Fish Odour Syndrome – The Alienating Disorder

By Daniella Gimbosh

Trimethylamine (TMA) is an organic compound produced by the gut microbiota from a variety of dietary methylamines, such as choline and L-carnitine. TMA then, normally, gets oxidised to trimethylamine N-oxide (TMAO) in the liver, thus reducing the circulating levels of TMA (Ayesh et al., 1993). In the metabolic syndrome trimethylaminuria, also known as fish-odour syndrome, a mutation in the flavin-containing monooxygenase 3 (FMO3) gene results in the absence of the regular TMA to TMAO conversion. The consequences of this mutation are that affected individuals, therefore, have high circulating TMA levels, leading to a ‘rotting fish’ odour in urine, breath, saliva and reproductive fluids (Rehman, 1999). 

The physiological and psychological consequences of trimethylaminuria are significantly distressing, with sufferers describing it similar to “living with a death sentence” (Lewis and BBC News, 2020). Sweating, stress and specific diet components are amongst some of the factors that exacerbate the ‘fish odour’ smell, leading to patients being advised to avoid strenuous exercise and specific foods such as milk, eggs and seafood. The effects of this alienating disorder on the confidence, employment and social behaviour of patients often results in social isolation and even suicidal tendencies (Mackay et al., 2011), highlighting the importance of scientific research on this disorder. According to Mackay et al., approximately 0.5 – 1% of people in the UK are carriers for trimethylaminuria, and this disorder is inherited in an autosomal recessive pattern. 

Many studies have proposed, logically, a reduction in TMA levels in order to relieve trimethylaminuria symptoms (Chalmers et al., 2006). Dietary adjustments, such as the administration of riboflavin (vitamin B2), as well as the reduction of choline and its precursors (phosphatidylcholine) in the diet, have been suggested in order to lower TMA levels (Bouchemal et al., 2019). Nonetheless, deficiencies in nutrients such as choline may lead to the development of non-alcoholic fatty-liver disease as well as muscle damage (Spencer et al., 2011), making such solutions difficult and improbable, as a very fine balance in nutrients must be kept. Major drawbacks in previously proposed long-term solutions for trimethylaminuria mean that a gap in the scientific literature exists, and many current solutions that require an extremely stringent diet and further restrictions on the daily life of patients are definitely not ideal. 

However, pioneering research indicates great potential for the use of methanogenic archaea in reducing trimethylaminuria TMA levels (Brugère et al., 2014). Naturally occurring methanogenic archaea in the human gut convert TMA into methane in the gut, using methyl compounds to perform methanogenesis. Although the novelty in this area of research is undeniable, experimental evidence in mice has shown that methanogenic archaea, such as Methanobrevibacter smithii (M. smithii), may decrease TMA concentrations by converting it into methane, prior to it reaching the liver (Ramezani et al., 2018). This mechanism can therefore be looked into in order to investigate the effects of introducing methanogenic archaea such as M. smithii into humans and observing the effect that this has on their circulating TMA levels.

If this proposed treatment using methanogenic archaea has a significantly greater effect in reducing TMA levels than previously proposed treatment such as riboflavin administration, this could indicate great potential for the therapeutic use of methanogenic archaea in relieving symptoms of trimethylaminuria, greatly improving the social and psychological aspects of the lives of as many as 1 in 40,000 people (Shephard, Treacy and Phillips, 2015). This treatment could possibly be further extended to aid in different conditions involving TMA and its metabolic pathways. Atherosclerosis, known as the most dominant cause of cardiovascular disease (Frostegård, 2013), is a major health issue linked to high systemic concentrations of TMAO. Using M. smithii as treatment would mean that TMA is metabolised before it can be absorbed by the gut. Therefore, this treatment could act as a preventative measure of diseases such as atherosclerosis through therapeutic intervention reducing the amount of TMA available to be converted into TMAO (Ramezani et al., 2018), as well as possibly reducing symptoms of those suffering with trimethylaminuria. 

