TMAU Hints for a new therapeutic option with Desmopressin - translation into English

This is a translation of Dr. Detlef Werner's article, “Die Trimethylaminurie (Fischgeruchsyndrom) – Hinweise auf Ein neue Therapiemöglichkeit mit Desmopressin", which he authorized that we can use for the blog to promote research. On May 27, 2008, Dr. Werner had also provided his English Summary and Advice for Doctors/Patients related to this paper, which we posted in this blog. Thank you Dr. Werner for your contribution to this cause.

Trimethylaminuria (fish-odour syndrome):
Hints for a New Therapeutic Option with Desmopressin

Introduction

Trimethylaminuria (fish-odour syndrome) is still a relatively unknown and therefore relatively seldom diagnosed illness. However, it is estimated that a significant number of unknown cases exist. Individuals affected with this disease are noticeable by a strong fish-like body odour, especially after the consumption of fish. In particular, the breath and sweat carry this unpleasant odour, but also other bodily fluids such as urine, saliva and vaginal secretion. The negative consequences of this disease are predominantly of a psychological/social nature, and are particularly difficult for women.

The illness is caused by an enzyme defect in the microsomal hepatic flavin-containing monooxygenase (FMO). Thereby the physiological metabolism of trimethylamine (consumed as food or originating in the digestive tract) to trimethylamine oxide is hindered. Subsequently the fishy-smelling chemical trimethylamine is released via the breath and bodily secretions. The laboratory diagnosis involves the measurement of the TMAO/ (TMAO + TMA) quotient in the urine.

Trimethylamine is a biogenic amine and is formed from the microbial breakdown of certain nitrogen compounds. Its precursor trimethylamine oxide is found in particularly high concentration in seafish . Here its specific content or the sum of all volatile nitrogen compounds are analysed to establish the freshness of the fish.

The symptoms of fish-odour syndrome are consequently particularly noticeable following the consumption of fish. The first therapeutic approach is to eliminate fish and other 'odour-creating' foods such as eggs and vegetables from the diet. Trimethlyamine however is also created in the digestive system, in particular through the effects of the microbial flora in the large intestine. Therefore a further therapeutic approach is short term medication with neomycin or metronidazole.

Case Study

A patient, (male, 5 years old) was treated for significant nocturnal enuresis (bedwetting) with Desmopressin-acetate (Minirin) in the form of a nasal spray at the recommended dosage. Subsequently, his mother reported that the therapy was ineffective in treating his night-time bed-wetting. Interestingly, she also noted that her child's constant fish odour became unnoticeable during the course of the treatment. Up to that point she had been unaware that her son was potentially affected with fish-odour syndrome.

Discussion

Desmopressin is a synthetic oligopeptide, derived from a natural hormone called ADH (anti-diuretic hormone). ADH has a physiological effect on the distal renal tubuli where it causes a higher level of water reabsorption. In unphysiologically high dosage it also has a vasoconstrictive effect, therefore it is also called vasopressin.

Desmopressin (DDAVP) has, because of its structure modification, approximately 12 times higher antidiuretic effect as compared with ADH. Its other action is a 0.004 times pressure effect. This suggests that the key to the observed effects on trimethylaminuria lies not in its pressure effect but upon the mechanism of the antidiuretic effect.

The investigated molecular mechanism of action of ADH is based upon the translocation of aquaporin-2 water channel in the tubulus membrane. Interestingly it is known that quarternary ammonium-compounds (eg the ph-dependently formed trimethylamine cation) are potent blockers of these water channels.

It may, therefore, be surmised that the possible mechanism of action lies with the ph-sensitive binding of the amine to the aquaporine, which is mobilised by the Desmopressin. This would also explain the simultaneous inactivation of the desired effect of preventing night time bedwetting.

Conclusion

Fish-odour syndrome can as yet not be treated pharmacologically. At present a cosmetic masking of body odours with deodorants, the reduction of sweat-formation through anti-perspirants or the avoidance of fish in the diet are the therapeutic interventions available.

The coincidental observations as described above, however, could indicate a potential pharmacological therapy for the future. Meanwhile a diagnosis of fish-odour syndrome can easily be obtained. It would be interesting to determine whether the observations noted in this individual case could be replicated elsewhere.

The off-label use of Desmopressin for this indication, however, is potentially prohibited after a risk-benefit analysis due to the considerable anti-diuretic effect. The clues to a fundamental mechanism of action can, however, be used as a starting point for further research for suitable substances.

Full paper in German available at : Yahoo Trimethylaminuria forum files

Dr. Werner's English Summary and Advice for Doctors/Patients: Email from Dr Werner : Author of recent anecdotal TMAU-desmopressin paper

links on desmopressin :
http://emc.medicines.org.uk/emc/industry/default.asp?page=displaydoc.asp&documentid=661
http://www.rxlist.com/cgi/generic/desmoprt.htm

Recent FDA warning (Dec 2007) : http://www.fda.gov/CDER/DRUG/InfoSheets/HCP/desmopressinHCP.htm
Web MD article on warning : http://www.webmd.com/news/20071204/2-deaths-spur-bedwetting-drug-warning