Fiddle, Fiddle, & More Fiddling (a.k.a. “What is a maintenance dose?”)

Pic of the day - Cajun Music Party

THE DOSES

This is the distilled down description of what I did, without the explanation, for those who are coming back to this post and just want a quick reference of the numbers. Remember to talk dosing and timing over with your doctors!

Note:
mg = milligram
mcg = microgram
1 mg = 1000 mcg

In the Early Days

1 mg 5-L-methylfolate daily in morning
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin daily at evening

After Injury

2 mg 5-L-methylfolate daily in morning
1 mg 5-L-methylfolate daily at lunch
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin daily at evening

When Healthy

400 mcg 5-L-methylfolate in morning twice a week (usually M/Th)
1 b-complex (without folate or folic acid) daily at lunch
1 mg methylcobalamin at evening once a week

THE STORY

I’ve been taking extra methylfolate for a few years now. I started out following the general ideas from Dr. Ben Lynch’s MTHFR site, but without following his protocol (since that meant buying the vitamins that he sells, and I couldn’t find information about them anywhere other than on his site). So I’ve been cobbling things together on my own, through experimentation and how my own body reacts. This is absolutely the hard way to do things, but I haven’t found a doc who knows enough about it to give me advice. Dr. Lynch makes one very important point in his protocol:

“Now – the supplement recommendations need to be tailored to the individual – again – regardless of which genetic variants you have. Working with a physician trained in this area of medicine is key. The recommendations of supplements are merely suggestions and ones that I may recommend to a patient or physician. They are not flat out must-haves nor must one take all of them.”

Personalize it. Tweak. Fiddle. Refine. Change things up. Experiment. Customize. Listen to your body. Here’s what I’ve found myself doing over the past few years, and what I’m doing now.

When I started, I’d been very sick for a lot of years. Decades. So, my body was in pretty bad shape, and had a lot of healing to do. I wasn’t sure at that point if the methylfolate would actually help, or what was the right dose for me. I started out with small doses (400mcg), and couldn’t even tell I was taking them, so I bumped it up, and up. I ended up taking a daily dose of about 1 mg (1000 mcg) for the first year or so. For a while I felt amazing. Then I started to have some of the side effects mentioned on Dr. Lynch’s site, so I started mixing things up, and added in some methylcobalamine (methyl-B12).

I was feeling decent, but then I had another illness, and felt crummy. I found that when I was sick, I needed a little extra. I bumped the dose up to 2mg (2000mcg), and when I felt better, I bumped it back down to 1mg/day. Then, about two years ago, I had a major injury. It took me a few months to even think of it, but I found again I needed to take a LOT when I was healing from the injury! I ended up taking 3mg a day for a while! And I had to take it all before noon, or it kept me awake at night. I split the doses 2mg when I woke up and another 1mg at lunch. For the record, while this is an enormous amount for me, this is nothing compared to what is typically prescribed by docs. One prescription form of methylfolate is called Deplin, and the lowest dose given for it is 9mg, THREE TIMES what I was taking at the highest level. During this time, I took another methylcobalamin at night, since that was supposed to help with sleep. I cringe at the thought of taking prescription levels of this, and have read innumerable comments from patients on Deplin in various online forums.

I was in physical therapy for almost two years, but finally ‘graduated.’ That’s when I really started to have trouble with the methylfolate. I had settled into a combination of vitamins that worked for me, and I felt pretty good most of the time. But now I wasn’t feeling good. I’d take my vitamins, and feel worse. I’d feel so tired, I’d take an extra methylfolate sometimes just to try to come up with enough energy to get through the day. Then I’d be so severely fatigued that I was convinced I had been glutened and that this was in reaction to hidden wheat in my diet. I was baffled trying to find how I’d been glutened. Sometimes I was so fatigued that I would forget to take my vitamins in the morning. Eventually I noticed that when I forgot to take my vitamins, I actually felt BETTER. I did some digging online and found a new-to-me post from Dr. Lynch about exactly this happening to people, where their bodies would start to have a reverse reaction to the methylfolate. The important part for me was way at the end.

“Just think of a bell-shaped curve. Before you started taking methylfolate, you felt terrible. You began taking it and started to feel good. Day after day goes by and you continue to improve. In time if the above things are not corrected, you will begin to slide down the other side of the bell-shaped curve.”

OK, so I stopped taking methylfolate. Briefly. After a few days, I started to feel awful again. I’ve found that right now, if I take even a small dose of methylfolate every day, I feel awful. But if I don’t take it for 3 or 4 days, I feel awful then, too. So right now, I’m in the process of trying to figure out what is the right maintenance dose for me. There’s these ideas in healthcare of therapeutic dose (what is needed to treat a problem), loading dose (kind of how to get to the therapeutic dose faster), and a maintenance dose (what it takes to feel OK when you aren’t sick anymore but still need at least a little of the med).

