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Sunday, August 9, 2015

TMAU article for PhD project

Lakisha is a PhD student in a subject not related to health. For a project to write an 'article' about a rare disorder, she wrote the following article on TMAU. It is so good that we asked her permission to publish the article in the blog, which she kindly allowed.

Here is the text of the article in full


Some People Actually Smell Like Fish Because Of Their Genes

A person that smells like rotting eggs, rotting fish, or garbage may smell that way because of their genes.

By LaKisha David | Thursday, August 6, 2015

Unless you just left from working all day in a fish market, you probably wouldn’t go around smelling like fish. And yet, for some people with genetic mutations, this is exactly what happens. Despite attempts with obsessive hygiene practices, they emit a fishy smell everywhere they go. But it’s not always a fishy smell. Sometimes they smell like urine, rotting eggs, or rotting garbage. At the job interview, at the employee meeting, at the social gathering, they put their most courageous face forward while their strong fishy smell assaults the nostrils of just about everyone in the room. Somehow, explaining to everyone “I smell like fish because of a rare genetic disorder” doesn’t quite fit into introduction conversations. This rare genetic disorder is called trimethylaminuria (TMAU) or “fish malodor syndrome” and affects about 1% of the U.S. population.

It appears that Shakespeare himself was inspired by a person with TMAU for one of his characters. In The Tempest, Trinculo, the jester, spoke of Caliban saying:

“What have we here?
A man or a fish?
Dead or Alive?
A fish: he smells like a fish; a very ancient and fish-like smell;
A kind of not of the newest Poor John [a small European fish].”

Poor Caliban. Perhaps his disposition could have been helped if he knew the culprit was his genes.

Shakespeare was not the only writer inspired by TMAU sufferers. In 400 BC, there was written Mahabharata, a tale of earlier times about an Indian woman named Satyavati who was banished from society because she smelled like rotting fish. And in around 1265 BC, Thai folklore in the Sukhothai period spoke of concubines committing suicide because of fish malodor syndrome.

The first medical diagnosis through clinical testing occurred in 1970 with the unfortunate incident of a sickly 6-year old girl whose mother reported that the child sometimes smelled like fish. The physician realized that a compound called trimethylamine (TMA) smelled like fish so they gave TMA to the child to see what would happen. Sure enough, the child’s odor worsened and clinical tests indicated that there was too much unprocessed TMA in her system.

Researchers later recognized the fish malodor syndrome in other children and adults. But it also appeared in the fishy smelling eggs of Rhode Island Red chickens, fishy smelling milk of cows, and off flavor in pigs. In each case, this fish malodor syndrome called TMAU was the result of genetic mutations.

What goes on when we eat?

So what is it about a person with TMAU that causes his or her body to stink like warmed up garbage 10 minutes within taking a shower? It turns out that it’s in the FMO3 genes. There are over 40 known possible mutations of the FMO3 gene that singularly or collectively cause individuals to experience foods like broccoli or beef liver as if it was an edible stink bomb.

In a person with two properly formed FMO3 genes (one from mom, one from dad), digestion works like this. You decide to have one of your favorite meals. The good bacteria in your gut converts or metabolizes the choline in the food into a fishy smelling gas called trimethylamine (TMA). (Incidentally, TMA is the same molecule in fish that gives fish its fishy smell!) As part of the food digestion process, your FMO3 gene produces enzymes that would then convert the fishy smelling TMA into odorless trimethylamine N-oxide (TMAO or TMA N-oxide). TMAO (and some unconverted TMA) leaves your body through your urine. Your FMO3 enzymes also metabolize medications and chemicals that enter your body from the environment, a pretty important task.

