[en] [en] 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.
Disciplines :
Psychiatry
Author, co-author :
Bouchemal, Nadia ; CSPBAT, UMR 7244, CNRS, Université Paris 13, Sorbonne Paris Cité, Bobigny, France. nadia.bouchemal@univ-paris13.fr
Ouss, Lisa ; Université de Liège - ULiège > Département des sciences cliniques > Psychiatrie infanto-juvénile ; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, APHP, Paris, France ; Service de Pédopsychiatrie, Necker-Enfants Malades Hospital, APHP, Paris, France
Brassier, Anaïs; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, APHP, Paris, France
Barbier, Valérie; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, APHP, Paris, France
Gobin, Stéphanie; Unité de Génétique moléculaire, Necker-Enfants Malades Hospital, APHP, Paris, France
Hubert, Laurence; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, APHP, Paris, France
de Lonlay, Pascale; Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, Imagine Institute, Université Paris-Descartes, APHP, Paris, France
Le Moyec, Laurence; UBIAE, EA 7362, Univ Evry Université Paris-Saclay, Evry, France
Language :
English
Title :
Diagnosis and phenotypic assessment of trimethylaminuria, and its treatment with riboflavin: 1H NMR spectroscopy and genetic testing.
Messenger J, Clark S, Massick S, Bechtel M. A review of trimethylaminuria: (fish odor syndrome). J Clin Aesthet Dermatol. 2013;6(11):45-8.
Al-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. Trimethylaminuria: the detection of carriers using a trimethylamine load test. J Inherit Metab Dis. 1989;12(1):80-5.
Eugene M. Diagnosis of "fish odor syndrome" by urine nuclear magnetic resonance proton spectrometry. Ann Dermatol Venereol. 1998;125(3):210-2.
Eugène M. Trimethylaminurea; Orphanet Enc. 2002;1-3. http://www.orpha.net/data/patho/GB/uk-FOS.pdf.
Chalmers RA, Bain MD, Michelakakis H, Zschocke J, Iles RA. Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. J Inherit Metab Dis. 2006;29(1):162-72.
Abeling NG, van Gennip AH, Bakker HD, Heerschap A, Engelke U, Wevers RA. Diagnosis of a new case of trimethylaminuria using direct proton NMR spectroscopy of urine. J Inherit Metab Dis. 1995;18(2):182-4.
daCosta KA, Vrbanac JJ, Zeisel SH. The measurement of dimethylamine, trimethylamine, and trimethylamine N-oxide using capillary gas chromatography-mass spectrometry. Anal Biochem. 1990;187(2):234-9.
Johnson DW. A flow injection electrospray ionization tandem mass spectrometric method for the simultaneous measurement of trimethylamine and trimethylamine N-oxide in urine. J Mass Spectrom. 2008;43(4):495-9.
Mamer OA, Choiniere L, Lesimple A. Measurement of urinary trimethylamine and trimethylamime oxide by direct infusion electrospray quadrupole time-of-flight mass spectrometry. Anal Biochem. 2010;406(1):80-2.
Hsu WY, Lo WY, Lai CC, Tsai FJ, Tsai CH, Tsai Y, Lin WD, Chao MC. Rapid screening assay of trimethylaminuria in urine with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(12):1915-9.
Tjoa S, Fennessey P. The identification of trimethylamine excess in man: quantitative analysis and biochemical origins. Anal Biochem. 1991;197(1):77-82.
Maschke S, Wahl A, Azaroual N, Boulet O, Crunelle V, Imbenotte M, Foulard M, Vermeersch G, Lhermitte M. 1H-NMR analysis of trimethylamine in urine for the diagnosis of fish-odour syndrome. Clin Chim Acta. 1997;263(2):139-46.
Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome. Nat Genet. 1997;17(4):491-4.
Treacy EP, Akerman BR, Chow LM, Youil R, Bibeau C, Lin J, Bruce AG, Knight M, Danks DM, Cashman JR, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7(5):839-45.
Zschocke J, Kohlmueller D, Quak E, Meissner T, Hoffmann GF, Mayatepek E. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet. 1999;354(9181):834-5.
