Note on Cerebral Folate Deficiency

This book, edited by Carmel and Jacobsen (http://books.google.com/books?q=%22homocysteine+in+health+and+disease%22), is really good. In the section on folate deficiency, Carmel, who I think wrote that section of the book (I didn't have time to photocopy the section, but the author cites some more, older case reports showing neurological degeneration resulting from CSF folate depletion), discusses the fact that folate deficiency has generally not been thought to cause the kinds of neurological symptoms that vitamin B12 (cobalamin) deficiency has been known to produce (subacute combined degeneration or more minor symptoms). The author also mentions that this never has really made any sense, and I think it's just one of those things that isn't true but that came to be accepted. I accepted it. But, as I read more about folate metabolism, I found it made less and less sense. I think the standards for folate deficiency are much too narrow, but a really interesting point to come out of those articles on cerebral folate deficiency (see here or past postings of mine: http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22cerebral+folate%22) is that the serum folate can be "normal" in a person whose cerebrospinal fluid 5-methyltetrahydrofolate (MTHF) levels are depleted. These people never would have been treated if the researchers had relied on serum folate tests alone. They had to do the CSF MTHF measurements. Doing a lumbar puncture to measure the CSF MTHF level is a relatively invasive diagnostic procedure, and that's probably going to be an ongoing issue (in the absence of some other test that would provide a picture of folate metabolism in the brain).

Those articles on cerebral folate deficiency are really new and important, in a lot of ways, even though some of those reports of subacute combined degeneration due to CSF MTHF depletion were published in the early 1990s or even the late 1980s. The fact that most of the case reports are in children or adolescents makes cerebral folate deficiency seem as if it's an inherited metabolic disorder, but it isn't. Also, some of the case reports of cerebral folate deficiency refer to the condition as occurring in people with Rett's syndrome, and some people with Rett's syndrome have genetic mutations that have been identified. The term "cerebral folate deficiency" also sounds like the type of nomenclature that's used to describe genetic disorders, syndromes produced by any of the various mutations in a single gene. But a lot of the case reports of cerebral folate deficiency are in people who have no identifiable genetic disorder. I think one of the reasons the articles on cerebral folate deficiency haven't had the impact they otherwise might have, by now, is that some of the case reports don't immediately make that point known. It's no fault of the authors of the articles, and they can't go through the entire history of one-carbon metabolism in a case report. But when I looked at one of the articles the first time, I think the article didn't mention the fact that the people being treated had had no "identified" genetic disorders of folate transport or of enzymes in the folate cycle. It was only a year later, when I was reading a second article, that I realized most of the cases had been essentially idiopathic. Those articles help to lend credence to and put in context a lot of the animal research showing neuroprotective effects of adequate folate status or of exogenous folates.