Fish odour syndrome

Fig. 7.4.2 The origin and metabolism of TMA in man. This figure shows the molecular defect in the flavin-containing mono-oxygenase ( ) in trimethylaminuria or fish odour syndrome. The dashed line indicates the minor metabolic pathway in healthy volunteers. Enzyme steps marked with B are in the intestinal bacterial flora. DMA Dimethylamine, MMA monomethyl-...

Several methods are available in the literature for the measurement of aliphatic amines in biological samples [28]. Problems with specificity and separation and cumbersome derivatisation and/or extraction procedures have limited the use of these techniques on a larger scale in clinical practice. The lack of a simple analytical method may have led to an underestimation of the incidence of the fish odour syndrome. For diagnosing the syndrome, an analytical technique should be used that is able to simultaneously and quantitatively measure TMA and its N-oxide in the complex matrix of human urine. Two such methods are currently available for this purpose proton nuclear magnetic resonance (NMR) spectroscopy and head-space gas analysis with gas chromatography or direct mass spectrometry (see below). 

Fish odour syndrome is an autosomal recessive disease. Mutations have been found in the FM03 gene. Molecular genetic analysis can therefore be used as a diagnostic test. Many pathogenic mutations have been described. The defect should be documented in patients with trimethylaminuria at the metabolite level and the diagnosis confirmed at the molecular genetic level. This chapter describes the available tests at the metabolite level. 

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Humbert JR, Hammond KB, Hathaway WE, Marcoux JG, O Brien D (1970) Trimethylaminuria the fish odour syndrome. Lancet 2 770-771... 

Maschke S, Wahl A, Azaroual N, Boulet O, Crunelle V, Imbenotte M, Foulard M, Vermeersch G, Lhermitte M (1997) 1H-NMR analysis of trimethylamine in urine for the diagnosis of fish odour syndrome. Clin Chim Acta 263 139-146... 

Pike MG, King GS, Pettit BR, Leonard JV, Atherton DJ (1988) Lactulose in trimethylaminuria, the fish-odour syndrome. Helv Paediatr Acta 43 345-348... 

Treacy E, Johnson D, Pitt JJ, Danks DM (1995) Trimethylaminuria, fish odour syndrome a new method of detection and response to treatment with metronidazole. J Inherit Metab Dis 18 306-312... 

C.T. Dolphin, A. Janmohamed, R.L. Smith, E.A. Shephard, I.R. Phillips, Missense Mutation in Flavin-containing Mono-oxygenase 3 Gene, FM03, Underlies Fish-odour Syndrome , Nat. Genet., 17, 491-494 (1997). 

The Indian epic poem Mahabhara-ta of 400 AD tells the tale of the beautiful Satyavati who suffered from fish odour syndrome and was a social outcast, condemned to work as a ferry woman. However, one day a holy man fell in love with her and by... 

A nitrogen-containing compound, trimethylamine, is produced in a complaint called fish odour syndrome , where the sweat, breath and urine all smell of rotting fish. It is caused by a metabolic liver malfunction and releases trimethylamine in the bowel and gut. Drugs and dietary control can cure the condition. 

Dolphin CT, Janmohamed A, Smith RE, et al. Missense mutation in fiavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet 1997 17(4) 491-4. 

NMR spectroscopy can be used to find inborn errors of metabolism characterised by the presence of metabolites that cannot be detected with conventional screening methods. Trimethylaminuria or fish odour syndrome may serve as an example [9]. It is a hereditary disease based on an enzyme deficiency in the liver. Trimethylamine (=TMA) derives from bacteria that convert it from dietary choline. Normally there is an enzyme in the liver that oxidizes TMA efficiently. TMA and trimethylamine N-oxide (=TMAO) are both secreted in the urine. TMA has the smell of rotten fish causing a social problem for the patient. Until recently no technique could measure TMA and TMAO simultaneously to prove this deficiency at the metabolic level. This is very well possible with NMR spectroscopy. 

Though no metabolic harm has been associated with TMA accumulation, the compound is highly volatile and affected individuals are troubled by body odour similar to rotting fish - the fish odour syndrome (MIM 602079). The condition is often the cause of social stigmatization and quite severe psychologic distress to affected individuals. 

Dimethylglycinuria was recently described in one adult individual with the fish odour syndrome , muscle fatigability and increased serum creatine kinase [12]. 

Basarab, T., Ashton, G. H., Menage, H. R et al. (1999) Sequence variations in the flavin-containing mono-oxygenase 3 gene (FM03) in fish odour syndrome. Br J Dermatol 140, 164-167. 

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