Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children

Abstract

Persistent trimethylaminuria in children is caused by autosomal recessively inherited impairment of hepatic trimethylamine (TMA) oxidation due to deficiency of flavin monooxygenase 3 (FMO3) secondary to mutations in the FMO3 gene. Trimethylaminuria or 'fish odour syndrome' is due to excessive excretion into body fluids and breath of TMA derived from the enterobacterial metabolism of dietary precursors. The disorder is present from birth but becomes apparent as foods containing high amounts of choline or of trimethylamine N-oxide (TMAO) from marine (sea or saltwater) fish are introduced into the diet. In our experience, trimethylaminuria (FMO3 deficiency) in children is rare. We have compared the dynamics and diagnostic efficacy of choline loading with marine fish meals in six children with trimethylaminuria. Loading with a marine fish meal provides a simple and acceptable method for confirmation of diagnosis of suspected trimethylaminuria in children, with the effects being cleared more quickly than with a choline load test. However, oral loading with choline bitartrate allows estimation of residual oxidative capacity in vivo and is a useful adjunct to molecular studies. Patients homozygous for the 'common' P153L mutation in the FMO3 gene showed virtual complete lack of residual TMA N-oxidative capacity, consistent with a nonfunctional or absent FMO3 enzyme, whereas a patient with the M82T mutation showed some residual oxidative capacity. A patient compound heterozygous for two novel mutations, G193E and R483T, showed considerable residual N-oxidative capacity. A further patient, heterozygous for two novel sequence variations in the FMO3 gene, consistently showed malodour and elevated urinary TMA/TMAO ratios under basal conditions but a negative response to both choline and marine fish meal loading. Comparison of the effects of administration of antibiotics (metronidazole, amoxicillin, neomycin) on gut bacterial production of trimethylamine from choline showed they all reduced TMA production to a limited extent, with neomycin being most effective. 'Best-practice' diagnostic and treatment guidelines are summarized.

Flavin-containing monooxygenases: mutations, disease and drug response

“…Despite understanding its genetic basis, the disorder has no cure and causes much misery to those who are affected. Treatment strategies rely on dietary restriction of TMA precursors and suppression of intestinal production of TMA [17,18,[23][24][25].…”

Clinical utility gene card for: Trimethylaminuria

“…However, one individual developed an adverse reaction, with fever and vomiting, after a choline challenge. 33 …”

“…Strategies for treatment of the disorder 6,31 and bestpractice guidelines 23,33 have been published. In general, the greater the effect of a mutation on the activity of FMO3, the more severe the symptoms and the less responsive the individual will be to treatment.…”

“…33,35,36 In the case of mutations that do not completely abolish FMO3 activity, supplements of riboflavin, a precursor of the flavin adenine dinucleotide prosthetic group of FMO3, might help maximize residual enzyme activity. At present there is only anecdotal evidence of efficacy, and oral riboflavin supplementation requires careful monitoring because gastrointestinal intolerance can occur, especially in children.…”

A Pilot Study of the Effect of (E, E)-2, 4-Undecadienal on the Offensive Odour of Trimethylamine

“…Trimethylaminuria (TMAU) (OMIM # 602079) is a metabolic disorder characterized by decreased ability to oxidize and convert dietary-derived trimethylamine (TMA), an aliphatic tertiary amine, to odourless trimethylamine N-Oxide (TMAO) (Humbert et al 1970;Chalmers et al 2006). This disorder results in affected patients secreting volatile and malodorous (like rotting fish) TMA in their breath, sweat, urine and other body secretions.…”