The Cause of My Mental Illness
How a Zinc, and Partial Purine Nucleoside Phosphorylase Deficiency, ruined my life.
In 2014, and again in 2017, I had my Genome sequenced by 23andMe, and in the years following I discovered I had some uncommon polymorphisms (SNPs) in a gene called Purine Nucleoside Phosphorylase (PNP). When I researched these SNPs I had I found a study that proved that one of them, rs1049564, caused a functional inhibition of the PNP that was shown to increase interferon in people with Lupus:
I was a homozygous carrier of both of the minor alleles which meant that my PNP gene was slower than most other European Caucasians. Having both of these minor alleles only occurs in about 2% of Europeans. This is me:
And these are some of my other SNPs in that same gene. It is obvious I carry a series of uncommon SNPS in PNP.
This lit up my mind since I had signs of Lupus for years, such as Discoid lesions on my face and arms, Malar Rashes, and Shuster’s Sign in my right ear. And this went along with lab tests constantly showing low White Blood Cells and my general feeling of being unwell.
I mostly put it on the back burner since most of my worst symptoms were neurological until I found out about Neuropsychiatric Lupus (NPSLE). Was this uncommon SNP causing both my physical and mental health problems? I had a number of Autoimmune tests and they all kept coming back normal except for a mild positive Cardiolipin AB IgM, which has been shown to be higher in NPSLE. The one test they have not done is an Anti-NMDA antibody test. (And that is unfortunate because I feel that would have revealed an issue.)
The one issue I had was that searching for PNP Deficiency all you saw were stories of children who died early from a severe immune deficiency. This was certainly not me, I felt I was somewhere in between. I lost hope in this gene and kept researching in other areas.
But in 2020 Eyal Grunebaum published a study titled:
Partial Purine Nucleoside Phosphorylase Deficiency Helps Determine Minimal Activity Required for Immune and Neurological Development
It changed everything. It revealed that my PNP gene was probably very slow, but not extremely slow, and that it meant I would not necesarrly feel the effcts from the polymorphism until I was in my thirties.
Conclusions: Patients with partial PNP deficiency can present in the third decade of life with mild-moderate immune abnormalities and typical development. Near-normal immunity might be achieved with relatively low PNP activity.
I could have broken my jaw it dropped so hard. Even though I suffered a lot since I was a child, my worst symptoms began when I was 33! That is when I lost my job as a Network Engineer and three years later had to get on Disability. Not only that, a quick search revealed that they have long suspected Purine Pathway abnormalities in mood disorders.
Since then I have been trying to understand how this gene change affected me and what I could do about it. And last month I discovered my answers adn since then I have had a consitent stabilization of almost all of my symptoms. So let’s look at this enzyme, what it does when it works right, and what happens when it is too slow to keep up.
Purine Nucleoside Phosphorylase plays a role in purine metabolism. You might have heard about purines if you have Gout. Here is the Purine Pathway. Gout is caused my high uric acid which is the end product of the Purine Pathway.
In the image below I marked the PNP enzyme in red. As you can see, it plays a role early in the purine pathway.
If I assume my PNP enzyme is slow I would not only get a build up on Guanosine and Inosine, but everything that comes before it like GMP, IMP, AMP, GTP and ATP. And it also means I have lower production of hypoxanthine, xanthine, and uric acid.
While there are several implications to having increases and decreases in each of these metabolites of the purine pathway, for now I am going to focus only one of them which I believe caused most of the symptoms of my Mental Illness; GTP.
You might have heard of ATP (Adenosine triphosphate):
Adenosine triphosphate (ATP) is a nucleotide that provides energy to drive and support many processes in living cells, such as muscle contraction, nerve impulse propagation, and chemical synthesis. Found in all known forms of life, it is often referred to as the "molecular unit of currency" of intracellular energy transfer.
But many of you may not have not heard of GTP (Guanosine triphosphate)
GTP..
…also has the role of a source of energy or an activator of substrates in metabolic reactions, like that of ATP, but more specific. It is used as a source of energy for protein synthesis and gluconeogenesis.
