Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort. B.R. Akerman¹, D.M. Lambert¹, H. Lemass⁵, L.M.L. Chow³, C. Greenberg⁴, O.A. Mamer², E.P. Treacy¹. 1) Biochemical Genetics Unit, McGill Univ./Montreal Children's Hosp, Montreal, QC, Canada; 2) Mass Spectrometry Unit, McGill Univ., Montreal, QC, Canada; 3) Hospital for Sick Children, Toronto, ON, Canada; 4) Children's Hospital, Winnipeg, MB, Canada; 5) Mater Hospital, Dublin, Ireland.

   Flavin-containing monooxygenases (FMOs) are microsomal NADPH-dependent enzymes that catalyze the oxygenation of nitrogen, sulfur, phosphorous and other heteroatom-containing chemicals, drugs and pesticides. Currently known FMOs comprise a 5-member family. In adult human liver, FMO3 constitutes the predominant form that metabolizes the above to polar readily excreted oxygenated metabolites. Trimethylaminuria (TMAuria; McKusick 136131) is an autosomal recessive condition caused by a partial or total incapacity to catalyze the N-oxygenation of the odorous compound trimethylamine (TMA), derived from dietary choline and lecithin. The result is a severe body odor and associated psychosocial conditions. This inborn error of metabolism, previously considered rare, is being increasingly detected in severe and milder presentations. We have previously shown that 4 mutations of the FMO3 gene are causative of TMAuria in Australians (Treacy et al. 1998; Akerman et al. 1999). Of 28 individuals referred to our Unit for investigation of malodor from N. America, 10 had severe TMAuria (less than 50% of TMA oxidation) as measured by a FAB-MS assay of TMA and TMA N-oxide. We performed mutation analysis in 8 of these probands. In addition to three previously described FMO3 mutations (P153L, E305X and R492W), we detected 4 new mutations: 2 missense (A52T, (1); R387L, (2)) and one nonsense mutation (E314X). The fourth allele is apparently composed of 2 relatively common polymorphisms (K158-G308) found in the general population. Screening for known FMO3 mutations indicates that severe TMAuria alleles are rare in a Quebec control population and thus TMAuria is predicted to be rare in this population. We conclude that one predominant mutation (P153L) and an increasing number of private mutations of different ethnic origins will account for TMAuria in North Americans.