Genotypic spectrum and genotype-phenotype correlation of trimethylaminuria

Trimethylaminuria (TMAU) or Fish odor syndrome is an autosomal recessive disease that is characterized by pungent body odor with subsequent psychosocial complications. There are limited studies of the sequence variants causing TMAU in the literature with most studies describing only one or two patients and lacking genotype-phenotype correlations. Also to date, there is no laboratory in the US or Europe that offers TMA genetic testing on a clinical basis. We have recently validated genetic testing in the University of Colorado DNA Diagnostic Laboratory. We have a database of a few dozen patients with a biochemical diagnosis of TMA at the University of Colorado at Denver Health Sciences Center (UCDHSC) which includes a few patients with the classical form of the disease. We have used the newly established clinical test in our institution to attempt to characterize the genotype (sequence variants including mutations and polymorphisms) of classical TMAU patients and to establish a genotype-phenotype (biochemical and clinical) association. The questionnaire results confirmed most of the previously reported epidemiological findings of TMAU and also indicated that TMAU patients use multiple intervention measures in attempt to control their symptoms with dietary control being most effective. Despite the complexity of intervention, most patients did not have any medical follow up and there was underutilization of specialist care. In a set of our patients, two deleterious mutations were identified in 4/12 patients including a novel T237P sequence variant, while the majority of our patients (8/12) did not reveal any mutations. Some of the latter were double heterozygous for the E158K and E308G polymorphisms which could explain a mild phenotype while others had only the E158K variant which raised the question of undetected mutations. These results indicate that further experiments are needed to further delineate the full mutational spectrum of the FMO3 gene. ^