Trimethylaminuria is a genetic disorder
Submitting InstitutionsUniversity College London,
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Genetics
Summary of the impact
Research by Professor Elizabeth Shephard at the UCL Research Department
of Structural and Molecular Biology has led to identification of the
genetic origin of Trimethylaminuria (TMAU), commonly known as fish-odour
syndrome. This has led to genetic diagnosis and genetic counselling for
TMAU in the UK, Europe, USA and Canada, and the publication of guidelines
for treatment and diagnosis. Shephard has engaged closely with patient
groups over the years to publicise her findings. There is now an increased
understanding among medical practitioners and the public that the body
odour produced is due to a metabolic defect of genetic origin, and is not
due to poor hygiene.
Trimethylaminuria (TMAU) is a rare but distressing disorder in which
sufferers excrete large amounts of trimethylamine (TMA) in the breath,
urine and sweat, resulting in an unpleasant body odour similar to rotting
fish, or, in some individuals, rotting garbage. The incidence is about 1
in 40,000 and all ethnic groups are affected. The impacts reported here
stem from basic molecular biology, biochemistry and molecular genetic
research undertaken from the mid-1990s to the present at UCL, in
collaboration with Ian Phillips, Queen Mary, University of London (now
retired) and initially also with R. Smith (now retired), St. Mary's
It was known that TMA could be converted to its N-oxide by a
flavin-containing monooxygenase in liver and that individuals responded
differently to a trimethylamine challenge. Thus a genetic origin for TMAU
was suspected. This research took place without the benefit of the rapid
sequencing and genome resources available today. A systematic cDNA cloning
strategy identified five different flavin-containing monooxygenase (FMO)
mRNAs (FMOs 1, 2, 3, 4 and 5) and the five genes were mapped to the long
arm of chromosome 1 . Analysis of expression patterns in human
tissue  identified FMO3 as the best candidate for the disorder.
Using a then-novel method for exon determination, the gene structure for FMO3
was determined . Amplification and DNA sequencing of exons
revealed a mutation in an affected individual that changed pro153 to
leu153. The child was homozygous for the mutation and the parents were
heterozygous for this mutation. The mutant protein was expressed from its
cDNA and shown not to be able to convert TMA to TMA N-oxide.
These results led, in 1997, to a paper in Nature Genetics reporting for
the first time a genetic basis for TMAU . This was accompanied
by media coverage across the world and began the process of understanding
of the genetic contribution to TMAU. Subsequently we, and others,
identified additional mutations in the FMO3 gene that cause TMAU
in different families. Over thirty mutations are now known to cause TMAU.
Some cases proved to be caused by compound heterozygosity .
In 2003 we created an online database of FMO3 mutations to inform
researchers, patients and medical practitioners . Since 2013
the database, which is curated at UCL, has been hosted by the Leiden Open
Variation Database (LOVD) Server, which permits researchers to submit new
mutations and thus increases the resource for genetic testing services and
patients who elect for testing. This is an ongoing project.
In 2013 we were awarded funding under the MRC DFPS/DCS: MICA scheme for
translational research to carry out a preclinical trial for a therapeutic
we have devised, with industry, for TMAU. This preclinical trial project
is in collaboration with an industrial partner.
References to the research
 Phillips IR, Dolphin CT, Clair P, Hadley MR, Hutt AJ, McCombie RR,
Smith RL, Shephard EA. The molecular biology of the flavin-containing
monooxygenases of man. Chem Biol Interact. 1995 Apr 28;96(1):17-32. http://dx.doi.org/10.1016/0009-2797(94)03580-2
 Dolphin CT, Cullingford TE, Shephard EA, Smith RL, Phillips IR.
Differential developmental and tissue-specific regulation of expression of
the genes encoding three members of the flavin-containing monooxygenase
family of man, FMO1, FMO3 and FM04. Eur J Biochem. 1996 Feb
 Dolphin CT, Riley JH, Smith RL, Shephard EA, Phillips IR. Structural
organization of the human flavin-containing monooxygenase 3 gene (FMO3),
the favored candidate for fish-odor syndrome, determined directly from
genomic DNA. Genomics. 1997 Dec 1;46(2):260-7.
 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 Dec;17(4):491-4. http://dx.doi.org/10.1038/ng1297-491
 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 Dec;10(9):799-807. http://doi.org/bxqpnn
 Hernandez D, Addou S, Lee D, Orengo C, Shephard EA, Phillips IR.
Trimethylaminuria and a human FMO3 mutation database. Hum Mutat. 2003
• I.R. Phillips (Queen Mary and Westfield), E. A. Shephard (UCL), R.
Smith (St Mary's Medical School) — Wellcome Trust: The flavin-containing
monooxygenase family of man and the molecular genetics of fish-odour
syndrome; The Wellcome Trust; (1995-8) (£168,799).
• E. A. Shephard (UCL), I. R. Phillips (Queen Mary) — Wellcome Trust: The
flavin-containing monooxygenase family: regulation, function and inherited
disorders (1998-2004) (£636,853).
• E.A. Shephard (UCL) — MRC DFPS/DCS: MICA. Therapy for the body and
breath malodour disorder Trimethylaminuria (TMAU) (2013-5) (£358,123.90;
FEC £445,436). Industrial contribution in kind, £510,000.
