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Abstract Background Many people suffer from body and breath malodour syndromes. One of these is trimethylaminuria, a condition characterized by excretion in breath and bodily fluids of trimethylamine, a volatile and odorous chemical that has the smell of rotting fish. Trimethylaminuria can be primary, due to mutations in the gene encoding flavin-containing monooxygenase 3, or secondary, due to various causes. To gain a better understanding of problems faced by United Kingdom residents affected by body and breath malodour conditions, we conducted a survey. Methods Two anonymous online surveys, one for adults and one for parents/guardians of affected children, were conducted using the Opinio platform. Participants were invited via a trimethylaminuria advisory website. Questions were a mix of dropdown, checkbox and open-ended responses. Forty-four adults and three parents/guardians participated. The dropdown and checkbox responses were analysed using the Opinio platform. Results All participants reported symptoms of body/breath odour. However, not all answered every question. Twenty-three respondents experienced difficulties in being offered a diagnostic test for trimethylaminuria. Problems encountered included lack of awareness of the disorder by medical professionals and reluctance to recognise symptoms. Of those tested, 52% were diagnosed with trimethylaminuria. The main problems associated with living with body/breath malodours were bullying, harassment and ostracism in either the workplace (90%) or in social settings (88%). All respondents thought their condition had disadvantaged them in their daily lives. Open-ended responses included loss of confidence, stress, exclusion, isolation, loneliness, depression and suicidal thoughts. Respondents thought their lives could be improved by greater awareness and understanding of malodour conditions by medical professionals, employers and the general public, and appreciation that the malodour was due to a medical condition and not their fault. Conclusions Breath and body malodour conditions can cause immense hardship and distress, both mentally and socially, having devastating effects on quality of life. It would be advantageous to establish a standardised pathway from primary care to a specialist unit with access to a robust and reliable test and diagnostic criteria. There is a need to recognise malodour disorders as a disability, giving affected individuals the same rights as those with currently recognised disabilities.

Background: Many people suffer from body and breath malodour syndromes. One of these is trimethylaminuria, a condition characterized by excretion in breath and bodily fluids of trimethylamine, a volatile and odorous chemical that has the smell of rotting fish. Trimethylaminuria can be primary, due to mutations in the gene encoding flavin-containing monooxygenase 3, or secondary, due to various causes. To gain a better understanding of problems faced by United Kingdom residents affected by body and breath malodour conditions, we conducted a survey. Methods: Two anonymous online surveys, one for adults and one for parents/guardians of affected children, were conducted using the Opinio platform. Participants were invited via a trimethylaminuria advisory website. Questions were a mix of dropdown, checkbox and open-ended responses. Forty-four adults and three parents/guardians participated. The dropdown and checkbox responses were analysed using the Opinio platform. Results: All participants reported symptoms of body/breath odour. However, not all answered every question. Twenty-three respondents experienced difficulties in being offered a diagnostic test for trimethylaminuria. Problems encountered included lack of awareness of the disorder by medical professionals and reluctance to recognise symptoms. Of those tested, 52% were diagnosed with trimethylaminuria. The main problems associated with living with body/breath malodours were bullying, harassment and ostracism in either the workplace (90%) or in social settings (88%). All respondents thought their condition had disadvantaged them in their daily lives. Open-ended responses included loss of confidence, stress, exclusion, isolation, loneliness, depression and suicidal thoughts. Respondents thought their lives could be improved by greater awareness and understanding of malodour conditions by medical professionals, employers and the general public, and appreciation that the malodour was due to a medical condition and not their fault. Conclusions: Breath and body malodour conditions can cause immense hardship and distress, both mentally and socially, having devastating effects on quality of life. It would be advantageous to establish a standardised pathway from primary care to a specialist unit with access to a robust and reliable test and diagnostic criteria. There is a need to recognise malodour disorders as a disability, giving affected individuals the same rights as those with currently recognised disabilities. [ABSTRACT FROM AUTHOR]

BACKGROUND: Oral malodor, also known as halitosis or bad breath can be defined as an offensive odor that emerges from the oral cavity and can be easily detected by others. The etiology of halitosis is multifactorial and can include several intra- and extraoral factors such as gingivitis, periodontitis, chronic sinusitis, nasal inflammation, diabetes mellitus, lung carcinoma, liver insufficiency, cirrhosis, uremia, trimethylaminuria, and postnasal drip. Chlorine dioxide associated with chlorite anion results in the oxidative consumption of amino acids such as cysteine and methionine, which are precursors of volatile sulfur compounds (VSC). Thus, it can reduce the concentrations of VSCs which help in the reduction of oral malodor. Due to the lesser availability of literature to prove the effectiveness of this chlorine dioxide formula, this study is conducted to evaluate the inhibiting effect of commercially available chlorine dioxide-containing mouthwash - FRESHCLOR to combat oral malodor in patients. MATERIALS AND METHODS: The study was conducted among the patients reporting at the outpatient department of periodontics who visited with the chief complaint of bad breath and bleeding gums at KAHER'S VK Institute of Dental Sciences, Belagavi. Patients were selected according to inclusion criteria and divided into test and control groups. Post scaling Freshclor mouthwash was distributed to all test group participants. The organoleptic ratings for halitosis, gingival index (given by Loe H and Silness J, 1963), and plaque index (given by Loe H and Silness J, 1964) were recorded at baseline and 2 weeks for the group. RESULTS: There was a statistically significant reduction in halitosis with a reduction of gingival and plaque indices at 2 weeks from baseline in the test group. CONCLUSION: With the results, it can be concluded that chlorine dioxide-containing mouthwash - freshclor is effective in reducing halitosis. [ABSTRACT FROM AUTHOR]

