Trimethylaminuria. Fish odor syndrome.
Incidence
The prevalence is estimated to be approximately 1 %, but is difficult to evaluate due to poor clinical awareness of the disorder.Two common FMO3 mutations, P153L and E305X appear to account for the majority of severe cases of fish odor syndrome.
Clinical Characteristics
Trimethylaminuria, also known as "fish odor syndrome", refers to a rare inborn error of metabolism caused by impaired oxidization of the malodorous trimethylamine (TMA) into odorless trimethylamine N-oxyde (TMAO), leading to the characteristic fishy smell. TMA oxidation occurs in the liver and is mediated by members of the flavine monooxygenase (FMO) family. Clinical description: Trimethylaminuria is clinically characterized by a strong body odor of rotting fish resulting from abnormal excretion of trimethylamine in the breath, urine, sweat, saliva and vaginal secretions. The smell manifests in childhood, or later. Trimethylamine production can be intermittent and is exacerbated by puberty, sweating, menstruation, liver diseases, and mainly by a high dietary intake of sea fish, or meals rich in choline. In general, patients have no other trimethylaminuria-related health problems. Their problems are mainly psychosocial as they encounter difficulties in forming personal relationships at school, at work. Prevalence: The prevalence is estimated to be approximately 1 %, but is difficult to evaluate due to poor clinical awareness of the disorder. The number of detected patients increases with the greater medical awareness, and with the development of techniques, such as proton NMR spectroscopy, which enable fast and easy quantification of TMA and TMAO. More cases are detected among women, probably as a result of their greater concern with the disease symptoms. Differential diagnosis (i) Dimethylglycinuria, a malodor syndrome recently described, has been uncovered by proton NMR spectroscopy, a method also used for the detection of TMA and TMAO. (ii) Other malodor syndromes.
Precipitants
A transient urinary excretion of TMA may occur at the onset and during menstruation, even in the absence of any primary genetic cause.
Provocation Tests
TMA precursor overload (especially in heterozygote form). Aliments containing TMA precursors such as choline and carnitine, or large doses of choline (10 to 20 g/day) (used in diseases such as Huntington's chorea), can exceed the enzymes capacity to oxidize TMA.
Diagnostic Procedures
Diagnosis is based on the measurement of urinary TMA and TMAO before and after an oral load of 600 mg of TMA. The classical biochemical method is based on the quantification of TMA excreted in urine by liquid chromatography. The amount of TMAO can be calculated indirectly as an increase in TMA, after its quantitative reduction by aqueous titanous sulfate. When available, proton NMR spectroscopy is the preferential method of diagnosis. This technique enables the simultaneous determination of urinary TMAO and TMA, the calculation of the ratio TMAO / (TMAO+TMA), and the measurement of dimethylglycine (DMG) for the differential diagnosis from dimethylglycinuria. Proton NMR spectroscopy is a fast method which does not require any sample preparation, and enables the detection of any molecules whose concentration is higher than 10 µmolar. The ratio TMAO / (TMAO+TMA) is 96± 2% in unaffected patients following a normal diet. A drastic decrease in this ratio is observed in patients homozygote for trimethylaminuria. But an oral load of 600 mg of TMA is required to distinguish between ratios of unaffected patients (95±2%) and heterozygote patients (76±3%). Diagnosis at the molecular level shows that two common mutations of the FMO3 gene, P153L and E305X appear to account for the majority of severe cases of fish odor syndrome.