GTP is essential to signal transduction, in particular with G-proteins, in second-messenger mechanisms where it is converted to guanosine diphosphate (GDP) through the action of GTPases.
Therefore, if I have this Partial PNP Deficiency, I would have a higher level of GTP in my cells, including my neurons. So lets look at what role it performs in the cell.
GTP is used in cells to provide energy for G Protein Coupled Receptors. Since there are over 750(!) of these receptors in humans, for now I will focus on two of them which pertain to mood disorders, the Serotonin and Dopamine receptors, and how GTP effects the receptors and my mood.
First, watch this quick video:
You can see that GTP is needed to make the receptor “active” or “sensitive”. And an active receptor is ready to fire, or “amped up” if you will. The cell has tremendous potential energy. So when there is a release of serotonin or dopamine, these receptors activate and do all the thing the serotonin and dopamine neurons do.
So GTP increases what I am calling “Receptor Energy”. The more receptor energy a receptor has the more intensely it will fire.
Now, the serotonin neurons influence learning, memory, happiness as well as regulate body temperature, sleep, sexual behavior and hunger. And the dopamine neurons influence voluntary movement and a broad array of behavioral processes such as mood, reward, addiction, and stress.
So do you see what this means yet? In someone like me who has way too much GTP in my neurons will express the symptoms of Bipolar Mania and Schizophrenia. So they were right on the money when they diagnosed me with Schizoaffective Disorder Bipolar Type!
(This also means people with low GTP will suffer the opposite effect; depression and Addiction but that is a future blog post…#LongCOVID #MECFS)
Now imagine not only having these two receptors over active (or over energized or over sensitive…still looking for the right term) but all 750 of them. Welcome to my life.
So it is as simple as that. It is not that I make too much serotonin and dopamine, I am just extremely sensitive to any serotonin and dopamine I release. This explains the hallucination I had since I was a child via the over activation of the Serotonin 2A receptor, and the hyperactivity triggered by the over activation of the dopamine 2 receptor.
So how do I get rid of all this GTP? I believe the answer is high dose zinc.
Zinc has helped me as far back as I remember. I made me feel more calm and centered and I noticed this effect even more after I stopped all my medications six years ago (but for Klonpin as needed which was the only thing that would break my psychotic episodes). And zinc plays a crucial role in this early metabolism of purines.
Let me present a simplified metabolic pathway of GTP:
You can see that zinc is needed as a cofcator for 5'-nucleotidase (NT5E) to turn GMP into Guanosine which releases a phosphate. That phosphate can be used to help the PNP enzyme to get rid of the Guanosine and let it continue to make Uric Acid.
Wow. So low intracellular zinc will starve the PNP enzyme of Phosphate slowing it down even further. Is this why my health issues became worse after I was thirty, when zinc status starts to become more of a problem? Looks like it.
But there is another enzyme, cGMP-specific 3',5'-cyclic phosphodiesterase, (PDE5A) which uses zinc as a cofactor as well. This has the function of lowering cGMP which has effects which I will go into another day, but briefly it modulates various downstream biological effects, including vasodilation, retinal phototransduction, calcium homeostasis, and neurotransmission.
So by taking zinc I will also lower cGMP, turning it into GMP, and will get rid of some more of my symptoms. And increasing GMP will also end up increases GDP which lowers receptor energy. And they have shown that these PDE5 enzymes are linked to mood disorders (faster function linked to depression, slower function is linked to mania. So it was no surprise for me to read that a well known erectile dysfunction mediation, sildenafil, has been know to cause mania is some people.
The other thing I need to do is eat less and eat less sugar, that former I am working on, but the later as been something I hav been doing for years. Lowering calorie intake will lower GTP in general. This will limit my need for zinc as well. Manganese also plays a role in helping me but that is another post.
I can tell you that my recovery in the last month has been dramnatic. I am still working out the kinks, but already my friends can even hear it in my voice and behavior.
So I hope you can appeciate what I am expaining here and what I discovered in myself. I feel this insight can have implications for everyone who is living with mental illness, chronic pain, addiction, and many other chronic illnesses.
I would love to hear from you about all of this and hope you can spread my story and my substack to as many people as you can. I am tired of all