Purpose: To design a prospective study on endovascular closure of congenital portosystemic shunts. The primary endpoint was to assess the safety of endovascular closure. The secondary endpoint was to evaluate the clinical, analytical and imaging outcomes of treatment. Methods: Fifteen patients (age range: 2 days to 21 years; 10 male) were referred to our center due to congenital portosystemic shunts. The following data were collected prior to treatment: age, sex, medical history, clinical and analytical data, urine trimethylaminuria, abdominal-US, and body-CT. The following data were collected at the time of intervention: anatomical and hemodynamic characteristics of the shunts, device used, and closure success. The following data were collected at various post-intervention time points: during hospital stay (to confirm shunt closure and detect complications) and at one year after (for clinical, analytical, and imaging purposes). Results: The treatment was successful in 12 participants, migration of the device was observed in two, while acute splanchnic thrombosis was observed in one. Off-label devices were used in attempting to close the side-to-side shunts, and success was achieved using Amplatzer™ Ductus-Occluder and Amplatzer™ Muscular-Vascular-Septal-Defect-Occluder. The main changes were: increased prothrombin activity ( p=0.043); decreased AST, ALT, GGT, and bilirubin ( p=0.007, p=0.056, p=0.036, p=0.013); thrombocytopenia resolution ( p=0.131); expansion of portal veins ( p=0.005); normalization of Doppler portal flow (100%); regression of liver nodules ( p=0.001); ammonia normalization ( p=0.003); and disappearance of trimethylaminuria ( p=0.285). Conclusion: Endovascular closure is effective. Our results support the indication of endovascular closure for side-to-side shunts and for cases of congenital absence of portal vein. Keywords: Portosystemic shunt; Portal vein; Ammonia; Trimethylaminuria [ABSTRACT FROM AUTHOR]

There is discrepancy in the phenotypic manifestations of trimethylaminuria (TMAU) between patients suggesting a certain diversity of etiological-pathogenic factors. Primary TMAU is linked to mutations in the FMO3 gene but a proportion of patients do not carry mutations in it or carry single nucleotide polymorphisms (SNPs) that do not have an impact on the gene’s product, the enzyme FMO3. It remains to be established what other factors are pathogenic in TMAU underpinning the various phenotypes. We hypothesized that defective chaperones could contribute to the pathogenesis by, for example, failing to assist FMO3 in its folding and refolding cycles. In the initial screening reported here we investigated two chaperone genes, HSPA8 and HSPA1A in twelve TMAU patients and found that variants in the former were highly represented in comparison with controls. Further studies, including more patients are underway to firmly establish the prevalence of the variants and to begin elucidating molecular mechanisms.

Trimethylaminuria is a rare, autosomal recessive, metabolic disorder that results in accumulation of trimethylamine (TMA), which smells like rotten fish. The chemical is excreted in sweat and urine owing to a deficiency in the enzyme flavin monooxygenase 3 (FMO3). We report a case of trimethylaminuria in a 12-year-old girl. The patient failed treatment with diet and hygiene modification, but achieved symptomatic improvement after a four-month course of metronidazole.

Abstract Background Trimethylaminuria (TMAU) is a metabolic disorder characterized by the excessive excretion of the malodorous compound trimethylamine (TMA). The diagnosis of TMAU is challenging because this disorder is situated at the boundary between biochemistry and psychiatry. Here, we used nuclear magnetic resonance spectroscopy to assess TMAU in 13 patients. We also sequenced the FMO3 gene in 11 of these patients. Treatment with vitamin B2 was prescribed. Results Two patients (aged 3 and 9 years at the initial consultation) had a particularly unpleasant body odor, as assessed by their parents and the attending physicians. The presence of high urine TMA levels confirmed the presence of a metabolic disorder. The two (unrelated) children carried compound heterozygous variants in the FMO3 gene. In both cases, vitamin B2 administration decreased TMA excretion and reduced body odor. The 11 adults complained of an unpleasant body odor, but the physicians did not confirm this. In all adult patients, the urine TMA level was within the normal range reported for control (non-affected) subjects, although two of the patients displayed an abnormally high proportion of oxidized TMA. Seven of the 9 tested adult patients had a hypomorphic variant of the FMO3 gene; the variant was found in the homozygous state, in the heterozygous state or combined with another hypomorphic variant. All 11 adults presented a particular psychological or psychiatric phenotype, with a subjective perception of unpleasant odor. Conclusions The results present the clinical and biochemical data of patients complaining of unpleasant body odor. Contrary to adult patients, the two children exhibited all criteria of recessively inherited trimethylaminuria, suspected by parents in infancy. B2 vitamin treatment dramatically improved the unpleasant body odor and the ratio of TMA/Cr vs TMAO/Cr in the urine in the children. Other patients presented a particular psychological or psychiatric phenotype.

What is known and objective: Trimethylaminuria is a metabolic disorder characterized by excessive excretion of trimethylamine in body fluids following FMO3 gene mutations. Secondary forms of the disease may be due to consumption of trimethylamine precursor‐rich foods or metabolism of some xenobiotics. Case summary: A HIV patient developed secondary trimethylaminuria following antiretroviral treatment. Riboflavin supplementation ameliorated his phenotype. 1H‐NMR confirmed increased urine level of TMA. Several genes involved in choline catabolism harboured missense mutations. Riboflavin supplement improved enzymatic activity of mutated enzymes promoting TMA clearance. What is new and conclusion: Antiretrovirals may increase the concentration of TMA precursors. The present study reports antiretroviral treatment as risk factor for such secondary trimethylaminuria. Riboflavin is an effective treatment. [ABSTRACT FROM AUTHOR]

