Meetup discussion Nigel Manning's paper and handouts

HANDOUTS DISTRIBUTED AT THE NASHVILLE 2010 MEETUP

1. ‘TMAU – diagnostic testing at Sheffield Children’s Hospital’ by Nigel Manning, Principal Scientist, Sheffield Children’s Hospital,Sheffield, England
2. Nashville Meetup Handout: Links and references to Body Odor/Halitosis related professional journals, organizations, papers, and blog posts
3. Pedigree of Service Dog at Nashville Meetup by Pawsibilities Unleashed, Pet Therapy of Kentucky, Inc.
   

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Due to the broad spectrum of substrates oxidized by FMO3, TMAU1 patients may suffer from adverse reactions with many drugs including codeine, tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine

As previously mentioned in a post in this blog, we have received a paper, which we discussed at length on Sunday at the Nashville Meetup, written by Nigel Manning, Principal Scientist, Sheffield Children’s Hospital,Sheffield, England entitled, ‘TMAU – diagnostic testing at Sheffield Children’s Hospital’. All TMAU urine tests in the UK, Ireland, and some from other parts of the world are done in his lab. Nigel wrote this paper specifically for our meetup, and I wanted very much to discuss it with everyone on Saturday so that we may all learn from it. However, since I was sick, Glenna was kind enough to go over it on Saturday, and we discussed it again on Sunday when I was able to participate as well. More about our discussion of this paper will be forthcoming on another post.

In this six-page paper, Nigel explains to us the formula he uses to arrive at either a Primary TMAU or a Secondary TMAU diagnosis. In the US, only the Primary TMAU diagnosis is used.

Nigel explains in his paper that the liver enzyme FMO3 not only oxidizes TMA, but in addition, oxidizes a wide range of substrates including many drugs. He explains,

Due to the broad spectrum of substrates oxidized by FMO3, TMAU1 patients may suffer from adverse reactions with many drugs including codeine, tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine. Hypertension may result from ingestion of red wine and cheese (and chocolate), which produce the neurotransmitter tyramine, another FMO3 dependent compound. Many people suffer from migraines associated with tyramine containing foods and perhaps FMO3 deficiency may explain some of these cases, but overall this demonstrates the adverse medical consequences of TMAU1 as well as the odour related psychosocial aspects.

Nigel also elaborates on the condition diagnosed as Secondary TMAU (TMAU2). He defines this diagnosis as being an acquired form of TMAU where TMA excretion is high even though FMO3 activity is normal.

Most TMAU2 patients produce too much intestinal TMA due to excessive bacterial growth of TMA-generating species. The TMA burden is so great that FMO3 oxidation produces large amounts of TMO but (in most cases – but not all) is still unable to oxidize enough TMA to prevent an excess…

…TMA itself is generated in the large intestine by bacterial degradation of compounds such as choline (high in liver, eggs and beans/peas), carnitine (meat) and TMO [TMA-oxide] from seafood (TMA from fish ‘spoilage’ has been attributed to several species of Vitrio and Shewanella bacteria)…

In this paper, Nigel provides us with three graphs,

1. TMA testing- urines analysed at Sheffield Children’s Hospital: of 1,150 urines tested from 716 individuals from 1997 tP 2009, of which 379 results indicated significant TMAU.
2. Free Trimethylamine v Free TMA / TOTAL [%] – end of 2009 n = 716: This graph is a summary of samples analysed from 1998 to 2009 – TMAU1 and TMAU2 differentiation by the ratio of Free TMA to Total TMA (TMA+TMA-oxide). Free TMA normal range 1-11.
3. A case of choline load to aid diagnosis in a case of TMAU (results indicated a treatable TMAU2)

In the Discussion section of his paper, Nigel discuses the treatment of both TMAU1 and TMAU2 and the types of odours associated with these conditions,

…the type of odour is often difficult to describe, but ranges from ‘chemical’ to faecal’. ‘Rotten fish’or ‘ammonia-like’ is not always mentioned, but TMAU seems to have become a focus for all malodours, possibly due to awareness of the disorder, the availability of a test and the possibility of a diagnosis.

A significant cohort of sulphurous or faecal odours have been reported by individuals who contact the laboratory. This may be another enterobacterial problem, but although Shewanella species are known to produce both hydrogen sulphide and TMA, we have yet to measure an increased TMA or TMO as a secondary marker for enterobacterial overgrowth in these cases.

FOR ADDITIONAL INFORMATION, see Parts 1 & 2 of Nigel Manning's interview for this blog, along with other experts' interviews.

What we did in the 2010 Nashville Meetup

Our 2010 Meetup in Nashville, Tennessee was an experience I will never forget. We all came together from far away places like London, and a few people did a road trip of a couple of days in each direction to attend from far away places like Connecticut, Texas, New York, Washington DC, Maryland, Virginia, the Carolinas, Georgia, Florida, Ohio, and areas surrounding Nashville. Those who could not attend joined us in the webinar on Saturday! It was truly a pilgrimage - a life altering experience for so many of us.

We bonded so well as we shared our experiences and knew that those we spoke with could relate totally, as we listened to see what worked for some and thus found some direction. I was finally able to meet so many of my friends in the US in person! I can't say enough about how important this whole event was for me. I feel that so many close ties were solidified. We will never again feel distant from each other as we had before.

Let me tell you a little about how our weekend unfolded. I began with my flight to Kentucky on Thursday to meet with another sufferer to then go together to Pawsibilities Unleashed to pick up our prospective Service Dog, Vallie (Valentine Snow), and to meet Liz Norris, Master Dog Trainer. Liz showed us alot of training techniques, and our purpose for bringing 4-month old Vallie to the meetup was intended to be part of her ‘social training’. It was quite impressive just how very well trained Vallie already was in the short few months of her life!

