Trimethylaminuria: causes, symptoms, diagnosis, and treatment

Trimethylaminuria, also known as fish odor syndrome (FOS), is a rare and very characteristic metabolic disease. The urines, sweats, exhaled breaths, and other body fluids contain trimethylamine (TMA) that have fish odors.


Causes

FOS has an autosomal recessive inheritance, and the pathogenic gene FMO3 is located on chromosome 1q23-25 and encodes flavin-containing monooxygenase 3. Under normal circumstances, dietary trimethylamine N-oxide (TMAO) and other TMA precursors such as choline are reduced to TMA in the intestine, and TMA is oxidized by flavin-containing monooxygenase 3 in the liver to odorless TMAO. When this enzyme is deficient, TMA is overproduced.

The dietary sources of TMAO include marine fishes, choline, lecithin, carnitine, eggs, soybeans, peas, and animal livers and kidneys. TMAO is degraded by intestinal bacteria to form TMA and is excreted with body fluids.

In addition, there are also reports of acquired FOS in adulthood. These patients have no familial or personal history of the disease, but often have a history of liver disease. It is believed that these acquired FOS is caused by interferences with FMO3 gene expression due to viral DNA insertion into the genome.

There are also reports of transient FOS in childhood, which may be related to the immature development of flavin-containing monooxygenase 3, mostly in infants fed with choline-containing diets. The symptoms subside after changing the formula of diets, and generally the subsequent choline-containing diets do not cause the disease.


Signs and Symptoms

Patients often find that they have abnormal body odors or obvious bad breaths in childhood, and fish odors worsen during adolescence. The symptoms are exacerbated after oral contraceptives and before or during menstruation in female patients, which may be related to inhibition of TMA oxidation by hormones. Because patients can gradually figure out ways to reduce odors, such as regular baths and avoidance of certain foods, the odors may not always be obvious.

FOS is not life-threatening and there are no abnormalities in the physical examination, but the odor has caused great distress to patients. Many patients develop psychological problems, including avoidant personality disorder, social isolation, compulsive bathing, interpersonal tension, dropout, and even depression.


Diagnosis

The diagnosis of FOS is based on clinical manifestations, analysis of TMA and TMAO concentrations in urine, and genetic testing if necessary. The formula TMAO / (TMAO + TMA) x 100% can be used. In FOS patients, the ratio is less than 84%, while the ratio is greater than 92% in normal individuals. To avoid false negatives caused by diets, urine analysis should be performed after ingestion of 300 grams of marine fish.


Treatment

There is no specific treatment for this disease. Treatment regimen is dietary changes. Explanations of the biological characteristics and exacerbating factors such as menstruation of the disease can help relieve nervousness.

Dietary adjustments include avoidance of choline-rich foods such as egg yolks, mustards, animal livers and kidneys, soybeans, peas, and marine fishes. However, absence of choline may cause choline deficiency, resulting in liver damage, neurological diseases, and even increased risk of cancer. Limited ingestion of brussels sprouts may be beneficial because they have an inhibitory effect on flavin-containing monooxygenase 3.

In addition, slightly acidic soaps can help reduce odors. Small doses of oral antibiotics such as metronidazole, amoxicillin, and neomycin for a short period of time can inhibit bacteria in the intestinal tract, reducing TMA production. Oral sorbents such as activated carbon can also reduce odors.