If you were unfortunate enough to have been born with one or more mutations in your FMO3 genes resulting in the disorder trimethylaminuria (TMAU), digestion works more like this. You decide that dinner at a friend’s home sounds good, so you help yourself to a portion. The good bacteria in your gut will still metabolize the choline in the food you ate into fishy-smelling TMA. Nothing wrong here. But having a mutated FMO3 gene, your FMO3 would produce enzymes that either didn’t work well or were completely nonfunctional. So now, that fishy-smelling TMA gas roams through your body and exits through your sweat, your breath, your urine, and, for females, through vaginal fluids. Within minutes of eating an otherwise healthy meal (and certainly from eating fast food), your body would smell anywhere from lightly scented feces to sewage on a hot day. For those with certain singular mutations or collection of mutations, this offensive body odor emits from the body all the time, varying depending on diet, stress levels, or, for females, times of menstruation.

The wonderful world of genomics!

Thanks to genomics, the TMAU disorder is not the complete Shakespearean mystery that it once was, and there’s growing interest in FMO3 mutations because of the gene’s role in metabolizing drugs. Some studies helped us to learn that TMAU is an inherited recessive trait. Children who inherit one mutated FMO3 gene would likely experience at least mild or intermittent TMAU symptoms under stressed conditions. Children who inherited a mutated FMO3 gene from both parents are more likely to experience more severe forms of TMAU.

 In a study conducted by Ayesh and colleagues, 11 people were diagnosed with the TMAU disorder. People without mutated FMO3 genes converted over 80% of the fishy-smelling TMA to odorless TMAO both after eating a regular meal and after a TMA dose. Unfortunately for the TMAU sufferers, less than 55% of the fishy-smelling TMA was converted to odorless TMAO. To understand how the TMAU trait may be inherited, Ayesh and colleagues tested the parents of 6 of the TMAU sufferers. For every single parent, the TMA conversion rates were within acceptable rates after a regular meal but was less than 80% after receiving a TMA dose. Remember, people without mutated FMO3 genes can convert this additional TMA just fine. The results for the parents indicates that a person with only one mutated FMO3 gene could still experience the fish malodor syndrome if they eat more choline-laden foods than the daily recommendation. It also means that the parents are recessive carriers for TMAU, which could be inherited by their children. For the unfortunate children who receive a mutated FMO3 gene from both parents, they are likely to emit fishy-smelling odor even when eating meals within recommended daily choline levels.

 In 1990, Elizabeth Shephard and Ian Phillips discovered the FMO3 gene. With a  growing database of mutations in this gene, we now know that there are plenty of opportunities for TMAU to be inherited. But that some mutations seem to be inherited according to the person’s ancestral ethnic background. For instance, a European person with TMAU is likely to have different FMO3 mutations than someone of Japanese descent and different still when compared to someone of African descent. Maski Fujidea and colleagues discovered that as of 2003, none of the known FMO3 mutations found in the European population could be found in Japanese TMAU patients. The researchers identified two FMO3 mutations unique to the Japanese group. In the same year, Virginie Lattard and colleagues conducted a study with African Americans and non-Hispanic white people from the United States. They discovered two unique FMO3 mutations found in African Americans that were not found in non-Hispanic white people. Other common mutations were found in both African American and white populations. Could that be because most African Americans also have European ancestry?

Genomic researchers aren’t sure why FMO3 gene mutations vary according to ethnicity or if mutations are related to other factors such as differences in metabolism by ethnic origin. And researchers haven’t determined if any of this makes a difference in terms of TMAU expression. After all, stinky is stinky. For every ethnic group, the odor from TMAU is consistently described as smelling like rotting garbage, rotting eggs, fish, or urine. Ethnic differences in FMO3 mutation may not impact how TMAU is expressed as body odor, but it is possible that TMAU treatment plans may work well for one ethnic group, but not another.

Okay, but is there a cure?

Unfortunately, genomics has not yet provided a cure for TMAU. The best recommendation so far has been for TMAU suffers to reduce their intake of choline, but choline is in just about every food! A diet with a choline-deficient diet means a reduction or elimination of foods such as egg yolk, organ meats (chicken liver, beef liver), cruciferous vegetables (cauliflower, cabbage, broccoli, others), legumes (alfalfa, peas, beans, lentils, soybeans, peanuts, and others), milk, fish, beef, and pork.