We drove to Nashville with Vallie from Frankfort, Ky on Friday, and began meeting with other people who came to the meetup. I was very pleasantly surprised when a young man approached me as we entered the hotel and introduced himself as a member of our community who wanted to know the schedule of the meetup so that he may attend. Everything was just uphill from there! By the time the Manger’s Reception started around 5:30pm, many of us had arrived. We gathered in the lovely atrium where we enjoyed the cocktails (alcoholic and non-alcoholic) with popcorn and/or tortilla chips, as we listened to live entertainment.

Afterwards, we decided to go eat at Ruby Tuesday’s in the 5 cars some of us had done their road trip on. Vallie was so well trained that she stayed under our table, as Service Dogs are supposed to do, throughout our whole dinner experience. By this point, we had already had the opportunity to talk about our experiences with our conditions to each other, and the bonding was really coming to fruition. We felt like we had always known each other and would be friends forever although it had only been a few hours into the meetup. We returned to our hotel to rest in order to start our meetup refreshed on Saturday after our breakfast buffet.

Even though I had only had one drink with very low alcohol content on Friday and ate healthy, I unfortunately developed a very bad migraine at 5:00a.m., with constant vomiting and diarrhea for 5 ½ hours, to the point of dehydration. I had to miss the main event of our meetup at the Governor’s Suite, since I couldn’t open my eyes because I couldn’t stand light or sound. However, as I laid in bed in total darkness, I could hear everyone talking and sharing in the main room, and I could tell everyone was feeling good, especially as I heard and enjoyed the spontaneous outbursts of laughter throughout the session and the heart-felt clapping when it was over. People would come into my room from time to time to let me know just how wonderful it was turning out. I was so very happy to hear this!

I also heard that Arun and about 16 people joined the other 17 of us in the social webinar, making it over 30 participants in our meetup. Blue Sky Collector and Glenna did their presentations as others helped in whichever way they could, including passing out the samples of body odor/halitosis products for us to give feedback to the manufacturers on. Nonetheless, I hear that there were significant technical difficulties and that alternative platforms may be used in the future.

Unfortunately, I couldn’t leave my room the whole day, but everyone enjoyed going to Ellendale’s for a luncheon buffet in a private room at the restaurant. All returned to the Manager’s Reception again on Saturday night, as Vallie kept me company in my room. I was able to hold down a bowl of soup and toast for dinner, and later in the evening, a small group of people came to visit with me at the Governor’s Suite and stayed well into the night.

During Sunday’s buffet breakfast, I met all the other wonderful people that I had not met on Friday or Saturday. I was sooo happy to have met them after all! I felt so close to them, and they all seemed to have such a peaceful ‘look’ about them in contrast to their more tense and nervous initial one when they arrived in Nashville. It was at that moment that I was convinced that our meetup had been successful. I could see the ‘high’ in their eyes. This is what it’s all about!

So we went back up to the Governor’s Suite, after Sunday’s breakfast, and we went over the paper written by Nigel Manning, Principal Scientist, Sheffield Children’s Hospital in England entitled, ‘TMAU – diagnostic testing at Sheffield Children’s Hospital’. All TMAU urine tests in the UK, Ireland, and some from other parts of the world are done in his lab. Nigel wrote this paper specifically for our meetup, and I wanted very much to discuss it with everyone on Saturday so that we may all learn from it. However, since I was sick, Glenna was kind enough to go over it on Saturday with the group, and we discussed it again on Sunday when I was able to participate as well. More about our discussion of this paper will be forthcoming on another post.

As our discussion came to an end on Sunday, more of us had to leave to catch our flights or to hit the road, and the remaining group went to eat at Chili’s and to visit the Parthenon. It was a rainy day, so after some quick shopping, we went back to the Governor’s Suite again to spend the rest of our time together well deep into the night.

And so ends our meetup, as we each go our own separate ways, but with a new heart and a new sense of belonging to a very ‘rich’ and bountiful community capable of giving ‘life’ and hope to each of us. I can't help but feel inspired knowing that this is just our first meetup in the US. Quite a few of us were talking about flying to London in September to attend the London meetup at the Thames Festival as well. It is an addictive experience.

My heartfelt thanks goes to everyone who attended in Nashville, all who joined us in the webinar and in spirit.

María

Comparing UK trimethylaminuria results with USA results

It has been noted on body odor forums; that in the USA and elsewhere, the person usually understand their result as a percentage, but this % does not seem to be commonly used by British testers giving their results.

The percentage is actually the total amount of TMA that the person managed to metabolize to TMA-oxide, giving an idea of the person's FMO3 metabolic capacity (at least, for that test sample). Trimethylamine is probably the 'best' marker for testing FMO3 function, since unlike most other substrates, it cannot go any alternative route for oxidation. That said, you need to make sure enough TMA is in your system to give it a thorough test of TMA oxidation capacity.

For anyone wishing to calculate their 'FMO3 capacity %', it is based on the TMA/TMAO ratio given in the results.

The calculation is :

TMA-oxide/(TMA + TMA-oxide) x 100

This is the % of TMA present you managed to metabolize into TMA-oxide.

With regards what is the % function of normal people, it does not look as if there is a standard 'cut-off' point which all labs agree. A French paper gave the cut-off point for normals as 95%, whereas others seem to go for around 90% or even a bit lower.
(PDF) Dr Eugene Michel 2002 paper : FMO3 capacity greater than 95%

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It would seem unlikely that those around 80% would be 'classic' TMAU cases, since the textbooks say a TMAU is someone with 2 mutant copies, which would mean almost no function or a very low % reading. Unfortunately in the case of TMAU, the smell is in the nose of the beholder, and if someone is told they smell and do not have 2 mutant copies, you have to assume that it's not just 'classic' cases that fail the 'smell test'. It would seem more likely that 'mild cases' would be transient. Also, it seems FMO3 may vary at times, such as during menstruation.
2007 TMAU paper : FMO3 and menstruation

With a general glance at genetics, it seems that geneticists class the function of genes into 3 basic groups :
mutant (very poor function. null-alleles etc)
variants/polymorphisms (milder loss of function. Can vary depending on physiological factors)
wild type (milder still ?)