Loading Dose vs. Maintenance Dose

So, what I’m doing currently with respect to methylfolate (which will probably need to be tweaked again later) is this. I take the smallest dose I can find (400 mcg) twice a week, and 1mg of methylcobalamin once a week. I exercise a lot now (which is a big difference from what I could do before), and I eat a lot of green leafy vegetables. As I eat more of those, I may need less of the methylfolate. We’ll see.

Now, it’s important to mention that these are not the ONLY vitamins I take. There are several others which my docs recommended as supplements because of my celiac and gluten-free diet. There are vitamins I take for other conditions. They all fit together and there may be interactions between them. Obviously, there are also other conditions that can … intersect with MTHFR. For example, we know that having one copy of the MTHFR defect is protective against some kinds of cancer. That’s a good thing, right? And it helps explain why MTHFR defects are so common and wide spread. But this also could mean that there are possible issues for methylfolate supplementation for people who either have or are at risk of having cancer.

I try to bring up these various issues with my doctor when I have appointments, and I try to sort things out on my own as much as possible. I know, not everyone can do that. It’s really tricky. Part of the problem is that we just don’t KNOW what we need to know yet about this. It’s becoming obvious in the research literature that MTHFR genetic status and testing is important in many many conditions, but this isn’t widely known among clinicians, and what to do about it is even more obscure. Talk to your docs, but don’t leave this entirely in their hands. Join forums at MTHFR.net and at Patients Like Me, where many folk generously answer questions. Don’t trust all those answers, but use them as a starting point to learn more, research, and for what questions and conversations you should be bringing to your own doctors.

I Hate Having Conversations Like This With a Doctor

At the Doctor's Office

This is a rant. Just being honest up front. I’m frustrated right now. Part of this touches on a new diagnosis I was going to blog about here, because it derives directly from the MTHFR genetics. I promise, I’ll come back to that more fully later, in another post. Right now, this post is about communication.

First some background. Last week I phoned my clinic to make an appointment for chest pain upon exertion, that stopped when exertion stopped. I was instead (quite properly, but frustratingly) sent to the ER, where I spent another 24 hours insisting that I felt FINE before being transferred to the Cardiovascular Center, where I spent ANOTHER 24 hours. Of course, in those circumstances you are poked and prodded, hooked up to various machines that don’t like you, get a bunch of tests, etc. If you are lucky, like I was, you get to come home with some new diagnoses, a bunch of instructions, and maybe an extra temporary hole or two. Being my kind of luck, I was also seriously glutened by the hospital’s glutenfree food, spent a few days feeling horrid and sleeping, and another few days breaking out in hives (front, back, arm, and face). Jolly.

Now, that was the GOOD part! Because every nurse and doctor I spoke with was knowledgeable, competent, courteous, engaged, and compassionate. Most of them were also informative, interested, entertaining and amusing, which was a definite plus. I had interesting conversations with them, and was honored to hear phrases like, “I didn’t know that! Thank you for teaching me about it.” “You’re more special than you think.” “I’m glad I met you.”

I had gone in with chest pain, a classic presentation but not a classic cardiac cause. One positive stress test and one negative cardiac catheterization later, it was clear that it was time to move on to the next step of the differential diagnosis. In the last couple hours before I was discharged, 1 cardiologist, 1 cardiology resident, 1 nurse practitioner, and 1 nurse all at different times looked me in the eyes and said, “You have an appointment coming up with your primary care doctor. It isn’t soon enough. Get them to move it up.” You see why I thought this might actually be important?

By the time I made it home on the day of discharge it was too late and I was too tired to phone the clinic, so the next morning that was the first thing I did. They couldn’t get me in with my primary care provider, but they found an appointment for someone on her team. That’s where I was this morning, and I came home cranky because I was unhappy with how the communication was handled. I’m venting some examples of the communications that bothered me. Pay attention to the pattern of information sources, and the flow of information in the conversation. That’s probably more important than what was actually said. Think of flipping the clinic, and then think again about just how that ought to work.

[NOTE: These are excerpts from a longer conversation, not a complete transcript.]


Cardiac or Not? Anemia or Not?

DR: Looks like they did a good job. [recites list of what I’ve had done medically in the past week] Do you want a referral to a cardiologist for that left bundle branch block? There really isn’t anything they can do, but I can do that.

ME: I think the cardiology people have done what they can for now.

DR: Well, it really isn’t your heart. And you’re not anemic.

