OBSERVATION Trimethylaminuria (Fish-Odor Syndrome) A Case Report

Gehan Arseculeratne, MRCP; Alvin K. C. Wong, MRCP; David R. Goudie, FRCP; James Ferguson, MD, FRCP

Background: Trimethylaminuria (fish-odor syn- tation on exon 4 of the FMO3 , FMO3/P153L drome) is a rare metabolic disorder characterized by a (c.458C→T). The patient found that information he sub- body malodor similar to that of decaying fish. The con- sequently obtained about his condition on the Internet dition results from affecting the flavin- and discussion with friends and family members to be containing monooxygenase 3 (FMO3) gene. Affected in- the most useful therapeutic approach. dividuals may exhibit a variety of psychosocial phenomena. A high index of suspicion for this disorder Conclusions: Trimethylaminuria is a rare metabolic dis- needs to be maintained when treating individuals pre- order. Psychological accompaniments are recognized as senting with a history of real or perceived . major sources of distress to affected individuals. We dis- cuss the features of this syndrome and highlight the im- Observation: We evaluated a 41-year-old man who pre- portance of counseling and support in the treatment of sented with a long medical history of a fishy body odor. such patients. Results from biochemical investigations confirmed a di- agnosis of primary trimethylaminuria, and results of mo- lecular genetic studies revealed homozygosity for a mu- Arch Dermatol. 2007;143:81-84

RIMETHYLAMINURIA IS A cion was that of trimethylaminuria (fish- relatively rare condition, odor syndrome), he was evaluated for that characterized by a body disorder. While on his normal diet, the uri- odor similar to that of de- nary (TMA) level was 14.7 caying fish. µmol/mmol of creatinine (reference range, T 1.5-11.0 µmol/mmol). The TMA-N- oxide level was 34 µmol/mmol of creati- REPORT OF A CASE nine (reference range, 17-147 µmol/ mmol), and the TMA/TMA-oxidase ratio A 41-year-old man presented with his- was 0.43 (reference range, 0.01-0.21). The tory of a fishy odor that had been com- significantly high excretion of TMA with mented on by friends since he was 13 years a raised TMA/TMA-oxidase ratio was con- old. Neither the patient nor his family sistent with the diagnosis of primary tri- members has been able to detect this mal- methylaminuria. The patient was re- odor, which was a cause of considerable ferred to a dietitian for advice on foods that social embarrassment to the patient. He contain low amounts of and leci- had used topical antiperspirants without thin. Two months later, his TMA level was much benefit. His medical history re- 9.6 µmol/mmol of creatinine (reference vealed a minor head injury, arthroscopy range, 1.5-11.0 µmol/mmol), which re- and meniscectomy, corneal foreign-body flected successful dietary modification. removal, reflux esophagitis, a duodenal ul- However, his urinary TMA level was el- Author Affiliations: cer, and panic attacks, the latter treated evated at 102.8 µmol/mmol of creati- Photobiology Unit, with propranolol hydrochloride. The fam- nine; the TMA-N-oxide level was 263.4 Departments of Dermatology ily medical history revealed parental con- µmol/mmol of creatinine, and the TMA/ (Drs Arseculeratne, Wong, and Ferguson) and Clinical sanguinity, a brother who thought he had TMA-N-oxide ratio was 0.39 when inves- Genetics, Unit the same condition as our patient, and an tigations were subsequently repeated, pos- (Dr Goudie), Ninewells unaffected sister. No malodor or skin ab- sibly a reflection of dietary relaxation. He Hospital and Medical School, normalities were detected at the initial ex- received a trial dosage of 500 mg of oral Dundee, Scotland. amination but, because the clinical suspi- twice daily for 10 days,