It seems possible that many genetic 'smelly' cases may not be '2 mutant copy' cases, and more a combo of other sub par functioning combinations :
for instance:
1 mutant and a normal copy (? meaning in some cases it may be autosomal dominant)
2 variants
etc

However only the collection of genetic results will be able to clarify this. All of this does not seem to conclusively explain a complaint such as fecal body odor syndrome that most seem to complain of, which seems to imply other factors may be involved with that (either as well, or instead of). MeBO hopes to keep looking for answers to these questions.

New FMO3 paper : A physiological role for flavin-containing monooxygenase (FMO3) in humans?

Flavin mono oxygenase 3 enzyme seems to be very much the ignored xenobiotic enzyme in medical research, despite dealing with probably thousands of substrates in humans, usually oxidizing soft-nucleophilic heteroatom compounds containing sulfur, nitrogen, or phosphorous to non-toxic excretable oxides. There seem to be few researchers interested, and fewer research papers. Someday the pharmaceutical industry will realize it may be a factor in drug metabolism, as can likely be taken for granted by the amount of TMAU people who anticipate bad reactions to drugs. Currently the only 'downside' of having poor FMO3 function is regarded as trimethylaminuira, so it is likely that without our own actions, it will not be until the pharmaceutical industry realizes the 'drug metabolism' factor that frequent serious research will be done into this enzyme.

One of the 'pioneers' in FMO3 research has been Dr Stephen Mitchell of London, who did most of his FMO3 papers in the late 80's and 90's. He also seemed to have a role in organizing the 1st TMAU workshop in 1999.

He has not published an FMO3 paper for most of the last decade, but recently published a new FMO3 paper along with RL Smith, who also has a history in FMO3 research (again, not recently).

The paper is entitled :
A physiological role for flavin-containing monooxygenase (FMO3) in humans?
http://www.ncbi.nlm.nih.gov/pubmed/20230247

Unfortunately for us there is not even an abstract available to the public, so we cannot get a summary of what the paper is about. If anyone has access, it would be interesting to know more.

Teaching your dog to detect a scent

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The cruel irony of having body odor and/or halitosis is that normally the person cannot smell themselves, making it impossible to monitor their problem. This is why we are looking at ways of detecting human scents, such as using a scent dog, or investigating other ways such as TMA urinalysis paper (currently it is unlikely we could convince a manufacturer to produce this, due to them thinking TMAU is rare). Although it is probably best to get an expert to help train a dog to detect a scent (such as trimethylamine), in theory it should be possible to train most dogs, no matter the age (according to one drug-detection dog trainer on youtube). Apparently as long as the dog has the drive, it should be possible. Another obstacle may be in getting trimethylamine. Perhaps urine of a high TMA level could be tried. Or perhaps even rotting fish (?). This post is focussing on trimethylamine. We are not quite sure how we could get a dog to discriminate the myriad of bowel smells most people seem to complain of.

In this video, the dog trainer is training the dog to first associate the paw behavior with a treat, and then pawing the scents for treats. Obviously it should be easy to train a dog to detect trimethylamine, but it may be more difficult to detect it at various levels of intensity. Perhaps to a dog, all humans have a trimethylamine odor. Anyhow, this is posted in case any dog-owners wish to learn more about training a dog how to detect a scent. There are many more videos on youtube. If you get anywhere, please let us know.

Final day in Nashville

Howdy ya' all,

Those of us who didn't have to return home today met again in the Governor's Suite and discussed Nigel Manning's paper that he wrote specifically for our meetup. We waited to no avail for the rain to ease up to go out to see the town. So we took off in two cars to the Pathenon anyways and took some pictures of this very beautiful place. Please excuse the 'wet chicken look'. We had a nice lunch/dinner at Chili's and took one of us to the airport.

Vallie was such a good puppy! She always goes under the table and sleeps while we eat. She's so good, the waitress didn't even realize we had a dog with us! What a good girl! She's so loving and nurturing. And she's such a fun-loving pup!

We're back in the hotel now. Vallie was initially very much afraid of the glass elevators that just seemed to be going upwards! She would ' hit on the breaks' with her front pause when we tried getting her into the elevator, but now she's gotten more used to it. She doesn't like the loud birds in the cage at the lobby - they're too loud. She couldn't understand why she couldn't drink from the lobby fountain, after all, she was thirsty. I must have seemed like a terrible person to her, and she silently cried...

Well, Vallie is going to start her first TMA scent odor lesson. Those of us remaining are going to do saliva swabs with a cotton swab and put each in a container and freeze it. Tomorrow they will be taken to Franfort, Kentucky, and the one of the person diagnosed with TMAU will be used to teach Vallie to identify the scent. Then the other opened containers of the saliva swabs will be lined up about 10 feet away, and Vallie will be asked to find the ones with the same scent. She will be performing her first TMA search and find job! She's done it with other scents already. Then we'll see if she detects it in our other samples, and the sufferer will be advised. Afterwards, the sky is the limit!!!

Hope you enjoy our pictures and upcoming videos in the weeks to come.

Maria

Informal webinar tomorrow. Watch or join

Tomorrow we will host an online webinar live from the body odor & halitosis meetup in Nashville at 11am Central Time. It is scheduled to last an hour. Come and join in with your webcam, or just to watch. You can watch it here if you want or join the event.

Thanks to everyone who attended. There was around 13 viewers at anytime. For your information about privacy in Vokle, no-one outside the room can see the chatroom. They seem to be enjoying themselves in Nashville, with about 17 present in the room, and are now going to dine out at Ellendales.

