UK DUETs to help prioritise new research in NHS takes interest in FMO3 deficiencies

As Karen James and others in the UK and in the US have implemented initiatives to raise awareness in the UK’s medical establishment, we are beginning to see signs of having received the attention of the National Health System's department that could potentially make a difference in research possibilities and clinical guidelines. As we wrote emails and letters to the NHS officials that Karen selected for us, she was referred to,

Mark Fenton, Project Manager,
UK Database of Uncertainties about the Effects of Treatments
(UK DUETs*)
NHS Evidence,
National Institute for Health and Clinical Excellence, (NICE)

*NOTE: UK DUETs is a service of the National Health Services (NHS) in the United Kingdom that draws on three main sources to identify uncertainties about the effects of treatments, patients, carers, and clinicians. It is,"A resource to make uncertainties explicit and to help prioritise new research."

As Mark writes to Karen in response to the literature we sent from sufferers in the UK and US,

What a challenging submission…What I am trying to do is form a statement which reflects the Intervention (in this case enzyme replacement therapy), Comparator, Patient/Population and Outcome (ICPO). You specifically ask about UK research for treatment, but my approach would be is there any research worldwide. A brief search on the Cochrane Library and other such databases leads me to believe there is little, if any, quantitative research anywhere. A search for trimethylaminuria on NHS Evidence produces very few returns, which does return five treatment hits…It seems to me that your submission is truly an uncertainty, and if you are in agreement, I think should be one of the two statements above about what the uncertainty is, unless you can assist me in forming a more indicative question…I'm more than happy to call you if it would be off assistance.

[Mark Fenton, Project Manager , UK Database of Uncertainties about the Effects of Treatments (UK DUETs), NHS Evidence, National Institute for Health and Clinical Excellence]

After Karen told Mark that she was, “liaising with MEBO Research (registered charity for odour-producing disorders) to see if they can help us with formulating a question…”

Mark replied, “I'm happy to wait and see what happens with your response from MEBO Research for an indicative question. I can get the two supplementary questions into UK DUETs.”

As a result, I have tried to compile information, including a list of experts who MEBO has consulted with throughout the years, articles published in scientific journals, and 5 indicative questions that perhaps Mark might consider for his ICPO, especially beneficial may be question #5 below for ICPO.Below is a copy of the report MEBO Research submitted to Mark Fenton.

Dear Mark,

Ms. Karen James asked me to write to you in an attempt to address your concerns that you state in your email below. Thank you very much for expressing interest in our cause. I do apologize for such a lengthy email, but I would like to touch upon the some of the most important questions most in our community believe need to be researched to address the causes and treatment of persons who may be suffering from FMO3 deficiency, including Trimethylaminuria (TMAU). I have raised five questions below that I think would be interesting research topics that would probably help a great deal of people from around the world that suffer from uncontrollably systemic body odour and halitosis (alveolar halitosis).

We have attempted to compile in these blogs as many relevant professional articles as we can find published in professional journals as well as our interviews with experts.

First of all, let me introduce myself, I am the founder of MEBO Research, a Public Charity in the US and a Not For Profit Limited by Guarantee Company in England and Wales aspiring to become a Charity. We are a patient advocacy international campaign whose primary aims are to seek funding for scientific and medical communities to perform formal research into body malodour conditions, probably FMO3 related, such as but not limited to, trimethylaminuria (TMAU). In our efforts to achieve this goal, MEBO has created two blogs (in English and in Spanish) in which we strive to unite sufferers and experts from around the world to pursue research into the causes of malodorous conditions. We have attempted to compile in these blogs as many relevant professional articles as we can find published in professional journals as well as our interviews with experts. These are a few of the interviews we have posted that might be of interest to you,

• Professor Elizabeth Shephard TMAU/FMO3 slideshow – an overview of TMAU in relation to the genetic deficiency of FMO3 enzymes, and in the end discusses interesting studies currently taking place or that need to be carried out.
• More papers by Professor Elizabeth Shephard and Ian Phillips on FMO3.
• Interview : Dr John Cashman of HBRI in San Diego, of the Human Biomolecular Research Institute (HBRI) in San Diego, California.
• Table of FMO3 variants provided by Dr John Cashman of HBRI
• Interview : Nigel Manning : The tester of almost all TMAU urine samples in the UK Nigel Manning, Principal Clinical Scientist, Dept. Clinical Chemistry, Sheffield Children’s Hospital, UK.
• >Interview with Dr. Robin Lachmann, PhD, MRCP, Consultant in Metabolic Medicine
• Dr. Ronald Hine’s TMAU Article for MEBO’s blog.