This treatment is more successful with mild to moderate TMAU and specific FMO3 mutations. Part of the reason for partial success, other than the difficulty of maintaining such a strict diet long-term, is that diet is not the only influence on TMAU symptoms. Environmental chemicals, gut bacteria, stress, and menstruation also contribute to symptom expression in TMAU. Furthermore, choline is an important component for, ironically, liver function as well as cardiovascular health and brain development. Restrictions on choline long-term would have adverse effects such as liver dysfunction. Occasionally, a round of antibiotics is used to reduce bacteria in the gut. However, antibiotics, like dietary restriction, help only some TMAU suffers and is not suitable long-term.

Although there is no known cure, one line of genetic research seems promising. For TMAU, TMA is a methylamine that causes the body to emit the fish odor. Ann Wood and colleagues are conducting research on methylotrophic bacteria which metabolizes methylamines like TMA in the place of regular FMO3 function. Early research suggests that methylotrophic bacteria could play a role in odor control for people with TMAU, but there’s still a lot of work to be done in this area. Other suggested future research for treatments or cures include gene therapy, gut absorbents like charcoal, genetically modified microorganisms (with a human FMO3 gene designed to metabolize trimethylamine (TMA)), riboflavin supplements (to increase the function of working FMO3 enzymes), and specially designed hygiene products.

Turkey on rye

For now, TMAU suffers contend with whether drinking a cup of coffee on one particularly slow morning is worth smelling like urine for days at the office. One cup could ruin days of being on a strict, choline-reduced diet of turkey sausages on rye bread and liquefied raw fruits and vegetables. But sometimes, you just got to have coffee.



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7 comments:

Steph D said...

Great article! Who is Ann Wood and can we hear more about her research?

Aug 11, 2015, 1:03:00 AM
Anonymous said...

It would be nice to hear back from researchers on how the research is going, haven't heard from them in a while now. I think sufferers has the right to know about the research thats being done on them from the researchers every 2 to three months at least. I think they owe us that much.

Aug 11, 2015, 11:10:00 AM
Maria de la T., Founder and Executive Director, MEBO Research said...

The scientists and MEBO have been trying to get funding for the next few years. Herbal Hill is one of those efforts. However, we are very much aware that we need serious investors, and that's where our primary focus is.

This first phase of this research was a very good one, but more phases are needed to complete this.

Aug 14, 2015, 4:36:00 PM
blogcontributor2 said...

Hi Steph. We had not heard of Ann Wood before Lakisha mentioned it. An email was sent and a reply from an emeritus professor friend received. He was pessimistic about methylotrophs playing a role in a therapy, although I believe Dr Christodoulou's research proposal was based on this, probably after reading Ann Wood et al paper. Methylotrophs do seem like something worth exploring as a therapy. They metabolises trimethylamine in a different way than FMO. I think perhaps the 'archaea' French professor may/may not be doing an ad-hoc experiment with a methylotroph (it's all hush hush as with most researchers).

The FMO microbes used in the Paris student project metabolise TMA the same way as FMO3, so I guess may be more suitable, but FMO needs oxygen rich environments.

Aug 15, 2015, 3:09:00 AM
Anonymous said...

Hi will the below be any use for us sufferers?

Cleveland Clinic researchers will work with Cincinnati-based P&G to develop an over-the-counter product that can assist people manage their TMAO levels

Aug 28, 2015, 11:22:00 PM
blogcontributor2 said...

My first guess is that they may try to develop a TMA-blocker (a drug enzyme blocker) that stops TMA being created from choline/betaine in the gut etc. That sort of drug would help for TMAU.

They won't want to create a TMA-TMAO blocker as it would make everyone smell. So I guess they need to create a TMA blocker.

Let's hope that's what they are doing. I hoped they would be.

I hadn't heard of this news. Thanks for mentioning. I will look further.

Aug 29, 2015, 7:07:00 AM
Anonymous said...

I hope so too.

Here's the link:

http://www.crainscleveland.com/article/20150819/NEWS/150819777/cleveland-clinic-partners-with-procter-gamble-to-fight-heart-disease

Aug 29, 2015, 10:55:00 AM
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