Hopefully webinars will become a part of our community communcication processes.

We are still investigating if we could possibly have webinars with FMO3/TMAU and body odor experts over April/May, although we are having difficulty finding a suitable webinar program, due to suitability and/or price. Some experts have kindly offered to give us pre-recorded video presentations on their work, and a powerpoint slideshow. Ideally we would also like to have webinars, but will need to find a way to overcome the obstacle of finding the right program at a reasonable price. Our initial feedback from the experts was extremely positive, but unfortunately we have stumbled on the webinar program technically.

At Pawsibilities Unleashed in Frankfort Kentucky to see our TMAU service puppy

Liz Norris is preparing Vallie for us to take her to the meetup in Nashville for the weekend. Liz spent so much of her valuable time teaching us how to handle and train Vallie, along with the harness, Service Dog bags and official SD documents, food, treats, toy and literature, including pictures and writeups of Vallie's prize winning extended family.

Vallie is a very happy energetic puppy who LOVES to train with Liz (and now with us), and want to keep on doing it even after Liz stops. Liz and Vallie gave us a demonstration on the training technique utilizing a treadmill to teach Vallie how to walk on a moving sidewalk. They also showed us how she works in tunnels and slides for find and rescue jobs, and to play with children on a slide. Vallie kept returning to the tunnels and slide even after the training session ended. SHE LOVES IT!

I was so discretely moved to tears with Vallie's beauty and potential for our community. Vallie noticed because of the scent of odorous compounds in tears, and she stopped what she was doing and came over to me to give me some love and to cheer me up! Talking about a Mental Health Service Dog! This came spontaneously from within her! It was an innate nurturing response to sadness, depression, happiness, and joy all bundled up together into a swelling tear in each of my eyes. WE NEED HER SO MUCH! We need many more like her too.

Vallie was naturally drawn to a specific body odor emitted from one of us. We noticed and Liz confirmed it without us having asked. Liz says that when a dog detects an odor, it doesn't matter whether it is detected by others or by scientific equipment - THE ODOR IS PRESENT! The dogs don't ever mistake this. A scent is a scent, is a scent, not to be confused by any other scent or denied, as it is real because the dog detected it. A trained service dog can be of great research and diagnostic assistance.

Vallie was naturally attracted to a scent I could not detect

Tomorrow we bring Vallie to our meetup. Let's see what she discovers in us at all levels, physically and emotionally. AND SHE'S ONLY 4 MONTHS OLD! Imagine when she's one year old, two years old, etc.

to be continued tomorrow...
Maria and Vallie

-- Sent from my Palm Pre

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Heading for Kentucky tomorrow then Nashville

International Body Odor & Halitosis informal webinar.
Live from Nashville 11am Central Time
Saturday, 20 March

Howdy y'awl. As you know, I will be in Nashville on Friday evening for the inaugural Grand Body Odor & Halitosis USA meetup at Embassy Suites Nashville Airport. All are welcome to attend. We are expecting around 20. We will be having an informal online webinar on Saturday at 11am Nashville time (Central Time), which you can all attend or watch, and then head out for a nice meal in the afternoon. The rest of the weekend can be decided spontaneously.

There will be samples of body odor and halitosis products donated by manufacturers, such as Jarrow Formula probiotics, Dr. Mist deoderant, Orabrush tongue scrapers, Garden of Life Probiotic Smile (for halitosis), Urea 42% Cloths (for foot care), and other goodies. MEBO Research is not endorsing any particular product, but rather these companies have supplied us with these samples asking us for feedback. There will be handouts, including a six-page paper Nigel Manning, Principal Clinical Scientist, Dept. Clinical Chemistry, Sheffield Children's Hospital, England, wrote for our meetup. Other handouts will give links to professional articles and papers on TMAU, halitosis, hyperhidrosis and bromhidrosis (a presentation on this topic may be given) as well as reference to organization specializing in one or more of these topics.

I am happy to announce that I will be leaving Thursday morning and heading for Frankfort, Kentucky, to see our future TMAU Service Dog, based at Pawsibilities Unleashed, to talk to the trainer, Liz Norris. She has kindly said we can bring the pup to Nashville! She hasn't begun TMAU training yet, but is trained to be around people.

I will keep you updated on the blog with my Palm Pre cell phone, as the days go by.

In the meantime I present the obligatory pre-meetup inspiration movie, to get us all in Nashville mode. Enjoy!



Informal webinar link :
http://vokle.com/events/1730-mebo-nashville-get-together
Current Nashville time

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MeBO Nashville get-together informal webinar

Informal webinar for worldwide body odor & halitosis sufferers to chat
Saturday 20th March
11 AM - noon Nashville time

Next weekend sees the grand Nashville Body Odor & Halitosis get-together get underway, with a good time guaranteed for all who attend. Not to leave people over the world out of the festivity, you can join the party online at 11am Nashville (Central Time) by joining the online webinar using the Vokle platform. If you want to participate audio/visually, all you need is a webcam and mic/headset. Those who do not wish to speak can just view, and would not need the cameria, but would need speakers for audio. If not, you can join us to chat only. This is a chance for all sufferers to have an online group hug.

http://vokle.com/events/1730-mebo-nashville-get-together

Note : the vokle webinar room will be viewable to the public . No experts will be giving a presentation in this webinar

current Nashville time : http://www.worldtimeserver.com/current_time_in_US-TN.aspx

Video : Trimethylaminuria case on British TV

Thanks to the lady who appeared on the UK TV show 'Embarrassing Bodies' with a case of trimethylaminuria. In her case, she was '45' for her first TMA reading, and then they put her on the TMAU diet and did a follow up test in which she was down to a reading of '15' (below 10.9 is 'normal' in the UK). It goes to show the benefit of monitoring, although doing the clinical test for monitoring is obviously not practical. This is why MeBO is looking into such areas as a scent dog or TMAU urine dipstick paper tests.