ME: Yes, I am.

DR: No, you’re not.

ME: It’s on my active problem list.

DR: It shouldn’t be. Your hemoglobin is fine.

ME: Of course, it is. It’s the serum ferritin that isn’t.

DR: That’s not anemia, that’s low iron. See what I mean? You don’t have anemia.

ME: My hemoglobin is ALWAYS fine.

DR: Then you were never anemic.

ME: Oh, God!

DR: What?!

ME: [deep breath] OK. My hemoglobin is always fine. And I almost died of carbon monoxide poisoning because all the docs thought hemoglobin was all they needed to check.

DR: Your serum ferritin has ranged from 70 to 40 in the past five years.

ME: Yes, but when this started, my serum ferritin was 11. My fingers were gray. My skin was gray. My eyes were gray. My hemoglobin was low normal. And I almost died of carbon monoxide poisoning before someone would check my ferritin and start treating me for anemia.

DR: But you’re not anemic.

ME: I’m not anemic RIGHT NOW.(*)

DR: I don’t know why this is here.

ME: Please. Don’t. Don’t take it out of my diagnosis list.

DR: Well! I didn’t know you have strong feelings about that.

ME: It serves as an alert to my care providers that this is something that needs to be monitored.

(*) [NOTE: Yes, “Anemia is strictly defined as a decrease in red blood cell (RBC) mass.” So technically, on a simple level, he was accurate enough. The idea of what exactly IS “low normal” hemoglobin is something that is pretty hotly debated in the literature, including findings that “low normal” carries its own risks. For example this statement from UpToDate: “Studies in older adults with hemoglobin levels in the “low normal” range according to WHO criteria have linked these levels to declines in performance as well as increased morbidity and mortality.” And then there is the subtlety of what are differences in types of anemia. What I have/had is Anemia of Chronic Disease, which most likely originated with the then undiagnosed celiac disease and was exacerbated by the also then undiagnosed MTHFR deficiency.

“Hemoglobin values will generally reach a low normal range of 9.5–10.5 g/dL and remain there within this moderately low range until the underlying condition is cured. If disease that results in blood loss is present, the person will develop iron deficiency anemia (IDA). ACD and IDA can be distinguished with a serum ferritin test.” Iron Disorders Institute: Anemia of Chronic Disease. http://www.irondisorders.org/anemia-of-chronic-disease

What I never got a chance to say in this conversation was that the doc who diagnosed me with anemia (assistant department chair of family medicine at the time) told me that in long-standing severe anemia the body throws every scrap of iron it can find into the hemoglobin in an attempt to keep the body alive, and that a chronic reading of low hemoglobin can be a sign of severe anemia. The docs who treated my anemia over several years, getting my ferritin up to that 40-70 range (out of a normal target of 100), are the ones who put in the diagnostic code and active problem list identifications. Unless he has a better and more appropriate code to enter to describe this problem, I personally feel safer leaving it as it was found.

Yes, I’m a bit on the defensive here. It’s a personal safety issue, and feeling safe. I discovered in the hospital that someone had deleted from my medical record my most serious drug allergy, and that scared me.]


New diagnosis

ME: And they added a new diagnosis.

DR: I don’t see anything new.

ME: They added “with homocystinuria” to my MTHFR deficiency diagnosis.

DR: I don’t see that in the computer.

ME: [rummages in bag, pulls out discharge folder from hospital, ruffles through papers, finds the right one] See here, on page three of the hospital encounter description?

DR: That’s just your active problem list.

ME: But this line changed.

DR: Hunh. I don’t know what that is. I don’t know who added that.

ME: Dr. L took the patient history about it, so I’m guessing it was him.

DR: I don’t even know how you would diagnose that.

ME: I did some searching online. The screening questions he asked came directly from the NIH Genetic Home Reference.

DR: I don’t know what that is.

ME: It’s from NIH and National Library of Medicine.


Differential diagnosis

ME: Homocystinuria is associated with embolism and liver disease. I’m already on baby aspirin, but I’m not sure anyone has checked my homocysteine levels. And liver disease was on the differential they mentioned in the hospital.

DR: What do you mean?

ME: The cardiac cath can only check the large vessels. In women, it isn’t unusual for the coronary artery disease to start in the microvessels. But that’s really hard to diagnose.

DR: [Nods.]

ME: The easiest way to diagnose CAD in microvessels is to rule out everything else. In the hospital they ruled out heart and kidney, and liver was another thing I heard them mention. I don’t know what else there should be.

DR: Well, they didn’t check your homocysteine levels, but they did check an indicator for them a year ago, so that’s fine.