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 tential to form the carcinogen N-nitrosodimethyl- 9 Dietary Sources Hepatic Metabolism: Excretion and amine. The TMA N-oxidation is catalyzed by an FMO. Trimethylamine-N -oxide Secretion: of Choline: It is recognized that a process of isoform switching (from FMO1 to FMO3) occurs, FMO1 being the predominant Eggs Block Urine and Other Offal form in the fetus and FMO3 the main form of the en- Sweat Legumes Trimethylamine 10,11 Breath zyme present in the adult human liver. Primary tri- Brassica Vegetables (Dimethylamine, methylaminuria occurs as a result of in the FMO3 of Trimethylamine-N-oxide: Methylamine, and Carbon Dioxide gene, resulting in defective metabolism of TMA, and the Salt Water Fish + Ammonia) first such mutation detected was that of P153L, al- though several mutations are now known to give rise to Gut Bacterial Metabolism the primary form of the disease.12-14 Transient or mild forms of trimethylaminuria are recognized, and the de- velopment of trimethylaminuria in adulthood, without Figure. Metabolism of dietary precursors of trimethylamine (TMA) (eg, 15,16 choline, , and ) lead to production of a volatile tertiary amine, a medical history in childhood, is also recognized. and patients with trimethylaminuria excrete excessive amounts of the free Chronic hepatic disease, which leads to impaired me- amine as a result of defective hepatic N-oxidation of TMA. tabolism of TMA, leads to an excessive amount of TMA in the urine with a resultant fishy malodor.17,18 Second- ary trimethylaminuria has been described in a patient who which did help to some degree in reducing the degree of was also found to have a homozygous G→A nucleotide odor. The most useful therapeutic approach, however, substitution in exon 4, resulting in a to ly- had been the fact that he was able to communicate with sine substitution at residue 158.19 family members and friends about the condition, which Trimethylaminuria is suspected or declares itself when he subsequently read about on the Internet. Molecular children are weaned and/or when a food that contains a genetic studies confirmed homozygosity for a mutation TMA-precursor is introduced into their diet.20 Trimeth- in exon 4 of the flavin-containing monooxygenase 3 ylamine gives rise to an offensive odor in secretions, such (FMO3) gene, FMO3/P153L (c.458C→T), a mutation as sweat, saliva, and vaginal secretions, and trimethyl- known to be associated with complete loss of FMO3 en- aminuria is recognized as an important systemic cause zyme activity. of halitosis.21 Although the human sense of smell can be very sensitive to the odor of TMA (the olfactory thresh- COMMENT old is reported to be 0.00037 ppm), some individuals are less able to detect the odor of TMA.22 Body malodor is recognized as a distressing symptom for The cardinal feature is self-declaration of the mal- patients and poses a treatment challenge for clinicians.1 odor or detection by friends or relatives. The odor may Several descriptive terms have been used in relation to be enhanced following exertion, temperature rises, and body odor syndromes; dermatologists may experience the emotional changes; may occur intermittently; and is rancid odor of erythroderma, the cheesy smell of tricho- known to increase in women just prior to and during men- phyton infection, and the fishy odor of pemphigus.2,3 struation as a result of hormonal inhibition of TMA oxi- Trimethylaminuria, a rare metabolic disorder, re- dation. 23 Trimethylaminuria has been reported in asso- sults from a defect in the hepatic microsomal oxidase en- ciation with other clinical entities, such as the Prader- zyme system, which metabolizes TMA. The condition, Willi syndrome, seizures, and behavioral disturbances.24,25 characterized by an odor similar to that of decaying fish, Distressing psychosocial accompaniments of trimethyl- is inherited as an autosomal recessive trait and was first aminuria include withdrawn personality, social isola- described by Humbert et al4 in 1970. The rarity of the tion, obsessive personal cleansing, depression, inter- entity, the need for specialist investigations, and the in- rupted schooling, marital disharmony, and suicidal ability of some individuals to detect the malodor can lead intent.26,27 to delay in diagnosis. Metabolism of dietary precursors Early confirmation of the diagnosis is important when of TMA, such as choline, lecithin, and carnitine, lead to the condition is suspected owing to medical history or production of a volatile tertiary amine, and patients with clinical examination. Local causes of altered olfactory per- trimethylaminuria excrete excessive amounts of the free ception need to be excluded because trimethylaminuria amine as a result of defective hepatic N-oxidation of TMA has been reported in association with dysosmia.28 (Figure). Some breeds of chicken, such as the Rhode Is- Fishy odors may be perceived by individuals with land Red, are known to produce eggs with TMA odor as cacosmia (ie, abnormal odors perceived by persons ex- a result of defective N-oxidation.5 FMO3 deficiency is con- posed to neutral odors). The main confirmatory test is sidered to be rare in children.6 the estimation of free urinary TMA excretion. The lev- Most individuals within a British white population are els of trimethylamine as well as of TMA-oxidase could known to be able to convert over 90% of their dietary- be assessed while patients are eating a normal diet as well derived TMA to its N-oxide (TMNO).7 Ethnic variation as when they are eating a restrictive diet. Choline load- in the ability to N-oxidize TMA is recognized.8 The he- ing has been used as an aid to diagnosis in patients with patic TMA oxidase converts TMA to the non- trimethylaminuria.29 Oral challenge with TMA is help- odorous trimethyl oxide, which is then excreted in the ful as far as identifying possible carriers is con- urine. Trimethylamine and TMNO, although regarded cerned.30-33 The genotypic contribution to phenotypic ex- as being nontoxic, are now considered to have the po- pression in trimethylaminuria has been studied using the

