There is so much to write here, but I don't have a big block of time to do so. This section will be much less organized than the others, as I will be adding to it. Kind of like a collection of thoughts, studies, observations related to the RCCX Theory. it's a work in progress. Please join Facebook Group: RCCX and Chronic Illness Discussion Group to watch as all of this rolls out...
Interesting research developments:
Stephen PorgesPhD (Polyvagal Theory, world famous trauma neuroscientist) is interested in EDS!! He is an author on the 3/15/17 released psychiatric paper on EDS and he is looking into the the enhanced danger response in this population and how to measure it. He is the one researcher I would have chosen to pursue this idea. I believe that this is going to blow the lid off of psychiatry and lead to help for all of us! I have written to him (4/7/17) to tell him about CAPS and CYP21A2. He wrote back and says he will be in touch when he returns from his travels!
End of MARCH 2017: Ron Davis PhD is talking about a personality feature in people who develop CFS/ME which involves pushing through stress when we shouldn't (CAPS?). He also is thinking that a carrier form of a known homozygous disease may be the problem (?Carrying CYP21A2 mutations rather than homozygous CAH).
Stephen Porges PhD and Robert Naviaux MD PhD are working together, looking at fibromyalgia per Porges webinar. I wrote to both of them 4/7/17 to introduce them to the RCCX hypothesis, via email and snail mail...Word back from Porges (above), none from Naviaux.
Very high rate of mental anguish in the gay population. High suicide rate and high rate of physical illnesses like allergies. http://highline.huffingtonpost.com/articles/en/gay-loneliness/
Link between polycystic ovaries and autism: https://www.scientificamerican.com/article/a-new-autism-risk-factor-moms-with-polycystic-ovaries/
Autism genes may be evolutionarily advantageous due to ways of processing information if not severe enough to cause autism (CAPS) http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006618
Generalized Anxiety Disorder is associated with a high pro-inflammatory cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-10. https://www.ncbi.nlm.nih.gov/pubmed/28161475
Dr Castori (EDS expert) now listing some RCCX subgroups of HEDS:
Tenascin X-deficient AR TNXB
AR TNXB, CYP21A2.
TNXB-CYP21A2 contiguous gene syndrome(which clearly has the potential to NOT be rare like the others as new mutations are being found every couple of months. So, the EDS statement that "TNXB is a rare cause of HEDS" may not be true.
The New EDS nosology was revealed 3/15/17 and on the positive side, the new Hypermobility Spectrum Disorder (not bendy enough for EDS) is felt to be common and associated with the same comorbidities as EDS. (I'll stay out of the fray on this one...)
CFS dysautonomia has been shown to originate in the brain. Limbic retraining, mindfulness, embodiment help CFS/ME/PTSD patients with triggered dysautonomia responses (shift brain circuitry responses away from danger physiology). As above EDS dysautonomia is now being investigated as an evolutionary brain danger response.
The acute stress response was found to be exaggerated in CFS/ME this year, is high in EDS, high in CYP21A2 carriers.
PTSD and childhood trauma (ACES) lead to CFS/ME, dauer
There seem to be 2 populations of CFS/ME patients which can be separated by immunological response and course, the atypical Peterson subset and the regular CFS/ME patients. I believe that the former group could be explained by CYP21A2 AND C4 mutation co-inheritance. They would have a compromised immune system prior to getting sick and a potential for a high rate of later autoimmune diseases due the C4 mutation (again wide phenotype)
Ron Davis PhD's daughter was diagnosed with EDS, showing very publicly that EDS and CFS/ME run in the same families and sometimes the most ill person doesn't have enough hypermobility to warrant the diagnosis of EDS. I sent another packet to Ron Davis PhD via FAX, email and snail mail outlining the RCCX Theory quickly and showing how the CFS/ME research and some of his statements are dovetailing nicely with the RCCX Theory:
CFS/ME as a syndrome likely represents the body’s response to overwhelming stress
Inheritance of CYP21A2 mutations creates a built in stress switch (21hydroxylase overwhelm) which, via CRH, initiates a cytokine cascade in a population which is known to have an exaggerated stress response from before getting sick.
CFS/ME may be the heterozygous/carrier version of a homozygous disease.
Between 10-20% of the population are carriers for a wide variety of CYP21A2 which likely produce a wide phenotype of stress adaptability. The few characterized mutations likely represent the most severe and individuals who are homozygous for them have congenital adrenal hyperplasia with full blown adrenal failure and salt wasting requiring steroid treatment usually in infancy. Those with CFS/ME often have adrenal insufficiency (complicated by low ACTH most likely due to the common downstream effect of raised ICP/empty sella); EDS folks have low blood volume, lose salt.