Le « Fish odor syndrome » (FOS) est un désordre métabolique rare qui se manifeste par une odeur corporelle de « poisson pourri » qui est due à l'excrétion de triméthylamine (TMA) dans les fluides biologiques. Cette pathologie peut avoir un impact négatif sur la vie sociale des patients atteints. Nous rapportons le cas de deux patientes qui consultaient pour des symptômes de mauvaise odeur corporelle. Le diagnostic de FOS a été confirmé par la mise en évidence d'une triméthylaminurie par spectroscopie-RMN, puis par le séquençage du gène FMO3. Un régime pauvre en choline, associé à une décontamination digestive, a permis d'obtenir une régression des mauvaises odeurs corporelles et une amélioration de la vie sociale de ces deux patientes. Le « Fish odor syndrome » est une pathologie rare et méconnue susceptible d'altérer la qualité de vie des personnes atteintes. Après diagnostic biologique, le traitement s'avère souvent efficace. Fish odor syndrome (FOS) is a rare metabolic disorder that manifests as "rotten fish" body odor and is caused by the excretion of trimethylamine (TMA) in body fluids. This disease can have a negative impact on the social life of affected patients. We report the case of two female patients complaining about unpleasant body odor. The diagnosis of FOS was confirmed by the demonstration of trimethylaminuria by NMR spectroscopy and by molecular analysis of the FMO3 gene. A restrictive choline diet combined with digestive decontamination reduced odor symptoms and improved the social life of these 2 patients. Fish odor syndrome is a rare and unrecognized disease that can affect the quality of life of affected persons. Following laboratory diagnosis, treatment is often effective. [ABSTRACT FROM AUTHOR]

Abstract Trimethylamine (TMA) is a metabolite overtly present in patients suffering from trimethylaminuria (TMAU), a rare genetic disorder characterized by a strong “fishy” body odor. To date, no approved pharmacological treatment to sequester excess TMA on the skin of patients exists. Here, transmembrane pH gradient poly(isoprene)‐block‐poly(ethylene glycol) (PI‐b‐PEG) polymersomes are investigated for the topical removal of TMA. PI‐b‐PEG amphiphiles of varying chain length are synthesized and evaluated for their ability to form vesicular structures in aqueous media. The optimization of the PI/PEG ratio of transmembrane pH gradient polymersomes allows for the rapid and efficient capture of TMA both in solution and after incorporation into a topical hydrogel matrix at the pH of the skin. A subsequent double blind olfactory study reveals a significant decrease in perceived odor intensity after application of the polymersome‐based formulation on artificial skin substrates that has been incubated in TMA‐containing medium. This simple and novel approach has the potential to ease the burden of people suffering from TMAU.

Trimethylamine (TMA) is a metabolite overtly present in patients suffering from trimethylaminuria (TMAU), a rare genetic disorder characterized by a strong "fishy" body odor. To date, no approved pharmacological treatment to sequester excess TMA on the skin of patients exists. Here, transmembrane pH gradient poly(isoprene)‐block‐poly(ethylene glycol) (PI‐b‐PEG) polymersomes are investigated for the topical removal of TMA. PI‐b‐PEG amphiphiles of varying chain length are synthesized and evaluated for their ability to form vesicular structures in aqueous media. The optimization of the PI/PEG ratio of transmembrane pH gradient polymersomes allows for the rapid and efficient capture of TMA both in solution and after incorporation into a topical hydrogel matrix at the pH of the skin. A subsequent double blind olfactory study reveals a significant decrease in perceived odor intensity after application of the polymersome‐based formulation on artificial skin substrates that has been incubated in TMA‐containing medium. This simple and novel approach has the potential to ease the burden of people suffering from TMAU. [ABSTRACT FROM AUTHOR]

The review focuses on genetic variants of human flavin-containing monooxygenase 3 (FMO3) and their impact on enzyme activity, drug metabolism and disease. The majority of FMO-mediated metabolism in adult human liver is catalyzed by FMO3. Some drugs are metabolized in human liver predominantly by FMO3, but most drug substrates of FMO3 are metabolized also by other enzymes, particularly cytochromes P-450, and the FMO3-catalyzed reaction is not the major route of metabolism. Rare variants that severely affect production or activity of FMO3 cause the disorder trimethylaminuria and impair metabolism of drug substrates of FMO3. More common variants, particularly p.[(Glu158Lys);(Glu308Gly)], can moderately affect activity of FMO3 in vitro and reduce metabolism of drug substrates in vivo, in some cases increasing drug efficacy or toxicity. Common variants of FMO3 have been associated with a number of disorders, but additional studies are needed to confirm or refute such associations. Elevated plasma concentrations of trimethylamine N-oxide, a product of an FMO3-catalyzed reaction, have been implicated in certain diseases, particularly cardiovascular disease. However, the evidence is often contradictory and additional work is required to establish whether trimethylamine N-oxide is a cause, effect or biomarker of the disease. Genetic variants of other FMOs are also briefly discussed. [ABSTRACT FROM AUTHOR]

Trimethylaminuria (TMAuria), known as “fish odor syndrome,” is a congenital metabolic disorder characterized by an odor resembling that of rotting fish. This odor is caused by the secretion of trimethylamine (TMA) in the breath, sweat, and body secretions and the excretion of TMA along with urine. TMAuria is an autosomal recessive disorder caused by mutations in flavin-containing monooxygenase 3 (FMO3). Most TMAuria cases are caused by missense mutations, but nonsense mutations have also been reported in these cases. Here, we describe the identification of a novel FMO3 gene mutation in a patient with TMAuria and her family. A 3-year-old girl presented with a strong corporal odor after ingesting fish. Genomic DNA sequence analysis revealed that she had compound heterozygous FMO3 mutations; One mutation was the missense mutation p.Val158Ile in exon 3, and the other was a novel nonsense mutation, p.Ser364X, in exon 7 of the FMO3 gene. Familial genetic analyses showed that the p.Val158Ile mutation was derived from the same allele in the father, and the p.Ser364X mutation was derived from the mother. This is the first description of the p.Ser364X mutation, and the first report of a Korean patient with TMAuria caused by novel compound heterozygous mutations.