ME: I don’t know the last time anyone checked my liver function. There is a blood test for that, isn’t there?

DR: Yes. Hmmm. No one has run that test in five years. Hmmm. OK, I can order that.


Physical

[COMMENT: Pay attention. This is where something started to go right, sort of.]

DR: So, how’s that incision?

ME: It’s fine. I had a little problem with it yesterday, but it’s fine now.

DR: Let’s listen to your heart and lungs. Unhunh. Lay back, please. Does that hurt? That? There? Please sit up. Hmmmm. Do you have asthma?

ME: Yes. Well, I did. After the carbon monoxide poisoning, my lungs were badly scarred.

DR: But it went away?

ME: Yes, the scar tissue shrank as it healed.

DR: Do you use an inhaler?

ME: No, I can’t. I’m allergic to them.

DR: What happens?

ME: I pass out.

DR: OH! Well, hmmm. I’m going to request a pulmonary function test, and we’ll mention that. So you don’t use an inhaler?

ME: I used to use Intal, but they quit making it. I stockpiled a couple, but I found the mechanism quit working after a while, even if there was spray left.

DR: Well, you can follow up on that with your regular doctor.


DISCUSSION

That was pretty much the end of the conversation. And it doesn’t seem quite as awful now that I’ve written it down, but it was very frustrating at the time. Why? The doc listened to me about some things and not others, didn’t seem interested in doing a differential diagnosis, and the impression I came away with was that this doctor didn’t take the other doctors or me seriously. I thought the argument about anemia was entirely unnecessary, and it alarmed me and undermined my trust in the doctor. He could have explained which definition of anemia he was using, and that would have helped, and perhaps opened the conversation to some of the other aspects of anemia that concern me. Since it wasn’t relevant to today’s meeting purpose, it only served to alarm me.

The information and explanations flowed mainly from me to him. He admitted not knowing certain things, but didn’t say he was interested or willing to learn or find out. Still, he didn’t shut me down when I tried to explain. He did listen and integrate the information. I was alarmed again that he wanted to send me right back to the docs I had just left, and I felt I had to work so hard to get him pointed in the direction of continuing the differential diagnosis process. After leaving, in doing more reading, I discovered that testing pulmonary function is indeed a logical next step for differential diagnosis of atypical chest pain, but that wasn’t something he discussed or explained, so I had the impression at the time that he was sidetracked from the purpose of the visit.

The visit wasn’t a total waste, and actually did achieve useful productive goals. I’m pleased to have the pulmonary function test and the liver function test in progress. Something will move forward while waiting for my next appointment with my primary doc over a month from now. It could have been a great deal easier and more clear. I could have gone away AWARE that he was genuinely trying to help, instead of feeling alarmed and distrustful. That would have been nice. Deep down, I think it worried me that I was providing medical information that he didn’t know, and he wasn’t giving me information that I didn’t already know. He wasn’t demonstrating his expertise. The dynamic around the information flow and sharing in these conversation snippets was patient-driven, yes, but imbalanced. Maybe I’m just being nitpicky?

Good Lord, People, 23andMe is NOT Dead!

23andMe

Good Lord, people, 23andMe is NOT dead! Or closed, or no longer taking orders, or anything like that. I hear this a lot.

“You know, I always wanted to get my genome tested. I was going to try 23andMe, but then the FDA shut them down. Oh, well, missed my chance. [sigh]”

NO! You did NOT miss your chance. Firstly, 23andMe is not closed for business. They still will take your money and your sample. They still will analyze the sample and give you results. From what I’ve been seeing in the results from folk I’ve been helping to look at their data, 23andMe seems to be running the test exactly the same way they always did, for the same SNPs.

They simply are, at this time, not offering their health reports to new customers. It isn’t the data that has changed – it iw what analysis is shared with the customer. Old fogies like me who got their tests done before the FDA folderol” still have access to our old 23andMe health reports, and they continue to improve them.

I have heard nothing to indicate that 23andMe are not working with the FDA to try to make it possible to release health reports again in the future. Issues around that get complicated and I’m going to save them for a later post. Right now, what if you wanted a test for some genetic health information? Can you do it? How long will you have to wait to find out the answers to your health questions?

You can still do it. It isn’t as easy as it was before, but it can be done. I’ve been spending a lot of time talking people through how to do this, and it is time to write it down. If nothing else, it will save me time. This will be the short short version, and I can answer more detailed questions and describe specifics, maybe give an example or two or three.

