Research Collection Review Article Treatments of trimethylaminuria: where we are and where we might be heading Author(s): Schmidt, Aaron C.; Leroux, Jean-Christophe Publication Date: 2020-09-09 Permanent Link: https://doi.org/10.3929/ethz-b-000423705 Originally published in: Drug discovery today 25(9), http://doi.org/10.1016/j.drudis.2020.06.026 Rights / License: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library Drug Discovery Today Volume 00, Number 00 June 2020 REVIEWS Treatments of trimethylaminuria: POST SCREEN where we are and where we might be heading Reviews Aaron C. Schmidt and Jean-Christophe Leroux Q2 Q1 Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland Q3 Trimethylamine (TMA) is a volatile, foul-smelling, diet-derived amine, primarily generated in the colon and metabolized in the liver to its odorless N-oxide (TMAO). In primary trimethylaminuria (TMAU), an Q4 inherited deficiency in flavin-containing monooxygenase 3 leads to elevated systemic TMA levels. The excretion of elevated amounts of TMA in sweat, breath, urine and other bodily secretions gives individuals affected by TMAU a smell resembling that of rotten fish. Although the disorder might not seem an important health problem, its social and psychological burden can be devastating. To date, no treatment modifying the disorder exists and only a few pharmacological therapies provide modest and transient benefits. This review provides an overview of investigated TMAU treatments and outlines promising new research directions. Introduction Although the first case of TMAU was described in literature Primary trimethylaminuria (TMAU) is a rare metabolic disorder around 1970 [3], to date, only a few hundred cases have been where abnormally high levels of the aliphatic amine trimethyla- reported in the literature since [4,5]. A study on the incidence of mine (TMA) are excreted through sweat, breath, urine and other TMAU revealed a rate of 1% of heterozygous carriers within the bodily secretions, giving the patients a smell resembling that of white British population [6], whereas studies in other ethnic rotting fish. TMAU has thus been referred to historically as fish groups, such as the New Guinean population, revealed a carrier odor syndrome. TMA is a diet-derived amine that originates from rate of 11% [7]. Although passing one affected allele of the condi- TMA N-oxide (TMAO) (which is present in marine fish), choline tion to the next generation, heterozygotes usually do not have any and carnitine. Although at physiological pH most TMA is in its symptoms of TMAU, unless they are challenged with a TMA protonated form (pKa 9.80) [1], it is in equilibrium with a small precursor overload [8]. fraction of the free base. The free base is highly volatile and readily TMAU usually manifests itself in childhood or early adult life detected by the human olfactometric receptors in the ppb range but remains underdiagnosed. Online resources often attribute this [2]. In unaffected individuals, the free base is metabolized in the to the fact that people having mild symptoms rarely tend to seek liver to the odorless TMAO and excreted in the urine. Primary help. In addition, some physicians might be unaware of the TMAU is a direct consequence of an impairment in this oxidation disorder, not recognizing the symptoms and potentially being process. Secondary TMAU, however, is caused by an excess of unable to distinguish them from other conditions that result in dietary precursors or other factors exacerbating the production an unpleasant body odor (http://rarediseases.org). In fact, a study of TMA, therefore causing substrate overload for the enzyme, including 353 patients complaining of idiopathic malodor which is unable to oxidize the elevated burden of TMA. In both revealed that approximately one-third of them suffered from forms of the disorder, the metabolite accumulates in bodily secre- TMAU [9]. Although the disease is considered benign, its psycho- tions and gives them the characteristic odor. logical burden can be devastating. Studies have mentioned various psychosocial reactions of sufferers, such as strong feelings of shame, embarrassment, social isolation and even suicidal tenden- Corresponding author: Leroux, J.