Introduction: Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs., Methods: Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization., Results: It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy., Conclusion: Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study aimed to report three new cases of an association between two rare conditions, congenital portosystemic shunts (CPSS) and trimethylaminuria (TMAU), and the efficacy of endovascular closure of the CPSS for resolving TMAU. Between November 2014 and April 2017, 15 patients with CPSS were enrolled in this prospective study to assess the efficacy of percutaneous endovascular shunt closure. Three patients presented with clinical symptoms of TMAU that were confirmed by urine analysis of trimethylamine (TMA) and TMA n-oxide. One year after endovascular closure of the congenital portosystemic shunt, the same parameters were evaluated were obtained and the values were compared to the pretreatment values. The results indicated the disappearance of clinical symptoms of TMAU and normalization of the urine test parameters in two patients and no changes in one patient, who developed new portosystemic communications. [ABSTRACT FROM AUTHOR]

Olfactory reference syndrome (ORS) is a rarely diagnosed psychiatric disorder in which individuals falsely believe that they emit an offensive body odor. This retrospective cohort study characterizes the clinical and demographic features of 54 individuals who presented to a Canadian genetics clinic for query trimethylaminuria (TMAU), an inherited disorder in which a pungent fishy odor is produced. The majority (83%) were found to have a likely diagnosis of ORS and a high rate (73.3%) of concomitant psychiatric disorders; only two patients were diagnosed with TMAU. This study highlights the genetics clinic as an unexpected and major ascertainment point for ORS, and shows that ORS can be differentiated from TMAU by age of onset (~28 years), odor characterization (refuse-related), and the presence of associated comorbid psychiatric diagnoses. There is a low diagnostic rate of ORS, attesting to the need for improved education and awareness. [ABSTRACT FROM AUTHOR]

Introduction: Background: primary trimethylaminuria or fish odor syndrome is a genetic metabolopathy characterized by the accumulation of trimethylamine, a very volatile compound in body secretions. Case report: we present the case of a healthy 8-month-old patient who, after the introduction of fish in the diet, starts a bad body odor that does not disappear with bathing. The mother visits the pediatrician repeatedly but no disorder is identified. The diagnosis is delayed until the patient is three years old. Due to maternal insistence, the patient is referred to our hospital unit, where genetic diagnostic tests are performed, enabling the paternal diagnosis that had gone unnoticed for 35 years and detecting three different mutations in the family. Discussion: primary trimethylaminuria is a genetic disease with specific symptomatology of bad body odor that can go unnoticed for many years. An adequate clinical suspicion and the request of adequate complementary tests allow its diagnosis and facilitate its clinical management. [ABSTRACT FROM AUTHOR]

Trimethylaminuria (TMAU) is a rare metabolic condition characterised by an unpleasant smell resembling rotting fish. Currently, the only measure of treatment efficacy is urine trimethylamine levels which do not always reflect the patient's experience of symptoms. A literature review did not find a specific tool to assess treatment efficacy from the patient's perspective. The aim of this study was to develop an assessment tool to provide a quantitative measure of treatment efficacy in patients diagnosed with TMAU before and after treatment and assess its acceptability (feasibility of use and face and content validity) to people living with TMAU. Mixed methods; a modified, four‐round Delphi by email and semi‐structured interviews conducted after clinical appointments. Delphi; Eight individuals living with TMAU from the TMAU forum, six medical consultants, and four dieticians in Metabolic Medicine in four National Health Service hospitals in England. Semi‐structured interviews; three patients with TMAU in two National Health Service hospitals, United Kingdom. The assessment tool contains 27 items distributed across four domains; Odour characteristics with 6 items, mental well‐being with 13 items, social well‐being with 5 items, and healthcare professionals support with 3 items. Semi‐structured interviews; views on the content and design of the tool. The co‐produced tool was successfully developed and considered acceptable to people living with TMAU. While further testing is needed to evaluate the validity and reliability of the assessment tool, the tool may serve as a prompt for questioning for clinicians diagnosing and treating TMAU. [ABSTRACT FROM AUTHOR]

Polymorphic human flavin-containing monooxygenase 3 (FMO3) is associated with the inherited disorder trimethylaminuria. Several FMO3 variants have been observed in a variety of ethnic groups, including a Japanese cohort suffering from trimethylaminuria. The aim of this study was to screen another self-reported Japanese trimethylaminuria cohort for novel FMO3 variants and to investigate these new variants. Subjects with low FMO3 metabolic capacities were identified by measuring the urinary trimethylamine and trimethylamine N-oxide concentrationsin171 Japanese volunteers. The FMO3 genes from these subjects and their family members were then sequenced. Heterozygotes or homozygotes for novel single-nucleotide polymorphisms c.20 T>C p.(Ile7Thr), c.122 G>A p.(Trp41Ter), c.127T>A p.(Phe43Ile), c.488 T>C p.(Leu163Pro), and c.1127G>A p.(Gly376Glu) and a heterozygote for the novel duplication c.850_860dupTTTAACGATGA p.(Glu287AspfsTer17) were identified. In addition, the known (but as yet uncharacterized) single-nucleotide polymorphism c.929 C>T p.(Ser310Leu) was found. Pedigree analysis revealed the p.(Ser310Leu) FMO3 allele in cis configuration with c.929 C>T p.(Glu158Lys). These variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased N-oxygenation activities toward trimethylamine and benzydamine. Although the allele frequencies of these seven variants were low, the present results suggest that individuals homozygous or heterozygous for any of these novel missense or duplicationFMO3 variants or known nonsense mutations such as p.(Cys197Ter) may possess abnormal activities toward trimethylamine N-oxygenation.

