Trimethylaminuria: An under-recognised and socially debilitatingmetabolic disorderjpc_1978 153..155
John Christodoulou
Genetic Metabolic Disorders Service, The Children’s Hospital at Westmead and Disciplines of Paediatrics and Child Health and Genetic Medicine, Sydney
Medical School, University of Sydney, Sydney, New South Wales, Australia
Abstract: Primary flavin mono-oxygenase 3 deficiency, an inborn error of choline metabolism, leads to an accumulation of trimethylamine,which because of its associated pungent odour of rotting fish, is a socially crippling disorder. Although it often has its onset in early childhood,it may take years or even decades before the diagnosis is established. In this review the clinical biochemical and genetic features of the disorderare reported. The principles of therapy will also be covered, including dietary, pharmacological approaches, as well as techniques used tomanipulate the gastrointestinal environment as a strategy to reduce the gastrointestinal load of trimethylamine.
Key words: fish odour syndrome; FMO3; inborn error of metabolism; trimethylaminuria.
It took 47 of my 52 years to find out why I had an odourproblem. Sadly, most GPs have never heard of TMAU. I suf-fered since childhood and saw doctor after doctor, only to betold repeatedly that there was nothing physically wrong withme – the problem was psychological. It was all in my head.Either that or I wasn’t paying enough attention to personalhygiene. Imagine the confusion and ongoing misery thatresult from such a situation over the long term – social isola-tion because of the stink, stunted careers and repeated boutsof major depression. These miseries are the common lot ofpeople with TMAU.
School was a nightmare. I was taunted with ‘You smell!’ At6 years old our teacher told me in front of the rest of the firstgraders to ‘Go home and tell your mother to wash you. Therest of the class shouldn’t have to put up with it’ she said. Iwas excluded. Bullied. I learnt that I was not a good person soat 14 I tried to kill myself. What’s the point in living whenevery time you walk into a room people say something like,
‘What died?’ And yet I could smell nothing. I often felt I waslosing my sanity. In fact I think I did a couple of times.
William Shakespeare, The Tempest, Act 2.Scene 2. (Trinculo’smonologue):‘What have we here? a man or a fish? dead or alive? A fish: hesmells like a fish; a very ancient and fish-like smell; a kind of not ofthe newest Poor-John. A strange fish! Were I in England now, as onceI was, and had but this fish painted, not a holiday fool there butwould give a piece of silver: there would this monster make a man;any strange beast there makes a man: when they will not give a doitto relieve a lame beggar, they will lazy out ten to see a dead Indian.Legged like a man and his fins like arms! Warm o’ my troth! I do nowlet loose my opinion; hold it no longer: this is no fish, but anislander, that hath lately suffered by a thunderbolt.’
The consequences of trimethylaminuria (TMAU) were recogn-ised by Shakespeare (The Tempest, Act 2. Scene 2), and aselegantly stated in Trinculo’s monologue, once the diagnosis hasbeen made, it is similar to a bolt from the blue for affectedindividuals and their families. The commentary earlier from aman with TMAU in whom the diagnosis was not made until hewas in his late 40s highlights the years of social torment thatTMAU sufferers may endure before the diagnosis of this treat-able inborn error of metabolism is entertained.
Excess dietary choline is metabolised by anaerobic micro-organisms in the large intestine to trimethylamine, which, inturn, is converted to odourless trimethylamine N-oxide by thelast step in the choline degradative pathway, flavin mono-oxygenase 3 (FMO3).1 Primary or secondary accumulation oftrimethylamine has no deleterious physical effect but can causedevastating social debilitation because trimethylamine, wheneliminated in urine, sweat or breath, saliva and other bodyfluids, has a very distinctive odour of decaying fish. The odourbecomes more prominent during periods of stress, with fever
Key Points
1 Timethylaminuria (TMAU) is an under-diagnosed disorder,some taking decades to be identified.
2 Although it causes no overt physical health problems, failureto diagnose it can be socially crippling.
3 Biochemical diagnosis is relatively straightforward, and oncediagnosed, the disorder can be very effectively managed bydietary therapy and gut decontamination.