FIRST, THE DISCLAIMER

Risk is Not Just Genes

Making sense of genetic information is complicated even for experts, which most of us are not. Of course, part of the irony of looking at genetics for health conditions is that most of the time what causes the condition is not just the genetics, but genes PLUS something else. If you don’t find the genes for something, that doesn’t mean you can’t get it; if you do find the genes for something, it doesn’t mean you will get it. It is hardly ever a case of this=that.

What Does Risk Mean, Anyway?

There is also the challenge of figuring out how important the risk is, and whether or not to do something about it. So, my personal risk of celiac disease is over 4 times normal. Wow! That sounds like a lot, doesn’t it? But 4 times normal for celiac risk is still only 1 in 20 people, because normal is about 1 in a hundred. I know someone with celiac risk 17 times normal, which is 1 in 4 people. That’s getting to be pretty serious! But, while celiac is dangerous, it isn’t one of those conditions that is immediately deadly or painful. And my friend still has a 3 in 4 chance of NOT getting celiac, and that is a lifetime risk.

On the other hand, my risk of venous thromboembolism (VTE) is 1.5 times normal. That doesn’t sound like much does it? It’s higher, but only a little bit. So we don’t really need to worry about it, do we? Well, yes. VTE can kill you on the spot, and it is incredibly painful. And normal is 1 in 10 people for lifetime risk. For me, the risk is closer to 1 in 7.

Given that, according to 23andMe, my genetic risk of celiac is roughly 1/20 and my risk of VTE is 1/7, and adding in the comparative dangers of the two diseases, my docs got all excited about the VTE, and not terribly about the celiac. I hope you understand why now, and also a bit more about why genetic risk is complicated.

On Asking for Help

Last part of the disclaimer.

For both of these, celiac and VTE, 23andMe looks at SOME of the genes and SNPs known to be associated with the condition, but not ALL of them. So whatever 23andMe tells me about risk is only part of the picture. It looks at the most important genes, but is still only part of the picture. That’s why you need experts to put all the pieces together, and get more information to fill in the gaps from the 23andMe test.

Everyone always says, “Ask your doctor,” when it comes to finding something puzzling, confusing, contradictory, or worrisome in your genetic tests. I did, and found that most of my doctors didn’t have the expertise to make more out of it than I did. Some poohpoohed the 23andMe results, others made clinical decisions based on them without verifying with other tests, some asked for more medical tests to expand upon what 23andMe had, and one said, “You know more about this than I do, but I’m going to learn.” Here is a quote from an NEJM article a few months ago about the risks and benefits of trusting direct-to-consumer personal genomic services such as 23andMe.

“Clinicians will be central to helping consumer–patients use genomic information to make health decisions. Any regulatory regime must recognize this reality by doing more than simply adding the tagline on most consumer ads for prescription drugs: “Ask your physician.” That is insufficient guidance unless your physician has ready access to a clinical geneticist or genetic counselor.” Annas GJ, Elias S. 23andMe and the FDA. N Engl J Med 2014; 370:985-988. http://www.nejm.org/doi/full/10.1056/NEJMp1316367

Some of the personal genomics service offer phone-in access to genetic counselors. I tried that, and didn’t get helpful answers there, either. Even worse, one of the answers I got was blatantly wrong. It may have been just the genetic counselor who I happened to be talking with, so don’t judge the whole profession by that one person, but do be prepared to keep looking for info if needed. Where I found the most helpful information was in the 23andMe forums, BUT a lot of the info there was unreliable, and I had to sort out what was helpful and what wasn’t.

So, my recommendation is, absolutely DO ask your doctor, ask a genetic counselor if you can, but that might not be enough. You might need to do more research on your own, or find someone you trust to help you with this.

What Good Is It?

So, what good is it then? It gives you clues. Like a detective, you take the clues and look for more information, or ask for more thorough testing, or raise questions that weren’t being asked or addressed before. Some of the clues will be red herrings. Some of them may lead you to a prized solution. For me, these clues ended up dramatically improving my quality of life, and may have even saved my life.


So, now, the short short version. And PLEASE, if someone more expert than me with genomic data reads this and spots any errors, please say so!

PART ONE

1. Get your 23andMe test done.

Pic of the Day - PGenPGEN, Take 2

2. Log in at the 23andMe web site when you are notified that your results are ready.

23andMe

3. Click: Browse raw data.
23andMe: Getting to your raw data

It should look like this:

23andMe: Browse Raw Data

4. Click: Download raw data.
23andMe: Download Raw Data

5. Complete security procedure (log in again, answer security questions, etc.). It should look like this.

23andMe: Downloading Raw Data

6. Answer the question about what type of data and format you want. NOTE: I always choose ALL DNA, unless you have something else specifically in mind.

23andMe: Downloading ALL Your Raw Data Or ...

