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Editor—We read with interest the excellent review article on fish odour syndrome (trimethylaminuria) by Rehman.1 However the author does not address the clinical relevance of trimethylaminuria (TMA-uria) well beyond the intermittent unpleasant body odour. TMA-uria is caused by the deficiency of the flavin-containing mono-oxygenase isoform 3 (FMO3).2 3 TheFMO3 gene has been described, and disease causing mutations have been reported.2 3 In addition to TMA this enzyme is required for detoxification of many substances including endogenous amines, tyramine, nicotine, and drugs (for example, tricyclic antidepressants, ranitidine).4 Zschockeet al have followed up patients with mild TMA-uria, and have examined the FMO3 gene in them.5 The molecular analyses revealed compound heterozygosity for mis-sense mutations on one chromosome and a variant allele with two amino acid polymorphisms (E158K, E308G) on the other chromosome. E158K (allele frequency 48% and 43% in German (n=230) and Turkish (n=68) control chromosomes, respectively) has been reported to reduce enzyme activity in an in vitro assay, whereas E308G, which is apparently always linked to E158K, has been reported without functional data. The variant allele (E158K, E308G) is very common in the white population, with reported frequencies of 20% and 6% in German and Turkish controls respectively.5 Studies have shown that the variant allele is associated with markedly reduced FMO3 enzyme activity in vivo. Individuals homozygous for the wildtype sequence or compound heterozygous for wildtype/E158K showed normal TMAO (trimethylamine N-oxide)/total ratios in the same range as under physiological conditions (>94%). Individuals with mild TMA-uria showed very low TMAO/total ratios of about 30%. Homozygosity for (E158K, E308G), as found in 4% of controls, resulted in decreased TMA oxidation capacity (<50%), also indicative of mild TMA-uria.5
Thus FMO3 deficiency is not merely a rare recessive disorder but rather a spectrum of phenotypes of transient or mild malodour depending on environmental exposures. In view of its other physiological functions mild FMO3 deficiency may lead to an abnormal metabolism of drugs, hypertension, or increased cardiovascular risk. Two adults with mild TMA-uria (one homozygous for (E158K, E308G), one compound heterozygous for a severe mutation and the variant allele (E158K, E308G) presented with hypertension.5 Population studies are required to analyse the spectrum of molecular variation at theFMO3 locus, and to evaluate the clinical relevance of mild, normally unrecognised FMO3 deficiency.
The author responds:
I agree with Kashyap and Kashyap that TMA is required for detoxification of many substances including the ones mentioned by them in addition to TMA, amphetamine, metamphetamine,1-1clozapine,1-2 chlorpromazine, and methimazole. The FMO gene family has been localised to chromosome 1q and various mutations have been described to cause the metabolic defect. Individuals with theseFMO3 gene mutations may have defective metabolic activity for many clinically used drugs. The human flavin-containing mono-oxygenase (FMO) gene family comprises at least five distinct members (FMO1to FMO5) that code for enzymes responsible for the oxidation of a wide variety of soft nucleophilic substrates, including drugs and environmental pollutants.
Apart from the two adults with mild TMA-uria and hypertension described by Zschocke et al,1-3 I am not aware of any other related literature either to this particular association or with other cardiovascular risk factors. It could prove to be a chance association but I agree with Kashyap and Kashyap that population studies are required to evaluate the clinical of mild, unrecognised FMO3 deficiency.
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