Diagnosis and phenotypic assessment of trimethylaminuria, and its treatment with riboflavin:  1 H NMR spectroscopy and genetic testing

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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.

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Most cited references 46

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Missense mutation in flavin-containing mono-oxygenase 3 gene, FMO3, underlies fish-odour syndrome.

C T Dolphin, A Janmohamed, R. L. Smith … (1997)

Individuals with primary trimethylaminuria exhibit a body odour reminiscent of rotting fish, due to excessive excretion of trimethylamine (TMA; refs 1-3). The disorder, colloquially known as fish-odour syndrome, is inherited recessively as a defect in hepatic N-oxidation of dietary-derived TMA and cannot be considered benign, as sufferers may display a variety of psychosocial reactions, ranging from social isolation of clinical depression and attempted suicide. TMA oxidation is catalyzed by flavin-containing mono-oxygenase (FMO; refs 7,8), and tissue localization and functional studies have established FMO3 as the form most likely to be defective in fish-odour syndrome. Direct sequencing of the coding exons of FMO3 amplified from a patient with fish-odour syndrome identified two missense mutations. Although one of these represented a common polymorphism, the other, a C-->T transition in exon 4, was found only in an affected pedigree, in which it segregated with the disorder. The latter mutation predicts a proline-->leucine substitution at residue 153 and abolishes FMO3 catalytic activity. Our results indicate that defects in FMO3 underlie fish-odour syndrome and that the Pro 153-->Leu 153 mutation described here is a cause of this distressing condition.

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Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication.

D Danks, R Youil, James Chow … (1998)

Individuals with the recessive condition trimethylaminuria exhibit variation in metabolic detoxication of xenobiotics by hepatic flavin-containing monooxygenases. We show here that mutations in the human flavin-containing monooxygenase isoform 3 gene ( FMO3 ) impair N -oxygenation of xenobiotics and are responsible for the trimethylaminuria phenotype. Three disease-causing mutations in nine Australian-born probands have been identified which share a particular polymorphic haplotype. Nonsense and missense mutations are associated with a severe phenotype and are also implicated in impaired metabolism of other nitrogen- and sulfur-containing substrates including biogenic amines, both clinically and when mutated proteins expressed from cDNA are studied in vitro . These findings illustrate the critical role played by human FMO3 in the metabolism of xenobiotic substrates and endogenous amines.

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Flavin-containing monooxygenases: mutations, disease and drug response.

I. Phillips, E. Shephard (2008)

Flavin-containing monooxygenases (FMOs) metabolize numerous foreign chemicals, including drugs, pesticides and dietary components and, thus, mediate interactions between humans and their chemical environment. We describe the mechanism of action of FMOs and insights gained from the structure of yeast FMO. We then concentrate on the three FMOs (FMOs 1, 2 and 3) that are most important for metabolism of foreign chemicals in humans, focusing on the role of the FMOs and their genetic variants in disease and drug response. Loss-of-function mutations of FMO3 cause the disorder trimethylaminuria. More common variants that decrease enzyme activity are associated with increased drug efficacy. Most humans are homozygous for a nonsense mutation that inactivates FMO2. But a substantial proportion of sub-Saharan Africans express functional FMO2 and, thus, are predicted to respond differently to drugs and other foreign chemicals.

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Author and article information

Contributors

Nadia Bouchemal:

ORCID: http://orcid.org/0000-0001-8967-1457

nadia.bouchemal@univ-paris13.fr

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 18 September 2019

Publication date PMC-release: 18 September 2019

Publication date Collection: 2019

Volume: 14

Electronic Location Identifier: 222

Affiliations

[1 ]ISNI 0000000121496883, GRID grid.11318.3a, CSPBAT, UMR 7244, CNRS, , Université Paris 13, Sorbonne Paris Cité, ; Bobigny, France

[2 ]ISNI 0000 0001 2175 4109, GRID grid.50550.35, Reference Centre for Metabolic Diseases, Necker-Enfants Malades Hospital, , Imagine Institute, Université Paris-Descartes, APHP, ; Paris, France

[3 ]ISNI 0000 0004 0593 9113, GRID grid.412134.1, Service de Pédopsychiatrie, , Necker-Enfants Malades Hospital, APHP, ; Paris, France

[4 ]ISNI 0000 0004 0593 9113, GRID grid.412134.1, Unité de Génétique moléculaire, , Necker-Enfants Malades Hospital, APHP, ; Paris, France

[5 ]ISNI 0000 0004 4910 6535, GRID grid.460789.4, UBIAE, EA 7362, , Univ Evry Université Paris-Saclay, ; Evry, France

Author information

Nadia Bouchemal http://orcid.org/0000-0001-8967-1457

Article

Publisher ID: 1174

DOI: 10.1186/s13023-019-1174-6

PMC ID: 6751875

PubMed ID: 31533761

SO-VID: 07196b2c-4250-47b8-9b78-e073261629da

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 June 2018

Date accepted : 13 August 2019

Custom metadata

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: trimethylaminuria,olfactory reference syndrome,fmo3 gene,proton nuclear magnetic resonance spectroscopy

Data availability:

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: trimethylaminuria, olfactory reference syndrome, fmo3 gene, proton nuclear magnetic resonance spectroscopy