Paper title : Relationships between flavin-containing monooxygenase 3 (FMO3) genotype and trimethylaminuria phenotype in a Japanese population
link : Pubmed TMAU paper abstract
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| Prof Phillips and Shephard : involved with this TMAU paper |
Authors : Shimizu M, Allerston CK, Shephard EA, Yamazaki H, Phillips IR
It's quite rare for research papers on trimethylaminuria (TMAU) or flavin mono-oxygenese isoform 3 (FMO3) to be published, so it is interesting to note a new paper by a Japanese laboratory that has a long interest in TMAU/FMO3 colluding with Professors' Iain Phillips and Elizabeth Shephard of London who also have a long interest in the subject. Presumably the Japanese researchers and English researchers have known each other for a long time and collaborated previously. The Japanese lab has been known to offer TMAU urine testing to the public.
Object of the study : Judging from the abstract, the object of the study was to phenotype (urine) test 102 self-reported cases of a malodor problem which semed likely to be TMAU, and to see if their FMO3 genetic test result confirms the disorder as due to a genetic defect in the FMO3 gene. But interestingly they not only checked the 512 amino acid sequence for the DNA test, but also flanking introns ('junk' DNA) and some upstream sections. Normally for the DNA test the best someone can expect is for their 532 amino acid sequence to be checked, but you can have faults in the introns and upstream parts which can cause deficiency even if the coding part (532 sequence) is normal. This appears to be much further investigation of the FMO3 genetic makeup of a group of TMAU cases than ever before, using a much bigger number of cases.
Special points of interest from the abstract : We do not have a copy of the full paper, and can only make opinions from the abstract. But some points of special interest that stand out are :
They regard the cut-off point for normal TMAO in the urine test as >90%, which is quite a bit higher from some lab testers reference range. For instance the UK Sheffield lab has a TMAO cut-off point at around 79%. Having the cut-off point high at 90% means those in the 80% range will be TMAU positive. However, in the abstract of the paper they later mention they regard the mildest form of TMAU to be in the 73%-83% range, so perhaps at the moment even though they expect normal to be >90%, they may only be prepared to say you are TMAU1 if you are below 83%.
They class TMAU1 cases as severe, moderate and mild. They used the % level of TMA-oxide to class TMAU1 cases as severe, moderate and mild. Severe is a TMAO % of < 43%, moderate is 48% - 70%, and mild is 73% - 83%. In the study, of 102 self-reported cases of malodor, 78 were diagnosed within these 3 categories (presumably only genetic TMAU was tested for). 13 were severe, 56 were moderate, and 9 were mild.
27 gene mutations were found, 15 of which were in the coding region (the 532 amino acid sequence). Of these 15, 8 mutations which caused total or severe loss of function were found at codons 70, 197, 201, 205, 260, 388, 470 and 500. They also found 12 mutations in the upstream section analyzed, which normally would not be looked at in a DNA test. Normally DNA tests only look for either a list of known faults in the 532 sequence coding region, or test all 532 codons. They do not normally test the intron region or upstream region.
Conclusion : Their conclusion for severe FMO3 cases is straightforward. Of most interest is their conlusion about mild moderate cases.
"For moderate and mild cases the situation is more complex, with most resulting from factors other than FMO3 genotype"
It seems to imply these cases are not due to FMO3 defects, but without reading the full paper nothing can be concluded.
Overall it is an important research paper given the large size of cases involved (102) and the data collected from testing all the TMAU1 cases both from their phenotype (the urine test) and genetically (DNA test). It is probably the biggest such exercise in TMAU cases.
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10 comments:
I tested with Colorado labs(Dr. Fennesey) and was told that my conversion rate was 83% and I did not have TMAU. It was when I did the genetic test that it confirmed I did have TMAU. This is why the genetic test is the only way to really know if you have TMAU. Unless the urine test gives you 90%or above.
I wonder how we can find out what those other contributing factors are.
Mine is the following studies should focus on is how to alleviate the problem by enzyme replacement therapies.
Hi Anonymous, please clarify what you mean by "contributing factors" to what? It sounds like an interesting question, but I'm not sure what you are asking about.
Thiego, I totally agree. We need an effective treatment for the here and now, though realistically, for the near future. At the same time, I believe that it is very important to also research for the long-term. Genetics is the future, and may someday offer a cure to many diseases. Both are important, and I'm glad that Dr. Shephard got her grant for the therapeutic research, and both Drs. Shephard and Phillips in the UK and the Monell Center in the US are researching genetics. Our community has hope that something positive will come out of all of this for the somewhat immediate and distant future.
I also wish we had more information about the Japanese laboratory, and where in Asia TMAU testing (urine and/or blood) is taking place and where research is being conducted. If anyone can give us this information, it would be greatly appreciated.
Maria,
I was referring to the "other factors" that contribute to mild TMAU, other than the FMO3 gene.
Anonymous, I've been after the answer to your question since I first heard about TMAU. The first answer that comes to mind is what experts like Dr. Robin Lachmann, Dr. Stanley Hazen, Nigel Manning, Elizabeth Shephard, and many others refer to as Secondary TMAU, which is believed to be caused by gut bacteria that produces excessive amount of trimethylamine (TMA) that passes to the blood and overloads even a well functioning FMO3. Unfortunately, this bacteria in the human gut has not been studied scientifically to identify it, and thus be able to treat it better. There has not been enough interest or funding for this type of research. You can read some of these scientists papers, PowerPoint presentations, and webinars where they make mention of this, by typing in their names in the search engine of this blog.
There have been studies on TMA-producing bacteria in the fishing industry because it is very profitable for this market, and some species have been identified. However, there is no study that indicates that the species in the human gut is the same one.
There are other theories that link other types of body odor producing chemicals to other FMO3 metabolic pathway deficiencies, or other gut microbes that produce other odorous chemicals, such as in the case of Dimethylsufidemia, as noted in the PowerPoint and paper referred to in this blog, http://www.bloodbornebodyodorandhalitosis.com/search/label/dimethylsulfidemia (scroll down on this link). Again, more research is needed in these fields, but funding is hard to come by.
By contributing factors my guess is they mean things such as TMA overload or perhaps things that inhibit the gene, such as indole rich foods like broccoli. Secondary TMAu is meant to include anything that results in high TMA levels other than FMO3 deficiency but in practice it is most often associated with bacterial overgrowth resulting in too much TMA.
Personally I suspect that almost every case of 'FMO3 malodor' is due to genetic cause, many will be due to small errors that cause a state of 'no reserve capacity' or collapse under load. But at the moment the papers suggest that 'normal' people can get secondary TMAU.
The Japanese lab has a history of TMAU/FMO3 research, although I am guessing they find getting funded for such research difficult and it is perhaps a side project for them.
I think they have a history of TMAU testing.
http://www.bloodbornebodyodorandhalitosis.com/2009/11/new-fmo3-paper-from-japan.html
anything is good....this is good....is there any way to test fmo3 function...[im not asking about tmau....] is there a way to test fmo3 function, without knowing a specfic condition? [im not asking if testing is available to the public.] just is it possible?
The TMAU urine test is in theory a good test of FMO3 function because it is the only enzyme that oxidizes TMA. But I am not sure if this works out in practice except for obvious cases. Also the enzyme can be inhibited by certain compounds and perhaps acts differently under a load. So it seems that the TMAU urine test or DNA test are the best on offer but possibly they are prone to false negatives.