Some folks may be getting partially functioning mutations from both parents as I believe that people with CAPS choose mates with CAPS.
EDS and CFS/ME run in the same families and you don’t have to be very hypermobile at all to get CFS/ME.
Because the RCCX has such a great variety of mutations, the phenotype created by each of these genes is likely to be highly variable. In the case of TNXB, it may range from meeting EDS criteria to actually being stiff. The presence of a TNXB mutation, i.e. often some hypermobility, will confer a risk of having CYP21A2 mutations as well and thus the risk of developing ME/CFS. CYP21A2 mutations can probably travel alone as well.
CFS/ME sufferers may be reinjuring themselves over and over because they push through stress when they should not
The 21 hydroxylase stress switch is dynamic, blocking and unblocking, depending on stress load from moment to moment. The downstream effects of the block, like MCAS, POTS, salt and water loss and downstream issues, probably including dauer, etc. increase the demand for 21 hydroxylase to make cortisol, making this self-perpetuating.
The brain wired for danger (CAPS) with its heightened sense of urgency and high adrenaline can be adaptive in dangerous environments but in the long-term, it is very stress vulnerable. It is characterized by an exaggerated stress response, sensory sensitivities, hyper-focus, strong special interests, often mental gifts paired with learning disabilities/Asperger’s, an androgenized brain. If the acute stress response is too high or runs too long, bipolar energy shifts (large changes in arousal levels) can occur which is very taxing on the system (bipolar disorder is now known to be highly associated with EDS). With associated MCAS, psychosis can occur, and with co-inherited C4 comes abnormalities in dendritic pruning associated with schizophrenia and possibly full autism. Negative life experiences in combination with over-arousal are well known to induce conditioning/epigenetic wiring resulting in ever increasing perfectionism/rigidity, the emergence of other harm-avoidant psych issues (rituals/compulsions, obsessive worrying) and PTSD circuits. PTSD circuits result in an even more reactive brainstem dysautonomia loops (fight/flight, freeze, shutdown with opiate dumping), somatosensory dissociative loops (pain/sensory phenomena), flashbacks, etc. All of this keeps the acute stress response running, ramping up inflammation via CRH (see diagram for self-perpetuation).
Drugs/substances that help those with CFS/ME, EDS, toxic mold, Lyme, like ketamine, LDN, CBD also help PTSD, autism, depression, pain syndromes which I believe are also associated with CYP21A2 mutations.
Psychiatric Disorders and CYP21A2 carriers. An older study indicate a high rate of psych issues in male carriers, but a recent one refutes this and another one claims stress resilience. I believe that these latter 2 studies are true of most of us prior to becoming sick. We adapt better in stressful situations than others until we hit that enzyme block or develop psychiatric comorbidities. The ones who have too high of an acute stress response are the straight A students I see with terrible test anxiety.
Since this website was released, a large amount of psychiatric literature about EDS has emerged. To summarize all of it: EDS is now known to be highly associated with high functioning autism, OCPD (perfectionism), bipolar disorder, phobias, exaggerated response to dysphoric faces, ALPIM syndrome (anxiety, ligament laxity, pain, inflammation, mood disorder), larger than normal amygdalae (emotional and fear center, associated with high androgens, high stress cortisol during infancy in other conditions), smaller than normal anterior cingulate and the largest study (Swedish registry, over 1000 patients in EDS and hypermobility groups) showed that the same pattern of psych issues (autism spectrum, bipolar, ADHD) exists in people with EDS/hypermobility and their non-hypermobile family members. Stephen Porges PhD now investigating dysautonomia in EDS as evolutionary danger response. All of this is NOT consistent with many different more rare collagen genes causing specific psych issues which do not correlate with degree of hypermobility. These findings confirm comorbidities which can be explained by CAPS plus stress, CAPS plus negative events. Certainly consistent with a brain which predisposes to a spectrum of psych diagnoses and forms due to abnormal hormone milieu in utero and infancy.
A tryptase gene found by Milner may perhaps tie some people with EDS, MCAS and chronic illness together. This is a confusing finding and I believe a red herring. First of all, no one is claiming that this is causal. Further, most people with EDS and MCAS have low tryptase when tested and this gene causes high basal tryptase.
