Alzheimer’s, Cognitive Impairment, & MTHFR Genetics

November Trip: Visiting Grandma:

It’s been over a year since I posted here. There are lots of reasons why. In that time, just to touch on the high points, my mother died and I suffered a major injury to my right arm which makes it hard for me to type and write and such. There has been so much happening in this space about which I really WANTED to write! The whole brouhaha with 23andMe and the FDA was a big one. There have been a number of interesting research articles that have come out. I did a presentation about my condition and meant to share the slides here. I may still, someday, write about these things.

For today, I want to talk about the research connecting genetic changes to the MTHFR gene to Alzheimer’s, Mild Cognitive Impairment (MCI), Vascular Cognitive Impairment (VCI), and related cognitive challenges. Because of my ongoing challenges with typing, I’m going to keep this simple, by selecting examples of the research and giving very brief snippets of the key findings. In other words, what’s most important.

The reason why I want to do this is because a friend of mine was recently diagnosed with one of these conditions, and so many doctors are not aware of this connection and don’t look for it. I’ve heard that from a number of places, but have a particular story that really rammed it home for me. As a medical librarian who works with systematic reviews, I’m on a number of medical and library email lists with various medical experts in different disciplines. On one of those lists, a clinician posted a question about this question. He is a recognized expert in his field and an expert in seeking and finding quality medical information. The family of one of his patients had approached him. Their mother has Alzheimer’s and they were wondering about giving her methylfolate supplements to help slow or arrest her memory loss. He wasn’t convinced, and was reluctant to support the family with this request. But he found enough evidence in support of the idea that he wanted to ask other professionals about the idea, and whether any of them had strong feelings about this. I sent him my search strategy and a few selected citations, and hoped for the best. I wondered, though, if someone as expert as he is was unaware of this, and reluctant to go along with a family’s request, what hope do others have with doctors who may very well not even ask the questions he was asking.

That was someone far away, in another country. I have no idea what happened. Now it is my friend, and I’m not close enough to talk with her clinicians. I’m hoping that someone will show this to her doctor, and if that doesn’t happen, maybe it will help someone else.

For the record, this is also a topic I follow because of personal concerns. When I was 12 I was briefly a significant part of my grandmother’s caregiving team. I was told at the time that she had Alzheimer’s, and it frankly terrified me. Years later, following brain damage from longterm carbon monoxide poisoning (another story for another day), I not only had amnesia but seemed to be developing mild cognitive impairment. It took me years to admit this to my doctor, and then brought it up at every appointment for the next few years. I won’t bore you with what didn’t work, but when I serendipitously discovered the MTHFR deficiency and began taking methylfolate, all my memory problems disappeared. Poof! Just like that. It was pretty amazing, and they haven’t come back. (Well, as long as I don’t get glutened.) Then, in the final part of her life my mother had cognitive decline. We don’t know her MTHFR status because we couldn’t get her genome tested, but we do know from testing other family members that she had at least one copy of the A1298c polymorphism. So, yes, I have a personal bias regarding this. That’s an excellent reason for me to stick to the evidence and what it says instead of trying to interpret it for you.



There are several MTHFR variations which are considered potential problems. The big ones are C677t and A1298c, with newer and less well understood, the MTHFR 03 P39P. The SNPs (snips) for these are:
* MTHFR C677t = rs1801133
* MTHFR A1298c = rs1801131
* MTHFR 03 P39P = rs2066470
Each of these is associated with different health impacts. A study that shows that one of them does something (or does not) says absolutely nothing about the other variants. There isn’t enough research yet to look at all of them together across the board. For many of the MTHFR variations, one common association is for increases in homocysteine (hyperhomocysteinemia), which in and of itself causes much damage in the body.

The Search

So, to start off, here is the Pubmed search strategy I’m using to try to get to just high quality research on this topic.

(mthfr OR methylfolate OR L-methylfolate OR Methylenetetrahydrofolate OR 5-mthf OR l-5-mthf) (“alzheimer disease”[MeSH Terms] OR “Mild Cognitive Impairment”[MeSH Terms] OR “dementia, vascular”[MeSH Terms] OR “dementia”[MeSH Terms] OR “Cognition Disorders”[MeSH Terms] OR “memory disorders”[MeSH Terms] OR “amnesia”[MeSH Terms])

Today, that results in 121 citations. Since this topic actually has fairly deep roots in the literature, going back to at least the early 1990s, I’ll be selective and focus on newer articles. To be even more selective, I am limiting this to systematic reviews and meta-analyses, the very top quality evidence available, and only the most recent of those available in English. Systematic reviews and meta-analyses distill the best evidence available into recommendations for clinical practice. In other words, they look through the whole puzzle and say, “This is what doctors need to know, and what they should consider doing.” After that, I may add just a couple very new research studies that would not have been included in the reviews.

For me, I will say that while some of these show a strong connection and others only a weak connection, there aren’t any that show no connection or the opposite. The gathering of these large aggregated studies together confirms a solid connection in some populations and is suggestive that may not have enough data to know yet about other populations. If it was me or my loved one, I’d wonder if it is worth at least doing a test and considering possible low levels of supplementation with methylfolate as a low-cost, low-risk intervention, and then seeing how the patient responds.


Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23.

In addition to identifying the epsilon4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles).

