Friday, July 22, 2011

The fish odor syndrome

The fish odor syndrome

Also known as:
The fish malodor syndrome
Stale fish syndrome
Trimethylaminuria (TMAU)

The fish odor syndrome is a metabolic disorder characterized by the presence of abnormal amounts of the dietary-derived tertiary amine, trimethylamine, in the urine, sweat, expired air, and other bodily secretions. It affects men, women and children, from newborns to seniors, all races and ethnicities, in most countries around the world. Trimethylamine itself has the powerful aroma of rotting fish, and this confers upon an individual a very unpleasant body odor resembling that of rotting fish.
These “greater-than-normal” amounts of trimethylamine are present due to a failure in removing it via the usual oxidation route to the non-odorous metabolite, trimethylamineN-oxide, owing to a mismatch in the enzymes capacity to undertake this reaction and the substrate load it has to process.
Earlier thinking had associated fish malodor syndrome with Turner's and Noonan's syndromes but subsequent experience showed that this was incorrect.

Incidence of Fish Odor Syndrome:
In terms of frequency of occurrence, it appears that it should no longer be regarded as a “rare” disorder but more appropriately as an “uncommon” one. As of the present, it would seem that well over 200 cases of the condition have been described on a world-wide basis, and this figure is almost certainly underestimated.
The information available to date shows that the metabolic syndrome has been found in several countries, and the bias at the moment seems to be in favor of those areas that have populations derived from British/Scottish/Irish descent, but this leaning is probably more apparent than real. The condition has been observed in both males and females, although overall there appears to have been a preponderance of females reported with this condition.

Types of Fish Odor Syndrome:
 It appears that there are two major subtypes of fish malodor syndrome: first, those forms that are related to a dysfunction of the normal enzyme activity due to genetic, hormonal, or inhibitory-chemical influences; second, those forms arising from substrate overload of the enzyme activity (normal or depressed) such as an excess of dietary precursors of trimethylamine or variations in the gut microflora resulting in enhanced liberation of trimethylamine.

Proposed classification of various types of fish malodor syndrome
1. Primary Genetic Form.
In recent years, it believed that the flavin monooxygenase (FMO1) family is responsible for this reaction. The unraveling of the isoenzymic nature of the human flavin monooxygenase system has been achieved over the past decade as well as details of their individual molecular characterization. Briefly, this has shown that there are five distinct members of the human flavin monooxygenase family [FMO1, FMO2, FMO3, FMO4, FMO5, FMO6], which can vary in terms of their functional activities and tissue expression. The form that is most abundant in human liver and appears to be most closely involved in the N-oxidation of trimethylamine is flavin monooxygenase 3 (FMO3), and for this reason the molecular identification of candidate mutant forms has centered on this isozyme and with considerable success.
Point mutations of human FMO3 associated with fish malodor syndrome
2. Acquired Form.
There are more than three cases known of acquired types of fish odor syndrome. There was no previous history in childhood and there was no familial background to the disorder. What appeared common to the three cases was evidence of hepatitis, possibly viral, in adult life and this may have been responsible for precipitation of the condition possibly by insertion of viral DNA into the genome thereby affecting normal expression of the human FMO3 gene.

3. Transient Childhood Forms.
A preterm infant (29-weeks old) who developed a fish odor while being fed a choline-containing food supplement has been described. When the choline supplement was withdrawn the odor disappeared, and it failed to reappear at 8 months of age when the supplement was reinstituted. When the supplement was given to three other preterm infants of similar weights and ages, one of these developed a fish odor. The authors attributed the fish odor associated with the choline-containing supplement to the immaturity of the N-oxidase enzyme. Since then, other cases of pediatric fish malodor syndrome have been described. During early childhood a transient or mild form of trimethylaminuria may occur. Molecular analyses in some cases can reveal compound heterozygosity for several mutations. Recent studies suggest that both severe and variant mild trimethylaminuria is much more common than hitherto recognized.

4. Transient Form Associated with Menstruation.
Several of our female patients told us anecdotally of how their fishy odor seemed to intensify with the onset of menstruation. A subsequent study of a single female fish malodor patient showed that her trimethylaminuric condition deepened just before the onset of menstruation and that this biochemical feature related closely to her own subjective description. A systematic study has confirmed that in normal healthy women of menstruating age there occurs a short episode of trimethylaminuria just at the onset of and during menstruation that then disappears.

5. Precursor Overload.
A few cases of a transient form of the fish malodor syndrome have been attributed to precursor overload thereby saturating the existing levels of flavin monooxygenase. Trimethylamine is mostly derived from dietary precursors such as choline, carnitine, and trimethylamineN-oxide through enterobacterial metabolism. Exposure to unusually high levels of such precursors may hasten a fish malodor syndrome especially if the individual is a haplotype for certain mutations. Large oral therapeutic doses of choline (8–20 g/day) have been used to treat Huntington's chorea, and although there was some improvement in the clinical picture, patients complained of a striking fish-like odor, which was attributable to the generation of excessive amounts of trimethylamine that exceeded their enzyme's capacity to oxidize it to the non-offensive N-oxide. It is noteworthy that the precursors of trimethylamine, choline and lecithin, sometimes recommended in quite high doses in health foods, food supplements, and alternative diets could lead to the problems outlined above.

The diagnosis was made on the basis of clinical symptoms and biochemical assays of urine samples for either trimethylamine alone or in combination with its N-oxide metabolite. An oral challenge test involving the administration of 600 mg of trimethylamine has also been found useful for investigating family pedigrees and identifying carriers of the metabolic disorder. However, there could remain difficulties in identifying some of the other forms particularly those arising from various haplotype combinations or nongenetic causation. Basically, one has to recognize that trimethylaminuria/fish malodor syndrome can arise from the interaction of two entities, namely a dysfunctionalN-oxidation capacity (owing to genetic or nongenetic reasons)
And the burden of trimethylamine available to be oxidized.

There has been no systematic evaluation of the various treatments for the fish malodor syndrome. Many of the reports are anecdotal in nature or involve just small groups of patients. Attempts to reduce the intake of precursors of trimethylamine such as carnitine and choline, through dietary management, appear to have been successful in some patients but not in all. It appears likely that dietary management might be most effective in mild to moderate forms of fish odor syndrome arising from particular mutations or haplotypes. Occasionally, a short course of neomycin and metronidazole to reduce the activity of the gut microflora and suppress the generation of trimethylamine may be effective in some cases.