I believe that one of the symptom clusters in ME/CFS is coming from high 17OHprogesterone-sleepiness, severe orthostasis, tissue swelling, breathlessness, muscle weakness. I treat this in myself and in patients with berberine which induces CYP17, shunting 17 hydroxyprogesterone to androgens and estrogen. This, unlike the dysbiosis treatment effect, occurs within 12 hours of taking it. I get very sick with these symptoms within 4 days of stopping berberine. Of note, I believe that the standard hormone panels often miss the forms of hormones which are deranged in us. I believe that estrogen/androgen levels are high throughout, progesterone is low pre-block as is cholesterol. When the block happens and illness starts, cholesterol and progesterone greatly increase suddenly. This was my experience and the experience of many others in the groups. Cystic ovaries are almost universal in this population.
Interesting Developments in RCCX Discussion group, forums, my patients, vet medicine:
Link with Tawil Anderson Syndrome (periodic paralysis, cardiac arrhythmia, and dysmorphic features) and RCCX comorbidities
Link with glycogen storage diseases emerging in discussion group
Link with Ankylosing Spondylitis perhaps via CYP21A2
Ion channel abnormalities-high rate of PPP with intermittent low postassium in RCCX cohort-CFS/ME work showing ion channel abnormalities in that population. I get sudden whole body cramps relieved by sucking on NUUN tablet (high sodium and potassium).
While people with chronic illness and or CAPS alone report running better on protein/fats and prefer anaerobic exercise, they report that this DID NOT START WITH ILLNESS ONSET. It is life-long. This suggests that dauer may be present in mild form throughout life.
It may be that carrier status for any form of adrenal hyperplasia confers risk of CFS/ME? I have been contacted by a person with the much more rare POR deficiency, who reports the same psych profile and CFS/ME. Also contacted by someone else with another enzyme block in the cortisol pathway, same thing
Untreated CYP21A2 carriers seem to have CAPS with risk for MCAS, CFS/ME, autoimmune disorders (treatment during brain development alters psych profile and probably risks). I reached out to one of the few doctors who diagnoses and treats carriers presenting due to infertility. She reports MCAS, chronic illness and improvement with dexamethasone to some degree, in terms of fertility and overall wellness.
I have been contacted by many people with known CYP21A2 mutations who were untreated during brain development who now have MCAS, the psych profile (CAPS), CFS/ME and many have autoimmune diseases. Some hypermobile and some not
On the CAH forums, there are frequent reports of many RCCX comorbidities, including chronic illness and psychiatric issues in people and their family members and I have personally been contacted by many CYP21A2 carriers.
I have been contacted by many women with CAPS who report that progesterone cream made them very ill with sleepiness, increased orthostasis and sometimes, neuropathic pain. It is well-known that patients with EDS do not tolerate high progesterone states. There was a study many years ago showing high 17OHprogestereone in patients with ME/CFS.
Further, everyone in my FB discussion group who has pursued ACTH stim with pre and post measurements of 17OHprogesterone plotted and who shared results or experience with me has ended up getting sick from the ACTH stim and then plots in the carrier range, with the exception of one person who clinically really must be a carrier (this plot is not 100% accurate even for the known mutationswhich I assume are more dramatic in terms of results than these hidden ones).
When asked, women in my FB discussion group (1000 plus people) and my patients with CAPS, all report a longer ring finger than index finger, indicating higher than normal androgens in utero (with the exception of one). Very high rate of people being ambidextrous or left handed as well. Lots of gender fluidity, Aspergers and intellectual gifts in this population. Lots of female sex hormone abnormalities as well.
Cutting horses are well-known to be very smart (out-witting cattle) and they have a high rate of hypermobility
New treatment considerations from my own experience: Copper Back story: 2009 raised ICP (trouble tracking with eyes, trouble swallowing, headaches, poor fine motor coordination), starting of MCAS (migraines, burning eyes, hives diarrhea, etc), bursts of anxiety, tachycardia, hearing loss. Responds to magnesium quickly, but MCAS continues/recurs with POTS. Add B vits, vit D (based on levels and sun craving, sun craving goes away). Start quercetin, ketotifen. MCAS resolves. Severe fatigue, breast swelling, shortness of breath, orthostasis, fat deposition, candida in the gut. Add berberine, all of that fixed (kills dysbisosis and turns on CYP17 to decrease 17OHprogesterone). Stop berberine several times and severe fatigue, orthostasis returns and responds quickly to restart. Rescue prednisone 2.5 mg every couple of months when "hit the wall" with fatigue and stress. Add LDN, get my "gumption" back. Add activated chelated copper (mitosynergy) and lose all up and down energy cycles as long as 4-6 hours after taking. Increase to .5 twice daily. This is as high as I want to go as I am afraid of it. No energy outside of the 4-6 hour windows. Feel cured, much stronger than even baseline. Heme enzymes which weren't working before now seem to be working, including 21 hydroxylase. