Researchers Find Additional Genes Responsible for Foul Odor Disorder

A study using whole exome sequencing of patients with trimethylaminura (TMAU) may to lead to additional diagnostic criteria and therapeutic targets for this rare metabolic disorder, which until now has been generally attributed solely to mutations in the FMO3 gene.

The study, led by researchers from the Monell Center, provides new insight into genetically transmitted TMAU, a metabolic disorder due to accumulation of trimethylamine (TMA) in people with impaired TMA metabolism. TMAU is classified as a “rare disease” in that it affects less than 200,000 people in the United States, but its actual incidence remains uncertain in part due to inconclusive diagnostic techniques.

“Our findings may bring some reassurance to people who report fish-like odor symptoms but do not have mutations in the FMO3 gene,” said co-senior author Danielle R. Reed, PhD, of Monell Center.

The socially and psychologically distressing odor symptoms result from the buildup TMA produced naturally from many foods rich in choline (e.g. eggs, certain legumes, wheat germ, saltwater fish, organ meats). TMA, which has a foul odor reminiscent of rotting fish, normally is metabolized by the liver enzyme flavin-containing monooxygenase 3 (FMO3) into an odorless metabolite. People with TMAU are unable to metabolize TMA, which accumulates and is excreted from the body in urine, sweat, saliva, and breath.

Some people who report having the fish odor symptoms do not have severely disruptive mutations in the FMO3 gene. This led the researchers to suspect that testing for FMO3 mutations is likely insufficient in that other genes may also contribute to the disorder. In the study, they combined exome analysis with computer modeling to probe for additional TMAU-related genes. They compared sensory, metabolic, and genetic data from 10 individuals randomly selected from 130 subjects previously evaluated for TMAU at Monell Center. The metabolic test measured production of TMA following ingestion of choline. Each subject’s body odor was evaluated by a trained sensory panel before and after the choline challenge test.

Although the choline challenge test confirmed a diagnosis of TMAU by revealing a high level of urinary TMA in all 10 subjects, genetic analyses revealed that the FMO3 gene appeared to be normal in 4 of the 10. Additional analyses revealed defects in several other genes that could contribute to the inability to metabolize TMA.

“These new genes may help us better understand the underlying biology of the disorder and perhaps even identify treatments,” said Dr. Reed.

Although all of the subjects reported frequent fish-odor symptoms, none was judged by the sensory panel to have a fish-like odor at the time of the choline challenge. TMAU’s odor symptoms can occur in irregular and seemingly unpredictable intervals, which often adds to the difficulty of diagnosis.

Co-senior author George Preti, PhD, of Monell, commented on the diagnostic implications of the combined findings: “Regardless of either the patient’s current sensory presentation or FMO3 genetics, the choline challenge test will confirm the TMA accumulation that reveals the presence of the disorder.”

The researchers would like to repeat the genetic analyses in a larger cohort of TMAU patients without FMO3 mutations to investigate which other genes are involved in the disorder. “Such information may identify additional odorants produced by TMAU-positive patients, and inform the future development of gene-based therapies,” said Dr. Preti.

The study, by Guo Y et al, was published February 15, 2017, in the journal BMC Medical Genetics.