The synthesis and photochemical properties of two novel selenium zinc(II) phthalocyanines, a lipid-soluble 2,9(10),16(17),23(24)-tetrakis [(2-dimethylamino)ethylselanyl]phthalocyaninato zinc(II) ( 4 ) and its water-soluble quaternized derivative 2,9(10),16(17),23(24)-tetrakis [(2- trimethylammonium)ethylselanyl]phthalocyaninato zinc(II) tetraiodide ( 5 ), were investigated. Maximum absorption values were 689 nm and 684 nm for 4 and 5 in DMF, respectively. In addition, phthalocyanines were revealed to be very efficient singlet oxygen generators with high values of Φ Δ 0.74 and 0.84 for 4 and 5 in DMF, and they were photostable over the irradiation times studied. The photodynamic effect were evaluated on CT26 colon carcinoma cells. After light exposure, 4 and 5 were found to be cytotoxic, and IC 50 values were 0.5 ± 0.1 μM and 2.3 ± 0.6 μM, respectively. The production of a greater amount of reactive oxygen species after phthalocyanines irradiation would be responsible for its potent phototoxic action on CT26 colon carcinoma cells. [ABSTRACT FROM AUTHOR]

Determination of trimethylamine N -oxide (TMAO) and trimethylamine (TMA) in biological and environmental samples has drawn great attention recently due to their increasing association with human health and disease. It remains a challenge to simultaneously quantify TMAO and TMA in a simple, fast and cost-effective manner due to pre-analytical and analytical constraints. For the first time, we describe a dilute and shoot approach combined with LC-MS/MS detection for the simultaneous measurement of the analytes in spot urine samples with high throughput. Compared to the existing methods, the merits of the proposed assay include the use of a simple dilute and shoot approach (100-fold), small sample volume (10 μL), short LC run on a PFP column (4.0 min) and multi-analyte MS detection without sample cleanup, derivatization, evaporation and a HILIC column. Dilution, LC and MS parameters were optimized in detail. Method validation yielded a wide linearity for TMAO (1.0–400 μg/mL) and TMA (0.025–10 μg/mL) with a respective limit of quantitation of 1.0 and 0.025 μg/mL. The quantitation was not affected by 41 major urinary components, structurally-related drugs and metabolites. The intra- and inter-day assay precisions were ≤3.6% and recoveries were 93.3%–103.3% for spiked quality control samples. The clinical utility of the alternative spot urine sampling approach compared to conventional 24 h urine collection was supported by a significant correlation between the two sampling strategies (n = 20, p < 0.0001, r = 0.757–0.862; slope = 0.687–1.170) and no statistical difference in day-to-day biological variability (n = 20). The applicability and reliability of the assay was verified by the assessment of reference intervals in a cohort of 118 healthy people. The proposed assay would be beneficial for the rapid and accurate determination of the increasingly important TMAO and TMA demanded in clinical, environmental, pharmaceutical and nutritional fields. [ABSTRACT FROM AUTHOR]

Flavin-containing monooxygenase 3 (FMO3) plays a critical role in catalyzing the conversion of trimethylamine (TMA) to trimethylamine- N -oxide (TMAO) in vivo . Despite the well-documented association between FMO3 mutations and a ‘fishy’ off-flavor eggs in chicken and quail, little information is available regarding the molecular characteristic of goose ( Anser cygnoides ) FMO3 and its relationship with the yolk TMA content. To fill these gaps, we cloned the full-length cDNA sequence of goose FMO3 , which comprised 1851 bp encoding 531 amino acids. FMO3 mRNA was dramatically expressed in liver than in other tissues in the geese. Eight single nucleotide polymorphisms (SNPs) were detected in the entire coding region. The CC genotype at the T669C site, GG at the A723G site, and AA at the G734A site of FMO3 were highly significantly associated with elevated TMA content in goose egg yolk ( P < 0.001). Carriers of the A allele of G734A or C allele of T885C had yolk TMA content that had a high probability of being elevated after feeding with additional choline chloride ( P = 0.0429, OR = 4.1300, 95%CI = 1.0390–16.4270, and P = 0.0251, OR = 4.6060, 95%CI = 1.1620–18.2620, respectively). This work lays a foundation for studying the function of FMO3 and yolk TMA content in goose. However, studies using larger sample sizes and more goose breeds are required to determine whether the fishy off-flavor trait exists in goose. [ABSTRACT FROM AUTHOR]

Trimethylaminuria (TMAU) is an uncommon, inherited metabolic disease (IMD) characterised by an unpleasant rotting fish-like mouth or body odour. There does not seem to be any available study that addresses the psycho-social impact of this often missed and delayed diagnosed condition. Thus, this study explores adult patients' perspectives of living with TMAU, at one IMD department in the United Kingdom. A descriptive phenomenological approach was adopted to study 11 adult participants, selected from 19 eligible patients with TMAU. After gaining approval from a Local Research Ethics Committee, data from in-depth, semi-structured interviews were transcribed verbatim and inductively analysed. Four main themes were identified from the data: conceptualisation of TMAU; personal sensitivity in the conundrum of TMAU; life with TMAU; and moving forward with TMAU. The participants' highly emotive, insightful lived experiences suggest an overlooked and overdue need for awareness of TMAU among healthcare professionals and the public, as well as funded studies into appropriate treatment. [ABSTRACT FROM AUTHOR]