7. Find the file (which will be named something like genome_Firstname_Lastname_Full_12345678901234.txt)

PART TWO (A): Easier Way

Genetic Genie

Now you have choices. You can dig into the information the easier way, or the less easy way. Let’s start with the easier way.

1. Select a tool to do what you want with your data. There are LOTS of tools people have built to do useful things with 23andMe data files. One of my favorites is Genetic Genie, because it tells you about the MTHFR gene which has become so important in my life. I also am spending a lot of time with Promethease because it is so complete compared to most other 23andMe analysis tools. Lets start with these.

2. Go to the tool of your choice, such as:

Genetic Genie: http://geneticgenie.org/

Promethease: http://www.snpedia.com/index.php/Promethease

3. Follow the directions at the tool, but this almost always requires you to upload your 23andMe data file. Here are more details about doing this with Genetic Genie.

4. Last come what is always the tricky part — making sense of the information you get. That’s worth several posts, but for starters the main point to remember is that the 23andMe test is a place to start, not a final answer. In Genetic Genie, the code, analysis, and text are written by engaged amateurs, not by doctors or genetic counselors. They worked hard, collaborated with a lot of other people, and did a lot of research, but it isn’t going to say the same things your doctor might.

More Tools

23andMe: Tools for Everyone http://www.23andyou.com/3rdparty
NOTE: When 23andMe took out the health reports, they also edited this page to remove links to tools that provide health data from 23andMe data. So, this is interesting and useful, but not sufficient. You’ll have to look somewhere else for most tools.

23++ Chrome Extension: Get more from your data:
http://23pp.david-web.co.uk/getting-more-from-your-data/

Confessions of a Cryokid: Top 10 things to do with your FTDNA raw data (2011) http://cryokidconfessions.blogspot.com/2011/06/top-10-things-to-do-with-your-ftdna-raw.html

Genetic Genealogist: What Else Can I Do With My DNA Results: http://www.thegeneticgenealogist.com/2013/09/22/what-else-can-i-do-with-my-dna-test-results/

International Society of Genetic Genealogy: Autosomal DNA Tools: http://www.isogg.org/wiki/Autosomal_DNA_tools

Resqua: Q: What should I do after generating my Gene variance report? http://resqua.com/100005927200207/what-should-i-do-after-generating-my-gene-variance-report

Think Exponential: Get SNPd! http://thinkexponential.com/2013/01/10/why-you-should-get-snped/

PART TWO (B): Less Easy Way

Linking Disease Associations with Regulatory Information in the Human Genome

Actually, there are a LOT of different “less easy ways.” You can open the raw data file in a text editor and search manually for specific pieces of information. Or, if you code, you can write a little program to do some of the hard work for you.

Basically, it comes down to doing a lot of research, the hard way, by hand. But, believe it or not, I am doing it. I’ve had a lot of help from people who offered tips or comments in the 23andMe or MTHFR.net forums, on Facebook, on Twitter, and comments on these blogs. I am NOT an expert, but like most readers of this blog, just someone who wants or needs to know more. This is what I’ve learned and figured out on my own, offered as an example, nothing more.

Critical Background

23andMe gives SNP-based data. SNP stands for single nucleotide polymorphism. Polymorphism means something that can be itself but in different ways, our eyes are eyes whether they are blue or brown or hazel or violet or any other natural eye color. I won’t give an introduction to genetics here, but there are several online resources that explain these ideas, with one of the best resources being Genetic Home Reference from the US government. Depending on how much you want to know, you may wish to take the Coursera courses Introduction to Genetics and Evolution (Duke U) or Experimental Genome Science (U Penn).

1. What SNPs do you want to know about? Check here:

RegulomeDB (Stanford): Linking Disease Associations with Regulatory Information in the Human Genome: http://regulomedb.org/GWAS/

I have also found SNPs of interest in research articles, PUBMED, and other places, but this is a good start. The SNP identifier (what you need) will look something like this:

rs2187668

2. Find out which polymorphism is the one considered “healthy” or “normal”, and which one is the one associated with risk of disease? These maybe called “risk alleles” or
simply polymorphisms.

For example, for SNP “rs2187668” (one of the celiac risk SNPs) the risk indicator is (T), while the normal is (C).

3. Open your 23andMe raw data file in a text editor, like WordPad (Windows) or TextEdit or TextWrangler (Macintosh).

4. Search for the SNP you want to know about. The data will be in four columns:
– RSID
– Chromosome
– Position
– Genotype
You need to know about the first and last columns, RSID and Genotype. It will look a little like this.

rsid…..chromosome…..position…..genotype
… [many other rows of data] …
rs2187668…..6………32605884…..CT

So, this person (me) has for that SNP one risk allele “T,” (which I happen to know is from my dad, by comparing it to his scan) and one normal allele “C,” (which must, by default, be from my mom, since for every gene pair we have gotten one from each parent).

