Analysis of FMO3 gene variants in Argentine patients: Implications for the diagnosis of Trimethylaminuria.

Abstract

Primary trimethylaminuria (TMAu), also known as "fishy odor syndrome" is a metabolic condition characterized by the inability of flavin-monooxygenase 3 (FMO3) to convert foul-smelling trimethylamine (TMA) into odorless TMA N-oxide. The presence of TMA in the body fluids of affected individuals results in body odor causing severe psychosocial problems. Secondary trimethylaminuria differs from primary trimethylaminuria in that it is related to other underlying conditions, such as liver, kidney, or metabolic diseases, not genetic. The present work aims to analyze variants of the FMO3 gene in Argentinean patients with a phenotype suggestive of TMAu.

Genomic DNA from 22 patients was extracted from whole blood with the Roche MagNA Pure system. All coding exons of the FMO3 gene and adjacent intron sequences were amplified by polymerase chain reaction (PCR). Sequencing was performed on both DNA strands by direct sequencing (ABI 3130XL, Applied Biosystems).

In this cohort, 15 variants in the FMO3 gene were identified: 5 non-synonymous, 8 intronic, and 2 synonymous. The missense changes p.Glu158Lys, p.Glu308Gly, p.Arg387His, p.Val257Met, and p.Ala458Val have been previously described in patients with TMAu except for the p.Ala458Val variant. The diagnosis of primary TMAu was established in 4 individuals (18%). Of the remaining patients, no changes in FMO3 were detected in 5 (22%), and 13 (59%) had gene alterations that could be causative or predisposing to TMAu, but without reaching a diagnostic definition.

This is the first molecular study of fish odor syndrome in a cohort of Argentinean patients, and it allowed us to establish the genetic diagnosis of primary TMAu in our environment. The results obtained include the identification of a new variant, p.Ala458Val, with a possible pathogenic effect on the FMO3 protein. The recognition of this socially disabling disease in Argentina should alert specialists to its suspicion and highlight the need for effective therapeutic advances.