Trimethylaminuria (TMAuria), known as "fish odor syndrome," is a congenital metabolic disorder characterized by an odor resembling that of rotting fish. This odor is caused by the secretion of trimethylamine (TMA) in the breath, sweat, and body secretions and the excretion of TMA along with urine. TMAuria is an autosomal recessive disorder caused by mutations in flavin-containing monooxygenase 3 (FMO3). Most TMAuria cases are caused by missense mutations, but nonsense mutations have also been reported in these cases. Here, we describe the identification of a novel FMO3 gene mutation in a patient with TMAuria and her family. A 3-year-old girl presented with a strong corporal odor after ingesting fish. Genomic DNA sequence analysis revealed that she had compound heterozygous FMO3 mutations; One mutation was the missense mutation p.Val158Ile in exon 3, and the other was a novel nonsense mutation, p.Ser364X, in exon 7 of the FMO3 gene. Familial genetic analyses showed that the p.Val158Ile mutation was derived from the same allele in the father, and the p.Ser364X mutation was derived from the mother. This is the first description of the p.Ser364X mutation, and the first report of a Korean patient with TMAuria caused by novel compound heterozygous mutations. [ABSTRACT FROM AUTHOR]

Trimethylamine (TMA) contamination produces a strong 'fishy' odor and can cause pathological changes in humans. By screening native microorganisms from Sansevieria kirkii exposed to 100 ppm TMA, it was shown that endophytic bacteria number 1 (EN1) and number 2 (EN2) have a higher TMA tolerance and removal capacity than other bacteria species in a closed system. In addition, EN1 and EN2 demonstrated the ability to produce high quantities of indole-3-acetic acid (IAA) and use 1-aminocyclopropane-1-carboxylic acid (ACC), which is found normally in plant growth-promoting bacteria (PGPB). Moreover, 16S ribosomal DNA (rDNA) sequences of EN1 and EN2 identification showed that EN1 and EN2 was the same bacteria species, Bacillus cereus. B. cereus EN1 was chosen to apply with S. kirkii to remove TMA in a plant capsule, which was compared to control conditions. It was found that 500 g of soil with S. kirkii inoculated with B. cereus EN1 had a higher TMA removal efficiency than other conditions. Moreover, the flow rate of TMA-contaminated gas was varied (0.03-1 L min) to calculate the loading rate and elimination capacity. The maximum loading rate of 500 g soil with B. cereus EN1-inoculated S. kirkii was 2500 mg m h, while other conditions showed only around 250-750 mg m h. Therefore, a plant capsule with B. cereus EN1-inoculated S. kirkii had the potential to be applied in TMA-contaminated air. [ABSTRACT FROM AUTHOR]

In the pursuit of alkali stable cation as functional group for anion exchange membranes (AEMs), a novel adamantammonium (AdA) cation, which replacing methyl group of conventional trimethylammonium by an adamantyl group, was synthesized and investigated. 1 H NMR spectroscopy was employed to quantify the extent of decomposition and the results showed that > 99% adamantammonium remaining after 7 days immersion in 2 M NaOH (in D 2 O) at 80 °C. The AdA functionalized benzyl type poly(2,6-dimethyl phenylene oxide) polyelectrolytes, PPO-AdAs, were further prepared and characterized the AEM properties. Not only the chemical durability of these new PPO-AdA membranes, interestingly, but the conductivity and dimensional stability (water uptake and in-plane swelling) are superior to the benzylmethylammonium-benchmark PPO-based AEM (PPO-TMA). With the similar IEC values, the water uptake of PPO-AdA-41 sample is much lower than PPO-TMA-28, however, the conductivity of the former (15.7 mS cm -1 , chloride conductivity at 50 °C) is higher than the latter (13.3 mS cm -1 ). Overall, the results of this study offer a base-stable cation, adamantammonium, and the corresponding adamantammonium-based AEMs for fuel cell applications with the advantages of chemical stability, enhanced conductivity and excellent dimensional stability as well as facial functionalization technique. [ABSTRACT FROM AUTHOR]

Removal of trimethylamine (TMA) by 10 different livingSansevieriaspp. and their dried leaf materials was studied. The results showed that livingSansevieria kirkiiwas the most effective plant whileSansevieria masonianawas the least effective in TMA removal. Two major pathways were involved in stomata opening and epicuticular wax on the leaf surface. In the presence of TMA, the stomata opening inSansevieriaspp. was induced, which enhanced TMA removal under light conditions. Dried leaf powders ofSansevieriaspp. adsorbed TMA through their waxes. Therefore, both living and non-livingSansevieriaspp. can be effectively used for removal of TMA. [ABSTRACT FROM PUBLISHER]

The article presents case study of a 64-year-old woman with Currarino syndrome and trimethylaminuria disease and their characterizations. It states Currarino syndrome is characterized by partial sacral agenesis, presacral mass and anorectal malformation (ARM) which can be detected by detectable on magnetic resonance imaging (MRI). It discusses Trimethylaminuria which is caused by the deficiency of deficit of the flavin-containing monooxygenase 3 (FMO3) enzyme.

Usually the stretching vibration of the A-H group in hydrogen-bonded complexes gives an intense, broad absorption in the IR spectrum. However in a few complexes it has proved difficult to detect this absorption in low temperature matrices. In this work the Ratajczak-Yaremko vibrational model of the hydrogen bond has been applied to simulate the IR spectrum obtained for one such complex: the pentachlorophenol-trimethylamine, PCP-TMA, hydrogen bonded complex isolated in an argon matrix. Quantum chemical calculations have also been carried out to gain further insight into this complex. [ABSTRACT FROM AUTHOR]

Sensitive detection of trimethylamine both in aqueous and gaseous phases has been accomplished using an inexpensive colorimetric sensor array. Distinctive color change patterns provide facile discrimination over a wide range of concentrations for trimethylamine with >99% accuracy of classification. Calculated limits of detection are well below the diagnostically significant concentration for trimethylaminuria (fish malodor syndrome). The sensor array shows good reversibility after multiple uses and is able to cleanly discriminate trimethylamine from similar amine odorants. Portable sensing of trimethylamine vapors at ppb concentrations is described using a cell phone camera or a hand-held optoelectronic nose. Application of the sensor array in detecting mouth and skin odor as a potential tool for portable diagnosis of trimethylaminuria is also illustrated. [ABSTRACT FROM AUTHOR]

