Trimethylaminuria (TMAU)

• trimethylaminuria (TMAU) is inherited recessively as a defect in hepatic N-oxidation of dietary derived trimethylamine (TMA)
  • results in excess excretion of TMA which gives affected individuals a body odour resembling rotten fish
    • humans with a defect in the flavin-containing monooxygenase-3 gene (FMO3) develop fishy body odour because they accumulate trimethylamine, a breakdown product formed from choline by bacteria in the gut (1)
    • inherited as an autosomal recessive disorder
    • symptoms of the disorder arise because of the failure of flavin containing monooxygenase (FMO3) to catalyze the metabolic oxidation of trimethylamine (TMA), a volatile chemical which has an unpleasant smell characteristic of rotting fish
      • in individuals without this condition TMA is metabolized in the liver, where it undergoes FMO3-catalyzed N-oxidation to produce the non-odorous and non-volatile N-oxide
        
        
        
• many researchers believe that there are several types of TMAU caused by a "spectrum" of changes in the gene which controls the formation of the flavin-containing monooxygenase 3 (FMO3) enzyme. In humans, this is an important liver enzyme that controls the metabolism of substances such as TMA
  • most severe form of TMAU appears to be caused by mutations in the FMO3 gene; these mutations appear inherited in an autosomal recessive fashion
    • flavin-containing monooxygenases are NADPH-dependent enzymes that catalyze the oxidation of a wide range of foreign chemicals including therapeutic drugs, dietary components and pesticides
      • humans have five functional FMO genes, FMOs 1-5, all of which are located on the long arm of chromosome 1
        • most abundant form of FMO in adult human liver is flavin containing monooxygenase (FMO3), which is present in this organ in amounts as high as 0.5% of total microsomal protein
        • underlying problem is an impaired hepatic dysfunction of the flavin containing monooxygenase (FMO3) system to oxidize TMA to the stable, nonvolatile, odorless trimethylamine N-oxide (TMAO)
        • mutations in the FMO3 gene cause the inherited disorder TMAU
    • studies are leading many researchers to conclude that the less severe forms of TMAU are caused by several non-benign genetic polymorphisms in the FMO3 gene
      • genetic polymorphisms are changes in the gene structure that may be fairly common in the population; however, for reasons, which are not well understood, these changes lead to TMAU-symptoms in certain individuals
  • estimated that as much as one percent of the U.S. population may suffer from TMAU, but its true incidence is not known
    • condition affects people of both sexes and of all ages and races from around the world
    • currently there are more than 300 people with a malodour disorder on the Trimethylaminuria Support Group's mailing list, with many more preferring to remain anonymous because of the often-associated stigma, negative and harassing behaviors targeted at some, and the general lack of medical and other support (2)
• dietary management
  • a choline-restricted diet is useful in these patients because it diminishes body odour

Reference:

• 1) R. Phillips, E.A. Shephard, Trimethylaminuria in: GeneReviews at GeneTests: Medical Genetics Information Resource (database online) Copyright, University of Washington, Seattle 1997-2007.
• 2) Patrias K, Ahmed TT, Lambert D. Trimethylaminuriaand the flavin monooxygenases. Bethesda, MD: National Library of Medicine; 2002. http://www.nlm.nih.gov/pubs/cbm/trimethylaminuria_update.html (Accessed 21/7/2009).