How does late onset TMAU 1 happen?

Dr Dolphin was part of the team who first demonstrated that mutations in the FMO3 gene are the cause of the inherited (primary form) of TMAU.

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How does late onset TMAU 1 happen?

Postby trtr654 » Thu Sep 17, 2015 1:28 pm

Hi Dr.Dolphin. due to my dismal experience with TMAU last year I developed a huge anxiety for my future as well as an interest in biology overall. I must admit at that time I was half way through my A-levels and it's a turning point of my life. After the TMAU episode I developed a huge interest in genetics biology and started studying biology hard as well as further reading into the world of genetics. I was fascinated by the subject and now I study Natural Sciences in one of the UK's best university, I wish to further my study into genetic research if I have the opportunity in the future, but for now I have a questions I can't figure out myself for a while:

I've read many stories of how people developed severe TMAU in their teens up to the age of 30 (or at least, early childhood), and many have been diagnosed with TMAU 1, suggesting it's not due to organ damage or bacteria overgrowth but purely genetic. But from my understanding of how mutations work, if they inherited both copies of faulty FMO3 protein coding region then the enzyme will never fit the substrate as the primary hence tertiary structure of the protein(enzyme) is altered so active site no longer complementary to TMA, therefore symptoms should be present since birth as the structure hence quality of FMO3 produced will always be faulty, it will never be capable of oxidizing TMA so how is it possible that individuals were asymptomatic in a certain period of their life time? There could be an environmental trigger, however I can't visualize how that works.

I acknowledge there are missense mutations that only reduce but doesn't abolish enzyme function, but these shouldn't only occur from puberty as I recall FMO3 expression increases with age hence why there's a category called “Transient Childhood TMAU", hence it should only get better from childhood to adulthood not vice versa.

Another possible thing is that the patient is a heterozygous for TMAU, but I've read that carriers do not express symptoms as they still have 50% enzyme capacity enough for a normal diet. Even with a further drop in expression it should more than capable for daily balanced diet, avoiding fish. If such drop is severe to cause TMAU due to liver disease then I wouldn't classify it as TMAU1, but more like a combination of TMAU1&2.

The last thing I can think of is that the mutation occurred on non-protein coding part of the FMO3 gene (promoters enhancers etc...), or in the "junk" region millions of bp away that somehow has an effect, or maybe even on genes coding for transcriptional factors and splicing enzymes. But these are beyond my knowledge and I'm intrigued to know how these may have a variation with age.

Of course all of the above is based on my limited A-level knowledge and little extra reading, or maybe these people doesn't have strictly TMAU 1. I really don't mind anyone pointing out where I made a huge mistake but at the moment I can't visualize how someone with 2 faulty FMO3 coding region doesn't have TMAU since birth.

Kinds Regards
trtr654
 
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Re: How does late onset TMAU 1 happen?

Postby Dave99 » Sat Sep 19, 2015 9:58 pm

I have a possible thought for your question, maybe we've all had TMAU since birth but our family and friends or associates have been to nice to point out our odours.
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Re: How does late onset TMAU 1 happen?

Postby trtr654 » Sat Sep 19, 2015 10:18 pm

Dave I really can't agree with you. There is literally no way that someone will live till the age of 18 without being constantly told by others. If kids have odours then their classmate will 100% complain, there must always be people in school to comment about the odour, and teachers will most likely contact parents making a big fuss anout it. even if classmates try to be nice there will always be strangers commenting about smell of fish. I can't imagine anyone that insensitive as not to realise their odour for more than 18 years of their life.

I appreciate your answer but it's solely based on assumption not reasoning, It's unlikely that will happen to multiple people. What I'm looking for is scientific answer based on reasoning.
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Re: How does late onset TMAU 1 happen?

Postby FADworker » Tue Oct 13, 2015 8:43 pm

Your points are well made and I think you've essentially answered your own question - the situation, in some cases, quite complex.

As you know an individual homozygous for null (loss-of-function) FMO3 mutations will have zero, or very close to zero, TMA N-oxidase activity and thus any TMA reaching the liver from the hepatic-portal circulation will not be oxidised and odour breakthrough will occur. One thing that might be relevant here with respect to 'late onset TMAU1' is that in some people the gut microbe population may be producing very little TMA early on in life and that the species composition changes with age with a shift to more 'TMA producers'. The microbial enzymes that generate TMA from choline (1) and carnitine (2) have now been identified (although there may be others) and these are expressed in particular phyla so if these were absent or low in childhood then there may be little TMA production and odour will be reduced or absent perhaps helped by not eating much in the way of TMA-containing precursors. This may be more relevant in heterozygotes.

But to have TMAU1 then the subject needs to be at least heterozygous for some form of reduced-function or loss-of-function mutation. Of course there may well be 'mutations' that have yet to be identified that might be located in the FMO3 coding sequence or, indeed as you suggest, in the 'promoter' region that reduces expression of the gene.

I think the thing to remember is that the breakthrough of odour in TMAU1 or 2 is due to a dynamic interplay between TMA production by diverse gut microbes (which we're only just beginning to understand at an enzymatic level) and FMO3 'activity' at any particular time that can be affected by many things including, but not restricted to, genetics.

1) Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
By: Craciun, Smaranda; Balskus, Emily P.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Volume: 109 Issue: 52 Pages: 21307-21312 Published: DEC 26 2012
2) Carnitine metabolism to trimethylamine by an unusual Rieske-type oxygenase from human microbiota
By: Zhu, Yijun; Jameson, Eleanor; Crosatti, Marialuisa; et al.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Volume: 111 Issue: 11 Pages: 4268-4273 Published: MAR 18 2014
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Re: How does late onset TMAU 1 happen?

Postby Kezzy75 » Thu Jan 12, 2017 8:48 pm

I had no signs of tmau until I was 36 what on earth happened at that age to trigger it? I'm starting to worry incase I have liver or Kidney disease now. Over the last 5 years it has gotten worse first it was just eating fish so I stopped eating Fish, then it was anything cooked in the same oil that fish had been cooked in, now it's all red meat, I'm worried incase it gets to a stage when I'm always smelling of fish. Any answers?
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