Yamazaki H, Fujita H, Gunji T, Zhang J, Kamataki T, Cashman JR, Shimizu M. Stop codon mutations in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population. Mol Genet Metab. 2007;90(1):58-63.
Yamazaki H, Shimizu M. Genetic polymorphism of the flavin-containing monooxygenase 3 (FMO3) associated with trimethylaminuria (fish odor syndrome): observations from Japanese patients. Curr Drug Metab. 2007;8(5):487-91.
Shimizu M, Kobayashi Y, Hayashi S, Aoki Y, Yamazaki H. Variants in the flavin-containing monooxygenase 3 (FMO3) gene responsible for trimethylaminuria in a Japanese population. Mol Genet Metab. 2012;107(3):330-4.
Cashman JR, Bi YA, Lin J, Youil R, Knight M, Forrest S, Treacy E. Human flavin-containing monooxygenase form 3: cDNA expression of the enzymes containing amino acid substitutions observed in individuals with trimethylaminuria. Chem Res Toxicol. 1997;10(8):837-41.
Park CS, Kang JH, Chung WG, Yi HG, Pie JE, Park DK, Hines RN, McCarver DG, Cha YN. Ethnic differences in allelic frequency of two flavin-containing monooxygenase 3 (FMO3) polymorphisms: linkage and effects on in vivo and in vitro FMO activities. Pharmacogenetics. 2002;12(1):77-80.
Lattard V, Zhang J, Tran Q, Furnes B, Schlenk D, Cashman JR. Two new polymorphisms of the FMO3 gene in Caucasian and African-American populations: comparative genetic and functional studies. Drug Metab Dispos. 2003;31(7):854-60.
Al-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL. A genetic polymorphism of the N-oxidation of trimethylamine in humans. Clin Pharmacol Ther. 1987;42(5):588-94.
Guo Y, Hwang LD, Li J, Eades J, Yu CW, Mansfield C, Burdick-Will A, Chang X, Chen Y, Duke FF, et al. Genetic analysis of impaired trimethylamine metabolism using whole exome sequencing. BMC Med Genet. 2017;18(1):11.
Shimizu M, Yano H, Nagashima S, Murayama N, Zhang J, Cashman JR, Yamazaki H. Effect of genetic variants of the human flavin-containing monooxygenase 3 on N- and S-oxygenation activities. Drug Metab Dispos. 2007;35(3):328-30.
Lambert DM, Mamer OA, Akerman BR, Choiniere L, Gaudet D, Hamet P, Treacy EP. In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene. Mol Genet Metab. 2001;73(3):224-9.
Brunelle A, Bi YA, Lin J, Russell B, Luy L, Berkman C, Cashman J. Characterization of two human flavin-containing monooxygenase (form 3) enzymes expressed in Escherichia coli as maltose binding protein fusions. Drug Metab Dispos. 1997;25(8):1001-7.
Zhang AQ, Mitchell SC, Smith RL. Exacerbation of symptoms of fish-odour syndrome during menstruation. Lancet. 1996;348(9043):1740-1.
Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome. Drug Metab Dispos. 2001;29(4 Pt 2):517-21.
Manning NJ, Allen EK, Kirk RJ, Sharrard MJ, Smith EJ. Riboflavin-responsive trimethylaminuria in a patient with homocystinuria on betaine therapy. JIMD Rep. 2012;5:71-5.
Rocher F, Caruba C, Broly F, Lebrun C. L-carnitine treatment and fish odor syndrome: an unwaited adverse effect. Rev Neurol (Paris). 2011;167(6-7):541-4.
Podadera P, Sipahi AM, Areas JA, Lanfer-Marquez UM. Diagnosis of suspected trimethylaminuria by NMR spectroscopy. Clin Chim Acta. 2005;351(1-2):149-54.
Begum M, McKenna PJ. Olfactory reference syndrome: a systematic review of the world literature. Psychol Med. 2011;41(3):453-61.
