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Tuesday, March 9, 2010

New Trimethylaminuria document from Nigel Manning

The urine test consists of two measurements:
a. trimethylamine or ‘Free’ TMA
b. TMA-oxide [+ free TMA] = ‘Total’ TMA.
Regular readers will know that Nigel Manning, Principal Clinical Scientist of Dept. Clinical Chemistry at Sheffield Children's Hospital in England has always been very kindly communicative to us about trimethylaminuria, including giving an in-depth interview about TMAU testing last year. Nigel has kindly given us a pdf document that is very good as a reference to trimethylamunuria, as well as giving insight into the statistics of his testing lab in Sheffield, which is the only known TMAU genotype (urine) test lab in the UK.

Nigel has also kindly offered to be allowed to be contacted from around the world by people thinking of testing or wishing to discuss their results.

Below is the new document in pdf format, which is hosted on our MeBO Research website :


We have also included it in fulltext below for those without a pdf reader (minus the graphs)

TMAU – diagnostic testing at Sheffield Children’s Hospital.
Nigel Manning Dept. Clinical Chemistry, Sheffield Children’s Hospital,
Sheffield UK.

Introduction

The phenomenon of ‘fish odour’ has been reported for many centuries. More
recently attributed to the tertiary amine trimethylamine (TMA), the ammoniacal
body odour like the smell of rotting fish can have severely detrimental effects
on the lives of those suffering from ‘Fish Odour Syndrome’. Now more
commonly referred to as Trimethylaminuria or TMAU, patients with this
unfortunate condition exhibit increased excretion of TMA in urine as well as in
sweat and breath vapour. The main causes of TMAU, low hepatic TMA
oxidation and intestinal overproduction of TMA give rise to the two main types
of the disorder.

The inherited form of TMAU is known as Primary TMAU (TMAU1). The result
of a faulty autosomal recessive gene, TMAU1 patients have impaired activity
of a liver enzyme flavin-containing mono-oxygenase type 3 (FMO3) which
oxidises a wide range of substrates including many drugs. TMA is oxidised to
non-odorous TMA-oxide (TMO) by FMO3 which can then be excreted. TMA
itself is generated in the large intestine by bacterial degradation of compounds
such as choline (high in liver, eggs and beans/peas), carnitine (meat) and
TMO from seafood (TMA from fish ‘spoilage’ has been attributed to several
species of Vitrio and Shewanella bacteria).

TMAU1 therefore results from FMO3 deficiency with an increase in the ratio of
TMA to TMO in urine which can be used for diagnosis.

Due to the broad spectrum of substrates oxidised by FMO3, TMAU1 patients
may suffer from adverse reactions with many drugs including codeine,
tamoxifen, ketoconazole, nicotine, cimetidine, ranitidine and phenothiazine.
Hypertension may result from ingestion of red wine and cheese (and
chocolate), which produce the neurotransmitter tyramine, another FMO3
dependent compound. Many people suffer from migraines associated with
tyramine containing foods and perhaps FMO3 deficiency may explain some of
these cases, but overall this demonstrates the adverse medical
consequences of TMAU1 as well as the odour related psychosocial aspects.
The acquired form of TMAU is covered by the term Secondary TMAU
(TMAU2) where TMA excretion is high even though FMO3 activity is normal.
Most TMAU2 patients produce too much intestinal TMA due to excessive
bacterial growth of TMA-generating species. The TMA burden is so great that
FMO3 oxidation produces large amounts of TMO but (in most cases – but not
all) is still unable to oxidise enough TMA to prevent an excess. This problem
may be exacerbated by intestinal structural problems such as ‘blind loops’ or
post- operative complications. TMAU2 usually presents in adulthood although
children have been known to acquire excessive TMA-producing bacteria with
the resultant odour.

The diagnosis of TMAU2 depends on the detection of increased urinary TMA
and TMO with a normal TMA/TMO ratio indicating normal oxidation by FMO3.
Patients with liver or kidney disease have been known to produce a TMAU1-
like pattern of excretion, although due to a secondary cause. Importantly this
may also occur with a urinary tract infection (UTI) which results in TMA being
produced directly into the urine giving a false positive result. Whenever results
suggest TMAU1, therefore, UTI must always be excluded by microbial
analysis before a TMAU1 diagnosis can be confirmed in a follow-up sample.

Testing for TMAU

The urine test consists of two measurements:
a. trimethylamine or ‘Free’ TMA
b. TMA-oxide [+ free TMA] = ‘Total’ TMA.

The technique currently used in our laboratory is gas chromatography – mass
spectrometry (GCMS) analysis of the ‘headspace’ vapour of heated,
alkalinised urine. This method superseded a direct injection MS method used
from 1997 until 2002. Results from the two methods compared well, although
the current methodology allows for automated headspace sampling and
GCMS injection.

