene on the part of the affected individual.  As a result, people normally tend to respond to the sufferer in an overtly or covertly hostile manner.  One of the most traumatic aspects of this disorder is that the sufferer has no recourse in the medical system to find treatment and a cure, and finds it difficult to understand why the medical community is not well versed in this condition.  

One of the most traumatic aspects of living with this disorder is that the affected person has no recourse in the medical system to find treatment, and a cure is nowhere in sight due to lack of research in this field for lack of funding.  It is difficult to understand why the medical community is not well versed in this condition as a result of there being little dispersion of the limited research information sporadically published in professional journals.  Thus, a sufferer very rarely receives the necessary appropriate medical attention and treatment to control his or her odor.  



TESTING:
* The latest MEBO TMAU Urine Test program ran from July, 2016 until June, 2017. This program is currently re-structuring.
Please subscribe to our Blog if you wish to be notified when it is restarted.
MEBO's goal in creating a TMAU Urine test program, is to provide low-cost testing for all sufferers.

HISTORY OF THE DIAGNOSIS:

1970: Colorado lab doctors do TMA urine test on child with 'fishy odor' and discover high trimethylamine levels,
1987-89: First serious continuous research into TMAU begins. Researchers include Mitchell & Smith of London,
1992: First pubmed paper about TMAU featuring Dr Preti,
1997: DNA papers published about FMO3 : Cashman et. al., in Seattle, Dolphin in London,
1997-2005: Most TMAU papers written in this period, especially DNA. Notable researchers : Cashman, Treacy, Mitchell, Smith, Phillips, Shephard,
1999: 1st international TMAU workshop held,
2002: 2nd TMAU workshop held. Was supposed to become bi-annual,
2007: Dr. Fennessey says he sees TMAU mentioned in medical teaching literature for first time.


CURRENT TMAU ADVICE

In a publication in the Office of Rare Diseases Research (ORDR), Genetics and Rare Diseases Information Center GARD, the National Institutes of Health outlines the only treatment currently available for TMAU. The University of Washington, Seattle with the funding support of the National Institutes of Health, has published an article in GeneReviews, which includes the management and recommended "Strategies for the treatment of Trimethylaminuria". 

*Low Choline Diet : avoid eggs; liver; kidney; peas; beans; peanuts; soy products; brassicas (brussel sprouts, broccoli, cabbage, and cauliflower); and lecithin and lecithin-containing fish oil supplements. Trimethylamine N-oxide is present in seafood (fish, cephalopods, crustaceans). Freshwater fish have lower levels of trimethylamine N-oxide.

*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. 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 infection, emotional upset, stress, or exercise)

*Antibiotics: recommended for trimethylaminuria to suppress production of trimethylamine by reducing bacteria in the gut:
1. neomycin: appears to be the most effective in preventing formation of trimethylamine from choline
2. metronidazole: particularly effective against anaerobic bacteria and protozoa
3. amoxicillin

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. RIBOFLAVIN (Vitamin B2) SUPPLEMENTS: 30-40 mg three to five times per day with food to enhance residual FMO3 enzyme activity.

*Sequestering of trimethylamine produced in the gut:
1. Activated Charcoal: 750mg twice daily for 10 days 
2. Copper Chlorophyllin: 60mg three times/day after meals for 3 weeks 
3. *LAXATIVES, such as Lactulose: decrease intestinal transit time, may reduce the amount of trimethylamine produced in the gut. Neutralizes the pH of TMA odorous chemicals. Lactulose is a prescription item in the USA.

NOTES: Fresh water fish have a lower content of trimethylamine N-oxide AND THUS ARE NOT A PROBLEM. 

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. 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

NOTE:
pH factors:
 Trimethylamine is a strong base (pH 9.8) (Acids have a low pH)
Normal skin pH 5.5-6.5
***Recommended use of acid soaps and body lotions***

 


TMAU REFERENCE LINKS

Overview
TMAU : letter in journal
TMAU : Socially distressing
NIH TMAU article
TMAU gene card
Mitchell/Smith 2003 Overview
OMMBID TMAU abstract
Genome.gov TMAU article
Krueger/Williams 2007 overview of FMO
Orphanet 2002 TMAU overview (PDF)
Orphanet 2009 TMAU overview
FMO - the 'other' oxidase
Lancet letter : susceptibility of heterozygotes 
TMAU results in a UK group
TMAU : 8/12 had no mutations
2002 paper : FMO3 polymorphisms
letter to editor on mild FMO3 deficiency
Karen letter in Innovait Journal 
 
Reference
NCBI reference :  FMO3
Coding sequence for FMO3 protein
MEBO copy of FMO3 coding sequence
Sheffield TMAU testing by Nigel Manning
FMO3 database
TMAU in NHS 'DUET' database
Uniprot entry for FMO3
 
Case Studies
TMAU : 11% Ecuadorians in random test
2011 Monell TMAU paper
TMAU and dietary precursors
TMAU carrier test
2 FMO3 DNA cases
Portal Shunt with TMAU
 
TMAU diet & protocol info
USDA choline database 
Choline nutrient checker (shows foods highest in choline- to avoid)

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