There must be other similar metabolic problems and other chemicals which cause odour, but as we don't know precisely what they are...

In these articles and interviews, these experts give some ideas of the genetics, diagnostic testing, and current treatment of TMAU. In the U.S. National Library of Medicine and the Genetic and Rare Diseases Information Center (GARD) of the Office of Rare Diseases Research of the U.S. National Institutes of Health websites, you will find articles on Trimethylaminuria. Interestingly enough, the first of the two articles were written by British scientists, Professor Elizabeth Shephard and Ian R. Phillips, and they discuss the Clinical Description, Differential Diagnosis, Management of Trimethylaminuria, and Genetic Counselling. The second article also makes mention of laboratories that perform cinical diagnosis of TMAU in the US.

In their interviews, Nigel Manning, Dr. Robin Lachmann, and Dr. Phillips present to us the concept of Secondary TMAU, the acquired form of TMAU, which is a diagnosis given only in the United Kingdom, as opposed to Primary TMAU, the genetic form used in the United States. In Secondary TMAU, it is believed that some yet to be identified gut bacteria takes choline consumed in food and converts it to TMA, which then passes on to the bloodstream. This excessive TMA in the blood may overwhelm a healthy FMO3 metabolic enzyme resulting in body odour, and resulting in both elevated levels of TMA and of TMAO. In the case of FMO3 deficiency, TMA levels would be extremely high, while the overwhelmed FMO3 would still not be able to metabolize the trimethylamine, resulting in low TMAO.

QUESTION #1:
In Part 2 of his interview, Nigel Manning is asked if he knows what bacteria is responsible for producing trimethylamine (TMA) in the gut, and he states a question, whether the same microorganisms published by the fishing industry research microbiologists are the same ones that are responsible for human TMAU production. Even though Dr. Robin Lachmann treats patients diagnosed with Secondary TMAU with antibiotics, the TMA producing bacteria in the human gut that produces TMA has not been isolated and identified. However, antibiotic treatment has shown in urine tests to decrease the TMA levels in urine. Tests have also indicated that TMA levels increase again in some cases in time, and the embarrassing odour condition often persist. As Mr. Manning indicates in his interview, with the correct antibiotic therapy, a patient with normal FMO3 activity but an overproduction of TMA by gut flora may be effectively cured. But in order to achieve this, science would need to identify the particular TMA producing bacteria to then be certain of which antibiotics truly eradicate it from the gut. This research has yet to be done.

QUESTION #2:
This leads us to another questions and answer in Nigel Manning’s interview in which Nigel is asked if he expects Primary TMAU positives to have problems with other FMO3 substrates, adding to the TMA odour. His reply is,

FMO3 may have up to 1000 substrates ie compounds that can be oxidized by this enzyme in the liver. With deficient oxidation these compounds may stay in the body longer and have unwanted consequences. Many drugs may be included in this list and are currently know to include codeine, tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine. High blood pressure is also a known complication due to foods which contain large amounts of the neurotransmitter tyramine (cheese, red wine and chocolate are examples). FMO3 deficiency should be taken into account whenever drugs are prescribed in case of an adverse reaction.

Unfortunately, most if not all of the physicians in the world are not aware of this, and thus continue to prescribe medication to patients who might have FMO3 deficiency, greatly contributing to their odour condition. This happens because the appropriate tests for FMO3 deficiencies have not yet been developed. Some studies indicate that these under-metabolized substrates may trigger pre-existing conditions such as epilepsy, learning disabilities, anxiety, and possibly autoimmune conditions.

• Epilepsy and trimethylaminuria: A new case report and literature review. Pellicciari A, Posar A, Cremonini MA, Parmeggiani A.Brain Dev. 2010 Oct 20. [Epub ahead of print] PMID: 20970269 [PubMed - as supplied by publisher]
• Trimethylaminuria associated with seizures and behavioural disturbance: a case report.

