Trimethylaminuria Research Articles

5d transition-metal adsorption tailored valley splitting and magnetic anisotropy of Janus 2H-WSSe monolayer

Valley splitting and magnetic anisotropy of 5d TM (Hf, Ta, W, Re, Os, Ir, Pt, Au, and Hg) adsorbed Janus 2H-WSSe monolayers are investigated using first-principles calculations. The results show that 5d TM atoms adsorbed on the W-top site of Janus 2H-WSSe monolayer exhibit the lowest adsorption energy, regardless of the Se or S layer. The electronic states of Hf-SW and Re-SeW adsorbed systems cross the EF and show metallicity, while the other adsorbed systems still exhibit the semiconducting characteristics. According to the k·p model based on the effective Hamiltonian, the Zeeman effect arising from the local magnetic moment of 5d TM atoms lifts tunable valley splitting within 12.7-227meV owing to different SOC strength. A maximum valley splitting of 227meV is observed in the W adsorbed system, which is large enough to realize the valley Hall effect. Both perpendicular magnetic anisotropy (PMA) and in-plane magnetic anisotropy (IMA) can be adjusted by adsorbing different 5d TM atoms on the S/Se layer. Remarkably, the matrix elements differences (dx2–y2, dxy) decide the PMA and IMA behaviors, which are due to the competition of different TM-d orbitals based on the second-order perturbation theory. These results suggest that the 5d TM adsorbed Janus 2H-WSSe monolayer can be considered a good candidate for the spintronic and valleytronic devices.

Structural, magnetic, and optoelectronic properties of rock salt MgO co-doped with Eu-TM (TM = Cu, Ag, and Au) for spintronic and UV detector applications: SP-DFT investigations

This study analyzes how adding europium and transition metals (Cu, Ag, and Au) at a 12.5% concentration to magnesium oxide (MgO) affects its physical characteristics and potential uses. To do so, the full potential linearized augmented plane wave (FP-LAPW) method, based on spin-polarized density functional theory (SP-DFT), is used to derive the results. Wu and Cohen’s generalized gradient approximation (GGA-WC) described the exchange-correlation potential. The modified Becke-Johnson exchange potential (TB-mBJ) was also used to improve the findings of optoelectronic properties. When Eu and TM (Cu, Ag, and Au) impurities are co-doped into the nonmagnetic (NM) semiconductor MgO, the structural optimization results show that the lattice constants increase, and the bulk modulus decreases with increasing the atomic number of transition metals. The resulting dilute magnetic oxides (DMOs) are stable in the spin-polarized ferromagnetic (FM) phase, and the formation energy values confirm their stability in the [Formula: see text] cubic structure, with the lowest value belonging to Eu[Formula: see text]TM[Formula: see text]Mg[Formula: see text]O. Similarly, calculations of electronic properties using the WC-mBJ functional demonstrate that all compounds have an indirect half-metallic bandgap at L-[Formula: see text] equal to 2.53, 2.49, and 1.39 eV for Eu[Formula: see text]Cu[Formula: see text]Mg[Formula: see text]O, Eu[Formula: see text]Ag[Formula: see text]Mg[Formula: see text]O, and Eu[Formula: see text]Au[Formula: see text]Mg[Formula: see text]O, respectively. They have an integer magnetic moment of 6 [Formula: see text]. The density of states shows that at the Fermi level, the 4f-Eu, d-TM, and p-O states give rise to new energy levels. This indicates that the f–p–d hybridization provides this system with its FM properties. Also, these compounds’ dielectric function and absorption spectra are calculated and analyzed to learn more about their optical properties. The results provide insight into the optical behavior of the materials. It is observed that the co-doped compounds exhibit greater optical absorbance than their un-doped MgO counterparts do. This theoretical investigation opens the way to preparing high magnetic moment DMOs using TM and rare earth as dopants suitable for spintronic and UV devices.