Correspondence: Professor John Christodoulou, Western Sydney Genet-ics Program, Children’s Hospital at Westmead, Locked Bag 4001, West-mead, NSW 2145, Australia. Fax: +612 9845 1864; email: [email protected]
and with strenuous exercise as a consequence of increasedsweating.1 In addition, marine fish contain large amounts oftrimethylamine-N-oxide (TMAO) (which is believed to haveantifreeze properties), which can be converted back to trimethy-lamine by gut bacteria.2
Primary TMAU is most often caused by a functional defect ofFMO3 (Fig. 1),3 and the genetic disorder is inherited in an auto-somal recessive manner as a consequence of mutations in theFMO3 gene. At least 20 different mutations have been reportedwithin the nine coding exons of the FMO3 gene, which is locatedon the short arm of chromosome 1 and have been annotatedin a database accessible via the Internet (http://human-fmo3.biochem.ucl.ac.uk/Human_FMO3/; Fig. 2).4–6 The incidence ofTMAU due to FMO3 deficiency is not precisely known, but it hasbeen suggested that it may range between one in 100 and onein 1000.5 What is certain is many people remain undiagnosedfor unacceptably long periods of time.
Secondary TMAU has been described in patients with severeliver disease (which is the major site of activity of the FMO3
enzyme) and7 chronic renal disease (as a consequence of bac-terial overgrowth in the gut)8 and in patients treated with largedoses of betaine or possibly L-carnitine.1 In addition, transientTMAU has been reported in a preterm infant who was fed withcholine-rich food supplements9 and has been reported in somewomen just at the onset of menstruation.7
The key to establishing the diagnosis is suspecting it in the firstplace. TMAU sufferers have endured their disorder for years oreven decades, often subject to ridicule by their peers anddoubted by their health-care professionals before the diagnosishas finally been established. Quantitation of trimethylamineand TMAO in a random urine sample will confirm clinicalsuspicions; however, it should be remembered that excessivetrimethylamine excretion may be intermittent so a normalsingle result does not rule out the disorder.7 The diagnosis can bemore firmly established by conducting a choline or marine fishload test1 or by FMO3 mutational analysis.
The optimum management of TMAU usually needs to includea combination of approaches1,7,10 including:• Dietary restriction of choline-containing foods (including egg
yolk, liver and other organ meats, legumes and productscontaining lecithin (322) and choline (1001), which are putinto processed foods as emulsifiers) and marine fish (includ-ing cephalopods such as octopus and squid and crustaceanssuch as lobster, crab, prawns and Balmain bugs), low pH(5.5–6.5) soaps (e.g. goat’s milk soap), deodorants and bodylotions (e.g. Lactcyd)
Fig. 1 Biological basis of primary trimethylaminuria. Dietary sources of
choline, lecithin and trimethylamine-N-oxide (TMAO) are converted to trim-
ethylamine by anaerobic bacteria in the large intestine. Normally, any trim-
ethylamine absorbed from the gut into the bloodstream is converted back
to odourless TMAO by flavin mono-oxygenase 3 in the liver. However, when
this enzyme is defective (black bar), trimethylamine, which has the distinc-
tive odour of ‘rotting fish’, accumulates and is eliminated in sweat, urine
and breath.
Fig. 2 Molecular pathology of FMO3 deficiency. The FMO3 gene has 9
coding exons, with its mRNA being 1.6 kb in size, and the genomic
sequence spanning 27 kb of DNA on chromosome 1q23-q24. Shown here
are the known sequence variations, mutations that would result in a trun-
cated protein (below the gene structure schematic) and pathogenic mis-
sense mutations (above the schematic). Underlined variations do not
adversely affect FMO3 function, and those with a question mark are of
uncertain significance. Data derived from the FMO3 Allelic Variant Database
at http://human-fmo3.biochem.ucl.ac.uk/Human_FMO3/.