Laumet G, Chouraki V, Grenier-Boley B, Legry V, Heath S, Zelenika D, Fievet N, Hannequin D, Delepine M, Pasquier F, Hanon O, Brice A, Epelbaum J, Berr C, Dartigues JF, Tzourio C, Campion D, Lathrop M, Bertram L, Amouyel P, Lambert JC. Systematic analysis of candidate genes for Alzheimer’s disease in a French, genome-wide association study. J Alzheimers Dis. 2010;20(4):1181-8. doi: 10.3233/JAD-2010-100126.

We selected twenty genes from the “Top Results” list on the AlzGene database website and assessed their association with risk of developing Alzheimer’s disease (AD) in a large, genome-wide association study (using 526 SNPs from 2,032 AD cases and 5,328 controls) performed in France. The APOE, CLU, PICALM, and CR1 loci were excluded, since they had already been extensively analyzed. Ten genes/loci (TFAM, SORL1, CHRNB2, SORCS1, DAPK1, MTHFR, GWA 14q32.13, BDNF, NEDD9, and CH25H) showed weak nominal association with AD risk, in line with previous studies. In the remaining ten genes/loci (TNK1, ACE, CST3, IL1B, hCG2039140, PRNP, GAB2, LOC651924, IL1A, and TF), no single nucleotide polymorphisms were associated in our dataset. Of the genes showing nominal association in our cohorts, TFAM and CHRNB2 appear particularly interesting and warrant further genetic and functional follow-up analyses.

Liu H, Yang M, Li GM, Qiu Y, Zheng J, Du X, Wang JL, Liu RW. The MTHFR C677T polymorphism contributes to an increased risk for vascular dementia: a meta-analysis. J Neurol Sci. 2010 Jul 15;294(1-2):74-80. doi: 10.1016/j.jns.2010.04.001. Epub 2010 May 2.

RESULTS: A total of 11 studies, comprising 672 cases and 1038 controls, were included worldwide. Publication bias was not observed. This meta-analysis demonstrated that the MTHFR T allele or TT genotype had an increased risk for VaD in general populations (OR, 95%CI: 1.27, 1.01-1.59; 1.41, 1.06-1.88, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism (mainly TT genotype) is associated with developing VaD in general populations or Asian populations.

Zhang MY1, Miao L, Li YS, Hu GY. Meta-analysis of the methylenetetrahydrofolate reductase C677T polymorphism and susceptibility to Alzheimer’s disease. Neurosci Res. 2010 Oct;68(2):142-50. doi: 10.1016/j.neures.2010.06.011. Epub 2010 Jun 30.

No clear consensus has been reached at the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and Alzheimer’s disease (AD) risk. Thus in this meta-analysis, a total of 19 case-control studies was assessed to evaluate the possible association. The data demonstrated that the frequency of T677 allele (T vs. C) was significantly associated with susceptibility to AD in all subjects (OR=1.15, 95% CI=1.06-1.26) and in East Asians (OR=1.22, 95% CI=1.08-1.39). … A subgroup analysis in the subjects without APOE epsilon4 alleles showed T677 allele significantly increased risk of AD in all subjects (OR=1.21, 95% CI: 1.04-1.42) and in East Asians (OR=1.28, 95% CI: 1.06-1.55). However, no association was found in Caucasians. In conclusion, this meta-analysis supports that MTHFR C677T polymorphism is capable of causing AD susceptibility in East Asians, not in Caucasians.

Hua Y1, Zhao H, Kong Y, Ye M. Association between the MTHFR gene and Alzheimer’s disease: a meta-analysis. Int J Neurosci. 2011 Aug;121(8):462-71. doi: 10.3109/00207454.2011.578778. Epub 2011 Jun 10.

RESULTS: This meta-analysis demonstrated that the MTHFR T allele or dominant model for T allele (CT + TT) had an increased risk for AD in combined populations (OR, 95% CI: 1.13, 1.05-1.21; 1.18, 1.07-1.31, respectively), and a significant association was found in allele contrast, recessive, and dominant model in Asian populations, but not in Caucasian populations.
CONCLUSION: The MTHFR C677T polymorphism is associated with AD in Asian populations, but not in Caucasians.

Dwyer R, Skrobot OA, Dwyer J, Munafo M, Kehoe PG. Using Alzgene-like approaches to investigate susceptibility genes for vascular cognitive impairment. J Alzheimers Dis. 2013 Jan 1;34(1):145-54. doi: 10.3233/JAD-121069.

Vascular cognitive impairment (VCI), including vascular dementia, is the second most common dementia after Alzheimer’s disease. Despite its prevalence, the genetic etiology of sporadic VCI is largely unknown. … Associations of increased risk for VCI were found for APOE ε4 (1.818 (95% CI = 1.611-2.053), p < 0.001; n = 3,554 cases, n = 12,277 controls) and MTHFR rs1801133 (1.323 (95% CI = 1.061-1.650) p = 0.013); n = 659 cases, n = 981 controls). There was marginal evidence of a protective effect for APOE ε2 (0.885 (95% CI = 0.783-0.999), p = 0.048; n = 3,320 cases, n = 10,786 controls). This systematic study of all published genetic association studies of sporadic VCI supports MTHFR and APOE as susceptibility genes for VCI.

Grarup N, Sulem P, Sandholt CH, Thorleifsson G, Ahluwalia TS, Steinthorsdottir V, Bjarnason H, Gudbjartsson DF, Magnusson OT, Sparsø T, Albrechtsen A, Kong A, Masson G, Tian G, Cao H, Nie C, Kristiansen K, Husemoen LL, Thuesen B, Li Y, Nielsen R, Linneberg A, Olafsson I, Eyjolfsson GI, Jørgensen T, Wang J, Hansen T, Thorsteinsdottir U, Stefánsson K, Pedersen O. Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLoS Genet. 2013 Jun;9(6):e1003530. doi: 10.1371/journal.pgen.1003530. Epub 2013 Jun 6.

Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer’s disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations.


Mansouri L1, Fekih-Mrissa N, Klai S, Mansour M, Gritli N, Mrissa R. Association of methylenetetrahydrofolate reductase polymorphisms with susceptibility to Alzheimer’s disease. Clin Neurol Neurosurg. 2013 Sep;115(9):1693-6. doi: 10.1016/j.clineuro.2013.03.015. Epub 2013 May 6.

RESULT: Genetic analyses did not indicate a significant association between the MTHFR C677T mutation and AD (C/T: 63.15% versus 39%, p=0.087). However, the genotype prevalence of the missense variant MTHFR A1298C was significantly different between patients and controls (A/C: 55% versus 7%, p<10(-3)). Our data suggest an association between the MTHFR A1298C mutation and AD; however, the MTHFR C677T mutation did not contribute to susceptibility for AD.
CONCLUSION: The MTHFR A1298C polymorphism is a possible risk factor for Alzheimer's disease.

Farkas M1, Keskitalo S, Smith DE, Bain N, Semmler A, Ineichen B, Smulders Y, Blom H, Kulic L, Linnebank M. Hyperhomocysteinemia in Alzheimer’s disease: the hen and the egg? J Alzheimers Dis. 2013;33(4):1097-104. doi: 10.3233/JAD-2012-121378.

Hyperhomocysteinemia is associated with Alzheimer’s disease (AD). The causality of this association is controversial. … In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF.

Jin P1, Hou S, Ding B, Li D, Liu L, Li H, Li L, Zhao G, Shao Z, Liu X. Association between MTHFR gene polymorphisms, smoking, and the incidence of vascular dementia. Asia Pac J Public Health. 2013 Jul;25(4 Suppl):57S-63S. doi: 10.1177/1010539513492819. Epub 2013 Jul 15.

This study investigated the relationship between N5,N10-methylene tetrahydrofolic acid reductase (MTHFR) polymorphisms, smoking, and vascular dementia (VD). … The T allele frequency was significantly higher in the VD group than in the control group (P < .05). Among patients who smoked, the relative risk of VD in patients with the TT genotype and T allele was higher than in the control group (P < .05). Therefore, the smoking group with the T allele has the highest risk of VD, and synergy appears to exist between the MTHFR gene polymorphisms and smoking in susceptibility to VD.

About Genetic Risk & Celiac Disease

23andMe Celiac Disease Risk Markers

[This was a reply to an email question about genetic risk of celiac. I have so much to share here, but so little time for blogging, that I decided to grab this part, and hope to add more of my recent explorations in the future. Not TOO distant, I hope!]

Like so many people, I failed all the blood tests for celiac, despite having a boatload of symptoms. That was why I took the 23andMe test for celiac markers, with the results showing 4.07 times the normal risk of celiac. In the general population, risk is 0.24%; mine was 0.96%. There are currently 4 known genetic markers for celiac:

* HLA-DQA1 (SNP rs2187668)
* 4q27 (SNP rs6822844)
* 3p21 (SNP rs6441961)
* 3q28 (SNP rs9851967)

I have 3 of the 4, all except the last and least important one, which is what made for 0.96%. Now, ~1% that sounds awfully small, but the genetic risk combines with a variety of other risk factors.

“Estimates of the heritability of Celiac Disease vary. Risk factors other than the SNPs mentioned here include having European ancestry, family history of Celiac Disease, and a personal history of other autoimmune disorders. These disorders include Systemic Lupus Erythematosus, Type 1 Diabetes, Autoimmune Thyroid Disease, and Rheumatoid Arthritis.”

I have European ancestry, family history, and a family history (not personal history) of the autoimmune disorders listed as examples, with a personal history of autoimmune disorders not listed as examples. My diagnosis came from combining all of these:

* genetic risk factor PLUS
* family history PLUS
* ancestry PLUS
* other autoimmune disorders PLUS
* symptoms PLUS
* blinded trial

You see, the inclination of the docs was to read the symptoms as meaning a combination of a bunch of other possible conditions, which they’ve been attempting to treat for 10-20 years. Unsuccessfully. But we kept trying. Believe it or not, this made sense, specifically because, until we had all that information, the risk of the other conditions was higher than the risk of celiac, making it much more logical to explore those options.

They were reluctant to consider celiac, in part because it is a “fad” currently prone to self-diagnosis. Docs rightly tend to mistrust self-diagnoses of current fads, but then every now and then the fad was right! LOL! The other reason they were mistrusting this “self-diagnosis” was because I had atypical presentation of the symptoms. Most folk have primarily gut problems. I had mostly skin. Most folk with celiac related skin problems have those show up on limbs and back. Mine were worst on my face. Medically, it didn’t LOOK like celiac or dermatitis herpetiformis. They weren’t sure what it was, but it didn’t look like what it turned out to be. So you really can’t blame the docs.

But when you combined all these risk factors, you ended up with roughly 1/4 risk instead of 1/100. Big difference. Then the blinded trial tipped the balance. When you have someone with a 1/4 risk of celiac and symptoms and they pass a blinded trial, well, the reluctance to diagnose celiac faded.


I am adding a link to the article citation which was referenced in the test results. For those who want to explore more deeply.

van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, Feighery C, Jewell D, Kelleher D, Kumar P, Travis S, Walters JR, Sanders DS, Howdle P, Swift J, Playford RJ, McLaren WM, Mearin ML, Mulder CJ, McManus R, McGinnis R, Cardon LR, Deloukas P, Wijmenga C.
A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21.
Nat Genet. 2007 Jul;39(7):827-9. Epub 2007 Jun 10.

Lessons from Gaucher Disease and MTHFR Deficiency

Second Life: Relay for Life 2007: Angel in the Cherry Blossoms

A friend of mine was diagnosed with Gaucher’s Disease this week. (Gaucher is pronounced the French way, Go-Shay.) For most folk this would be a bad thing. For her, it was a gift. It reminded me of when I finally got my celiac diagnosis. I’d been sick at varying levels for at least 20 years. Finally having a diagnosis and being able to DO something about it was … unimaginable. Imagine eyes raised to heaven, and angels singing with serene beauty. A sense of humble joy, and relief.

Then, for me, finding the MTHFR aspect, and realizing it isn’t entirely clear where the celiac leaves off and the MTHFR begins, or visa versa. They seem to be pieces in the same puzzle, interacting in ways that are not necessarily straight forward. The MTHFR in particular is complicated, since it has been overlooked and neglected by the healthcare system until very recently, and like celiac in the USA, is often overlooked.

Well, surprise! Gaucher has some real similarities to this scenario. Like MTHFR deficiency, Gaucher disease has a very rare and severe (read: deadly) manifestation, AND a milder version often overlooked or misdiagnosed, but often disabling. Both Gaucher disease and MTHFR deficiency involve a genetic profile that creates a lack of an enzyme needed to break down a chemical in the body. Lack of the enzyme and inability to break down the chemical compound means that the body ends up with too much of something it doesn’t need and doesn’t want, and not enough of something it does need. And, for both these conditions, that imbalance then causes a wealth of confusing symptoms and a poverty of health and ease.

For MTHFR deficiency, the enzyme needed is Methylenetetrahydrofolate reductase (MTHFR). (Duh. Obvious.) MTHFR, when you have the right stuff, converts homocysteine (toxic, as in bad for you) into methionine (essential, as in something your body needs). Too much homocysteine is related to a lot of difference diseases, most commonly heart disease, nervous system and psychological diseases, and osteoporosis and fragile bones. Recently, there is research showing that too much homocysteine might be related to a number of cancers. There’s plenty more, but that gives you the idea that this can be trouble.

For Gaucher disease, the enzyme needed is the lysosomal enzyme glucocerebrosidase. That’s a mouthful, but I bet my friend manages to learn to make it roll off her tongue easily in no time! Just as with MTHFR, not being able to break down the chemical, means you end up with too much in your body, and then that causes damage. For Gaucher, instead of getting too much homocysteine, you have too much in the way of glucocerebrosides. What is supposed to happen with the glucocerebrosides is that they are broken down into the sugar called glucose and a fat called ceramide. Your body knows how to use those. But a person’s body kind of chokes on the glucocerebrosides. The cells that are supposed to break them down (a type of white blood cell called macrophages) actually get bloated and confused, and stop doing what they are supposed to do. In case you don’t already know, white blood cells are part of your immune system, so with the macrophages in trouble, that means EVERYTHING is in trouble, but especially the spleen, lungs, kidneys, and often the brain. Talk about scary! Early signs include anemia, easy bruising, bone pain, and easy fractures. Those early signs of Gaucher are coincidentally also sometimes early signs of celiac disease and MTHFR deficiency, BOTH. See why it is so hard to diagnose these things?

Here’s another similarity, but this one between me and my friend’s diagnoses, rather than the diseases. Both both of us, the symptoms we showed were not the expected presentation. We had the disease, but the docs missed it for years simply because what they were trained to look for was different from how it manifested in our bodies. Let me try to say that a different way. The symptoms for both of these come from the build up of the bad stuff in our bodies, but that build up can cause things to break down in more than one way. For most people, certain things break down, but for both of us the stuff that broke down was unusual. These are the kinds of diagnoses that make perfect sense after the fact. Hindsight is always 20/20, right? For my friend, her family had approximately the same symptoms for five generations, and no one ever figured it out. For me, we are less sure, and less clear, but I see echoes of my symptoms in old family stories. I wish I could go back in time and tell my beloved grandfather to change his diet so that he wouldn’t die crippled and in pain.

So with both of us having a disease that didn’t “behave right”, how did we end up with our diagnoses? You know mine — personal genomics. It took those genome scans to give the right clues, and then to combine those with some educated guesses about treatments. For her? Well, guess what? It was personal genomic again! Well, how do you figure that? What a surprise. Or maybe it is no surprise that both of us have become rabid evangelical supporters of personal genomics, especially for anyone with mysterious ongoing symptoms or chronic diseases that just don’t seem to get genuinely better no matter what you do.

Since my friend’s diagnosis, a bunch of us on Twitter have been reading up on Gaucher. I stumbled on this article today, and it set off a lightbulb in my mind.

Sidransky, Ellen. Gaucher Disease: Insights from a Rare Mendelian Disorder. Discovery Medicine October 27, 2012.

Here is the sentence that rang like a gong.

“It has become increasingly clear that “simple” recessive disorders provide unique insight into the complexities of common diseases.”

Deeper into the article there is a second similar sentence.

“These rare inherited disorders often offer a unique window into seemingly unrelated diseases.”

You start talking about “seemingly unrelated diseases” with celiac and you end up with a laundry list of associated conditions that cover the entire body and every major organ system. Ditto for MTHFR deficiency. And a lot of the conditions are the same ones. And they are also associated with Hashimoto’s Disease, chronic fatigue syndrome, myalgic encephalomyelitis, miscarriages, preterm labor, osteoporosis, bipolar, schizophrenia, depression, migraines, epilepsy, memory loss, cognitive decline and mental confusion, and simple things like joint pain, and weird things like hidradenitis suppurativa, and … and … well, I could go on a long time. I started to draw up a list once, to try to organize them all, but it was a bit overwhelming.

This article about Gaucher disease was describing the same sort of far ranging connections to other diseases.

“Studies of patients with Gaucher disease have led to unanticipated research directions impacting several distinct medical disciplines. Some notable examples include the link between mutations in the glucocerebrosidase gene and the development of Parkinson disease and related Lewy body disorders, elucidation of the role of glucocerebrosidase in skin barrier function and neonatal viability, and the connection between lysosomal transport and myoclonic epilepsy.”

Like Ellen Sidransky, I am now asking if there might be a significant pattern forming here. How many of our chronic diseases are actually caused by a cascade of events deriving from a simple bit of biochemistry gone wrong in our bodies? For me, this was easily addressed with a change of diet and new vitamins. For my friend it won’t be quite as easy (enzyme infusions), but it is still a LOT easier than all the meds she’s been taking and hospitalizations she’s been going through. Quality of life improvement is unbelievable, at least for me. Her treatment hasn’t started, but I expect the same phenomenal improvement in quality of life (QoL).

On the one hand, part of me says, “Why? Why did it have to take so long? Why was it so darned hard to figure out? Was there a point to all these years of struggle and pain?” On the other hand, I kind of ‘get it’, I can see how difficult it must have been to figure out. I still resent all the docs who tried to convince me it was in my head, but I am also so very very grateful that the personal genomics tests have reached the point where they are more accessible, and CAN help people like me. Like my friend. And hopefully, many many more.

A Few Resources

Gaucher Basics: Learning About Gaucher Disease:

Science Daily: Macrophages: The ‘Defense’ Cells That Help Throughout the Body:

NINDS Gaucher Disease Information Page:

More on folate genes, plus exomes, genomes, cancer, and Jay Lake

Veins & Cell Structure

Earlier this month it was National Folic Acid Awareness Week, which is now for me a whole lot more important than it used to be! (That is, of course, because of all the MTHFR stuff I’ve been talking about here.) I wrote a big long blogpost about folic acid and folate over at my main blog, talking about how this is a lot more complicated than I used to think.

Folic Acid, More Complicated Than You Might Think:

You can read it there. Sometimes I feel like the whole conversation about folate is being compromised by the conflation of folic acid with the many varieties of folate, and people misunderstanding that there are differences, and they are significant. The conversation is kind of like the old song, “You say tomato, I say tomahto”, except that the words are different and the concept is being treated as if they are the same thing when they aren’t. Anyone want to write a bad parody?

“You say folic, I say folate.
You say MTHFR, I say MTHFRD1″

The blogpost does go into a bunch of the research and evidence behind folic acid versus folate, and some of the gaps in the research. One of the points is that research keeps moving forward, meaning that what we know and what are best practices are a moving target as well. We do the best we can at any given point in time, but must be flexible and keep trying to learn more and improve not only our own life but the lives of others who might share concerns with us.

I now read a lot of the emerging research on MTHFR, and keep track of it. While doing so, today, I stumbled across two recent articles mentioning problems with folate metabolism (and cobalamine/B12) associated with some other genes.

Update and new concepts in vitamin responsive disorders of folate transport and metabolism.

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband.

Severe Combined Immunodeficiency Resulting From Mutations in MTHFD1.

Both of these mention MTHFD1 as contributing to folate metabolism problems, and that these problems with folate processing are leading to immunodeficiency (meaning that your body can’t fight off disease well or heal injuries). At this point the literature on MTHFD1 sounds a lot like the early literature on MTHFR — it only talks about the most severe problems that can be caused by mutations in the gene. I am wondering if this will turn out to be “the next MTHFR,” a gene for which mutations can have both severe and relatively mild ramifications for patients.

Jay Lake

I am also excited to see that some of these discoveries of new genes with clinical implications are coming from exome scans, and that exome scans and whole genome sequencing are both becoming more common. One of my Twitter friends, Jay Lake, is also a well-known and highly skilled science fiction and fantasy author. Jay is trying to raise funds to have whole genome sequencing to try to find a way to combat the terrible cancer he’s been fighting the past few years. As a person who is self-employed, he doesn’t have the kind of insurance I have, and even my insurance didn’t pony up for even the two small personalized genomic scans I had last year that resulted in turning my life around. Jay had his fifth major surgery since 2008 this week. According to the Kickstarter campaign, “Sci-Fi author Jay Lake has an 8% chance of surviving long enough to see his daughter graduate high school. What does a parent do?” The type of cancer Jay has also runs in my family — colorectal cancer. A lot of people get that, and it tends to go badly quickly. There are many reasons why I would love to see Jay get his genome scanned, and I’m betting it would help more people than just Jay and his family. What do we not learn because of only providing selective healthcare to the have’s? I wonder, I really do.