Additionally, a different methanogenic archaeon – such as Methanosarcina mazei or Methanomicrococcus blatticola – could be investigated in the future to assess its effectiveness in decreasing TMA levels compared to that of M. smithii, as this area of research is still flourishing, and the possibilities of treatment remain to be determined. 

References:

Ayesh, R., Mitchell, S.C., Zhang, A. and Smith, R.L. (1993). The fish odour syndrome: biochemical, familial, and clinical aspects. BMJ : British Medical Journal, [online] 307(6905), pp.655–657. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1678986/ [Accessed 30 Nov. 2020].

Rehman, H.U. (1999). Classic diseases revisited: Fish odour syndrome. Postgraduate Medical Journal, [online] 75(886), pp.451–452. Available at: https://pmj.bmj.com/content/75/886/451 [Accessed 30 Nov. 2020].

Lewis, L. and BBC News (2020). Fish smell syndrome TMAU “like living with a death sentence.” BBC News. [online] 9 Jan. Available at: https://www.bbc.co.uk/news/uk-england-bristol-51006604 [Accessed 29 Jan. 2021].

Mackay, R.J., McEntyre, C.J., Henderson, C., Lever, M. and George, P.M. (2011). Trimethylaminuria: causes and diagnosis of a socially distressing condition. The Clinical biochemist. Reviews, [online] 32(1), pp.33–43. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052392/ [Accessed 30 Nov. 2020].

Chalmers, R.A., Bain, M.D., Michelakakis, H., Zschocke, J. and Iles, R.A. (2006). Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children. Journal of Inherited Metabolic Disease, [online] 29(1), pp.162–172. Available at: https://pubmed.ncbi.nlm.nih.gov/16601883/ [Accessed 1 Dec. 2020].

Bouchemal, N., Ouss, L., Brassier, A., Barbier, V., Gobin, S., Hubert, L., de Lonlay, P. and Le Moyec, L. (2019). Diagnosis and phenotypic assessment of trimethylaminuria, and its treatment with riboflavin: 1H NMR spectroscopy and genetic testing. Orphanet Journal of Rare Diseases, 14(1).

Spencer, M.D., Hamp, T.J., Reid, R.W., Fischer, L.M., Zeisel, S.H. and Fodor, A.A. (2011). Association between composition of the human gastrointestinal microbiome and development of fatty liver with choline deficiency. Gastroenterology, [online] 140(3), pp.976–986. Available at: https://pubmed.ncbi.nlm.nih.gov/21129376/ [Accessed 1 Dec. 2020].

Brugère, J.-F., Borrel, G., Gaci, N., Tottey, W., O’Toole, P.W. and Malpuech-Brugère, C. (2014). Archaebiotics. Gut Microbes, [online] 5(1), pp.5–10. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049937/ [Accessed 1 Dec. 2020].

Ramezani, A., Nolin, T.D., Barrows, I.R., Serrano, M.G., Buck, G.A., Regunathan-Shenk, R., West, R.E., Latham, P.S., Amdur, R. and Raj, D.S. (2018). Gut Colonization with Methanogenic Archaea Lowers Plasma Trimethylamine N-oxide Concentrations in Apolipoprotein e −/− Mice. Scientific Reports, [online] 8(1), p.14752. Available at: https://www.nature.com/articles/s41598-018-33018-5 [Accessed 1 Dec. 2020].

Shephard, E.A., Treacy, E.P. and Phillips, I.R. (2015). Clinical utility gene card for: Trimethylaminuria – update 2014. European Journal of Human Genetics, [online] 23(9). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538216/ [Accessed 5 Dec. 2020].

Frostegård, J. (2013). Immunity, atherosclerosis and cardiovascular disease. BMC Medicine, [online] 11(1). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658954/#:~:text=Atherosclerosis%20is%20the%20dominant%20cause,especially%20where%20the%20vessels%20divide [Accessed 5 Dec. 2020].

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