Eculizumab is the therapy of choice for patients with atypical hemolytic uremic syndrome (aHUS). Dosing recommendations stem from two trials: one retrospective trial (19 children and 5 infants) and one prospective trial (22 patients and 5 infants). This case report highlights the need for more precise dosing recommendations in children, particularly in infants, and for smaller vials of the medication to facilitate more precise dosing. Such changes would ensure that adverse events are minimized and that the children with aHUS who are treated with eculizumab experience an optimal clinical response. [ABSTRACT FROM AUTHOR]

Primary trimethylaminuria (fish-odor syndrome) is a rare autosomal recessive inherited metabolic disorder due to decreased metabolism of trimethylamine by enzyme flavin-containing monooxygenase 3. We report an adolescent boy who was socially distressed with malodor and diagnosed trimethylaminuria by molecular analyses. The patient was previously found to have primary hypothyroidism at another center when he was being investigated for malodor. Our aim is to remind awareness of this rare, socially devastating metabolic disorder to physicians, especially family doctors and specialists such as pediatricians, adolescent doctors, psychiatrists and dermatologists. We also searched for a possible association between trimethylaminuria and hypothyroidism but didn't find out an exact pathophysiological link. Coexistence of primary trimethylaminuria and hypothyroidism might be coincidental. [ABSTRACT FROM AUTHOR]

Aim The aim of this study was to investigate relationships between flavin-containing mono-oxygenase 3 ( FMO3) genotype and phenotype (conversion of odorous trimethylamine into non-odorous trimethylamine N-oxide) in a large Japanese cohort suffering from trimethylaminuria. Methods Urinary excretion of trimethylamine and trimethylamine N-oxide was determined for 102 volunteers with self-reporting symptoms of trimethylaminuria. For each we determined the sequence of the entire coding region, plus 1.3 kb of flanking intronic and 2.5 kb of the upstream region of the FMO3 gene. The affect of upstream variants on transcription was determined with a reporter gene assay. Results Seventy-eight subjects were diagnosed as suffering from trimethylaminuria, based on urinary excretion of <90% of total TMA as TMA N-oxide. Of these, 13 were classified as severe, 56 as moderate and nine as mild cases, excreting <43%, 48-70% and 73-83% of trimethylamine as trimethylamine N-oxide, respectively. Twenty-seven mutations were identified in FMO3, 15 in the coding region, of which eight abolish or severely impair FMO3 activity ( Pro70Leu, Cys197fsX, Thr201Lys, Arg205Cys, Met260Val, Trp388Ter, Gln470Ter and Arg500Ter), and 12 in the upstream region. The mutations segregate into 19 haplotypes, including four different combinations of upstream mutations, each of which reduces transcriptional activity in comparison with the ancestral upstream sequence of FMO3. Conclusions Comparisons of genotype and phenotype reveal that severe trimethylaminuria is caused by loss of function mutations in FMO3. For moderate and mild cases the situation is more complex, with most resulting from factors other than FMO3 genotype. Our results have implications for the diagnosis and management of the disorder. [ABSTRACT FROM AUTHOR]

Trimethylaminuria, better known as fish odor syndrome, is a psychologically disabling condition in which a patient emits a foul odor, which resembles that of rotting fish. The disorder is most commonly caused by an inherited deficiency in flavin monooxygenase 3, the vital enzyme for the metabolism of trimethylamine, which is the compound responsible for the unpleasant odor. The condition is uncommon, but there has been recent research to suggest that the diagnosis may often be overlooked. Moreover, it is important to be cognizant of this condition because there are reliable diagnostic tests and the disorder can be devastating from a psychosocial perspective. While there is no cure, many simple treatment options exist that may drastically improve the quality of life of these patients. This article will review the literature with an emphasis on the psychosocial impact and treatment options. [ABSTRACT FROM AUTHOR]

Abstract: Trimethylaminuria (TMAu) or “fish odor syndrome” is a metabolic disorder characterized by the inability to convert malodorous dietarily-derived trimethylamine (TMA) to odorless TMA N-oxide by the flavin-containing monooxygenase 3 (FMO3). Affected individuals unable to complete this reaction exude a “fishy” body odor due to the secretion of TMA in their corporal fluids leading to a variety of psychosocial problems. Interindividual variability in the expression of FMO3 gene may affect drug and foreign chemical metabolism in the liver and other tissues. Therefore, it is important to screen for common TMAu mutations but also extend the search to other genetic variants in order to correlate genotype and disease-associated phenotypes. In this study, 25 Portuguese patients with phenotype suggestive of TMAu were evaluated for molecular screening of the FMO3 gene. Herein, we found 16 variants in the FMO3 coding region, some of which had not been previously documented (Gly38Trp, Asp232Val, Thr307Pro, Ser310Leu). Whenever common variants (Glu158Lys, Glu308Gly) were considered in combination a distinct pattern between the control population and patients was observed, mainly in what concerns the presence of Lys158 and Gly308 in homozygous state. Further studies are necessary to clarify the pathogenicity of novel variants identified in this study, as well as the effect of the common single nucleotide polymorphisms, which may play an important role in disease presentation and/or protective mechanism to xenobiotics drugs or environment. [Copyright &y& Elsevier]