Wanting to test in the UK ? Contact Nigel Manning at Sheffield Children's Hospital for advice, the only lab tester in the UK
To contact Dr Robin Lachmann : robin.lachmann@uclh.nhs.uk
If you wish to test without a Dr but having to pay for it (around £193)
contact Mullhaven lab (they send it to Nigel Manning)

BBC TMAU documentary 2007 : Help I smell of fish

Previously someone had uploaded the 2007 BBC documentary about trimethylaminuria to youtube : Help I smell of fish. Sadly it was deleted.

Thankfully, youtube user awayday1000 has kindly uploaded it for the body odor community, so it is viewable to all again. It has 6 parts.

Body Odor case on UK TV : Channel 4 Friday 9pm

Trimethylaminuria story on British Television

Friday 12th March 9pm Channel 4
Programme : Embarrassing Bodies

Friday sees a TMAU case on the popular UK TV programme, Embarrassing Bodies. The TMAU case will likely last about 10 minutes, and Dr Lachmann will appear in the story. This is a result of the programme makers contacting tmau.org.uk last October for a volunteer. Those in the UK can watch it over the next month on Channel 4oD online. The programme can get ratings of around 3 million. Thank you to the brave volunteer for participating and helping raise awareness.

We will try and get a copy of the story for the blog.

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Also, in the UK, look out for an article about TMAU in the April copy of Chat magazine. Forum member 'Gazela' posted about his story being accepted in the forum at tmau.org.uk

New Trimethylaminuria document from Nigel Manning

The urine test consists of two measurements:
a. trimethylamine or ‘Free’ TMA
b. TMA-oxide [+ free TMA] = ‘Total’ TMA.

Regular readers will know that Nigel Manning, Principal Clinical Scientist of Dept. Clinical Chemistry at Sheffield Children's Hospital in England has always been very kindly communicative to us about trimethylaminuria, including giving an in-depth interview about TMAU testing last year. Nigel has kindly given us a pdf document that is very good as a reference to trimethylamunuria, as well as giving insight into the statistics of his testing lab in Sheffield, which is the only known TMAU genotype (urine) test lab in the UK.

Nigel has also kindly offered to be allowed to be contacted from around the world by people thinking of testing or wishing to discuss their results.

Below is the new document in pdf format, which is hosted on our MeBO Research website :

TMAU – diagnostic testing at Sheffield Children’s Hospital

We have also included it in fulltext below for those without a pdf reader (minus the graphs)

TMAU – diagnostic testing at Sheffield Children’s Hospital.
Nigel Manning Dept. Clinical Chemistry, Sheffield Children’s Hospital,
Sheffield UK.

Introduction

The phenomenon of ‘fish odour’ has been reported for many centuries. More
recently attributed to the tertiary amine trimethylamine (TMA), the ammoniacal
body odour like the smell of rotting fish can have severely detrimental effects
on the lives of those suffering from ‘Fish Odour Syndrome’. Now more
commonly referred to as Trimethylaminuria or TMAU, patients with this
unfortunate condition exhibit increased excretion of TMA in urine as well as in
sweat and breath vapour. The main causes of TMAU, low hepatic TMA
oxidation and intestinal overproduction of TMA give rise to the two main types
of the disorder.

The inherited form of TMAU is known as Primary TMAU (TMAU1). The result
of a faulty autosomal recessive gene, TMAU1 patients have impaired activity
of a liver enzyme flavin-containing mono-oxygenase type 3 (FMO3) which
oxidises a wide range of substrates including many drugs. TMA is oxidised to
non-odorous TMA-oxide (TMO) by FMO3 which can then be excreted. TMA
itself is generated in the large intestine by bacterial degradation of compounds
such as choline (high in liver, eggs and beans/peas), carnitine (meat) and
TMO from seafood (TMA from fish ‘spoilage’ has been attributed to several
species of Vitrio and Shewanella bacteria).

TMAU1 therefore results from FMO3 deficiency with an increase in the ratio of
TMA to TMO in urine which can be used for diagnosis.

Due to the broad spectrum of substrates oxidised by FMO3, TMAU1 patients
may suffer from adverse reactions with many drugs including codeine,
tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine.
Hypertension may result from ingestion of red wine and cheese (and
chocolate), which produce the neurotransmitter tyramine, another FMO3
dependent compound. Many people suffer from migraines associated with
tyramine containing foods and perhaps FMO3 deficiency may explain some of
these cases, but overall this demonstrates the adverse medical
consequences of TMAU1 as well as the odour related psychosocial aspects.
The acquired form of TMAU is covered by the term Secondary TMAU
(TMAU2) where TMA excretion is high even though FMO3 activity is normal.
Most TMAU2 patients produce too much intestinal TMA due to excessive
bacterial growth of TMA-generating species. The TMA burden is so great that
FMO3 oxidation produces large amounts of TMO but (in most cases – but not
all) is still unable to oxidise enough TMA to prevent an excess. This problem
may be exacerbated by intestinal structural problems such as ‘blind loops’ or
post- operative complications. TMAU2 usually presents in adulthood although
children have been known to acquire excessive TMA-producing bacteria with
the resultant odour.

The diagnosis of TMAU2 depends on the detection of increased urinary TMA
and TMO with a normal TMA/TMO ratio indicating normal oxidation by FMO3.
Patients with liver or kidney disease have been known to produce a TMAU1-
like pattern of excretion, although due to a secondary cause. Importantly this
may also occur with a urinary tract infection (UTI) which results in TMA being
produced directly into the urine giving a false positive result. Whenever results
suggest TMAU1, therefore, UTI must always be excluded by microbial
analysis before a TMAU1 diagnosis can be confirmed in a follow-up sample.

