Depletion of Reduced Folates From the Brain, Mimicking Wernicke's Encephalopathy (Thiamine Depletion)

This article, by Eg Lever and coauthors, is really interesting and shows another example of neurological symptoms (in this case, symptoms that are consistent with both Wernicke's encephalopathy and subacute combined degeneration) due to the depletion of reduced folates (methylfolate in particular) from the CSF and brain:

http://jnnp.bmj.com/cgi/content/abstract/49/10/1203
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/3783183?dopt=Abstract)
(full text: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=3783183)

Given that there are all those articles on "cerebral folate deficiency," a disorder that can look like mitochondrial encephalopathies but that can result from many causes and be an acquired "disorder," (http://www.ncbi.nlm.nih.gov/pubmed/16365882) I'll bet neurological symptoms due to methylfolate depletion from the cerebrospinal fluid is more common than it's usually assumed to be.

That article by Lever et al. (1986) basically shows, in part, that cerebral folate depletion mimics Wernicke's encephalopathy, a depletion of thiamine (vitamin B1), from the brain, that usually occurs in heavy drinkers or people with a history of alcoholism. The authors talk about that and show that the patient actually showed a short-lived reticulocyte response to thiamine and vitamin B12. They cite some articles showing that folate repletion can actually increase thiamine transport into cells, and that's the opposite of the effect I would have predicted.

There's actually been a lot of research, since that 1986 article came out, on overlap between thiamine and reduced folate transport. This article, by Rongbao Zhao et al., shows that RFC1, one of the reduced folate carriers, can transport thiamine into cells:

http://ajpcell.physiology.org/cgi/content/full/282/6/C1512
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/11997266?dopt=Abstract)

There are lots of articles on this SLC19 family of transporters, and some of the thiamine transporters also transport biotin. In people with some genetic disorders, derangements of biotin transport can cause this devastating neurological disease that affects the basal ganglia (biotin-responsive basal ganglia disease) (http://ajpcell.physiology.org/cgi/content/full/291/5/C851 and pubmed: http://www.ncbi.nlm.nih.gov/pubmed/16790503?dopt=Abstract). Those authors (Veedamali Subramanian and coauthors) found evidence that the biotin wasn't exerting its effects by bypassing a deficient activity of one of the thiamine transporters, I think. The article is complicated, and I'm not so much up for re-reading parts of it now.

These articles on the overlap between thiamine and folate transport do tend to be complicated, and I used to think that an excess of reduced folates would impair thiamine transport. But that article by Lever et al. (1986) suggests and cites articles supporting the idea that the opposite is true, that depletion of reduced folates can reduce thiamine transport. This article, by Tatyana Vlasova and coauthors (http://www.ncbi.nlm.nih.gov/pubmed/15623830?dopt=Abstract), shows that biotin depletion reduces the expression of (mRNA transcripts encoding) a biotin transporter, SLC19A3, by the lymphocytes of humans.

But another implication of the article is that some patients with Wernicke's encephalopathy might have encephalopathy due to depletion of reduced folates from the brain. It also might help explain the effects of folate on glycolysis (http://hardcorephysiologyfun.blogspot.com/2008/12/folic-acid-ribose-megaloblastic-anemia.html and http://hardcorephysiologyfun.blogspot.com/2008/12/first-posting-folate-and-glycolysis-in.html) or PRPP levels (http://hardcorephysiologyfun.blogspot.com/2008/12/nonoxidative-pentose-cycle-prpp-and.html), this relationship between thiamine transport and the intracellular reduced folate levels (as opposed to just reduced folate transport).

There's probably a lot more research on the reduced folate/thiamine overlap, but I'm not so much up for searching on it now. It seems really mind-bending.