2008 dissertation paper on TMAU DNA : 8 out of 12 had no (known) mutations

http://digitalcommons.library.tmc.edu/dissertations/AAI1450285/

This January 2008 dissertation by Jaffar Alfardan poses a few questions regarding the trimethylaminuria diagnosis. Probably more questions than answers. Dr Alfardan has/had an association with the University of Colorado Denver Health Sciences Center (UCDHSC), which is where Dr Fennessey works. For a few years now, Dr Fennesseys lab has been the lab in the USA where perhaps 99.9% of USA TMAU urine testing has been done (mostly by mail).

The object seems to have been to match 12 'phenotype' (urine test) TMAU sufferers with the 'genotype' (DNA) test. Only 4 out of 12 matched this objective (TMAU = autosomal recessive disorder : 2 mutant copies). They also found a 'new' mutant amongst those 4, indicating how the current database of mutations is likely an underestimate, and how little research is done in this area. Amongst the other 8, some seemingly were double heterozygous for known 'polymorphic' FMO3 DNA copies. Polymorphisms are more common and are regarded as 'variations' in efficiency, rather than mutants that are severe. But there were even some with only one polymorph (E158K). Possible reasons for this may be that some/many mutants are still to be discovered, and/or that polymorphisms can cause problems ... and even that it may be an autosomal dominant problem if certain copies are involved (e.g. E158K).

Presumably no follow-up will be done on the dissertation.

...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.

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points of interest:

The 'textbook' explanation for trimethylaminuria would be it is autosomal recessive (2 mutations of the gene), but 8 of the 12 had no known mutations, and a new mutation was found. Polymoprphisms are usually regarded as being less severe and more common (more than 1% population), whereas mutations are often regarded severe and rare (such as null-allelle, where they are deemed almost useless), but the definitions are ambiguous. Perhaps the terms will make more sense as we learn more about DNA terminology. However, the main point here is that the 'textbook' explanation of trimethylaminuria being autosomal recessive wasn't strongly proven in this paper. The main problem for sufferers however, is that the dissertation was likely a one-off, and no further research is likely forthcoming on this subject in the near future. So the 'rare problem' tag will likely be around a while. Probably the best approach is for sufferers to become the motivator of research and awareness amongst decision makers, rather than the current situation.

Mutations and polymorphisms explained
Genetests.org glossary : double heterozygous