Trimethylaminuria
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What is trimethylaminuria?Trimethylaminuria is a disorder in which the body is unable to break down trimethylamine, a compound derived from the diet that has a strong odor of rotting fish. As trimethylamine builds up in the body, it causes affected people to give off a fish-like odor in their sweat, urine, and breath. The intensity of this odor may vary over time. In many cases, the strong body odor interferes with an affected person's relationships, social life, and career. People with trimethylaminuria may experience depression and social isolation as a result of this condition. How common is trimethylaminuria?Trimethylaminuria is an uncommon genetic disorder; its incidence is unknown. What genes are related to trimethylaminuria?Mutations in the FMO3 gene cause trimethylaminuria. The FMO3 gene makes an enzyme that breaks down nitrogen-containing compounds from the diet, including trimethylamine. This compound is produced by bacteria in the intestine as they digest proteins from eggs, meat, soy, and other foods. Normally, the FMO3 enzyme converts fishy-smelling trimethylamine into another molecule that has no odor. If the enzyme is missing or its activity is reduced because of a mutation in the FMO3 gene, trimethylamine is not broken down and instead builds up in the body. As the compound is released in a person's sweat, urine, and breath, it causes the strong odor characteristic of trimethylaminuria. Researchers believe that stress and diet also play a role in triggering symptoms. Although FMO3 mutations account for most known cases of trimethylaminuria, some cases are caused by other factors. A fish-like body odor could result from an excess of certain proteins in the diet or from an increase in bacteria that normally break down trimethylamine in the digestive system. A few cases of the disorder have been identified in adults with liver damage caused by hepatitis (an inflammation of the liver). Temporary symptoms of trimethylaminuria have also been reported in a small number of premature infants and in some healthy women at the start of menstruation. How do people inherit trimethylaminuria?Most cases of trimethylaminuria appear to be inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene. Carriers may have mild symptoms of trimethylaminuria or experience temporary episodes of fish-like body odor.
Source: National Institutes of Health
Reports summarize trimethylaminuria genetics research from University of Washington, Department of Medicinal Chemistry
2007 SEP 25 -- Scientists discuss in "Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria" new findings in trimethylaminuria. According to recent research from the United States, "Impaired conversion of trimethylamine to trimethylamine N-oxide by human flavin containing monooxygenase 3 (FMO3) is strongly associated with primary trimethylaminuria, also known as 'fish-odor' syndrome. Numerous non-synonymous mutations in FMO3 have been identified in patients suffering from this metabolic disorder (e.g., N61S, M66I, P153L, and R492W), but the molecular mechanism(s) underlying the functional deficit attributed to these alleles has not been elucidated." "The purpose of the present study was to determine the impact of these disease-associated genetic variants on FMO3 holoenzyme formation and on steady-state kinetic parameters for metabolism of several substrates, including trimethylamine. For comparative purposes, several common allelic variants not associated with primary trimethylaminuria (i.e., E158K, V257M, E308G, and the E158K/E308G haplotype) were also analyzed. When recombinantly expressed in insect cells, only the M66I and R492W mutants failed to incorporate/retain the FAD cofactor. Of the remaining mutant proteins P153L and N61S displayed substantially reduced (<10%) catalytic efficiencies for trimethylamine N-oxygenation relative to the wild-type enzyme. For N61S, reduced catalytic efficiency was solely a consequence of an increased K(m), whereas for P153L, both K(m) and k(cat) were altered. Similar results were obtained when benzydamine N-oxygenation was monitored. A homology model for FMO3 was constructed based on the crystal structure for yeast FMO which places the N61 residue alone, of the mutants analyzed here, in close proximity to the FAD catalytic center," wrote C.K. Yeung and colleagues, University of Washington, Department of Medicinal Chemistry. The researchers concluded: "These data demonstrate that primary trimethylaminuria is multifactorial in origin in that enzyme dysfunction can result from kinetic incompetencies as well as impaired assembly of holoprotein." Yeung and colleagues published their study in Archives of Biochemistry and Biophysics (Functional characterization of genetic variants of human FMO3 associated with trimethylaminuria. Archives of Biochemistry and Biophysics, 2007;464(2):251-9). For additional information, contact C.K. Yeung, University of Washington School of Pharmacy, Dept. of Medicinal Chemistry, Box 357610, Seattle, WA 98195 USA.. Publisher contact information for the journal Archives of Biochemistry and Biophysics is: Elsevier Science Inc., 360 Park Avenue South, New York, NY 10010-1710, USA. Keywords: United States, Box, Trimethylaminuria Genetics, Biochemistry, Biophysics, Genetics, Trimethylaminuria. This article was prepared by Life Science Weekly editors from staff and other reports. Copyright 2007, Life Science Weekly via NewsRx.com.
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