Details of the impact
The identification of the gene for FMO3 and the elucidation of TMAU as a
genetic disorder have transformed our understanding of why some
individuals have an extremely unpleasant `fishy' body odour. Prior to our
1997 paper , which proved that TMAU is caused by mutations in
the FMO3 gene, affected individuals were presumed to have poor
hygiene. Individuals with TMAU can suffer social isolation, depression,
rejection and higher than normal suicide rates. In some cases, because the
odour is episodic, medical practitioners assumed the symptoms to be
imaginary and resorted to psychiatric referral and prescription of
antidepressants or antipsychotics. This creates an even worse outcome,
because several of these drugs are substrates for FMO3, and the limited
enzyme activity that the patient has is then occupied by drug
Impact on clinical practice
Our work on TMAU has led to increased understanding by the medical
profession of the genetic basis of the disorder of body odour. In 2007, at
the invitation of the National Institutes of Health, USA (NIH), we
produced a TMAU resource for the medical profession, which was updated in
2011 [a]. The resource provides information on the disorder, its
treatment and its diagnosis. A spokesman for the patient advocacy group,
MEBO, states that "this is the resource which we recommend to everyone who
wants information on TMAU" [b]. Shephard also contributed to the
NHS Choices page on trimethylaminuria in 2013 [c].
The identification of a genetic origin has enabled increased understanding
of the condition by sufferers and those around them. For example, MEBO
report that: "One Kenyan TMAU sufferer was being persecuted by neighbours
and feared having to go to the police. She was able to send Dr Shephard's
scientific TMAU paper to the management committee of her housing block to
support her explanation of her condition
Following our discovery that TMAU is due to mutations in the FMO3
gene, private testing facilities began to offer a diagnostic test.
Subsequently, the NHS added the test to their list of genetic tests, and
testing is also available elsewhere in the world. Various companies have
reported the numbers of patients tested as follows for the period 2008-13:
- Sheffield Diagnostic Genetics Service: 236 patients tested (since
- Prevention Genetics, Wisconsin: 79 unique patients
- University of Colorado, Denver: 1-2 patients per month
- Mount Sinai Hospital, Toronto, Canada: 1 patient tested
- GENETAQ, Molecular Genetics Centre, Malaga, Spain: 13 families tested
Urine and genetic testing for TMAU are available on the NHS, but this is
not the case in most countries, where patients must pay for costly tests.
With the advent of cheaper DNA sequencing, some patients may elect to have
their FMO3 gene sequenced. In collaboration with the patient group
MEBO (see below), Shephard assists with the sequencing reads and
explanation to patients [b]. In 2011 we published the European
guidelines (Clinical Utility Gene Card) for genetic testing of TMAU [f].
This provides guidelines for the medical profession and genetic testing
Work with patients and patient groups
The unusual nature of TMAU has led to close links between researchers and
patients developing in the course of the research described above, which
continue today. In 2010, the patient advocacy group MEBO was founded, and
Shephard has acted as scientific advisor to this group since 2011 [g].
MEBO provides support and advice for those who suffer from TMAU with
registered branches in the US, UK and Europe. It now has around 1,200
members worldwide. In January 2012, Shephard assisted the organisation
with a submission to fast-track TMAU for Social Security support in the US
[h]. Later that year she was appointed to the Institutional Review
Board (USA) for ethical assessment of a breath test device as part of a
MEBO-initiated project. One member of the group has reported on the
following positive impacts that Shephard's work has had on the community:
"her approachability as a scientific advisor for MEBO Research; her
educational articles which have helped our TMAU community
internationally; her willingness to build bridges between the layperson
sufferer and the biomedical scientist, and her support in empowering the
TMAU community to take action to help itself" [i].
Shephard has presented lectures and webinars on her research for MEBO to
explain the science behind TMAU to those with the condition [i].
She presented at the MEBO Research Body Odor and Halitosis meet-ups in
Washington (April 2011) and Miami (June 2012) [j]. Shephard also
posts on the MEBO website and assists with lay postings on the disorder on
the organisation's blog. She has also helped patients to write articles
about their experience, for example, one such article was published in the
Daily Mirror and internationally. In 2012 she assisted another patient
with an article for the Royal College of General Practitioners' InnovAiT
journal [k].The disorder has been the subject of several TV
programmes (e.g. BBC 2011, Food programme), radio (e.g. BBC World Service,
March 2012 [l]) and the press. In each of these instances,
Shephard has acted as advisor or interviewee. This coverage has had a huge
`advertising' impact, helping to increase public awareness of the
Sources to corroborate the impact
[a] NCBI resource for Trimethylaminuria: http://www.ncbi.nlm.nih.gov/books/NBK1103/
(Page viewed 7,748 times in the period May 2012-April 2013)
[b] Letter of testimony available from MEBO's Managing Director which
corroborates details of the organisation and endorses the importance of
Shephard's work. Contact details provided.
[c] NHS Choices page on trimethylaminuria. Emails attesting to Shephard's
involvement in writing these pages can be provided on request.
[d] Letter of testimony from MEBO member available on request. Contact
[e] Genetic testing is now offered by a number of organisations. Emails
confirming patient numbers are available on request:
[f] Clinical utility gene card for Trimethylaminuria: http://www.eurogentest.org/index.php?id=668
[g] MEBO page giving details of Shephard's role as scientific advisor to
[h] Information on the MEBO Blog about Shephard's involvement in the
[i] MEBO Research — includes links to webinars by Shephard, and other
resources she has collaborated in: http://www.meboresearch.org/trimethylaminuria.html
[j] MEBO public engagement activities:
[k] Assisted patient with article. http://ino.sagepub.com/content/6/4/256.full.
Copy available on request.
[l] BBC World service programme, March 2012:
(1,248 plays at 15 July 2013)