5. Repeat for all the other SNPs associated with the condition you are researching.

6. Search for more information and articles about those SNPs, the condition, and more. You can’t make sense of this without more information. And ask lots of questions.

More Tools

ENCODE:
About: http://www.genome.gov/encode/
Data: http://genome.ucsc.edu/encode/

ENSEMBL Genome Browser: http://useast.ensembl.org/

OpenSNP: https://opensnp.org/ OR https://opensnp.org/snps/

SNPedia: http://www.snpedia.com/

UCSC Genome Browser: http://genome.ucsc.edu/

Trying Out SAM-e (Smart People Can Do Dumb Things)

Screen Shot of image search for SAM-e

Another girlfriend suggested SAM-e, and since it connects to methylation and we know I have mega-MTHFR challenges as well as other methylation problems like COMT, I figured I’d give it a try. Before you read too far, the end of the experiment for me is a big fat “NO, DON’T DO THIS.” But, of course, it isn’t that simple. I’m still not feeling well, so I’m trying to keep this simple. In part, this is an example of how to research something before you decide on a new course of treatment for yourself, and in part it is a cautionary tale.

WHY I THOUGHT IT MIGHT HELP

What is SAM-e used for? The big ones are depression, osteoarthritis, fibromyalgia, and liver disease, but these are also mentioned.

ADHD
anti-aging
Alzheimer’s
anxiety
back pain
bursitis
chronic fatigue syndrome (CFS)
dementia
depression
fibromyalgia
heart disease
lead poisoning
liver disease
migraines
multiple sclerosis
osteoarthritis
Parkinson’s
premenstrual dysphoric disorder (PMDD)
premenstrual syndrome (PMS)
seizures
tendonitis

Well, with a list like that, I figure a lot of folk think the same thing I did: “Gee, several of those apply to me or my family. Who knows? Maybe it might help. Let’s give it a try.” The first piece I looked at clustered these into categories of (1) bone and join problems, (2) nervous system problems, and (3) organ health. Two of those are themes in my life, so it was making sense that it might be part of the picture. And I really really wanted to feel better.

WHAT I RESEARCHED BEFORE TAKING IT

No, I’m not so foolish as to simply dive in and start taking something on a whim. Everything we ingest can have effects like a drug; everything has a minimum and maximum recommended dose; everything has interactions and side-effects, indications and contraindications. I looked it up, in major drug databases as well as Google Scholar, Pubmed, and some drug databases. I looked for the interactions and side-effects (there are LOTS). I looked at signs of an overdose. Turns out there are two kinds of overdose: (1) over-methylation, which makes you jittery, anxious, sleepless, etc.; and (2) serotonin syndrome, which can be fatal, and starts out with agitation, restlessness, confusion, tachycardia, high blood pressure, muscle twitches, sweating, diarrhea, headache, shivering, fever, goosebumps.

I felt pretty prepared at that point, but there were a few more things I wanted to know. The importance of SAM-e in the methylation process was obvious with even a superficial web search. Since I have MTHFR deficiency and that is also a big problem with the methylation cycle, I wanted to make sure the two don’t interact in nasty ways. So I searched for information about interactions between SAM-e and methylfolate, warnings, precautions, etc.

This was more interesting. First off, it turns out that methylfolate helps people make their OWN SAM-e! They are part of the same cycle, and SAM-e is one of the by-products from MTHFR processing. Regarding taking both, there was virtually no solid evidence floating up to the top, but an awful lot of opinion and personal experience. (Guess I’m adding to that body of unclear literature.) I saw a lot of people saying, “If you have MTHFR deficiency, do not ever take SAM-e!” This was balanced by an equal number of folk saying the opposite. The overall picture was unclear. There was a lot that said to take them together, almost nothing about if you have an MTHFR deficiency.

I found one woman who described it as helpful for brief periods, and she described her genetics as similar to mine — heterozygous MTHFR, homozygous COMT (H62H & V158M), and celiac. She described reacting with an over-methylation response after a couple weeks, and I had gone through that when I started taking methylfolate and felt I know what to do. Just to be careful, I started out with the smallest dose I could find – 200mg.

WHAT HAPPENED

Part of what was motivating this was that general feeling of being unwell that I’ve had ever since I returned from my trip. I really want to feel better, but am feeling crummy. I thought about waiting to start SAM-e until I feel better, but based on what information I’d found I thought I knew what to expect. Either it wouldn’t do much, or I’d feel better.