Testing for TMAU

The urine test consists of two measurements:
a. trimethylamine or ‘Free’ TMA
b. TMA-oxide [+ free TMA] = ‘Total’ TMA.

The technique currently used in our laboratory is gas chromatography – mass
spectrometry (GCMS) analysis of the ‘headspace’ vapour of heated,
alkalinised urine. This method superseded a direct injection MS method used
from 1997 until 2002. Results from the two methods compared well, although
the current methodology allows for automated headspace sampling and
GCMS injection.

A positive result is usually followed up with a routine second test after a report
of the initial findings. The turnaround time for the test is currently 4 weeks or
less. A GP or physician referral is essential, but we can offer advice by phone
or email about how to start the process.

DNA analysis for the FMO3 gene is also now available with a turnaround time
of 8 weeks. The genetic test provides the vital confirmation required for a firm
diagnosis of TMAU1 and has demonstrated that the TMA / TMA-oxide ratio
may normalise in TMAU1 due to spurious increases in urinary TMA-oxide.

Results and Diagnoses
We tested 1150 urines from 716 individuals from 1997 to 2009.
379 results indicated significant TMAU.

Many TMAU sufferers may restrict their diet before testing in an effort to
reduce odour. This may occasionally affect an initial diagnosis as TMA
excretion may be sufficiently reduced to normal or give a normal Free to Total
TMA ratio (less than 21%). For diagnostic clarity it is essential that the sample
is collected when odour is at it’s maximum. This may necessitate creating the
conditions which induce the odour such as dietary intake of choline (eg
pulses, eggs, liver), carnitine (red meat) and trimethylamine oxide (seafood).
Dietary ‘loading’ is possibly most effective when restricted to a simple high
choline meal of 2 eggs and 400g baked beans. Previously choline
monohydrate was an effective loading agent but has become difficult to obtain
as a chemical for patient administration. The effect of choline loading and
diagnostic clarification achieved by loading can be seen in the following case
report.

A case of choline load to aid diagnosis in a case of TMAU:

An adult presenting with a significant odour was tested for urinary TMA. The
results showed both an increased TMA and Free/Total TMA ratio, which
indicated a possible primary defect (TMAU1). [Fig.2]

A repeat 24 hour acidified sample however gave a normal Free/Total ratio,
with increases in both the Free and Total TMA – suggesting the possibility of
increased oxidation in response to an increased Free TMA burden (a possible
indication of TMAU2).

Antibiotic therapy was commenced and resulted in the normalisation of Free
TMA although the Total TMA was still increased (again an indication of
increased oxidation in response to increased intestinal output of Free TMA).
For clarification a 5 gram choline monohydrate load was given to the patient
and samples collected for 72 hours after load.

Total TMA showed a dramatic increase (with Free TMA) and the Free/Total
ratio remained within normal limits. Gradually the Free and Total TMA
reduced to nearly normal excretion values.

These results indicated a treatable TMAU2 . The first result was probably due
to a urinary tract infection or bacterial contamination of the inital sample which
had not been acidified). The patient was further treated with antibiotics to
eradicate enterobacterial overgrowth.

Discussion
GCMS analysis of headspace vapour of alkalinised urine with stable isotope
dilution provides a robust method to measure both free and total TMA for the
diagnosis of TMAU1and 2. Differential diagnosis can be hampered by genitourinary
infections and intermittent presentations which may reflect TMAU1
carrier status.

Treatment of both TMAU1 and TMAU2 is based on diet to restrict the sources
(precursors) of TMA and antibiotics to eliminate the TMA-producing bacteria.
TMAU2 can in fact be cured by eradication of the excess bacteria, although
stubborn colonies may re-grow to excess and require further courses of
treatment.

TMAU1, as a genetic defect, cannot be completely cured although therapy
(dietary and antibiotic) can successfully control the patient’s free TMA to a
less odorous level. Patient’s residual enzyme activity is variable depending on
the specific mutation and as such trials with the cofactor riboflavin have been
tried with some success. Milder TMAU1 patients can, however, reduce their
TMA to almost normal values with just diet and periodic antibiotic therapy.
Other forms of therapy are based on the neutralisation of TMA chemically.
Skin creams with a comparatively low pH (5.0) may neutralise alkaline TMA.
This creates a non-volatile salt of TMA which lessens any odour and can be
washed off by the patient later. Another solution lies in deodorising tablets
such as ‘activated charcoal’ or copper-chlorophyllin complex (marketed as
‘Nullo’). These ‘internal deodorants’ have been successfully used for many
years and would be ideal for more severely affected TMAU1 patients.
Detection and perception of odours varies between individuals. Some people
are odorous to friends, family and work colleagues but are unaware of an
odour, whilst others maintain they are odorous but those around them would
not agree. For those individuals who are sufficiently motivated to seek medical
help, the type of odour is often difficult to describe, but ranges from ‘chemical’
to ‘faecal’. ‘Rotten fish’ or ‘ammonia-like’ is not always mentioned, but TMAU
seems to have become a focus for all malodours, possibly due to awareness
of the disorder, the availability of a test and the possibility of a diagnosis.
A significant cohort of sulphurous or faecal odours have been reported by
individuals who contact the laboratory. This may be another enterobacterial
problem, but although Shewanella species are known to produce both
hydrogen sulphide and TMA, we have yet to measure an increased TMA or
TMO as a secondary marker for enterobacterial overgrowth in these cases.
For those with a significant TMAU, difficulties in diagnosis mainly stem from
the interpretation of TMA and free/total ratios given the background of diet,
variation of enzyme activity and variation of bacterial sources of TMA. This
can be summarised by the sub-types of presentation and biochemical
abnormality we have encountered over the past 12 years. The new FMO3
mutation service should help to clarify TMA results greatly in the years to
come.