Trimethylaminuria: recognition, diagnosis and management J Christodoulou
• Copper–chlorophyll or activated charcoal, which are notabsorbed across the gut and which can irreversibly bind totrimethylamine in the gut thereby limiting its systemicabsorption
• Probiotics to change the balance of gut flora• Intermittent oral antibiotics to reduce the gut bacterial load
(rarely needed).In summary, TMAU is probably more common than reported
and is a socially and emotionally devastating disorder if leftundiagnosed. The key to diagnosis is recognising that thedisorder exists, and once appropriate simple investigations haveestablished the diagnosis, very effective treatments can beimplemented.
Multiple Choice Questions1 In considering the diagnosis of TMAU:
a) It is not a very rare disorderb) The diagnostic urinary abnormality is always elevatedc) Initial urine screening testing should always be followed
by a confirmatory load test or genetic testingd) It is always a result of an inborn error of metabolisme) One of the parents usually also has a history of the
disorder
Correct answer: (a)Although it remains to be confirmed, it has been suggested thatTMAU may be found in as many as one in 1000 individuals.TMA and TMAO may only be intermittently elevated and so itis sometimes necessary to confirm a clinical suspicion with acholine or marine fish load. Genetic testing, while possible, isusually not necessary to establish the diagnosis. Primary TMAUis an autosomal recessive disorder, but secondary TMAU maybe found in individuals with severe liver of renal disease, inpatients on L-carnitine or betaine for other disorders and occa-sionally, in otherwise well women at the onset of menstruation.2 Treatment of TMAU includes the following:
a) Regular gut sterilisation with a short course of antibioticsevery month
b) Avoidance of dairy products, red meat and legumesc) Diureticsd) Avoidance of marine fish, legumes and eggse) Alkaline soaps
Correct answer: (d)While antibiotics to reduce the load of anaerobic gut flora maybe used, it should be considered a treatment of last resort.Diuretics have no place to play in the treatment of TMAU,although regular water consumption is recommended. Low pHsoaps, deodorants and body lotions are most effective. Dietarytreatment is focused on the avoidance of foods that containcholine and lecithin (egg yolk, organ meats, legumes, food prod-ucts containing the emulsifiers choline and lecithin) and foodsthat contain TMAO (marine fish, crustaceans and cephalopods(squid and octopus)).
2 Arseculeratne G, Wong AK, Goudie DR, Ferguson J. Trimethylaminuria(fish-odor syndrome): a case report. Arch. Dermatol. 2007; 143: 81–4.
3 Ayesh R, Mitchell SC, Zhang A, Smith RL. The fish odour syndrome:biochemical, familial and clinical aspects. B.M.J. 1993; 307: 655–7.
4 Hernandez D, Addou S, Lee D, Orengo C, Shephard EA, Phillips IR.Trimethylaminuria and a human FMO3 mutation database. Hum.Mutat. 2003; 22: 209–13.
5 Cashman JR. The implications of polymorphisms in mammalianflavin-containing monooxygenases in drug discovery anddevelopment. Drug Discov. Today 2004; 9: 574–81.
6 Yamazaki H, Fujita H, Gunji T et al. Stop codon mutations in theflavin-containing monooxygenase 3 (FMO3) gene responsible fortrimethylaminuria in a Japanese population. Mol. Genet. Metab. 2007;90: 58–63.
7 Mitchell SC, Smith RL. Trimethylaminuria: the fish malodor syndrome.Drug Metab. Dispos. 2001; 29 (Pt 2): 517–21.
8 Rehman HU. Fish odor syndrome. Postgrad. Med. J. 1999; 75: 451–2.9 Blumenthal I, Lealman GT, Franklyn PP. Fracture of the femur, fish
odour and copper deficiency in a preterm infant. Arch. Dis. Child.1980; 55: 229–31.
10 Busby MG, Fischer L, da Costa KA, Thompson D, Mar MH, Zeisel SH.Choline- and betaine-defined diets for use in clinical research and forthe management of trimethylaminuria. J. Am. Diet. Assoc. 2004; 104:1836–45.
Fig. 3 “Trinculo, Spirits, and Caliban”. Source Birmingham City Council.
Believing Trinculo to be yet another spirit who has come to punish him,
Caliban throws himself to the ground. Trinculo discovers Caliban, and at first
assumes him to be a fish because he has “a very ancient and fish-like smell”.
J Christodoulou Trimethylaminuria: recognition, diagnosis and management