Unravelling the Psychological Impact of Trimethylaminuria: Insights into the Management Strategies

Trimethylaminuria (TMAU), colloquially known as fish odour syndrome, is a rare metabolic disorder characterised by the body’s inability to properly metabolise Trimethylamine (TMA), resulting in a distinctive and unpleasant fishy odour in bodily secretions. This comprehensive review explores the pathophysiology, clinical manifestations, genetic basis, diagnostic challenges, and psychological impact of TMAU, along with management strategies. Genetic mutations affecting the flavin-containing monooxygenase 3 (FMO3) enzyme, which is responsible for TMA metabolism, contribute to the condition’s hereditary nature. Diagnosis can be challenging due to intermittent symptoms and overlaps with other conditions, such as Olfactory Reference Syndrome (ORS). The psychosocial impact of TMAU can be profound, leading to embarrassment, social isolation, and mental health issues. Management strategies include dietary modifications, supplements, antibiotics, and hygiene measures to alleviate symptoms. Despite advances in understanding TMAU, further research is needed to enhance diagnostic accuracy and therapeutic approaches, ultimately improving the quality of life for affected individuals.

FMO3 deficiency of duck leads to decreased lipid deposition and increased antibacterial activity

BackgroundMost duck eggs possess a fishy odor, indicating that ducks generally exhibit impaired trimethylamine (TMA) metabolism. TMA accumulation is responsible for this unpleasant odor, and TMA metabolism plays an essential role in trimethylaminuria (TMAU), also known as fish odor syndrome. In this study, we focused on the unusual TMA metabolism mechanism in ducks, and further explored the unclear reasons leading to the debilitating TMA metabolism.MethodsTo achieve this, transcriptome, proteome, and metagenome analyses were first integrated based on the constructed duck populations with high and low TMA metabolism abilities. Additionally, further experiments were conducted to validate the hypothesis regarding the limited flavin-containing monooxygenase 3 (FMO3) metabolism ability of ducks.ResultsThe study demonstrated that liver FMO3 and cecal microbes, including Akkermansia and Mucispirillum, participated in TMA metabolism in ducks. The limited oxidation ability of FMO3 explains the weakening of TMA metabolism in ducks. Nevertheless, it decreases lipid deposition and increases antibacterial activity, contributing to its survival and reproduction during the evolutionary adaptation process.ConclusionsThis study demonstrated the function of FMO3 and intestinal microbes in regulating TMA metabolism and illustrated the biological significance of FMO3 impairment in ducks.

Electronic, Magnetic, and Optical Properties of Metal Adsorbed g-ZnO Systems

2D ZnO is one of the most attractive materials for potential applications in photocatalysis, gas and light detection, ultraviolet light-emitting diodes, resistive memory, and pressure-sensitive devices. The electronic structures, magnetic properties, and optical properties of M (Li, Na, Mg, Ca, or Ga) and TM (Cr, Co, Cu, Ag, or Au) adsorbed g-ZnO were investigated with density functional theory (DFT). It is found that the band structure, charge density difference, electron spin density, work function, and absorption spectrum of g-ZnO can be tuned by adsorbing M or TM atoms. More specifically, the specific charge transfer occurs between g-ZnO and adsorbed atom, indicating the formation of a covalent bond. The work functions of M adsorbed g-ZnO systems are obviously smaller than that of intrinsic g-ZnO, implying great potential in high-efficiency field emission devices. The Li, Na, Mg, Ca, Ga, Ag, or Au adsorbed g-ZnO systems, the Cr adsorbed g-ZnO system, and the Co or Cu adsorbed g-ZnO systems exhibit non-magnetic semiconductor proprieties, magnetic semiconductor proprieties, and magnetic metal proprieties, respectively. In addition, the magnetic moments of Cr, Co, or Cu adsorbed g-ZnO systems are 4 μ B, 3 μ B, or 1 μ B, respectively, which are mainly derived from adsorbed atoms, suggesting potential applications in nano-scale spintronics devices. Compared with the TM absorbed g-ZnO systems, the M adsorbed g-ZnO systems have more obvious absorption peaks for visible light, particularly for Mg or Ca adsorbed g-ZnO systems. Their absorption peaks appear in the near-infrared region, suggesting great potential in solar photocatalysis. Our work contributes to the design and fabrication of high-efficiency field emission devices, nano-scale spintronics devices, and visible-light responsive photocatalytic materials.

Adaptive Modelling of Mutated FMO3 Enzyme Could Unveil Unexplored Scenarios Linking Variant Haplotypes to TMAU Phenotypes.

