Dr Eileen Treacy is an Irish Metabolic Consultant who has long had an interest in TMAU.
This includes while working at McGills Canada (who TMAU test) and now in Dublin.
3 new FMO3 mutations identified
Dr Treacy has lead a new study using test stats from some Irish patients, using Sheffield TMAU test lab.
From 13 people deemed TMAU1 (genetic TMAU), they found 3 new FMO3 variants that will likely affect FMO3 funtion (negatively).
Note about Sheffield lab (did they use the old test method ? i.e. done before 2017 ? )
It seems Nigel Manning is thanked in the acknowledsgments, which may mean the Urine Test was done using the old (more believable results ???) test method (pre-2017).
The new Sheffield method is similar to Denver and gives half less positive TMAU1 cases than the old test (from 33% down to 18%).
So little known about FMO3 variants/mutations
This shows how little is documented about FMO3 variants/mutations, that 3 can be found easily from such a small group. How many more are to be disscovered.
Excellent 'cheap' study
This shows what can be discovered from a study as simple as looking at the test stats of 13 positive results. Test stats are so vital information for a disorder not heard of by most.
It would be great if say UCLH (The Charles Dent Metabolic Clinic) or Denver followed suit.
The genetic and biochemical basis of trimethylaminuria in an Irish cohort
Full paper (Wiley Journal)
Samantha Doyle1,4| James J. O'Byrne1| Mandy Nesbitt2| Daniel N. Murphy3|Zaza Abidin1,4| Niall Byrne1,4| Gregory Pastores1,4| Richard Kirk2|Eileen P. Treacy1,4,5
1. National Centre for Inherited MetabolicDisorders, The Mater MisericordiaeUniversity Hospital, Dublin, Ireland
2. Sheffield Diagnostic Genetics Service,Sheffield Children's NHS Trust,Sheffield, UK
3. National Rare Diseases Office, The MaterMisericordiae University Hospital, Dublin,Ireland
4. School of Medicine and Medical Sciences,University College Dublin, Dublin, Ireland
5. Department of Paediatrics, Trinity CollegeDublin, The University of Dublin, Dublin,Ireland
Quotes from paper
Results:
A genetic diagnosis was made for seven patients, including for five of the nine moderate to severely affected cases. We noted the c.913G>T;p.(Glu305*) and c.458C>T;p.(Pro153Leu) mutations in this Irish population with severe TMAU which is consistent with our earlier findings in Australian and North American families of Irish and British descent.Three individuals were noted to be homozygous for the common variant haplotypec.472G>A;923A>G;p.(Glu158Lys);(Glu308Gly). We also identified three novel variants in this population, which are likely to be pathogenic: c.682G>A;p(Gly228-Ser), c.694G>T:p(Asp232Tyr), and c.989G>A;p.(Gly330Glu) ...
...The polymorphic haplotypes are prevalent in the popula-tion with undetermined penetrance. As the majority of indi-viduals carrying these common variants are likely to beasymptomatic, it may not be beneficial to identifyFMO3variants, which results in mild TMAU, which could leadto detrimental over-restriction of choline and other self-imposed dietary imbalances.
Interesting points :
FMO3 protein is made from a 532 amino acid sequence.
3 nucleotides make up an amino acid.
In DNA test they look at the Nucleotides, and so can work out the amino acid that will be made.
The 5 most common FMO3 'variants' (bracket = guestimation of commoness of variant)
FMO3 codon/amino acid (of 532)
158 (maybe 40% people ?)
285 (26%?)
308 (20% ?)
257 ( 8% ?)
147 (6%?)
So FMO3 variants are common.
The question then is why do some end up as a 'smell-risk' since e.g. 40% of people do not have TMAU ?
The taught theory is that only those who carry the same variant on both sides (homozygous) and it is a severe variant will be affected (e.g. 153-153)
Most are a mix of more than one variant ?
Another theory could be that 'severe' and most 'high-risk mild' people might carry 2 or more variants ?
e.g.
Carrying a severe mutation (alone ?) and 1 or more common variants.
Carrying 2 or more common variants ?
(note: Dr Treacy would probably not agree with this theory).
We thank Dr Treacy and Sheffield Children's Hospital for this important study.
This is possibly the first TMAU/FMO3 'stats' paper in 10 years.
It would be very helpful if test labs published the test stats, but this seems currently unlikely.
One aim for the community could be to get politicians to tell them to publish the stats (e.g. twice a year, yearly)
Links
Clinical Utility Card entry for TMAU
Prof Elizabeth Shephard FMO3 Variant Database
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