Question #3:
Research into an overall view on FMO3 metabolism to identify faulty metabolic processes of “...substrates containing a soft nucleophile, typically a nitrogen, sulphur, phosphorous, or selenium atom."[Krueger & Williams 2005]. In his interview, Dr. John Cashman also tells us, “Yes, FMO prefers smaller nucleophilic compounds: Sulfur-, Nitrogen-, Selenium-, and Phosphorous-containing compounds. But not all that contain these heteratom-containing compounds are nucleophilic as the atoms can be in aromatic rings and non-nucleophilic.” In his interview, when asked what happens to patients who get negative results on their TMAU test, Dr. Robin Lachmann states,

Just because someone tells you it’s not TMAU that does not change your symptoms. Unfortunately, we cannot be as rational about the treatment we recommend. There must be other similar metabolic problems and other chemicals which cause odour, but as we don't know precisely what they are, it is much more difficult to suggest definitive treatment?

You are absolutely correct in that there is no large scale research taking place right now anywhere in the world on TMAU or on discovering and developing FMO3 enzyme replacement therapy that I know of. However, there have been theories raised in the FMO3 scientific community about the possibility of introducing FMO3 probiotics aimed at reducing the bacterial TMA-production in the gut. There are two research proposals that I am aware of in this regard that raise questions about possible treatment for TMAU, and perhaps other types of FMO3 conditions, such as stated in questions #4 and #5 below,

QUESTION #4:
Development of Diagnostic and Therapeutic Approaches to Trimethylaminuria, by Professor John Christodoulou, Western Sydney Genetics Program, The Children’s Hospital at Westmead, University of Sydney, New South Wales, Australia. The goals of this research proposal are,

1. To develop comprehensive biochemical screening for trimethylaminuria.
2. To develop complete molecular genetic screening of the FMO3 gene for individuals suspected of having trimethylaminuria.
3. To develop an in vitro system for testing whether PTC124 can correct the functional consequences of premature termination mutations of the FMO3 gene.
4. To develop a mouse model with a premature termination mutation of FMO3 deficiency, and to study the biochemical and phenotypic consequence of this mutation in the mouse.
5. To test the in vivo efficacy of PTC124 in our mouse model of FMO3 deficiency. To test the therapeutic efficacy of Methylophilus methylotrophus as a therapeutic adjunct in our mouse model of FMO3 deficiency.

QUESTION #5:
The article, Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease links high plasma levels of trimethylamine N-oxide [TMA N-oxide or TMAO] to cardiovascular disease processes. This research in the U.S., which is intended to study CVD, has coincidently stumbled upon the effects of TMA producing gut flora metabolism of a certain type of choline, also known as Secondary TMAU in the UK, resulting in high levels of TMAO to be linked to CVD.

Again, I would like to give you my heart-felt gratitude for your interest in our cause. I hope this information is of help.

Maria de la Torre
Founder and Executive Director
MEBO Research

it would prevent odorous TMA from entering into the bloodstream allowing for a choline rich diet that does not produce uncontrollable TMAU related systemic body malodor or halitosis.

Additional comments to question #5.
These metabolomics studies identify phosphatidylcholine metabolites as precursors to TMA formation in the gut, which in turn are metabolized by FMO3 metabolic enzymes into higher than normal levels of TMAO, which the study identifies as a biomarkers of CVD. This condition of higher than normal TMA levels produced by bacteria in the gut resulting in high TMAO levels may very well be referring to the "classic" case of Secondary TMAU (not Primary TMAU). The well functioning FMO3 enzyme that catalyzes the metabolic process by adding oxygen (N-oxygenation process) to the odorous TMA in order to change it to its non-odorous state, TMAO, is indicative of a very well functioning metabolic process that effectively deals with a great deal of the excessive TMA produced by the bacterial overgrowth in the gut.

Likewise, it also stands to reason that the reverse would apply in the case of Primary (genetic) TMAU, in which the sufferer would probably have a very healthy cardiovascular system (not taking into account other possible genetic and environmental causes) because there would be very little FMO3 to produce TMAO. The primary benefit of this research to our community is that its aims are at blocking the TMA producing bacteria to not let the very odorous TMA go into the bloodstream. In this manner, not only would this treatment decrease plasma TMAO levels allowing for a healthier cardiovascular system, but in addition, it would prevent odorous TMA from entering into the bloodstream allowing the sufferer to consume a more choline rich diet that does not produce uncontrollable TMAU related systemic body malodor or halitosis.


María de la Torre
Founder and Executive Director

A Public Charity

www.meboresearch.org
maria.delatorre@meboresearch.org
MEBO's Blog (English)
El Blog de MEBO (español)

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