If you are interested in helping Jay, you can buy one of his books, or donate to one of the campaigns listed below. The incentive prizes alone are pretty astounding. And Jay’s not just laying back and waiting, but has come up with some really creative approaches. That’s why there are a couple different campaigns, with slightly different purposes.

Sequence a Science Fiction Writer:

Lakeside (A film about cancer in families):

What Works for Me. So Far. Right Now.

It's … Complicated

So, here’s the short version of what seems to be CURRENTLY working for me with the vitamin supplementation. (Additional details are in the “It’s Complicated” post.)

1. Diet, Part 1: Celiac

Gluten free is absolutely NOT optional for me.

2. Diet, Part 2: MTHFR

I eat a lot of high folate foods. Quinoa seems to especially make a difference, and I’ve learned that I should not go more than a day without quinoa. Red quinoa works better for me than white quinoa, but they are close. I thought black quinoa would be even better than red, but instead it’s the reverse. My body tells me that black is not as useful as white. Even with supplementing for folate, I find I still need a dose of quinoa at the least every 2 days. I have no clue what is in it that makes me feel better, but it’s health food, so I’m not going to quibble over it.

3. Vitamins, MTHFR

* 1 – 400 or 500 mcg tab of Methylfolate (a.k.a. 5-MTHF, L-5-MTHF, L-methylfolate, bioactive folic acid, Levomefolic acid, metafolin, metafolate, methylfolin, optimized folate)
Taken by mouth in the morning, swallowed, and again at lunch time.
DOSING: Standard recommendation is 1 mg, which is the same as 1,000 mcg. I am taking half that. Why? Because with all the folate in my diet, I thought I should start small.

* 1 – 500mcg OR half of one-1mg tab methylcobalamin (a.k.a. active cobalamin, mecobalamin, MeCbl, MeB12, Mevocon, meticobalamin, metacobalamin)
Taken by mouth in the morning, dissolved on tongue, and again at lunch time.


I am going to drastically oversimplify this. Briefly.

I’ve been having problems for many years now with cognitive functioning, severe enough that I talked with my doc about it, multiple times. Unfortunately, the problems are erratic, and when my brain works, it works pretty darn well. Not as well as it used to, not as well as I’m accustomed to, but well enough that the docs aren’t worried. Here’s what’s been worrying me.

– Deep fatigue
– Memory loss
– Short term memory impairment
– Confusion
– Disorganization

Basically, it is a lack of energy and sparkle, combined with feeling lost and uncertain. I used to be so productive, and loved keeping active. The last few years it’s been more of a case of struggling to make it through most days, trying to find times for extra rests and naps, planning my days to avoid pushing myself past my abilities.

What the folate with cobalamin is doing for me is this. I stay awake through the entire day, even if I’m glutened. Even if I’m tired, I’m more alert and clear-headed. I make better decisions. I have better follow-through on things I promise to do. I’m more coherent. I communicate more clearly. I remember things better. I’m more cheerful, and less snappish.

I’m not going to say the folate with cobalamin is a miracle answer. I’m still working out the right dosage for me, and the right timing of those doses. I still get tired. I especially get tired if I forget a dose, or take a dose late. I seem to bounce back about an hour after remembering to take the dose.

There are good days and bad days. The deal is that even the bad days are better. Heck, my bad days now would have been one of my good days a year ago. My good days now remind me of when I was twenty years younger. It’s not perfect, but it’s better. I’m hoping that as I figure out the right dosage and timing, I may yet find a sweet spot where I actually feel good consistently, and function well consistently, where I can makes plans with some assurance of what I’ll be able to do.

It’s … Complicated. (A.K.A. “MTHFR Deficiency, Sequel”)

Paper Quilt: SciMaps, Completed, Back View

This whole deal with MTHFR has ended up being so much more important than I first thought it would be. Pretty amazing to me. I’ve been meaning to talk about it here, but I’ve been so swamped with writing for work, and the information I’ve been collecting and developing has been a real up and down experience. Kind of confusing, at first glance.

It’s actually rather ironic. I started out learning about the MTHFR mutations last June, with a post that said, “I dug around a bit online and found out this is, shall we say, not a bit deal.” Then I heard things that made me think maybe it was a little more complicated, and worth a second look. I learned more. And more. And saw a trend toward this topic building in awareness among researchers. This lead to the point where I was saying, “I was tempted to run out and just buy pregnancy vitamins or folic acid vitamins.” The next step was talking this over with my doc (“I have the docs OK to start folate supplementation once I have my labs drawn.”).

Shall I warn you that the learning new things didn’t stop there? Briefly, with the changes the doc and I agreed to in my appointment, I should be off all prescription meds within six months. Pretty amazing, after the way things have gone the last ten, twelve years. We’ll reassess at that point, but I’m still heartened.

I received the lab results, with a note from the doctor that everything was fine. There was no reason not to go ahead and start the folic acid supplementation. I did wait a while, because the lab results I received gave NO indication of a normal range. I spent a couple weeks trying to find one, without any luck whatsoever. I ended up asking the wonderful folk at LabTestsOnline, who told me there is no universal normal, that it differs from lab to lab, and that the lab should have supplied that info. Darn them! They did for everything else, just not for the one piece which was the most important test result for me.

While I was looking, I did find a lot of research talking about the dangers of over-supplementation with folic acid leading to a variety of common cancers in folk with MTHFR. Oh. I also found that MTHFR protects against some cancers (mostly leukemias), while it predisposes to others. You figure with this being as widespread as it is in the general population, there almost had to be a benefit to it!