Background: Trimethylaminuria (TMAU) is a rare genetic disease characterized by the accumulation of trimethylamine (TMA) and its subsequent excretion trough main body fluids, determining the characteristic fish odour in affected patients. We realized an experimental study to investigate the role of several coding variants in the causative gene FMO3, that were only considered as polymorphic or benign, even if the available literature on them did not functionally explain their ineffectiveness on the encoded enzyme. Methods: Mutational analysis of 26 TMAU patients was realized by Sanger sequencing. Detected variants were, subsequently, deeply statistically and in silico characterized to determine their possible effects on the enzyme activity. To achieve this goal, a docking prediction for TMA/FMO3 and an unbinding pathway study were performed. Finally, a TMAO/TMA urine quantification by 1H-NMR spectroscopy was performed to support modelling results. Results: The FMO3 screening of all patients highlighted the presence of 17 variants distributed in 26 different haplotypes. Both non-sense and missense considered variants might impair the enzymatic kinetics of FMO3, probably reducing the interaction time between the protein catalytic site and TMA, or losing the wild-type binding site. Conclusions: Even if further functional assays will confirm our predictive results, considering the possible role of FMO3 variants with still uncertain effects, might be a relevant step towards the detection of novel scenarios in TMAU etiopathogenesis.

Quality consideration for the validation of urine TMA and TMAO measurement by nuclear magnetic resonance spectroscopy in Fish Odor Syndrome

ObjectivesTrimethylaminuria, also known as Fish Odor Syndrome (FOS), is a condition characterized by the presence of high concentrations of trimethylamine (TMA) in urine, sweat and expired air of affected patients. Diagnosis of this benign but unpleasant disease is mainly based on clinical presentation and assessment of TMA and its metabolite, TMAO (trimethylamine-N-oxide), concentrations in urine of patients. Material and methodsWe here described the validation of an analytical method for measurement of TMA and TMAO in urine using nuclear magnetic resonance (NMR) according to the specifications of the ISO 15189 norm. We used a fast validation protocol, based exactitude profile method, enabling to determine accuracy, intra and inter-day precision from a limited number of samples. ResultsThe linearity was established from 2.5 to 100 mg/L for TMA measurement and from 10 to 1000 mg/L for TMAO measurement, with good analytical performances i.e. accuracy, intra and inter-day precision. We also report a case diagnose for FOS from this method. ConclusionsThis method validation ensures the robustness of NMR in routine use for diagnosis of trimethylaminuria, as part of the reference center for inherited metabolic diseases at the Tours hospital.

A Case of Fishy Smell-Fish Malodor Syndrome

Introduction: Primary trimethylaminuria (TMAU), also known as fish malodor syndrome is a rare condition that is characterized by trimethylamine excess. The hallmark of this condition is a body malodor similar to decaying fish. As this metabolic disorder is uncommon, this case highlights the management options for an endocrinologist.Case presentation: A 56-year-old man was referred to the endocrine clinic for TMAU. Starting in puberty, the patient’s family and friends noted a malodor that he has never been able to detect. After several decades, the patient was diagnosed clinically by a dermatologist. Since then, the patient’s management had included avoiding cholines in his diet, which included egg yolks and salt-water fish. Additionally, for severe episodes occurring once to twice a year, he took a cup of charcoal daily plus Metronidazole 500 mg twice a day for ten days. The patient was the only member of his family with this condition. Physical exam was unremarkable expect for a faint malodor. Metronidazole, charcoal, and a genetics consult were ordered.Discussion: TMAU is a rare metabolic disorder in which an individual is not able to convert trimethylamine into trimethylamine N-oxide due to a defect in the hepatic oxidase system. It results from a mutation in the flavin-containing monooxygenase 3 gene (FMO3) that is inherited via autosomal recessive pattern. An excess excretion of trimethylamine in the urine, breath, sweat, and reproductive fluids results in a body malodor similar to that of decaying fish. The odor may be exacerbated by increase in body temperature, emotional changes, puberty, and prior to and during menstruation in women and often results in distressing psychosocial difficulties. Thus, early institution of dietary and pharmacological measures will likely have a major impact on quality of life.Treatment options are limited and include topical, dietary, and medications. Topical approaches include antiperspirants, deodorants, and pH-balanced soap. A diet low in choline-containing foods such as dairy, beans, and marine fish is beneficial as choline is metabolized to trimethylamine by the intestinal bacteria. For severe cases, antibiotics such as Metronidazole, Rifaximin, and Neomycin sulfate are helpful to reduce the intestinal bacterial load. Other therapeutic strategies consist of activated charcoal (750 mg twice a day for ten days) and copper chlorphyllin (60 mg three times a day for three weeks); both reduce urinary free trimethylamine and increase the concentration of trimethylamine N-oxide.