TMAU1 and TMAU2 possible sub-types:

a. TMAU1 transient neonatal – possible delay in switch from fetal enzyme
FMO2 to FMO3 TMA oxidation, but resolves during development.
b. TMAU1 severe childhood - parenting / schooling problems are possible.
c. TMAU1 adulthood – probably presented in childhood; long-term sociopathy.
d. TMAU1 heterozygote – may present only during dietary load / menses.
e. TMAU1 very mild – ‘double dose’ DNA polymorphisms – TMA borderline.
f. TMAU1 FMO3 mutation proven TMAU1 with increased TMO (like TMAU2)

a. TMAU2 severe neonatal -‘sepsis’ massive TMA responds to antibiotics.
b. TMAU2 childhood - antibiotic eradication prevents school / social problems.
c. TMAU2 adulthood – may have long history of odour, eradication possible.
d. TMAU2 intermittent – difficult diagnosis without precursor load.
e. TMAU2 due to UTI – presents biochemically as TMAU1 (urine-only odour).
f. TMAU2 due to renal or hepatic dysfunction – presents as TMAU1.

References:
Ayesh R, Mitchell SC, Zhang A, Smith RL (1993) The fish odour syndrome:
biochemical, familial, and clinical aspects. Brit Med J 307: 655-657.
Chalmers RA, Bain MD, Iles RA (2003) Diagnosis of trimethylaminuria in children:
Marine fish versus choline load test. J Inher Metab Dis 26 (Suppl 2): (448-P) 224.
Fraser-Andrews EA, Manning NJ, Ashton GHS, Eldridge P, McGrath JA, Menagé H
(2003) Fish odour syndrome with features of both primary and secondary
trimethylaminuria. Clinical and Experimental Dermatology 28: 203-205
Humbert JR, Hammond KB, Hathaway WE, Marcoux JG, O’Brien D (1970)
Trimethylaminuria: The fish-odour syndrome. Lancet 2:770-771.
Lee WG, Yu JS, Turner BB, Murray KE (1976) Trimethylaminuria: Fishy odors in
children. New Eng J Med 295: 937-938.
Mitchell SC (1996) The fish odour syndrome. Perspectives in Biology and Medicine
39 (4)
Treacy EP, Ackerman BR, Chow LML et al (1998) Mutations of the flavin-containing
monooxygenase gene (FMO3) cause trimethylaminuria. A defect in detoxication.
Hum Mol Genet 7: 839-845.
Treacy E, Johnson D, Pitt JJ, Danks DM (1995) Trimethylaminuria, fish odour
syndrome: a new method of detection and response to treatment with metronidazole.
J Inher Metab Dis 18: 306-312.

INTRODUCING OUR VERY OWN TMAU ALERT 'SERVICE DOG' PUPPY!

I would like to present the star of the show.....(drums rolling).....

OUR NEW TMAU ALERT 'SERVICE DOG' PUPPY!

She’s being taught how to discern objects (telling one object from another) and “get the keys”. We're going to see ALOT more of her in days to come. She will initially be trained to do the following:

Service Dog Manners
Public Access Work
Obedience Training
Scent work
Crate/House training

She’ll be trained to differentiate between high and low levels of TMA odor and to notify her handler upon command, and eventually, other BO/Halitosis volatile compounds as well.

So…what do we name our beautiful new member of our community??? Give us your thoughts. So far, we have two recommendations:

1. Tammy (our TMAU Medical Alert Service Dog)
2. Valentine Snow

What do you think? Other types of Medical Alert SDs have been names with cute names related to their handler's conditions, such as, diabetic dogs are named Shots, JD for Juvenile Diabetes, etc. Give us your ideas in the Comment link of this post…

SD News: Minnesota proposal would increase penalties for service dog abuse

TMAU SERVICE DOG PROGRAM BLOG
Click on picture

Medical Alert Service Dog Training

Pawsibilities Unleashed, Pet Therapy of Kentucky is a 501(c)3 non-profit organization completely run by volunteers and dependent upon donations. They do not use any “train by pain” methods like choke chains or pinch collars. Instead, they use the clicker training method. Their methods are proven in the show ring, at home and for assistance dog skills like seizure detection and diabetic alert.

Pictures and videos provided by Pawsibilities include the following:

• Diabetes Medical Alert Service Dogs works off three different odor levels, and alerts her handler when there is a low sugar level, normal level, and a high sugar level.

• Epilepsy Alert SD alerts child’s family to oncoming seizures up to 30 minutes in advance for some of the larger seizures - Dravet Syndrome

• Medical Alert Service Dog trained to alert to high and low mood swings for Bi-Polar Depression

The same technique, based on odor variances, would work with TMA or any other odorous compound emitted by a body odor/halitosis sufferer. These Service Dogs could be used for the daily benefit of a specific sufferer and/or assisting in diagnostic process, especially in the case of not yet understood odors that modern medicine has not diagnosed.


How clicker dog training Works:
This video shows how a Service Dog is trained with a clicker. Founder, Liz Norris Here’s Liz Norris, Master Trainer and AKC-CGC Instructor, and Therapy Evaluator of Pawsibilities Unleashed working with a 10 month old Weimie. Liz is teaching the dog to go out over an object and touch a target then come back over a jump and target to your hand. The Weimie got this in just an hour of clicker work.

Share time in class video: SDs are also taught to share; everyone shares the treats that are left over at the end of class and learn to not be food aggressive, but to share instead.

