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Urinary trimethylamine (TMA) and its oxide (TMAOx) are measured separately and as a mixture using (15)N-labeled internal standards and direct infusion electrospray with a quadrupole time-of-flight (Q-ToF) instrument. TMA is quaternized with trideuteromethyl iodide to avoid inclusion of endogenous tetramethylammonium ion in the TMA measurement, whereas TMAOx is measured as the protonated molecule. Measurements reported as percentage TMA made with separate and combined samples agree within 6% of the measured values and demonstrate that both TMA and TMAOx can be measured simultaneously in a single analysis. Moreover, the analysis is simpler and less tedious and time-consuming than some earlier methods., (2010 Elsevier Inc. All rights reserved.)

Trimethylaminuria is a rare metabolic disorder that is associated with abnormal amounts of the dietary-derived trimethylamine. Excess unmetabolized trimethylamine in the urine, sweat and other body secretions confers a strong, foul body odor that can affect the individual's ability to work or engage in social activities. This review summarizes the biochemical aspects of the condition and the classification of the disorder into: 1) primary genetic form, 2) acquired form, 3) childhood forms, 4) transient form associated with menstruation, 5) precursor overload and 6) disease states. The genetic variability of the flavin-containing monooxygenase (form 3) that is responsible for detoxication and deodoration of trimethylamine is discussed and put in context with other variant forms of the flavin-containing monooxygenase (forms 1-5). The temporal-selective expression of flavin-containing monooxygenase forms 1 and 3 is discussed in terms of an explanation for childhood trimethylaminuria. Information as to whether variants of the flavin-containing monooxygenase form 3 contributes to hypertension and/or other diseases are presented. Discussion is provided outlining recent bioanalytical approaches to quantify urinary trimethylamine and trimethylamine N-oxide and plasma choline as well as data on self-reporting individuals tested for trimethylaminuria. Finally, trimethylaminuria treatment strategies and nutritional support are described including dietary sources of trimethylamine, vitamin supplementation and drug treatment and issues related to trimethylaminuria in pregnancy and lactation are discussed. The remarkable progress in the biochemical, genetic, clinical basis for understanding the trimethylaminuria condition is summarized and points to needs in the treatment of individuals suffering from trimethylaminuria.

Trimethylaminuria (TMAU) results from an accumulation of an excessive amount of unoxidized trimethylamine that is excreted in urine and body secretions. Mutations of the flavin-containing monooxygenase 3 (FMO3) gene (a hepatic phase I drug-metabolizing enzyme) account for the severe recessively encoded form of this condition. We have previously described a number of FMO3 polymorphisms which in vitro exhibit reduced substrate affinity for several FMO substrates. Here we show that three prevalent polymorphisms (E158K, V257M, and E308G) inherited in particular combinations confer a slight decrease in TMA oxidation under normal physiological conditions, which may be clinically "silent." With the use of substrate loading or with the interaction of other known modulators of FMO3 activity such as hormonal influences, these genotypes may predispose to mild TMAU., (Copyright 2001 Academic Press.)

We report a method based upon fast atom bombardment mass spectrometry (FAB-MS) and stable isotope dilution techniques for the measurement of urinary trimethylamine (TMA) and trimethylamine N-oxide (TMAOx). TMA is extracted from urine that was spiked with (15)N-labeled TMA. The extracted TMA isotopomers are quaternized with trideuteromethyl iodide and analyzed in FAB-MS with hexaethylene glycol as matrix. TMAOx is measured by evaporation of another sample of the urine spiked with (15)N-labeled TMAOx on the FAB probe and analyzed as for the TMA. The method allows the ready and simple distinguishing of controls and patients with TMAuria, and is useful in monitoring patients with the disorder. We give examples of its use in determining normal control ranges for these metabolites and in evaluating patients., (Copyright 1999 Academic Press.)

Trimethylaminuria (TMAuria) (McKusick 602079) first described in 1970 is an autosomal recessive condition caused by a partial or total incapacity to catalyze the N-oxygenation of the odorous compound trimethylamine (TMA). The result is a severe body odor and associated psychosocial conditions. This inborn error of metabolism, previously thought to be rare, is now being increasingly detected in severe and milder presentations. Mutations of a phase 1 detoxicating gene, flavin-containing monooxygenase 3 (FMO3), have been shown to cause TMAuria. Herein we describe a cohort of individuals ascertained in North America with severe TMAuria, defined by a reduction of TMA oxidation below 50% of normal with genotype-phenotype correlations. We detected four new FMO3 mutations; two were missense (A52T and R387L), one was nonsense (E314X). The fourth allele is apparently composed of two relatively common polymorphisms (K158-G308) found in the general population. On the basis of this study we conclude that one common mutation and an increasing number of private mutations in individuals of different ethnic origins cause TMAuria in this cohort., (Copyright 1999 Academic Press.)