The piece about over-supplementation with folic acid being potentially dangerous to folk with two copies of the MTHFR mutations was VERY interesting! You see, folic acid is in most of our food supply, added in the manufacturing process with the encouragement of our government. This is logical, given what we knew about folic acid at the time the decision was made.

1. Folic acid is known to strongly help prevent birth defects of many sorts.
2. It is water soluble, and it is almost impossible to overdose with it. Extra folic acid just washes through the body.
3. Since it is difficult to get young women who might get pregnant to take extra folic acid when they aren’t planning to get pregnant, just in case, supplementing widely with folic acid is a great way to help get them just enough of the stuff to help prevent birth defects in the first few months of the pregnancy, when they might not yet know they are pregnant.
4. And it won’t hurt anyone else who doesn’t need it, because it is water soluble and the body will just get rid of what it doesn’t need.

Except it turns out that, while this is true for almost everyone, it is not true for those with two copies of the MTHFR mutation. In them, it looks as if the folic acid may not be properly processed by the body and doesn’t actually wash through. Instead it might be building up, and then predisposing this relatively small group of people to various new health problems they might not have had without the folic acid. However, this same group of people are the ones who need folate supplementation more than anyone else. They just can’t digest the most common way to treat that need. It’s complicated. Really complicated. And I didn’t figure this part out until later.

I’ve read things from a few different people suggesting that perhaps folic acid supplementation combined with what we are learning recently about the MTHFR mutations might explain some of the rise in certain chronic diseases, such as certain common cancers and autism and others. As far as I know, this hasn’t been examined closely, but I haven’t gone looking for it either. Something else to explore.

Learning what to do about MTHFR didn’t get easier at that point either. I started supplementing with folic acid when I received the test results, while I kept researching and reading and downloading articles. I was taking the smallest dose I could find, and felt better immediately. A week or so later, it didn’t seem to be working as well, so I upped the dose. Then I started to experience some of the signs of too much, mostly being jittery and having trouble sleeping. I started taking it in the morning instead of at night, with a second dose at lunch, none in the evening, and that fixed the sleeping problems. And then I started to feel worse again, as if I wasn’t taking anything. Around the same time, I was poisoned with trace amounts of gluten a couple times, so I wasn’t certain whether feeling worse was as a results of celiac+gluten or something related to the MTHFR.

Time for more digging. It took a little time, since I wasn’t feeling great. I did keep supplementing with the folic acid, however, because when I didn’t, I felt even WORSE. Also, I had noticed this incredibly surprising thing. When I was “glutenized” while taking the folic acid, I didn’t get as many gluten-symptoms. Briefly, I’ve noticed that I still get the hives (dermatitis herpetiformis), the joint aches, the generalized pain, and the intra-oral swelling. What I am NOT getting the severe debilitating fatigue, confusion, memory impairment, and other cognitive issues that normally accompany the other gluten symptoms. Very, VERY interesting! Unfortunately, this probably won’t work for other celiacs unless they also have two copies of the mutated MTHFR gene, so don’t go running out to try it. Certainly, not without talking to your doctor first!

This was about the time that I learned I should NOT be taking the folic acid, because of the problems and risks described above. There is another formulation that I should be taking. Oh, what is that, you ask? Good question. I’ve found quite a few different names for this. Ten. Ten different names for the folic acid alternative.

bioactive folic acid
Levomefolic acid
optimized folate

Now, try walking into a vitamin store and asking for help finding this. Really, I mean it. It’s awfully entertaining, unless you actually want to find it. Pick one of those names and ask. It won’t work. Trying listing all of them, and watch their eyes glaze over. Yeah. I did finally find some in town, at Whole Foods, but while they realized that the bottle labeled FOLATE said in fine print “metafolin”, they still had no clue what it was for, why anyone would want it, or the difference between “metafolin” and folic acid.

Another part of the question was how much to take. I couldn’t find much that was useful in the way of official recommendations. In the research literature, what I kept seeing were new articles from the last few years, in which the last few lines of the paper would say something like, “For patients with two copies of the MTHFR mutation, they might require more folate than other patients.” But I couldn’t find anything to give me any advice about what I should be doing, except this one naturopathic web site. Normally, naturopathic web sites are not my first choice, but I was looking for the best available evidence, and this was the best I could find. I liked that he was very conservative in his approach, starting small and titrating up as needed, and including dietary sources in the evaluation.

I eat a lot of high folate foods, and always have. Even as a child, I’d spend my allowance on fruits and vegetables instead of candy, and these days eat a lot of green leafy vegetables, tons of quinoa, and liver. Like I said before, I have cravings for high folate foods. So, I started on a low dose of the metafolin. So far, so good. The stuff I found at Whole Foods was awfully expensive. I bought more online.

The MTHFR.Net site said to take the methylfolate with methylcobalamin. I don’t know why. I wasn’t doing it yet, so bought some of that online at the same time. When the vitamins arrived in the mail a few days later, I took a tab of the methylcobalamin. The next morning, my brain felt more clear than it has in a very long time. The two together seemed to genuinely make a difference. The methylfolate alone was a huge help, but the addition of the methylcobalamin made everything just … click. It felt like something shifted into the right place.

Then I broke out in hives. That’s odd, I wonder where the gluten came from? After taking a second tab of the methylcobalamin (which turns out to be a formulation of B12), the hives got much worse. Oh. The vitamins have gluten in them. And I have four bottles of them. Jolly. I am hoping the store will take back the unopened ones. I found some without gluten at the People’s Food Co-op.

