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.