Stein DJ, Le Roux L, Bouwer C, Van Heerden B. Is olfactory reference syndrome an obsessive-compulsive spectrum disorder?: two cases and a discussion. J Neuropsychiatry Clin Neurosci. 1998;10(1):96-9.
Feusner JD, Phillips KA, Stein DJ. Olfactory reference syndrome: issues for DSM-V. Depress Anxiety. 2010;27(6):592-9.
Greenberg JL, Shaw AM, Reuman L, Schwartz R, Wilhelm S. Clinical features of olfactory reference syndrome: an internet-based study. J Psychosom Res. 2016;80:11-6.
Wise PM, Eades J, Tjoa S, Fennessey PV, Preti G. Individuals reporting idiopathic malodor production: demographics and incidence of trimethylaminuria. Am J Med. 2011;124(11):1058-63.
Suzuki K, Takei N, Iwata Y, Sekine Y, Toyoda T, Nakamura K, Minabe Y, Kawai M, Iyo M, Mori N. Do olfactory reference syndrome and jiko-shu-kyofu (a subtype of taijin-kyofu) share a common entity? Acta Psychiatr Scand. 2004;109(2):150-5 discussion 155.
Phillips KA, Menard W. Olfactory reference syndrome: demographic and clinical features of imagined body odor. Gen Hosp Psychiatry. 2011;33(4):398-406.
Takekita Y, Kato M, Sakai S, Suwa A, Nishida K, Tajika A, Yoshimura M, Kinoshita T. Olfactory reference syndrome treated by blonanserin augmentation. Psychiatry Clin Neurosci. 2011;65(2):203-4.
Olsen RK, Olpin SE, Andresen BS, Miedzybrodzka ZH, Pourfarzam M, Merinero B, Frerman FE, Beresford MW, Dean JC, Cornelius N, et al. ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency. Brain. 2007;130(Pt 8):2045-54.
Moolenaar SH, Poggi-Bach J, Engelke UF, Corstiaensen JM, Heerschap A, de Jong JG, Binzak BA, Vockley J, Wevers RA. Defect in dimethylglycine dehydrogenase, a new inborn error of metabolism: NMR spectroscopy study. Clin Chem. 1999;45(4):459-64.
Yamazaki H, Shimizu M. Survey of variants of human flavin-containing monooxygenase 3 (FMO3) and their drug oxidation activities. Biochem Pharmacol. 2013;85(11):1588-93.
D'Angelo R, Scimone C, Esposito T, Bruschetta D, Rinaldi C, Ruggeri A, Sidoti A. Fish odor syndrome (trimethylaminuria) supporting the possible FMO3 down expression in childhood: a case report. J Med Case Rep. 2014;8:328.
Yeung CK, Adman ET, Rettie AE. Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria. Arch Biochem Biophys. 2007;464(2):251-9.
Dolphin CT, Janmohamed A, Smith RL, Shephard EA, Phillips IR. Compound heterozygosity for missense mutations in the flavin-containing monooxygenase 3 (FM03) gene in patients with fish-odour syndrome. Pharmacogenetics. 2000;10(9):799-807.
Furnes B, Feng J, Sommer SS, Schlenk D. Identification of novel variants of the flavin-containing monooxygenase gene family in African Americans. Drug Metab Dispos. 2003;31(2):187-93.
Cashman JR, Camp K, Fakharzadeh SS, Fennessey PV, Hines RN, Mamer OA, Mitchell SC, Nguyen GP, Schlenk D, Smith RL, et al. Biochemical and clinical aspects of the human flavin-containing monooxygenase form 3 (FMO3) related to trimethylaminuria. Curr Drug Metab. 2003;4(2):151-70.
Phillips IR, Shephard EA. Flavin-containing monooxygenases: mutations, disease and drug response. Trends Pharmacol Sci. 2008;29(6):294-301.
Zuppi C, Messana I, Forni F, Rossi C, Pennacchietti L, Ferrari F, Giardina B. 1H NMR spectra of normal urines: reference ranges of the major metabolites. Clin Chim Acta. 1997;265(1):85-97.