A positive result is usually followed up with a routine second test after a report
of the initial findings. The turnaround time for the test is currently 4 weeks or
less. A GP or physician referral is essential, but we can offer advice by phone
or email about how to start the process.

DNA analysis for the FMO3 gene is also now available with a turnaround time
of 8 weeks. The genetic test provides the vital confirmation required for a firm
diagnosis of TMAU1 and has demonstrated that the TMA / TMA-oxide ratio
may normalise in TMAU1 due to spurious increases in urinary TMA-oxide.

Results and Diagnoses
We tested 1150 urines from 716 individuals from 1997 to 2009.
379 results indicated significant TMAU.

Many TMAU sufferers may restrict their diet before testing in an effort to
reduce odour. This may occasionally affect an initial diagnosis as TMA
excretion may be sufficiently reduced to normal or give a normal Free to Total
TMA ratio (less than 21%). For diagnostic clarity it is essential that the sample
is collected when odour is at it’s maximum. This may necessitate creating the
conditions which induce the odour such as dietary intake of choline (eg
pulses, eggs, liver), carnitine (red meat) and trimethylamine oxide (seafood).
Dietary ‘loading’ is possibly most effective when restricted to a simple high
choline meal of 2 eggs and 400g baked beans. Previously choline
monohydrate was an effective loading agent but has become difficult to obtain
as a chemical for patient administration. The effect of choline loading and
diagnostic clarification achieved by loading can be seen in the following case
report.

A case of choline load to aid diagnosis in a case of TMAU:

An adult presenting with a significant odour was tested for urinary TMA. The
results showed both an increased TMA and Free/Total TMA ratio, which
indicated a possible primary defect (TMAU1). [Fig.2]

A repeat 24 hour acidified sample however gave a normal Free/Total ratio,
with increases in both the Free and Total TMA – suggesting the possibility of
increased oxidation in response to an increased Free TMA burden (a possible
indication of TMAU2).

Antibiotic therapy was commenced and resulted in the normalisation of Free
TMA although the Total TMA was still increased (again an indication of
increased oxidation in response to increased intestinal output of Free TMA).
For clarification a 5 gram choline monohydrate load was given to the patient
and samples collected for 72 hours after load.

Total TMA showed a dramatic increase (with Free TMA) and the Free/Total
ratio remained within normal limits. Gradually the Free and Total TMA
reduced to nearly normal excretion values.

These results indicated a treatable TMAU2 . The first result was probably due
to a urinary tract infection or bacterial contamination of the inital sample which
had not been acidified). The patient was further treated with antibiotics to
eradicate enterobacterial overgrowth.

Discussion
GCMS analysis of headspace vapour of alkalinised urine with stable isotope
dilution provides a robust method to measure both free and total TMA for the
diagnosis of TMAU1and 2. Differential diagnosis can be hampered by genitourinary
infections and intermittent presentations which may reflect TMAU1
carrier status.

Treatment of both TMAU1 and TMAU2 is based on diet to restrict the sources
(precursors) of TMA and antibiotics to eliminate the TMA-producing bacteria.
TMAU2 can in fact be cured by eradication of the excess bacteria, although
stubborn colonies may re-grow to excess and require further courses of
treatment.

TMAU1, as a genetic defect, cannot be completely cured although therapy
(dietary and antibiotic) can successfully control the patient’s free TMA to a
less odorous level. Patient’s residual enzyme activity is variable depending on
the specific mutation and as such trials with the cofactor riboflavin have been
tried with some success. Milder TMAU1 patients can, however, reduce their
TMA to almost normal values with just diet and periodic antibiotic therapy.
Other forms of therapy are based on the neutralisation of TMA chemically.
Skin creams with a comparatively low pH (5.0) may neutralise alkaline TMA.
This creates a non-volatile salt of TMA which lessens any odour and can be
washed off by the patient later. Another solution lies in deodorising tablets
such as ‘activated charcoal’ or copper-chlorophyllin complex (marketed as
‘Nullo’). These ‘internal deodorants’ have been successfully used for many
years and would be ideal for more severely affected TMAU1 patients.
Detection and perception of odours varies between individuals. Some people
are odorous to friends, family and work colleagues but are unaware of an
odour, whilst others maintain they are odorous but those around them would
not agree. For those individuals who are sufficiently motivated to seek medical
help, the type of odour is often difficult to describe, but ranges from ‘chemical’
to ‘faecal’. ‘Rotten fish’ or ‘ammonia-like’ is not always mentioned, but TMAU
seems to have become a focus for all malodours, possibly due to awareness
of the disorder, the availability of a test and the possibility of a diagnosis.
A significant cohort of sulphurous or faecal odours have been reported by
individuals who contact the laboratory. This may be another enterobacterial
problem, but although Shewanella species are known to produce both
hydrogen sulphide and TMA, we have yet to measure an increased TMA or
TMO as a secondary marker for enterobacterial overgrowth in these cases.
For those with a significant TMAU, difficulties in diagnosis mainly stem from
the interpretation of TMA and free/total ratios given the background of diet,
variation of enzyme activity and variation of bacterial sources of TMA. This
can be summarised by the sub-types of presentation and biochemical
abnormality we have encountered over the past 12 years. The new FMO3
mutation service should help to clarify TMA results greatly in the years to
come.