Trimethylaminuria and Vascular Complications

Background: Trimethylaminuria (Fish-Odour Syndrome) is a rare metabolic disorder characterized by an unpleasant odour in body secretions similar to rotting fish. The disorder is most commonly caused from mutations affecting the Flavin containing monooxygenase 3 (FMO3) gene, the vital enzyme for the metabolism of trimethylamine. Although uncommon, it is important to be conscious of this condition, which can be devastating psychosocially even with reliable diagnostic tests. We present here an individual with this syndrome who, in addition to the psychosocial difficulties, presented physical complications that we relate to the disease’s physiopathology. Case: R.M.F., 56 years old, lawyer, self-diagnosed at 25 after identifying himself with a disease description in a local newspaper. He describes fish odour symptoms from infancy and his mother used to demand excessive hygiene habits. He has always suffered from social disturbances. At 44, a physician’s investigation detected FMO3 mutation. The patient is not obese, has never smoked and denies any comorbidity, except erectile dysfunction for 10 years. He presented 4 years ago extensive acute venous thrombosis in the right lower limb femoral veins, lateral and medial gastrocnemius, solar and fibular popliteal veins. Laboratory investigation excluded other causes and negative antibodies. Besides, ENMG confirmed last year peripheral motor sensitive polyneuropathy, axonal pattern, distal both lower extremities. The patient failed treatment with modifications in diet and hygiene, but achieved symptomatic improvement after metronidazole. Genetic analysis showed a new homozygotic variant in the FMO3 gene, with substitution of adenine for cytosine and exchange of Threonine for proline at position 307 of the FMO3 protein with protein dysfunction computably predicted. Comments: Considering the deep venous thrombosis and symmetrical peripheral neuropathy developed by the patient, we searched for a possible association with TMAU but we did not find previous reports. However, Weifei Zhu et al. (Circulation, 135(17), 1671–73,2017) have shown TMAO generated by gut microbes contributing to platelet hyper reactivity and causing a prothrombotic phenotype in vivo. Plasma TMAO levels could predict incident thrombosis risk. Also, direct TMAO exposure enhanced platelet activation from multiple agonists stimulus. Although the “chemical sensor” for TMAO within platelets remains unknown, these findings could increase our understanding of the relationship between TMAO and CVD risk. Although the disorder might not appear to be a significant health problem, its social and psychological burden can be devastating, since the few treatments available provide modest benefits. In addition, it may be associated with other complications, including CVD, to which we would like to draw attention with this report

Gut-Brain Axis Cross-Talk and Limbic Disorders as Biological Basis of Secondary TMAU.

Background: Trimethylaminuria (TMAU) is a rare metabolic syndrome characterized by the accumulation and the excretion of trimethylamine (TMA), a volatile diet compound produced by gut microbiota. Gut microbiota alterations are mainly involved in the secondary TMAU, whose patients show also different psychiatric conditions. We hypothesized that the biological activity of several molecules acting as intermediate in TMA metabolic reaction might be at the basis of TMAU psychiatric comorbidities. Methods: To corroborate this hypothesis, we performed the analysis of microbiota of both psychiatric suffering secondary TMAU patients and TMAU “mentally ill” controls, comparing the alteration of metabolites produced by their gut bacteria possibly involved in neurotransmission and, in the same time, belonging to biochemical pathways leading to TMA accumulation. Results: Microbiota analyses showed that Clostridiaceae, Lachnospiraceae and Coriobacteriaceae alterations represented the bacterial families with highest variations. This results in an excessive release of serotonin and an hyperactivation of the vagus nerve that might determine the widest spectrum of psychiatric disorders shown by affected patients. These metabolites, as short chain fatty acids, lactate and neurotransmitter precursors, are also related to TMA accumulation. Conclusions: Knowledge of microbiota-gut-brain axis may become a potential new strategy for improving metabolic diseases and to treat linked psychiatric disorders.

