Trimethylaminuria

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-...

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. 

Fig. 7.4.3a,b Nuclear magnetic resonance (NMR 500 MHz) urine spectra from a patient with severe trimethylaminuria, a Before eating sea fish (TMA = 44 pmol/mmol creatinine, TMA N-oxide not detectable), b After a 300-g sea fish meal [Nijmegen protocol urine collection during the 6-h postprandial period TMA = 322 pmol/mmol creatinine, TMA N-oxide (TMA + TMA N-oxide) = 84%]. The NMR spectrum shows the presence of increased TMA in the pre-load sample as well as the absence of TMA N-oxide. After eating fish the TMA concentration is very high and the ratio is clearly abnormal... 

For internal quality control, a urine sample from a known trimethylaminuria patient may be used. At the moment there is no official external quality control scheme available for trimethylaminuria. 

Normal persons excrete very little TMA in the urine. However, slight TMA excretion may be observed after meals with a high content of TMA precursors like choline or lecithin, or after eating marine fish due to its high TMA N-oxide content. Healthy women may have a short episode of trimethylaminuria at the onset and during menstruation. TMA has also found to be increased in the urine of some patients using carnitine supplementation. Advanced liver and renal disease may result in TMA excretion and this constitutes the so-called secondary trimethylaminurias. 

Healthy volunteers excrete 93.2-97.9% of the ingested TMA as TMA N-oxide. Parents of patients with trimethylaminuria excreted only 74.8-78.9% of the 600 mg TMA dose as TMA N-oxide [2]. Urine generally is collected during 6-8 h after the TMA ingestion. 

FMO enzymatic activity is also involved in the formation of theobromine from caffeine. Park et al. have used this to identify heterozygotes for trimethylaminuria [23]. They determined the theobrominexaffeine ratio in the urine after administration of a cup of coffee and were able to identify heterozygotes with this test. 

Fig. 7.4.4 Oral challenge test with a sea fish meal (300 g fresh sea fish) in two healthy volunteers (---) and one patient with the severe form of trimethylaminuria. The ability of the N-oxida-tion system to oxidise TMA into TMA N-oxide is expressed as the ratio TMA N-oxide (TMA N-oxide + TMA). In this patient both the baseline value and all other data points are abnormal...

A1-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL (1989) Trimethylaminuria the detection of carriers using a trimethylamine load test. J Inherit Metab Dis 12 80-85 Al-Waiz M, Mitchell SC, Idle JR, Smith RL (1987) The relative importance of N-oxidation and N-demethylation in the metabolism of trimethylamine in man. Toxicology 43 117-121 Anonymous (1980) Workplace environmental exposure level guide. Trimethylamine. Am Ind Hyg Assoc J 41 A35-A37... 

Calvert GD (1973) Trimethylaminuria and inherited Noonan s syndrome. Lancet 1 320-321... 

II. Danks DM, Hammond J, Faull K, Burke D, Halpern (1976) Trimethylaminuria diet does not always control the fishy odor. New Engl J Med 295 962... 

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

Mitchell SC, Smith RL (2001) Trimethylaminuria the fish malodor syndrome. Drug Metab Dispos 29 4,2 517-521... 

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

Podadera P, Ar as JAG, Lanfer-Marquez UM (2005) Diagnosis of suspected trimethylaminuria by NMR spectroscopy. Clin Chim Acta 351 149-154... 

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... 

---