I took a half dose on Monday. I felt basically the same as I’ve been feeling — generally crummy. Tuesday the same thing. I wasn’t sure if I’d been glutened or not. I took a couple days off, just to see. Then I thought maybe I hadn’t taken enough to notice a difference. [The problem with this was I had forgotten to look at how long it takes to feel an effect, and it varies depending on the problem.]

I was taking Friday as vacation, and thought I’d risk taking a larger dose, since I didn’t want to experiment if I was going to try to work. Instead of 200, I took 400. I continued to feel vaguely crummy, and then I started to feel as if I’d been glutened. I’d been eating “whole foods,” so I couldn’t imagine what it would have been, but I recognized the feeling. Fatigue. Brain fog. Wobbly. But not a hint of any digestive symptoms, no bloating, no hives. I was puzzled, but sleeping too much to figure it out. I had trouble sitting and standing, my joints hurt. I felt too weak to do much. Not normal symptoms included feeling hot, sweaty, feverish, flushed, confused, congested, chilling, spaced out, distractible. Then I got a headache, and my head feels strange in the back. So far, this has lasted three days. Each day has had a couple brief periods when I felt ok, before it would start up again, slightly milder than the day before.

WHAT I LEARNED AFTERWARDS

I went back and looked again at SAM-e overdose. Nope, these symptoms don’t match up, except for the headache. My symptoms were more like those indicators that someone needs more SAM-e. Very puzzling. I kept digging into literature about SAM-e. I tried taking extra methylfolate, but didn’t notice a difference. I did notice that my clear-headed time was in late afternoon, and every day I take a B-complex vitamin with my lunch. Then I stumbled into some information that SAM-e can cause problems if someone is deficient in B-vitamins (like me). Basically, it creates a lot of homocysteine, which the body can’t clear out because it needs more B-vitamins to do so.

I put 3 and 3 together. Maybe this was a SAM-e overdose, but my body couldn’t properly process the SAM-e? I tried taking extra B-vitamins to see if this helps clear the fog and confusion and fatigue. I’m not trying to do it all at once. I took a B12 and my usual B-complex, then waited a few hours and took another B-complex. So far it seems to be working. I’ll add an addendum tomorrow.

SOURCES

About.com, Alternative Medicine: SAMe, What Should I Know About It? http://altmedicine.about.com/od/treatmentsfromatod/a/SAMe.htm

Mayo Clinic: SAMe: Safety: http://www.mayoclinic.org/drugs-supplements/same/safety/hrb-20059935

Mayo Clinic: Serotonin syndrome: http://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/basics/definition/con-20028946

Natural Database: SAMe: http://naturaldatabase.therapeuticresearch.com/nd/PrintVersion.aspx?id=786

University of Maryland Medical Center:
S-adenosylmethionine http://umm.edu/health/medical/altmed/supplement/sadenosylmethionine

WebMD: SAMe: Uses, Side Effects, Interactions, and Warnings. http://www.webmd.com/vitamins-supplements/ingredientmono-786-SAMe.aspx?activeIngredientId=786&activeIngredientName=SAMe


UPDATE June 24, 2014:

Looks like I probably guessed right. The extra B-vitamins are helping, allowing me to get through the day. I couldn’t find anything about the length of time it takes to clear SAM-e from the body (personal reports range from on day to a couple weeks). I’ll probably have to take extra B-vitamins for a few more days.

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. http://www.discoverymedicine.com/Ellen-Sidransky/2012/10/27/gaucher-disease-insights-from-a-rare-mendelian-disorder/

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: http://www.childrensgaucher.org/about-gaucher/gaucher-basics/

Genome.gov: Learning About Gaucher Disease: http://www.genome.gov/25521505

Science Daily: Macrophages: The ‘Defense’ Cells That Help Throughout the Body: http://www.sciencedaily.com/releases/2010/08/100826141232.htm

NINDS Gaucher Disease Information Page: http://www.ninds.nih.gov/disorders/gauchers/gauchers.htm

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:
http://etechlib.wordpress.com/2013/01/19/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. http://www.ncbi.nlm.nih.gov/pubmed/22108709

Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband. http://www.ncbi.nlm.nih.gov/pubmed/21813566

Severe Combined Immunodeficiency Resulting From Mutations in MTHFD1. http://www.ncbi.nlm.nih.gov/pubmed/23296427

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: http://www.youcaring.com/medical-fundraiser/sequence-a-science-fiction-writer/38705

Lakeside (A film about cancer in families): http://www.kickstarter.com/projects/1060155945/lakeside-0

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.


WHY

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.