Trimethylaminuria
Trimethylaminuria (TMAU), also known as fish odor syndrome or fish malodor syndrome, is a rare metabolic disorder that causes a defect in the normal production of an enzyme named flavin-containing monooxygenase 3 (FMO3). When FMO3 is not working correctly or if not enough enzyme is produced, the body loses the ability to properly convert trimethylamine (TMA) from precursor compounds in food digestion into trimethylamine oxide (TMAO), through a process called N-oxidation. Trimethylamine then builds up and is released in the person's sweat, urine, and breath, giving off a fishy odor. Primary trimethylaminuria is caused by genetic mutations that affect the FMO3 function of the liver. Symptoms matching TMAU can also occur when there is no genetic cause, yet excessive TMA is excreted - this has been described as secondary trimethylaminuria (TMAU2). Metabolic pathway Trimethylamine enters the body via the consumption of certain foods and supplements: When food is consumed that contains TMA and/or TMAO (predominately seafood; saltwater fish, shellfish, seaweed and kelp). TMAO is converted by bacteria in the lower gastrointestinal tract (gut) into TMA. When a food substance, supplement or medicine that contains a TMA precursor (choline or carnitine) is ingested. Some precursor is absorbed into the bloodstream in the small intestine before reaching the gut (the RDI of choline is 450–550 mg per day, which is absorbed this way), however there is a limit to the transport capacity of the intestine, and not all precursor is exposed to the process. Unabsorbed precursor ends up in the gut. Certain bacteria in the gut can convert those precursors to TMA, the proportion of precursor converted to TMA is related to the amount of specific bacteria in the gut but on average 63% of excess choline, and 31% of carnitine (±13%) are converted to TMA. TMA in the gut is absorbed through the intestinal lining and enters the bloodstream, where it is processed by the liver. A healthy liver produces an abundance of the enzyme FMO3, which neutralises the TMA by oxidising it to an odourless TMAO. If FMO3 enzyme production is compromised, or there is too much TMA for the amount of enzyme, then TMA will continue to circulate in the bloodstream until enough enzyme is produced. While TMA is in the bloodstream, it is filtered out via the kidneys (95% over 24 hours) to the bladder, and slowly exits the body in bodily fluids; urine, sweat, saliva, reproductive fluids and breath. TMA has no known interactions with any known internal or organ function. Although lecithin, creatinine and betaine are technically precursors to TMA, pilot studies have shown no significant effect on the production of excess TMA/TMAO in urinary analysis at normal dietary levels of consumption. When taken in large quantities (12g/day) betaine has been known to cause fish odor symptoms, meaning that there is some conversion of betaine to TMA if supplements are taken regularly. Symptoms and signs Trimethylamine is most noticeable in urine, as it is captured, concentrated and released in intervals. Fishy smelling urine is a primary