Abstract: The N-oxygenation of amines by the human flavin-containing monooxygenase (form 3) (FMO3) represents an important means for the conversion of lipophilic nucleophilic heteroatom-containing compounds into more polar and readily excreted products. In healthy individuals, virtually all Trimethylamine (TMA) are metabolized to Trimethylamine N-oxide (TMAO). Several single nucleotide polymorphisms (SNPs) of the FMO3 gene have been described and result in an enzyme with decreased or abolished functional activity for TMA N-oxygenation thus leading to TMAU, or fish-like odor syndrome. Three coding region variants, c. G472A (p.E158K) in exon 4, c. G769A (p.V257M) in exon 6, and c.A923G (p.E308G) in exon 7, are common polymorphisms identified in all population examined so far and are associated with normal or slightly reduced TMA N-oxygenation activity. However, simultaneous occurrence of 158K and 308G variants results in a more pronounced decrease in FMO3 activity. A fourth polymorphism, c. G1424A (p.G475D) in exon 9, less common in the general population, was observed in individuals suffering severe or moderate trimethylaminuria. The aim of this study was to determine the allelic and genotypic distributions of these four FMO3 variants in 528 healthy individuals collected from the Sicilian and Sardinian populations together with haplotype and linkage analyses. Finally, we present data on the genotype–phenotype correlation by ESI-MS/MS TMA/TMAO urinary determination in 158KK/308EG individuals. Variant 158K shows the same frequency in Sicilian and Sardinian populations while variant 257M was not observed in the Sardinian sampling. No significant differences were found for 308G and 475D variants among two populations. Cis-linkage between 158K and 308G was confirmed with the compound variant (158K–308G) being found in a proportion of 0.9% and 0.3% of Sicilian subjects, and 0.01% and 0.5% in Sardinian population. Urinary determination of TMA/TMAO ratio in 158KK/308EG individuals showed a considerable reduction in FMO3 activity although they do not show the classical features of trimethylaminuria as a strong body odor and breath. Our data support the conclusion that trimethylaminuria is not always accompanied by a fish-like odor, despite the coexistence in the same individual of the two variants 158K and 308G, and other factors account for the expression of that phenotype. [Copyright &y& Elsevier]

Choline and trimethylamine (TMA) are small molecules that play central roles in biological processes throughout all kingdoms of life. These ubiquitous metabolites are linked through a single biochemical transformation, the conversion of choline to TMA by anaerobic microorganisms. This metabolic activity, which contributes to methanogenesis and human disease, has been known for over a century but has eluded genetic and biochemical characterization. We have identified a gene cluster responsible for anaerobic choline degradation within the genome of a sulfate-reducing bacterium and verified its function using both a genetic knockout strategy and heterologous expression in Escherichia coli. Bioinformatics and electron paramagnetic resonance (EPR) spectroscopy revealed the involvement of a C-N bond cleaving glycyl radical enzyme in TMA production, which is unprecedented chemistry for this enzyme family. Our discovery provides the predictive capabilities needed to identify choline utilization clusters in numerous bacterial genomes, underscoring the importance and prevalence of this metabolic activity within the human microbiota and the environment. [ABSTRACT FROM AUTHOR]

Abstract: Loss-of-function mutations of flavin-containing monooxygenase 3 (FMO3), the enzyme responsible for trimethylamine N-oxygenation, cause the inherited disorder trimethylaminuria, or fish odor syndrome. The aim of this study was to further investigate the inter-individual variations of FMO3 activity in a Japanese cohort that we had studied previously. The subjects were 640 Japanese volunteers with self-reported trimethylaminuria; genomic DNA was sequenced in those that had 10–70% FMO3 metabolic capacity in urine tests. A heterozygote for the novel single nucleotide substitution p.Ile441Thr (proband 1) and a heterozygote for the novel single nucleotide substitution p.Ser195Leu (proband 2) were identified. The biological parents of probands 1 and 2 were heterozygous and had >90% trimethylamine N-oxygenation metabolic capacity. In addition, single nucleotide substitutions p.Val58Ile, p.Pro70Leu, and p.Gly421Val in FMO3 were found in probands 3–7. In the course of DNA sequencing, another FMO3 variant, p.Thr488Ala, was found in two unrelated heterozygous subjects. Variant FMO3 proteins recombinantly expressed in Escherichia coli membranes exhibited decreased activity toward typical FMO3 substrates. Although the allele frequencies of these six novel variants were low (<1%), the present results suggest that individuals homozygous or heterozygous for any of the six novel missense FMO3 variants or known nonsense mutations such as p.Cys197stop or p.Arg500stop may possess abnormal trimethylamine N-oxygenation. [Copyright &y& Elsevier]

Abstract: Background: Individuals with the metabolic disorder trimethylaminuria may sporadically produce malodors despite good hygiene. The psychosocial impact of trimethylaminuria can be considerable. However, trimethylaminuria is difficult to diagnose without specialized tests, in part because odor production is diet-dependent, and malodors may not be present during medical examinations. Thus, the prevalence and demographics of trimethylaminuria remain unclear. Methods: We tested 353 patients who had unexplained (idiopathic) malodor production for trimethylaminuria using a standard choline challenge. We also collected basic demographic information. Results: Approximately one third of patients (118) tested positive for trimethylaminuria. Consistent with previous reports, women, particularly African American women, were significantly overrepresented among trimethylaminuria-positive patients. Of note, the same pattern was seen among trimethylaminuria-negative patients. Also consistent with previous reports, trimethylaminuria-positive women who were still menstruating tended to produce higher levels of trimethylamine within ±7 days of menses, although this trend was statistically marginal (P = .07). Conclusion: If our patient sample is representative of patients with idiopathic malodor, demographic information (race and gender) may not be useful in a differential diagnosis of trimethylaminuria. However, undiagnosed cases of trimethylaminuria may be fairly common among patients with idiopathic malodor. If so, choline challenge testing should be indicated for all such patients because trimethylaminuria is responsive to dietary and other treatments. We speculate that testing also might reveal cases of trimethylaminuria among those diagnosed with certain psychologic disorders, including olfactory reference syndrome. [Copyright &y& Elsevier]