A Patient of Fish Odour Syndrome with Recurrent Tinea Corporis

This was a case of the 43-year-old male complaining of severe well-demarcated irregular-shaped, centrally non-cleared, extensive, non-scaly plaques with raised borders. The patient was having severe itching all over the body. The interesting fact about this case is that this patient's sweat has had the smell of rotten fish for the last 5 years. This patient is a known case of Fish odour syndrome diagnosed by the presence of trimethylaminuria in his urine 5 years back. The patient informed us that when he didn't have the bad odour in his sweat, he did not develop the above-mentioned lesions of tinea corporis. The patient was very frustrated and socially isolated because of severe itching and the bad odour in his sweat. The role of trimethylamine (TMA) causes bad odour in the sweat, mouth and urine. We don't encounter cases like this very often and we are reporting this case because after a detailed inquiry about the patient's family history the same condition persists with 4 other patient's family members but they did not report themselves as they are mostly less educated, live in a rural area and they don't want to visit any doctor. We want to increase the knowledge of the medical fraternity to deal with these cases in a better way and maybe we are opening a new horizon for the researchers.

PSXII-34 The evaluation of the influence of FMO3 gene polymorphism on the milk productivity of Ayrshire breed cows

Abstract Russian Ayrshire population of cattle is the second largest in number the world population of animals of this breed. Trimethylaminuria (TMA) is the monogenic disease manifesting in the ‘‘fish off-flavor” of the milk from the sick cows and caused by R238X mutation in the flavin-containing monooxidase 3 gene (FMO3). The aim of our investigation was the analysis of the FMO3 gene polymorphism of Ayrshire cattle breed and its relationship with the milk productivity of the first lactation. The analysis of FMO3 gene polymorphism has been carried out on 352 animals of 5 herds, and associations with the milk productivity due 305 days have been evaluated on 20 healthy cows (RR) and 6 ones-carriers of the mutation (RX). DNA has been extracted by means of the kit “DNA-Extran” (“Syntol”, Russia). The identification of the FMO3 genotypes has been conducted by PCR-RFLP in according to the previously developed method with using TaqI restriction endonuclease. The frequency of animals-carriers of X allele associated with the defect of “fish off-flavor” of milk was in the range 10.21–12.82%. The frequencies of RR, RX and XX genotypes were 76.9, 20.5 and 2.6 %, respectively. The study of relationship between the genotypes on FMO3 gene and productivity traits has shown that the homozygous RR-individuals in comparing to RX-ones had significantly higher levels of the milk yield (+918.6 kg, P ≥ 0.05) and content of the milk protein (+28.8, P ≥ 0.05). Adaptive abilities of RR-cows of Russian selection allowed them to surpass animals of Finnish origin with a similar genotype in milk yield 5,655.6 ± 254.2 against 5,105.0 ± 238.6 kg. The investigations has shown the significant superiority the animals-non carriers of the “fish off-flavor” defect in the milk yield and content of the milk protein. This research was supported by the Ministry of science and higher education АААА-А18-118021590138-1.

Antiretroviral treatment leading to secondary trimethylaminuria: Genetic associations and successful management with riboflavin

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. A HIV patient developed secondary trimethylaminuria following antiretroviral treatment. Riboflavin supplementation ameliorated his phenotype. 1 H-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. 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.

Novel variants in outer protein surface of flavin-containing monooxygenase 3 found in an Argentinian case with impaired capacity for trimethylamine N-oxygenation

Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.(P73L; E158K; E308G) FMO3 in trans configuration with the second new one p.(F140S) FMO3. Recombinant FMO3 proteins of the wild-type and the novel two variants underwent kinetic analyses of their trimethylamine N-oxygenation activities. P73L; E158K; E308G and F140S FMO3 proteins exhibited moderately and severely decreased trimethylamine N-oxygenation capacities (~50% and ~10% of wild-type FMO3, respectively). Amino acids P73 and F140 were located on the outer surface region in a crystallographic structure recently reported of a FMO3 analog. Changes in these positions would indirectly impact on key FAD-binding residues. This is the first report and characterization of a patient of fish odor syndrome caused by genetic aberrations leading to impaired FMO3-dependent N-oxygenation of trimethylamine found in the Argentinian population. We found novel structural determinants of FAD-binding domains, expanding the list of known disease-causing mutations of FMO3. Our results suggest that individuals homozygous for any of these new variants would develop a severe form of this disorder.