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 combination of proton nuclear magnetic resonance spec- ment of these patients. Genetic counseling needs to be troscopy and gene sequencing methods.34-37 Gas chro- considered in relation to the primary form of the syn- matography, isotope dilution, and solid-phase microex- drome. Providing patients with relevant information and traction are other techniques that have been used to detect introducing patients to support groups form an impor- increased amounts of TMA in the urine of patients with tant aspect of the management strategy. Further re- suspected trimethylaminuria.38-40 search is likely to lead to novel concepts, which will add Of prime importance is explanation of the condition to therapeutic strategies available to clinicians who treat to patients. Genetic counseling needs to be discussed in patients with this rare and distressing disorder that has relation to primary trimethylaminuria. Antiperspirants, a major impact on quality of life. deodorants, and frequent bathing to rid the skin of the malodorous secretions are useful approaches.41 Soaps with Accepted for Publication: June 29, 2006. a pH level of 5.5 to 6.5 have been reported to be useful Correspondence: Gehan Arseculeratne, MRCP, Photo- in the reduction of body odor.42 A choline-controlled diet biology Unit, Department of Dermatology, Ninewells to reduce intake of choline-containing food (eg, eggs, peas, Hospital and Medical School, Dundee DD1 9SY, Scot- beans, marine fish, liver, and kidney) may be benefi- land ([email protected]). cial.43 In a study of several food items tested in individu- Author Contributions: Analysis and interpretation of data: als, increased urinary levels of TMA and the oxide oc- Arseculeratne, Wong, Goudie, and Ferguson. Drafting of curred only following ingestion of fish and seafood.44 Milk the manuscript: Arseculeratne, Wong, Goudie, and Fer- elimination was found to be useful in a case in which in- guson. Administrative, technical, and material support: gestion of large quantities of milk was associated with Wong, Goudie, and Ferguson. excessive TMA excretion in urine.45 Brussels sprouts are Financial Disclosure: None reported. known to be a rich source of the substance progoitrin, Acknowledgment: We thank the staff at the Depart- which reduces the TMA oxidation capacity in hens. It has ment of Paediatric Chemical Pathology, Sheffield Chil- been suggested that reduction of the intake of veg- dren’s Hospital, for conducting the diagnostic biochemi- etables of the Brassica family may be of potential benefit cal test in this patient. We are grateful to the staff at the for patients with trimethylaminuria.46 Antibiotic therapy Institut fur Humangenetik-Im Neuenheimer Feld, Heidel- may also benefit patients, particularly at times of stress, berg, Germany, for performing the molecular genetic stud- exercise, emotional upset, and menstruation or when di- ies. We thank Professor R. A. Chalmers, DSc, PhD, etary restriction is relaxed. Reduction of the intestinal bac- CChem, FRSC, CBiol, FIBiol, FRCPath, FRCPCH, for cre- terial load with lactulose, metronidazole, and neomycin ating the figure and allowing its use in this article. sulfate can be helpful.47-49 In a study of 7 Japanese pa- tients with trimethylaminuria, activated charcoal and cop- REFERENCES per chlorophyllin were found to reduce urinary free TMA and to increase the concentration of TMAO, thus hav- 1. Ayesh R, Mitchell SC, Smith RL. Body malodour syndromes. Lancet. 1995;345: ing therapeutic potential in the treatment of patients.50 1308-1309. 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