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MEBO - UBIOME study 2018



MEBO Gut Microbiome Study
"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"
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"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"

Dynamics of the Gut Microbiota in
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TMAU Petition world
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Denver TMAU Test Lab survey click here
click to Read more/less

USA survey for anyone who wants to improve Denver TMAU test

begun : Dec22
end : no ending for now

A trainee genetic counselor is working at the Denver TMAU test lab. Probably as part of her training. As a project she wishes feedback on any aspect of the Denver TMAU test and process. You can fill in the survey and/or email her (email address is in survey). It's meant for USA people, but perhaps others can give their view too (as we have so few opportunities).

quote from her rareconnect post

"Hello all! I wanted to make you aware of a research study being conducted to better understand the experience and needs of individuals with trimethylaminuria with a goal of being able to create improved patient and healthcare provider education materials. Any participation is completely voluntary and all responses remain confidential. Feel free to use the contact information within the link with any questions or share the survey with others with TMAU."

see this post for more details

Sunday, November 3, 2013

New Portuguese paper on TMAU

A new research paper on trimethylaminuria (TMAU) has been published by a group of medical professionals associated with the Portuguese Newborn Screening Program. It would be encouraging if TMAU has been added to their list of disorders to test in the Newborn Screening Program, as it would be the first known country to add TMAU to their screening program. Only the abstract of the paper is available for free, but a full copy of the paper has been read.

Link to Pubmed abstract : Trimethylaminuria (fish odor syndrome): genotype characterization among Portuguese patients

Ferreira F, Esteves S, Almeida LS, Gaspar A, da Costa CD, Janeiro P, Bandeira A, Martins E, Teles EL, Garcia P, Azevedo L, Vilarinho L.
Newborn Screening, Metabolic and Genetics Unit, Department of Human Genetics, National Institute of Health Dr Ricardo Jorge, 4000-055 Porto, Portugal.

The following is a non-expert interpretation of the paper, and should not be considered as totally precise :

The study was to see how patients with 'positive' TMAU urine (phenotype) results co-related with FMO3 DNA results (genotype). They found 25 patients, all of them under age 8 apart from one patient who was middle aged, and compared their FMO3 DNA to a control group (100 normal people). What is especially interesting is the lengths they went to notice any potential 'faults' in the FMO3 DNA. The paper does not say what reference ranges they used to identify' positive' urine samples.

They have also deeply researched the previous papers on TMAU. Here are some notes they made of previous TMAU research papers :

FMO3 is a NADPH-dependent enzyme that catalyzes the oxidation of a wide range of foreign chemicals including therapeutic drugs, dietary components and pesticides

Interindividual variability in the expression of FMO3 gene may affect drug and foreign chemical metabolism in the liver and other tissues
Genetic variants associated with the FMO3 gene range from those associated with the most severe symptoms to those associated with mild symptoms that are polymorphic at the population level

According to Cashman et al. (2001), the incidence of TMAu may range from 1% to 10%

Findings from their paper :

What is of special interest in this paper is the length they went to notice 'faults' in the FMO3 DNA of the TMAU group. This involved full sequencing and noting any 'variants' at all, then to suggest if they may cause a fault in FMO3 efficiency, even if perhaps not alone but in tandem with other small faults. Also, anyone reading research into TMAU may take it for granted everything about the FMO3 mutations or variants is known, but research as thorough as this shows more variants are still being found (in this case 4) and a brief look through recent TMAU papers show that new variants were found in those too,and the paper expects more to be discovered. So if anyone is given a medical FMO3 DNA result which says 'no known mutation found', it means no mutation found that that lab is yet aware of. A mutation is regarded as causing fault, whereas a 'variant' is regarded as not being a fault until proven.

Variants : variants are small changes in the coding region of DNA (in this case FMO3 DNA). They are not regarded as causing 'fault' until being proven to. In this study they found 4 new variants in the TMAU group. An FMO3 protein has a 532 amino acid coding sequence. In this case they found 'variants' at codons 38, 232, 307, and 310. They say that none of the control group has these variants, which arouses suspicion that they may cause FMO3 deficiency to some degree.

The paper then goes on to discuss the findings of a few of the genetic faults in the TMAu group in depth.

Glu158Lys and Glu308Gly variants :
It then goes on to discuss the common variants at codons 158 and 308. Many of the population carry these faults (in this study 48% TMAu patiants carry 158 variant and 49% in the control group carry 158 variant. Around 20% whites are thought to carry 308 variant). At a clinical level, a patient is likely to be told that carrying these does not affect FMO3 function. However this paper notes a 1999 paper said that some carriers of these variants could have decreased FMO3 function when they carry these variants heterozygously or if they are homozygous for either (e.g. 158-158). The 2 variants are recorded as possibly having slight deficiency but perhaps moreso if both are carried from the same parent (in cis) or in combination with one copy of a known mutation (a compounded problem). They suggest that these type of combinations might lead to transient TMAu issues (depending on factors such as TMA levels etc). They also note that none of the control group carried the 158 or 308 faults 'homozygously' (that means having the same fault on both allelles)

Val257Met variant :
They then go on to discuss another common FMO3 variant at codon 257. They also wonder if it's effect on FMO3 function may currently be underestimated. Most of the TMAU group in this study seem to carry the 'common' variants such as 158, or 308, or 257. Usually in a combination or sometimes homozygously (e.g. 158-158)

They go on to discuss how carrying variants alone may have no effect but carrying them in compounded ways may have some detrimental effect.  They also go on to say what is already known, that faults can occur in the non-coding part of FMO3 (the junk part, e.g. introns) and still have an effect on FMO3 function.   

The paper ends by saying further research is needed.


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