-C. ([email protected]) cies, among others [8,10,11]. To date, the disease has no cure and 1359-6446/ã 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.drudis.2020.06.026 www.drugdiscoverytoday.com 1 Please cite this article in press as: Schmidt, A.C., Leroux, J.C. Treatments of trimethylaminuria: where we are and where we might be heading, Drug Discov Today (2020), https://doi.org/ 10.1016/j.drudis.2020.06.026 DRUDIS 2726 1–8 REVIEWS Drug Discovery Today Volume 00, Number 00 June 2020 Diet Choline TMAO Oxidation Reviews L-carnitine TMA POST SCREEN Bacterial fermentation TMAO Choline TMA Excretion L-carnitine Drug Discovery Today FIGURE 1 Dietary precursors and metabolism of TMA. The main precursors include choline, TMAO and L-carnitine, which are metabolized to TMA within the intestine. The dietary breakdown of these precursors depends on a range of bacteria, among them: Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes [17]. TMA is subsequently oxidized to TMAO by FMO3 in the liver and excreted through the kidneys. only palliative measures exist, such as washing with acidic soap in broad spectrum of xenobiotics and dietary amines [20–22]. So far, combination with dietary restriction of TMA precursors [12,13]. >40 variants of the gene have been associated with TMAU [23,24], Other available pharmacological treatments aim to reduce the most of which are missense mutations. Some of these are inacti- generation and absorption of TMA or focus on improving oxida- vating mutations whereas other less severe ones reduce the thresh- tion to the odorless TMAO. old of TMA oxidation of FMO3 [25]. The resulting impairment in N-oxidation capacity accounts for most cases of TMAU reported in Trimethylaminuria the literature. TMA is produced in the gastrointestinal tract from dietary pre- cursors such as choline, which is present in eggs, liver and poultry, Secondary TMAU among others [14]. In the colon, choline is metabolized to TMA by Often referred to as acquired or sometimes transient TMAU, people anaerobic microorganisms carrying the enzyme choline TMA lyase becoming afflicted with secondary TMAU might show prolonged (Fig. 1). TMAO and carnitine, which are mainly present in marine symptoms. This form of the disorder can occur in a variety of fish [15] and in red meat [16], respectively, are additional TMA different scenarios. Treatment with choline in Huntington’s and precursors that are metabolized in the gut [17]. However, in the Alzheimer’s diseases has been associated with the development of case of TMAO, the exact mechanism of conversion to TMA in a strong fishy body odor [26,27], and is a classic example of humans remains unknown. TMA is readily absorbed by passive precursor overload where the enzyme is unable to completely diffusion and enters enterohepatic circulation. It is subsequently oxidize the TMA burden. Liver failure and portosystemic shunting oxidized in the liver to the non-odorous N-oxide form. The en- of the blood can also result in increased TMA levels, owing to zyme, responsible for this oxidation process, is of the flavin-con- interference with first-pass metabolism [28,29]. Other factors that taining monooxygenase (FMO) family [18,19]. The N-oxide is then have been reported to cause or exacerbate the condition (including readily excreted in the urine. As mentioned previously, TMAU can primary TMAU) encompass menstruation [30,31], asymptomatic be classified in two forms of the disorder, which are described viral hepatitis [32] and testosterone treatment [33], and have been below. reviewed elsewhere [4]. Primary TMAU Diagnosis Primary TMAU is caused by a mutation in the FMO3 gene, which is Diagnosis of TMAU is usually done by urinary analysis after oral inherited in a Mendelian autosomal recessive fashion [18]. The precursor challenge using choline [9] or TMA [8,34]. TMAO has affected enzyme has a widespread substrate specificity, including a also been indicated to drastically shift the total combined TMA 2 www.drugdiscoverytoday.com Please cite this article in press as: Schmidt, A.C., Leroux, J.C. Treatments of trimethylaminuria: where we are and where we might be heading, Drug Discov Today (2020), https://doi.org/ 10.1016/j.drudis.2020.06.026 DRUDIS 2726 1–8 Drug Discovery Today Volume 00, Number 00 June 2020 REVIEWS (TTMA) content (TMA + TMAO) toward TMA species after oral where degradation of carnitine to TMAO could be demonstrated administration in the past, in affected individuals as well as [57]. A recent report on the mechanism of carnitine transforma- heterozygous carriers of the disease [35,36]. However, it is not a tion to TMA identified a Rieske-type protein (a two-component recognized diagnostic tool for TMAU. Upon precursor challenge, Rieske-type oxygenase/reductase) as the main protagonist [58,59]. the urinary samples are assayed for TMA as well as TMAO, and their L-carnitine is present in high levels in red meat, poultry and some respective amounts are compared to the TTMA. Because neither dairy products, which is why TMAU sufferers are recommended to TMA nor TMAO have a native chromophore, quantitative urine avoid these in their diet [60]. Interestingly, allicin, an organosulfur 1 analysis is performed using H NMR spectroscopy [37,38], head- compound obtained from garlic, lowered TMAO levels when space MS [39,40] and electrospray ionization mass spectrometry supplemented in addition to L-carnitine in male mice [61], an [41].