TMAU SERVICE DOG PROGRAM BLOG
Click on picture

MeBO accepted in FIU Legal Clinic for entity formation as 501(c)3 non-profit org in US

I am happy to announce that MeBO Research has been accepted by the Legal Clinic Program of the College of Law of my Alma Mater, Florida International University, for pro-bono legal representation. They will advise us on how to best form an entity in the US with ties to MEBO Research, Limited by Guarantee Company registered in England, sharing the same mission. Under the supervision of faculty who are experienced legal practitioners, the program will represent us in registering MeBO, first as a company, and then as a 501(c)3 non-profit organization, so that we can proceed to pursue grants from renown Foundations to support research and treatment of TMAU, other FMO3 deficiencies and other metabolic causes of body odor, the genetics of body odor conditions, microbial causes of systemic odor (including but not limited to the digestive tract), diagnostic and therapeutic (odor management and mental health) possibilities including but not limited to the use of Medical Alert Service Dogs, and other such causes. John Little, Attorney at Law, Adjunct Clinical Professor, will be the supervising attorney for our case.

After finalizing the formation of this 501(c)3 non-profit organization in the US, I will then apply to the FIU College of Business Clinic to see if they will also assist us pro-bono in the grant-writing process so that we may do so in a professional and effective manner. I will also apply for assistance in setting up reliable and accurate accounting practices, as we work with multiple currencies from multiple countries. It is MeBO’s goal not only to effectively meet all the legal federal tax filing requirements of both countries, the United States and England, but to also set up a transparent accounting system as feasibly possible, so that all members and grantors can see where the funds are being disbursed.

The Community Development Clinic at Florida International University in Miami, Florida is an interdisciplinary program that provides their clients with legal and business assistance as needed to become a nonprofit organization and to operate it effectively. All of us at MeBO Research are most appreciative of the FIU Community Development Clinic reaching out to the community to help non-profit groups who are often unrepresented because of the high cost of legal services.
This $800 filing fee should generate a good return on investment, as it is the only way MeBO Research will have the leverage to receive tax-deductible grants from Foundations, since according to their respective by-laws, most can only give to 501(c)3 non-profit organizations.
The initial filing fee is almost $100 to register MeBO Research as a company, which should be initiated within a month. Afterwards, it will cost approximately $800 to file for a 501(c)3 non-profit status, a process that will probably begin in August 2010. This $800 filing fee should generate a good return on investment, as it is the only way MeBO Research will have the leverage needed to receive tax-deductible grants from Foundations, since according to their respective by-laws, most can only give grants to 501(c)3 non-profit organizations. Anyone wishing to do so may donate by clicking on the ‘Donate’ button on the sidebar of this blog or on the MEBO website.

María de la Torre
President and Executive Director
MEBO Research
maria.delatorre@meboresearch.org
www.meboresearch.org

FIU FAST FACTS:

• FIU Law grads passed the Florida Bar at the highest rate in February 2009.
• FIU Law ranked 8th best value in the U.S. by The National Jurist.
• FIU Law faculty ranked 2nd most diverse in the U.S.
• FIU Law educates highest percentage of Hispanic students in the U.S.

A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS)

A common FMO3 polymorphism may amplify the effect of nicotine exposure in sudden infant death syndrome (SIDS)

Poetsch M, Czerwinski M, Wingenfeld L, Vennemann M, Bajanowski T.
Institute of Legal Medicine, University Hospital Essen, Hufelandstr. 55, 45122, Essen, Germany

http://www.ncbi.nlm.nih.gov/pubmed/20198379

Smoking during pregnancy has been identified as one of the major modifiable risk factors of sudden infant death syndrome (SIDS). It has been demonstrated that the risk of SIDS increases with increasing cigarette consumption. A variety of hypotheses have been proposed for explanation, including a genetic predisposition. The flavin-monooxygenase 3 (FMO3) is one of the enzymes metabolising nicotine, and several polymorphisms have already been described in this gene. Here, we studied variations in the exons and introns of the FMO3 gene by direct sequencing analysis and minisequencing in 159 SIDS cases and 170 controls. The three common variants G472A (E158K), G769A (V257M) and A923G (E308G) in the exons of the FMO3 gene were identified. The homozygote 472AA genotype occurred more frequently in SIDS cases than in controls (p = 0.0054) and was more frequent in those SIDS cases for which the mothers reported heavy smoking (p = 0.0084). This study is the first to demonstrate a gene-environment interaction in SIDS. The findings suggest that the common polymorphism G472A of FMO3 could act as an additional genetic SIDS risk factor in children whose mothers smoke. Parents who could pass on the 472A allele should be informed of the increased risk associated with smoking. Smoking mothers should be strongly advised to give up smoking during pregnancy and for at least the first year of the child's life.

As previously mentioned in this blog, FMO3 enzyme deals with 1,000's of substrates, probably mostly oxidizing them for detoxification. Considering the amount of substrates it deals with, it is surprising that the pharmaceutical industry probably neglect the enzyme when testing new drugs for bad reactions. As well as many drugs, FMO3 will deal with many other sulfides, amines and phosphorous containing compounds. Dr Cashman has mentioned previously that FMO3 plays a minor but very important role in detoxifying nicotine.

These German researchers have been involved at looking at the possible cuases of Sudden Infant Death (SID) Syndrome. Apparently one hypothesis was that pregnant women who smoke heavily may be genetically predisposed to SID, with the FMO3 enzyme being investigated for a possible genetic connection in this study.

They checked the mothers of SID cases for common polymorphs (variants) of the FMO3 enzyme. They found that there was a higher rate of those homozygote (i.e. 2 copies) of the 472AA polymorph, especially among some of the heaviest smokers, and regard it as statistically significant. They also say it is the first study to show a genetic-environmental relation to SID.

Hopefully this will interest other researchers around the world to investigate FMO3, which seems to be the 'neglected' xenobiotic enzyme, despite possibly being the busiest of them. Any research into FMO3 is likely to be beneficial to TMAU sufferers, and possibly other systemic odor sufferers, given the range of sulfides and amines it deals with.