TMAU1 and TMAU2 possible sub-types:

a. TMAU1 transient neonatal – possible delay in switch from fetal enzyme
FMO2 to FMO3 TMA oxidation, but resolves during development.
b. TMAU1 severe childhood - parenting / schooling problems are possible.
c. TMAU1 adulthood – probably presented in childhood; long-term sociopathy.
d. TMAU1 heterozygote – may present only during dietary load / menses.
e. TMAU1 very mild – ‘double dose’ DNA polymorphisms – TMA borderline.
f. TMAU1 FMO3 mutation proven TMAU1 with increased TMO (like TMAU2)

a. TMAU2 severe neonatal -‘sepsis’ massive TMA responds to antibiotics.
b. TMAU2 childhood - antibiotic eradication prevents school / social problems.
c. TMAU2 adulthood – may have long history of odour, eradication possible.
d. TMAU2 intermittent – difficult diagnosis without precursor load.
e. TMAU2 due to UTI – presents biochemically as TMAU1 (urine-only odour).
f. TMAU2 due to renal or hepatic dysfunction – presents as TMAU1.

References:
Ayesh R, Mitchell SC, Zhang A, Smith RL (1993) The fish odour syndrome:
biochemical, familial, and clinical aspects. Brit Med J 307: 655-657.
Chalmers RA, Bain MD, Iles RA (2003) Diagnosis of trimethylaminuria in children:
Marine fish versus choline load test. J Inher Metab Dis 26 (Suppl 2): (448-P) 224.
Fraser-Andrews EA, Manning NJ, Ashton GHS, Eldridge P, McGrath JA, Menagé H
(2003) Fish odour syndrome with features of both primary and secondary
trimethylaminuria. Clinical and Experimental Dermatology 28: 203-205
Humbert JR, Hammond KB, Hathaway WE, Marcoux JG, O’Brien D (1970)
Trimethylaminuria: The fish-odour syndrome. Lancet 2:770-771.
Lee WG, Yu JS, Turner BB, Murray KE (1976) Trimethylaminuria: Fishy odors in
children. New Eng J Med 295: 937-938.
Mitchell SC (1996) The fish odour syndrome. Perspectives in Biology and Medicine
39 (4)
Treacy EP, Ackerman BR, Chow LML et al (1998) Mutations of the flavin-containing
monooxygenase gene (FMO3) cause trimethylaminuria. A defect in detoxication.
Hum Mol Genet 7: 839-845.
Treacy E, Johnson D, Pitt JJ, Danks DM (1995) Trimethylaminuria, fish odour
syndrome: a new method of detection and response to treatment with metronidazole.
J Inher Metab Dis 18: 306-312.



2 comments:

Anonymous said...

my daughter has very fishy breath at times and sometimes smells like excrement, not all the time but intermittently.For many years now I have mentioned this to her dentist and she has good oral hygiene. I have only just found out about this rare genetic disorder and feel my GP will simply dismiss it as previous. I would like her to be tested as I feel she is becoming more sensitive and aware of her problem and some of her friends have commented on it. We live in Yorkshire and would greatly appreciate your advice.

Nov 29, 2013, 3:00:00 PM
blogcontributor2 said...

Hi. You are right to be concerned for your daughter. Probably the best thing to do is to try and get her tested via Nigel Manning at Sheffield Children's Hospital ( the only UK tester). You could try via your GP to get the test ordered, perhaps by giving your GP some info on the subject such as Nigel Manning's letter in this post and this one in the blog sidebar ... http://www.meboresearch.org/Nigel%20Manning%27s%20letter%20and%20TMA%20page%20to%20doctors%20outside%20UK.pdf )

Or you could try to get your daughter referred to a NHS metabolic clinic (if over 16, a Adult Metabolic Clinic). I know that the clinic in Manchester is aware of TMAU. Or you could even contact Nigel Manning. Do you have his email address ? Perhaps she could get tested at Sheffield Children's Hospital. I am sure he would at least arrange some way.

Or you could order the test privately via smartnutrition in Brighton who send out a test kit and the sample is sent to Nigel in Sheffield
http://www.smartnutrition.co.uk/health-tests/tmau-fish-odour-syndrome/

There is also a UK forum for TMAU people
http://www.tmau.org.uk/

Hope this helps. If you have any other questions feel free to ask.

Nov 29, 2013, 8:42:00 PM
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