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Saturday, April 4, 2009

TMAu article from 1999 for Science News

http://www.sciencenews.org/sn_arc99/5_15_99/bob2.htm

It's been 10 years since this article on trimethylaminuria was written by a science journalist for Science news , and it possibly remains the best article for the public on TMAu. Partly because so few (if any) are written, and partly because there is very little interest in the condition, but also because it is so well-written too. An abridged version turns up on searches for student's to 'plagiarize' for their studies. Most of the names mentioned seem well-known by regular readers, although Dr Harry W McConnell seems to have been very helpful in the article but does not seem to appear in any recent TMAu literature.

It lists the main 'facts' about TMAu up until that time (1999). One confusing point is that the article says 1% could carry a mutant FMO3 copy, but other TMAu literature suggests 1% could be at risk. Although the article suggests that 'carriers' may be vulnerable to smelling when ingesting precursor overloads, you may imagine that in practice this is the situation for many, and may include carriers. In the end, the test is whether you smell enough times for it to have a negative impact on your life, rather than if you have 2 bad FMO3 copies or only one bad copy. Very few, if any, seem to smell all the time (although if you can't smell yourself, it's not that much help to know this. If you smell all the time then your doctor will have smelt you ?). In Dr Preti's paper on breath odors, the 2 with very low FMO3 function only smelt after choline challenges. Another expert has mentioned they never smelt anyone at the 2nd TMAU workshop. It seems likely that if someone has one bad or variant copy and feels that they smell, there is a good chance of a connection. Probably the most than can be said is that there is likely a very big 'gray' genetic area with the condition.

Some interesting quotes:

The first case of trimethylaminuria was described in the medical literature in the 1970s

...Studies in the last few years have shown that trimethylaminuria results from defects in an enzyme that breaks down trimethylamine, a byproduct of protein digestion released by bacteria living in the gut. This small molecule—the compound that gives fish their fishy odor—smells foul or garbagelike at low concentrations and fishy in larger amounts...

...People with the disorder can release trimethylamine through breath, sweat, and urine. A few have a strong odor all the time, but most others experience a less severe smell that fluctuates over time. Researchers speculate that the variability of symptoms indicates that a range of genetic mutations can cause the disease and that stress and diet play a role in triggering symptoms...

...Because bacteria in the gut produce most of the trimethylamine in the body, some people have found that low doses of antibiotics, which kill off these bacteria, temporarily help keep odor down...

...says Harry W. McConnell of King's College Hospital in London. "The name [fish odor syndrome] contributes greatly to the stigma of this disorder," he says, adding that the name "is misleading since the odor is variable."...

...The odor problems in some children seem to disappear as they age, but researchers don't know why...

...Nor do they know why the syndrome seems to be more common in women than in men. Scientists suspect that sex hormones exacerbate symptoms. A variety of reports say that the disease in women gets worse around puberty, just before and during menstrual periods, after taking oral contraceptives, and around menopause...

...Finally, some cases of trimethylaminuria may have no genetic component: Several patients seem to have developed the disorder after liver or kidney disease...

...Scientists discovered the gene implicated in trimethylaminuria in 1997. Located on the end of a chromosome, it encodes one of a series of enzymes called flavin monooxygenases (FMOs). Researchers suspect that these enzymes' most important role is in eliminating environmental toxins from the body. The enzyme known as FMO3, for example, helps break down diet-derived nitrogen-containing compounds, including trimethylamine, and possibly drugs containing nitrogen, sulfur, and phosphorus.

The gene for FMO3 can suffer from any of about 10 different mutations. Most people showing symptoms of trimethylaminuria have inherited two mutated copies of the gene. Scientists suggest that the variety of genetic mutations might explain differences in the timing of disease onset and how strong the odor is.

Environmental factors may also play a role. Some types of bacteria that people have in their guts might produce more trimethylaminuria than other types, speculates Paul V. Fennessey, a pharmacologist at the University of Colorado Health Sciences Center in Denver. Alternatively, if the enzyme that breaks down trimethylaminuria is just barely keeping up, sudden increases in the amount of trimethylamine eaten or produced in the body could trigger symptoms, he adds.

Animal studies have provided evidence that a compound known as indole-3-carbinol, found in broccoli and other dark green vegetables, blocks the function of the enzyme system that breaks down trimethylamine, says David E. Williams, a molecular toxicologist at Oregon State University in Corvallis. If this holds true in people, avoiding broccoli and other leafy greens, in addition to limiting protein intake, might help reduce odor problems, he says.

Some studies have suggested that people who carry only one copy of a mutated gene may be susceptible to transient fish-odor attacks during periods of stress or after eating foods that contain large amounts of trimethylamine or its chemical precursors, says Stephen C. Mitchell of the Imperial College School of Medicine. Doctors can use this observation to identify carriers of the mutated gene. When they receive a high dose of choline, people with at least one copy of a mutated gene for FMO3 excrete high levels of smelly trimethylamine in their urine. This test is also used to diagnose trimethylaminuria...

...Because FMO3's functions in the body are not well understood, doctors don't know what symptoms, other than odor, might be linked to trimethylaminuria. Researchers suspect that the enzyme breaks down many substances besides trimethylamine. For example, various drugs, such as antidepressants, may be broken down by FMO3. If the enzyme isn't working properly, people might suffer additional side effects from some of these drugs, they suggest. A few people with trimethylaminuria at the conference reported that they had taken antidepressants, but the drugs did not seem effective and actually worsened their odor.

Animal studies also support the idea that FMOs break down drugs. Indole-3-carbinole, which inhibits FMO3 and its relatives, seems to increase the effectiveness in mice of the pain medication codeine, Williams reports. These findings suggest that the drug is broken down differently when the FMO system is not working, he says. Test-tube experiments in his laboratory suggest that the enzyme system may also help break down nicotine and the anticancer drug tamoxifen.

The liver, a reservoir of digestive enzymes, produces most of the body's FMOs. Production of these proteins has also been detected in midbrain nerve cells, skeletal muscle, adrenal and salivary glands, thyroid and lung tissue, and the skin. The functions of the enzymes in these various locations remain unknown.

Although the vast majority of people so far diagnosed with the disorder appear to have normal mental and physical abilities, some researchers suspect that the enzyme deficiency itself may cause depression and trigger seizures. For example, a Pennsylvania teenager with trimethylaminuria and a tendency to suffer seizures found that his seizures stopped when he went on a protein-restricted diet, says McConnell...

...The unanswered questions about trimethylaminuria seem endless, yet money to support studies of the disease is scarce, say researchers. Because the Wellcome Trust in England has sponsored several studies of the disease, Britain has the dubious distinction of having the most reported cases of fish odor syndrome in the world.

At the recent NIH conference, researchers called for development of a new diagnostic test that will be less off-putting—the current assessment procedure temporarily makes the symptoms worse. The researchers also saw a need for a consortium that would coordinate clinical research so that studies could include more than a few participants. The meeting organizers hope that patients will form an advocacy group to raise money for research into this rare disease...

...If mutations in the FMO3 gene are as common as scientists suspect, it might be worth developing a screening test to be used at birth, says Eileen Treacy of the Montreal Children's Hospital...

...Treacy points to the metabolic disorder known as phenylketonuria, or PKU. The disease causes mental retardation and nervous system problems in about 1 child in 12,000. Because PKU can be treated successfully with diet and drugs, every child born in a U.S. hospital is screened for the disease. Trimethylaminuria and PKU probably affect roughly similar numbers of children, meaning screening for trimethylaminuria is a realistic possibility, she says...

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