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  • Trimethylamine (TMA) is a tertiary amine derived from the enterobacterial metabolism of precursors such as choline and phosphatidylcholine present in the diet. Trimethylamine is also a bacterial metabolite of TMA-N-oxide (TMANO), a normal constituent of salt-water fish. Trimethylamine and its N-oxide are normal constituents of human urine. Dietary-derived trimethylamine is almost entirely N-oxidized to and excreted as TMANO by the enzymes known as flavin-containing monooxygenases (FMOs), primarily the liver isoform, FMO3.

  • Most individuals (with normal TMA N-oxidation capacity) excrete >95% of the combined TMA/TMANO load as TMANO or have a urinary TMA concentration of <18 μmol/mmol creatinine.

  • Trimethylaminuria (TMAuria) (OMIM 602079) is a condition associated with excess excretion of TMA in urine and other body fluids and associated severe pungent body odor (fish-like smell). Trimethylaminuria, previously called fish odor syndrome, is caused by mutation in the gene encoding flavin-containing monooxygenase-3 (OMIM 136132). Significant psychosocial consequences are related to this disorder. The condition is panethnic, with the initial cases coming from the British and Australian populations. There are a number of clinical presentations of trimethylaminuria: (1) Severe classic trimethylaminuria (primary genetic form, autosomal recessive) appears to be the most common type described, resulting generally from homozygosity or compound heterozygosity for missense or nonsense mutations of the FMO3 gene with severely diminished FMO3 oxidation. (2) A childhood form, "poor metabolizer phenotype," can present with an episodic, variable odor phenotype related to precursor load, which may resolve with maturity. In a number of cases reported in childhood, milder mutations or polymorphisms of the FMO3 gene have been described. (3) There is also mild or transient trimethylaminuria; several females have noted symptoms and exacerbations of symptoms at the onset of menstruation related to a hormonal effect on FMO3 function. Transient symptomatology may occur in individuals who carry FMO3 polymorphisms associated with decreased FMO3 activity when exposed to excessive precursor load choline or with the intake of dietary FMO3 inhibitors. Conditions leading to bowel bacterial overgrowth syndromes may enhance production of TMA causing secondary TMAuria. (4) An acquired type has been described uncommonly in adults following viral illness.

  • Standard therapy of trimethylaminuria includes supportive care, counseling, and dietary intervention. The dietary treatment consists of a restriction of dietary choline and lecithin and restriction of FMO inhibitors (dietary indoles and glucosinolates), which may resolve symptomatology in milder cases. Folate supplementation and a diet balanced in vitamins (including riboflavin) is recommended. The use of riboflavin (FAD donor), a cofactor for FMO, to enhance FMO3 activity is currently under investigation. Copper-chlorophyllin tablets have been reported to modulate the enterobacterial production of trimethylamine and to sequester free trimethylamine. Metronidazole or neomycin may be used intermittently to decrease gut anaerobic conversion of choline to TMA but should be used cautiously.

  • Microsomal FMOs (EC are NADPH-dependent flavoprotein enzymes that catalyze NADPH-dependent monooxygenation of nucleophilic nitrogen-, sulfur-, and phosphorus-containing drugs, pesticides, xenobiotics, and endogenous amines. FMO3 (OMIM 136132) is the main catalytically active isoform expressed in liver, the site of first-pass ...

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