Engineered Polymersomes for the Treatment of Fish Odor Syndrome: A First Randomized Double Blind Olfactory Study.

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.

Fabrication of Biobased Hydrophobic Hybrid Cotton Fabrics Using Molecular Self-Assembly: Applications in the Development of Gas Sensor Fabrics.

Inadvertent inhalation of various volatile organic compounds during industrial processes, such as coal and metal mining, metal manufacturing, paper and pulp industry, food processing, petroleum refining, and concrete and chemical industries, has caused an adverse effect on human health. In particular, exposure to trimethylamine (TMA), a fishy odor poisonous gas, resulted in numerous health hazards such as neurotoxicity, irritation in eyes, nose, skin, and throat, blurred vision, and many more. According to the environmental protection agency, TMA in the level of 0.10 ppm is generally considered as safe, and excess dose results in “trimethylaminuria” or “fish odor syndrome.” In order to avoid the health hazards associated with the inhalation of TMA, there is an urge to design a sensor for TMA detection even at low levels for use in food-processing industries, medical diagnosis, and environment. In this report, for the first time, we have developed a TMA sensor fabric using a sequential self-assembly process from silver-incorporated glycolipids. Formation of self-assembled supramolecular architecture, interaction of the assembled structure with the cotton fabric, and sensing mechanism were completely investigated with the help of various instrumental methods. To our surprise, the developed fabric displayed a transient response for 1–500 ppm of TMA and a stable response toward 100 ppm of TMA for 15 days. We believe that the reported flexible TMA sensor fabrics developed via the sequential self-assembly process hold great promise for various innovative applications in environment, healthcare, medicine, and biology.

Trimethylaminuria (fish odor syndrome)

Fish-odor syndrome is due to a rare metabolic defect in which there is massive excretion of the volatile tertiary amine, trimethylamine (TMA) in the urine. The typical fish-like odor of TMA also appears on the breath or in the sweat of affected individuals. In normal man TMA is oxidized to its odorless N-oxide derivative. TMA is of dietary origin, formed by intestinal bacterial degradation of the choline in egg yolk, liver, soybeans, etc., or by reduction of TMA-oxide present in high concentrations in marine fish. 2 sisters with the tentative diagnosis of trimethylaminuria are presented.

Combination of variant P.PRO153LEU and P.GLU158LYS polymorphism in FMO3 gene cause of “MILD” fish odor syndrome in a child of 2 years

Combination of variant P.PRO153LEU and P.GLU158LYS polymorphism in FMO3 gene cause of “MILD” fish odor syndrome in a child of 2 years

The genetic and biochemical basis of trimethylaminuria in an Irish cohort.

BackgroundInherited trimethylaminuria (TMAU), a rare genetic disorder of hepatic metabolism of trimethylamine (TMA) causing excessive accumulation of malodorous trimethylamine (TMA), is a socially distressing disorder. Diagnosis is made by biochemical analysis of urine, with the calculation of flavin monooxygenase trimethylamine conversion capacity. Genetic testing, sequencing the entire coding region of the FMO3 gene has been recommended for affected individuals who convert less than 90% of the total TMA load to TMAO.MethodsGenetic analysis was undertaken for 13 Irish patients with TMAU of varying phenotypic severity (three severe, six moderate, and four mild).ResultsA genetic diagnosis was made for seven patients, including for five of the nine moderate to severely affected cases. We noted the c.913G>T;p.(Glu305*) and c.458C>T;p.(Pro153Leu) mutations in this Irish population with severe TMAU which is consistent with our earlier findings in Australian and North American families of Irish and British descent.Three individuals were noted to be homozygous for the common variant haplotype c.472G>A;923A>G;p.(Glu158Lys);(Glu308Gly). We also identified three novel variants in this population, which are likely to be pathogenic: c.682G>A;p(Gly228Ser), c.694G>T:p(Asp232Tyr), and c.989G>A;p.(Gly330Glu).ConclusionUrinary biochemical analysis probably remains the first line diagnostic approach to classify the various types of TMAU. FMO3 gene analysis is likely only to be informative for certain presentations of TMAU.

The Nose Knows… or Does it? Olfactory Reference Syndrome in Patients Presenting for Assessment of Unusual Body Odor.

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.