What has happened for me? I feel pretty awesome. I mean, actually, I feel NORMAL. Like I used to feel before I had kids. Well, not completely, but at least I can remember what that felt like. I am hoping that now I’ll be able to start doing some of the other things to reassemble my brain and body.

Typically, for me, when I find a solution that helps me feel better, it works for a while, then the benefits start to wear off as my body adjusts. I am really hoping that doesn’t happen this time, but I am expecting it. I am wondering how long I’ll feel good this time. We’ll see. In the meantime, I’m grateful.


I started this blog on May 15th. On May 24th came my first post about my trials and tribulations with trying to get a celiac diagnosis. Well, LOOK AT THIS:

Pic of the day - At Last!!!

OK, now between May and now, there have been a lot of changes. The big one has been that my primary care doctor moved to another country. That is kind of a biggie when it comes to moving forward with any kind of health questions. ;)

I was assigned to a new doc, and wasn’t any too sure about this, since I knew nothing about the person. I was thinking about possibly switching clinics, since I knew more primary care folk I don’t trust at my current clinic than folks I do trust, and there are a couple who I wouldn’t trust to throw me a lifesaver if I fell overboard in a boat. They would either think they knew a better way, or they’d be busy asking other people’s advice and not listening to me. So I’ve been judiciously reserving judgment.

I asked around a lot. Many people told me that the doc I’d been assigned to was mentored by my previous primary care doc (who is the first doc I trusted and who has earned that trust by both listening and saving my life a couple times). People told me the new doc is geeky, like me; that he’s interested in e-patients, like me; that he’s open to using email for communication about minor issues; etcetera. So I made a “new patient / establish care” appointment, which takes a while to get. That was today.

I was very careful preparing for the appointment. After all, I have longstanding complicated unresolved health issues. I’m a participant in this PGEN study, and some docs really aren’t into that. And I’m aggressively self-educated about my own health issues. I’m a medical librarian. I’m a really GOOD medical librarian. I specialize in systematic review searches. I have both co-taught on this topic with Cochrane folk, and am on Cochrane review teams. Docs will tell you there is no worse patient than another doctor, or another healthcare provider. Well, they might make an exception to that guideline for me, and if not, I’m darn close to being just as awful.

A few months ago one of the docs I work with was chatting with me. I was rambling on at fairly high speed about some of the new research in her area of interest, or something like that. She hadn’t seen it yet. When we changed topics, I did the same thing in the new topic. She just looked at me with a combination of humor, horror, and awe in her eyes, and asked, “What kind of doctor has to deal with YOU as a patient?” I told her, and she said, “Thank goodness! He can handle it!” Of course, that was before I found out he was moving to another country. Oh. A new doctor? Oh. Uh oh.

For this first meeting, I established my priorities, and clustered them: celiac/skin; MTHFR/folate; osteoporosis/HRT. I made notes in my phone. I printed off a highly selected subset of pages from the genetic studies. I brought copies of a couple other articles just in case. I researched the available expertise on celiac in the system. I hunted down the newest clinical guidelines for diagnosis of celiac. I reviewed the guidelines. I reviewed the articles by the only in-system clinician who remotely comes close to being a celiac “expert.” I made two copies of everything I planned to share with him. I went through the list, & cut it in half. I then hid my copies, and my extra back up single articles. I debated bringing my box of vitamins, but finally decided to. The nurse was glad, which made it ok.

The doc had a student with him today, an MD/PhD fellow. She and I had a lovely chat, but it became rapidly clear that this was too complicated for the amount of time available, so she passed the baton along to him. Because of the time crunch, the conversation was rapidfire, with lots of interruptions back and forth. It wasn’t the best communication I’ve ever had with a doc, but it was far far from the worst, also.

His top priority was the osteoporosis. That’s fine. So we talked about bisphosphonates for a while, and why I don’t want to take them. It’s a risk/benefit issue. I’m not persuaded that I’m badly enough off for it to be worth it to me to take them. I could bore you with the details, but to make it short, this is an area where I’m not an expert, but I know a lot of folk who are, and I’m able to talk about bisphosphonates moderately intelligently. What was important for me was for the doctor to believe that. I was able to show that I’d read some of the same literature that he had, and this helped (I hope) establish some sort of credibility baseline for me. (The genomic content came into play a few moments later, with the doc deciding that the potential value of the HRT is just not worth the potential risk of DVT, given my genetic scan results, and he has me tapering off it.)

Then he was willing to take a look at the genomic info I’d selected out. Some of these we’ll have to deal with later. He and I agreed that most of what healthcare currently knows about MTHFR is suspect and insubstantial. He asked why I’d decided it was important. I pointed out some superficial similarities between my body type and the more severe form of MTHFR; showed him my brief distillation of Pubmed searches on emerging trends in MTHFR research; and then emphasized that a major driver was my constant craving for foods high in folate. Since he was already doing bloodwork, he agreed to add in the baseline test for a few vitamins and minerals.

We have a long talk about the skin issues and antibiotics and dermatitis herpetiformis and rosacea and celiac … what to do, and why a diagnosis matters if it doesn’t change my determination to remain gluten free. My computer crashed so I’m going to just wind this up now and perhaps continue another day. The end point is that the genomic tests DID change my healthcare practice. I walked away with a piece of paper that says I have a celiac diagnosis; we are removing the HRT; and I have the docs OK to start folate supplementation once I have my labs drawn. Pretty good starting point!