The Motherfucker Gene

August 21, 2016 § 1 Comment

One of the things that’s haunted me most about living with mental illness is my inability to explain or account for it–to myself or to others. My earliest internal experiences of anxiety, for instance, was of being strange to myself, having thoughts and feelings that not only overwhelmed me but that didn’t make sense, thoughts and feelings that felt somehow other to myself. Part of me but different from me at the same time. I had no language for what I experienced, which caused secondary trauma when I could not communicate my distress to anyone–or when I tried, later, and was met with confusion, skepticism or inadvertent invalidation. After all, the things I felt and thought didn’t make sense to me–why should they make sense to others? It didn’t make sense: that I would fear vomiting so much, for instance, that the arrival of a letter in the mail after school one day in 4th grade, stating that I had been randomly selected to audition for a kids’ game show, would make me ball up on the couch crying. To do that I would have to travel out of town! And if I traveled away from home I might get sick! I knew it didn’t make sense, and I was embarrassed. I knew I couldn’t tell anyone the real reason I was scared. It was too weird. But I was filled with dread and despair and a desperate feeling of being unsafe nonetheless.

So I just lived with this inner otherness that has been there seemingly since my earliest childhood, alternately hiding symptoms and managing them maladaptively via various magic tricks like not eating (if you don’t eat, you can’t throw up, of course) or staying up all night to keep watch over internal bodily sensations (if you allow your body to relax, it might betray you in the night). I couldn’t recognize the trauma of feeling invalidated and unprotected as such, and instead acted out on it, obliquely–starving, cutting, seeking out self-destructive relationships, anything to communicate as loudly and passionately as possible the intensity of the distress I was experiencing, goddammit!

In my late 20s and early 30s I learned a lot more about how anxiety conditions work physiologically and also how trauma functions, and as a result I was able to work more directly to manage my symptoms in non-self-injuring ways–medication, meditation, therapy, exercise. And yet I’ve continued to wonder why I experience what I experience, why I am neurodivergent, and to search for something that might explain everything, all the weird, unexplainable thoughts and feelings and sensations. Could it be an unrecognized traumatic brain injury sustained when I was three and cartwheeled down the basement stairs at my aunt’s house? Could it be some kind of birth trauma? I was born Caesarean. Could it be an early manifestation of the bipolar I was later diagnosed with?

To that extent, I am filled with awe and wonder and humility at having finally seemed to stumble on, if not the sole explanation, then a major component of it: MTHFR, aka the motherfucker gene. I’m excited to share what I’ve learned in the hopes that it can help others not just to understand their condition but to access effective treatment. I’m excited that what has felt so hugely and profoundly inscrutable and has had such enormous consequences for my health and quality of life has turned out to be so seemingly simple.

MTHFR stands for “methylenetetrahydrofolate reductase.” It is both an enzyme and a gene that controls production of that enzyme, both of which regulate the metabolism of dietary folate (Vitamin B9), converting it from folic acid to a form our bodies can actually use. I first heard about its role in psychiatric symptoms from a naturopathic doctor I saw when I was trying to handle depression and anxiety without psych meds and osteoporosis without biphosphonates (which mostly involved gulping handfuls of huge stinky pills several times a day–tho in the process I did learn some tricks that made me a better pill swallower, i.e. ice cream). In addition to having the equivalent of an MD in naturopathic medicine, this doctor is also a registered nurse and licensed clinical nutritionist, and what she explained to me is that folate metabolism is centrally involved in neurotransmitter production. For this reason, defective MTHFR genes can express themselves as psychiatric conditions, primarily depression but also anxiety. That’s not to say that MTHFR is implicated in all depression or anxiety or that if you have this defect that it will manifest psychiatrically. But there is an association, and it is a fairly common genetic defect. Something like 30-40% of the general population doesn’t metabolize folate from the diet at full efficiency.

The recommendation of the naturopathic doc was thus to take a supplement called l-methylfolate, which is a digested, bioavailable form of folate. Basically, it’s what your body would be producing at the endpoint of the folate metabolic chain if your genes were working correctly. She prescribed a liquid form, 5 drops a day, which is about 2mg. I noticed significant improvement almost right away, but this tapered off after about six weeks and my anxiety returned. I’ve had similar experiences with psych meds, specifically SSRIs, so I chalked it up to another ineffective treatment, and when I ran out I didn’t buy more.

A few months later, during a routine meds check-in with my psychiatrist, he also brought up MTHFR. We had tried Luvox for the anxiety (worked, but made me insanely sleepy and killed my libido) as well as St. John’s Wort (didn’t seem to do anything but dampen libido, albeit with more subtlety). The best regimen seemed to be to manage mild and moderate levels of anxiety best I could without drugs, saving benzos like Xanax for severe anxiety spikes. At that time I had been mood tracking daily for a couple of years, and I was having two to four episodes of moderate anxiety a month and one severe episode, and mild anxiety most other days of the month.

Corroborating what the naturopath had initially explained, my psychiatrist told me that a lot of recent research had found significant links between MTHFR and psychiatric symptoms. You could have one defective copy of the gene or two, he said, which would represent a more significant impairment in folate metabolism. You could also be tested for the gene, he said. Technically it was a test that looked at how well your body metabolized different kinds of medications, but one of the things they were looking at was whether you had healthy copies of the MTHFR genes.

So I had the genetic test done–no blood draw involved, just a cheek swab–and as it turns out, I have two defective copies. More specifically, my lab report reads:

Gene                                Genotype                                     Predicted Phenotype
MTHFR                           C/C (C677T)                                Reduced Activity
                                          C/C (A1298C)

—Patient is expected to have decreased folic acid metabolism
—Patient has the MTHFR genotype (C677T or A1298C variants) associated with improved depression treatment outmodes with l-methylfolate treatment adjunctive to SSRI/SNRI antidepressants.

The short explanation: I have a homozygous mutation for the A1298C variation of MTHFR, or two defective copies of this gene. However, I have two healthy copies of the C677T gene.

(Want the longer explanation? Here’s how I understand it. There are about 50 mutations that affect the MTHFR gene; the most common are C677T and A1298C.
The numbers refer to the location on the gene, letters to the specific kind of mutation (transposition of C with T and A with C). If you remember the basic genetics unit from high school biology, DNA is constructed from four basic chemical building blocks: adenine, cytosine, guanine, and thymine, better known by their initials (A, C, G, T). This refresher helps us understand what it means to say we have a genetic mutation or not. For proper functioning, the MTHFR gene at location 677 should have two copies of cytosine, one inherited from each parent; this is written as 677CC or referred to as genotype C/C. With a heterozygous mutation, or with one mutated copy of the gene, cytosine is transposed with thymine (677CT or genotype C/T). With a homozygous mutation, or two mutated copies, thymine replaces both cytosines (T677T). This is why the general name for this “single-nucleotide polymorphism” is C677T or, less confusingly to my mind, 677C—>T. My lab results say I have a genotype of C/C for the C677T mutation, so what that really means is I’m good to go here.

Where it gets confusing is that the C/C genotype means the opposite at the 1298 location. Here, a healthy copy of the gene would have two adenine bases—1298AA. So a C/C genotype means that both Adenines have been transposed with Cytosine. In other words, I have two faulty copies of this gene, one inherited from each parent.)

Of the two most common mutations, C677T is much more well-researched compared to A1298C. As well as mental health and mood conditions, C677T has been implicated in cardiovascular problems due to its disruption of the amino acid homocysteine, which MTHFR helps break down. Thus, if MTHFR activity is reduced, homocysteine levels build up in the blood, which irritates arteries/veins and can lead to an increased risk of stroke, coronary artery disease, and blood clots.

A1298C is less well understood, but from what I’ve read, it is more associated with neurotransmitter levels and thus psychiatric conditions. This is because a defect at this specific location on the gene inhibits utilization of methylfolate, or the bioactive form of dietary folate, in producing something called tetrahjydrobiopterin (BH4), which is a co-factor in neurotransmitter production. However, it is also the less severe of the two mutations: whereas two defective copies of C677T results in 60-70% loss of folate metabolic functioning, two defective copies of A1298C result in only about a 40% loss, according to this study.

Interestingly, this same study–basically a big lit review of other studies examining the association between MTHFR mutations and psychiatric conditions–asserts a positive association between mutations at both locations and depression, schizophrenia, and bipolar; yet it can only make definitive claims for C677T, as just three studies of those reviewed focus specifically on A1298C (one in relation to depression, two in relation to schizophrenia). As the researchers report:

Our main finding was that the MTHFR C677T polymorphism is associated with major depression, schizophrenia, and bipolar disorder [note: their review did not find an association with anxiety, although this was based on only one population-based study]. The magnitudes of the associations were moderate but statistically significant. Emerging evidence of an association with the MTHFR A1298C polymorphism was also found. However, in line with other reviews, associations with this variant have been less extensively researched. Further research on disease associations with this MTHFR polymorphism is needed.

Unfortunately, then, data on the lived impacts of homozygous A1298C on mental health remain speculative, relegated to MTHFR discussion boards and websites for DIY genetic test kits. :/

In any case–based on my test results, my psychiatrist suggested that I try Deplin, which is a souped-up, fancy, brand name version of the liquid l-methlyfolate supplement I had been taking. Compared to the drops, it’s super concentrated–one capsule has 15 mg compared to the 2 mg I had been taking (via 5 drops). I asked my pdoc if I could just take more of the liquid supplement, but he wasn’t familiar enough with the brand to compare. Then I ran his suggestions by the naturopath just to get her take on Deplin vs drops, and she kind of poo-poo’ed the Deplin, mostly based on cost (and by extension, I think, unstated criticism of Big Pharma psychiatric drug pushers). But as it turns out, at $30 for a month’s supply, the over-the-counter option is not necessarily more cost-effective. My insurance doesn’t cover Deplin, true, but there’s a discount program you can access if you purchase directly from the manufacturer, where you pay three monthly installments of $60 for a three-month supply, stretched to six months since I take one 15 mg capsule every other day rather than daily. Plus, I figured–since I had tried the drops already, why not give the other a shot?

Y’all: I have had an almost complete cessation of anxiety since I started taking the Deplin 6 months ago. I even stopped tracking moods, because there was nothing really to track. I went from 1 severe episode, 2-4 moderate episodes, and anxiety most days of the month to almost nothing. Nor are there any side effects, because it’s basically just a big fancy vitamin–“medical food” is what the label reads.

My pdoc said that to pronounce one’s self better as the direct result of changes in meds, diet, habits or whatever other tinkering, you should give it a year to see if the changes stick. In my case, he said, that’d be a year from when I stopped mood tracking. I’m not even taking the mood stabilizer anymore, just the Deplin. Could it be that the motherfucker gene explains everything, even the two manic/depressive cycles that landed me the bipolar diagnosis on top of the anxiety? We’ll see, I guess.

But in the meantime, the effects have been so dramatic that it’s hard not to feel that I’ve finally figured out and addressed the underlying issue. I’ve had the increasing sense as an adult that my issues stem from something biophysical–because they began so early, seemingly independent of any trauma (although the symptoms in themselves and the issues they caused were sources of trauma), but also because of some inexplicable, lived sense of having always been there, somehow, as part of my architecture.

Now I know, deductively, from the test and from the way I’ve responded to the Deplin, that this is in no small part true. It’s kind of staggering to think that so much of mental suffering and resultant life chaos that has organized my time on earth is attributable to a nutritional problem, essentially. Equally strange to consider that if my anxious and depressive tendencies are genetic, there’s a big chance my sister’s are too–part of a common inheritance. And that if our psychiatric stuff is genetically shared, that is because it’s been inherited. My parents don’t have anxiety or depression, but OCD runs strong on my mom’s side of the family–her mother took medication for anxiety and so does her one of her sisters.

An addendum that adds a bit of intrigue and amusement to my maternal inheritance theory:

I was born with a dimple above my butt which I long thought was a feature idiosyncratic to me, like a birthmark or something, before learning only in adulthood that it’s actually something called a sacral dimple, which indicates something else called spina bifida occulta. Regular spina bifida is of course a very serious birth defect that occurs when the vertebrae fail to fuse properly, leaving spinal cord exposed. Spina bifida occulta, by contrast, is very mild. I’ve never had any physical problems from it; it’s always been more of a curiosity (“look at my second butthole!”). I’ve never even really seen it full on, only peripherally, squinting over my shoulder in the mirror. The internet suggests that if I could examine it directly, it would look something like this:

sacral dimple

 

Basically, what it means is that I have a very mild neural tube defect.

What causes neural defects like spina bifida? Lots of things, but one known factor is if your mother didn’t get enough folate in early pregnancy–which is why in 1992 the US Public Health Service began recommending that pregnant women take 400 micrograms of folic acid through their first trimester to prevent neural tube defects, and why the FDA’s requirement in 1998 that cereals and enriched grains be fortified with folic acid cut rates of neural tube defects by 20-30%, according to a CDC report evaluating the impact of the 1992 recommendation ten years later (see here).

If I have a confirmed genetic defect in my ability to process folate, though, that seems to suggest that maybe my mom did too. Which shaped not only my neurotransmitter production, but also my neural tube development.

Which finally explains the second butthole. Not to mention all my other weirdnesses.

Guess it’s not called the motherfucker gene for nothing.

***

Here is the point of this entry: I recommend to anyone who struggles with significant mental intensity to see if MTHFR is a factor. Could be it’s not. But could be there’s a really helpful treatment that is easy to boot.

One more note: if you google MTHFR, about half of what comes up is confusing and smells like quackery. But for further reading, this article is a good, basic starting point, consistent with what both docs informed me.

Advertisements

Tagged: , , , , , , , , , ,

§ One Response to The Motherfucker Gene

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

What’s this?

You are currently reading The Motherfucker Gene at leavings & survivors.

meta

%d bloggers like this: