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March20 podcast Dr Hazen
anti-TMA pill in a year or 2 ? (scroll 12 mins)

Additional info: https://youtu.be/811v7RLXP9M
MEBO Karen
at UK Findacure conf 2020

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MEBO TMAU TESTING DISCONTINUED
(2012-2017)

MEBO Map Testing & Meetups


Full details : https://goo.gl/TMw8xu
want listed ? contact info@meboresearch.org

MEBO - UBIOME study 2018

'PRESS RELEASE'

NCT03582826
ClinicalTrials.gov

MEBO Gut Microbiome Study
"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"
Funded by uBiome Research Grant

"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"

Dynamics of the Gut Microbiota in
Idiopathic Malodor Production
& PATM

Started May 2018 - Ongoing

Current people sent kits : 100/100
3 kits per person

NO LONGER RECRUITING

Participation info : LINK English

MEBO Private Facebook Group
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BO Sufferers Podcasts

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Petitions

TMAU Petition world
TMAU UK end total:262
TMAU UK ends 23/01/20
TMAU Petition USA end total 204
USA : Moveon open
TMAU (Dominican)
Metabolomic Profiling Study
NCT02683876

Start : Aug 2016
Stage 1 : 27 Canadian volunteers to test
Latest click here (26 oct) :
17 samples returned


Note : Stage 1 is Canada only.
Return cut-off date : passed
Analysis can take 6/8 weeks
Analysis start in/before Nov
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MEBO Metabolic Malodor Survey (international) for Dr Hazen click here
click to Read more/less

survey for ANYONE who identifies with METABOLIC MALODOR

begun : Oct20
end : no ending for now

Regular readers will know that Dr Stan Hazen et al at Cleveland Clinic are developing a TMA-blocker pill, as they proposed in a 2011 paper that TMAO is a factor in CVD. Recently Dr Hazen and colleagues contacted MEBO as they have always thought they could also help with TMAU. This survey is to give them an idea of the 'state of the community'. It is a "version 1". They may not even look (though they have access permission), but it could be useful to give them an overview of the community

MEBO had a zoom call with Dr Hazen and his team in October. Another zoom call is planned when they have time

This is a GOOGLE FORMS survey

short url for survey :
https://forms.gle/vem2TjepKobYZPBu8

current participants : 113 (update 18dec20)

Monday, December 6, 2021

Messina lab paper on FMO3 'haplotypes'

TMAU is taught as : person is normal or severe.

Severe is 2 very rare mutations as  a couple ... homozygous.

The Dr/patient approach to TMAU is ... do urine test. If negative, take no further action. 
If positive, do FMO3 gene test.

Re urine test :   
positive ... then test FMO3 gene. 'severe and rare' will show, but also many FMO3 results will not match concept of homozygous/coupled rare mutations. Most will be a patchwork of common variants taught as harmless etc. Dr not too bothered. 
negative ... and so do not test FMO3 gene (so all the 'FMO3 patchwork' cases in this group aren't spotted.)

a clinical lab in Messina Italy seems to be doing very relevant clinical TMAU/FMO3 that may help sufferers, especially those who are negative in the urine test (probably 95% cases).

They seem to be looking in to the theory that most cases of TMAU are not 'rare severe homozygous' cases as is taught, but rather combinations of mild common (or common taught as harmless) variants (heterozygous), which are known as Haplotypes. Or Compound Heterozygotes.

The blog opinion is that this theory is correct and will make up 95%+ of the cases, most of which will currently pass the urine test.

An analogy would be can someone walk or not.
Currently TMAU diagnosis and teaching is : 1 or other.
But we know many can't walk well or very far etc. Crutches, sprained ankles, whatever.
This gray-area is probably where most TMAU cases lie. Transient.

So for a clinical lab to put this theory forward in a paper would be very beneficial to the TMAU community in the sense it may change the attitude of the clinical health professionals for a diagnosis.

Probably they are still being conservative, in that they are likely trying to match positive urine cases to FMO3 results that don't fit the 'rare severe variant' teaching. This is already obvious, but nice for a lab to make a paper of it. 

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes

Simona Alibrandi, Fabiana Nicita, Luigi Donato, Concetta Scimone, Carmela Rinaldi, Rosalia D'Angelo, Antonina Sidoti
Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Division of Medical Biotechnologies and Preventive Medicine, University of Messina, 98125 Messina, Italy.

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.

Quotes:

"To date, 91 FMO3 variants were identified, and more than half of them are responsible for the TMAU phenotype (http://www.hgmd.cf.ac.uk/ac/index.php, accessed on 19 October 2021). Among the remaining variants, some are of uncertain clinical significance, while others are classified as “benign” and, therefore, should not affect the FMO3 enzyme activity

However, as such variants have a high frequency in TMAU patients, frequently without the contemporary presence of causative mutations, we hypothesized that their haplotypes could play a significant role in FMO3 activity reduction or alteration. To confirm this hypothesis, we performed a proteomic in silico analysis, using different platforms and software, with the final aim of revealing how these variant combinations could influence the enzyme folding, also simulating its dynamic behaviour with the TMA substrate."

Messina TMAU lab ask for DNA results !!!
In a previous post we mentioned Messina TMAU lab are always looking for FMO3 results from people who identify with TMAU. Although a small lab, it looks like their TMAU/FMO3 clinical research will continue. They are possibly 1 of only 2 labs (both small) who do direct TMAU/FMO3 research. The other lab in Argentina was only recently noticed, and will be a new post.   

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1 comments:

Anonymous said...

It's just wonderful that the Italian lab is doing such useful research on TMAU. Surely it will lead to a cure
someday.

I admit I had to look up "haplotypes" and read the article three times before I understood it! But it was
certainly worthwhile. Keep up the good work, everyone!

Dec 14, 2021, 5:57:00 PM
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