Trimethylaminuria is an syndrome characterized by excretion of excessive amounts of unoxidized trimethylamine in the urine, breath, sweat, and reproductive fluids. Trimethylamine is extremely volatile and has a pungent ammonia-like odor resembling rotten fish. For this reason, trimethylaminuria is commonly referred to as Fish Odor Syndrome. No other physical symptoms are associated with trimethylaminuria.

Trimethylamine is a volatile, malodorous chemical derived from dietary substances such as choline by bacteria in the GI tract. Trimethylamine is normally metabolized to the nonvolatile chemical , trimethylamine-N oxide,  by the liver enzyme flavin-containing monooxygenase 3 (FMO3).

Trimethylaminuria can be caused by either a congenital deficiency of FMO3 or excess production of TMA in the GI tract. Acquired trimethylaminuria may occur de novo during adulthood in patients with liver disease. Impaired hepatocellular function or portosystemic shunts are believed to impair clearance of TMA absorbed from the GI tract.

For individuals with primary genetic trimethylaminuria, symptoms are usually present from birth and may worsen during puberty. In females, symptoms are more severe just before and during menstruation, after taking oral contraceptives, and perimenopause, probably because of a decrease in expression of FMO3 in response to steroid hormones.

Congenital trimethylaminuria is inherited in an autosomal recessive manner. Parents of an affected individual are obligate heterozygotes and carry one mutant allele. Heterozygotes are asymptomatic. A mutation in the FMO3 gene is the only mutation that has been associated with trimethylaminuria so far.

Diagnosis of trimethylaminuria requires measurement of trimethylamine or the ratio of trimethlyamine to total trimethylamine (which is the sum of TMA plus TMA oxide) in urine. Testing is usually performed by  mass spectroscopy or proton nuclear magnetic resonance (NMR) spectroscopy.

A urinary concentration of TMA of 10 µg/mL (18-20 µmol/mmol creatinine) is the threshold that produces the fishy body odor. Patients with severe trimethylaminuria excrete more than 40% of total TMA as unmetabolized TMA. Patients with mild trimethylaminuria excrete 10%  to 39% of total TMA as unmetabolized TMA Unaffected individuals and heterogzygotes excrete less than 9% of total TMA as unmetabolized TMA.

Carriers can be detected using a TMA loading test in which 600 mg of TMA is given orally in a gelatin capsule. After a loading test, carriers excrete 20%-30% of total TMA as unmetabolized TMA, whereas unaffected individuals excrete less than 13% of total TMA as TMA.

If an individual excretes more than 10% of total TMA as TMA under normal dietary conditions, diagnosis can be confirmed by DNA sequencing of the FMO3 gene. More than 30 distinct mutations have been reported which inhibit FMO3 enzyme activity.

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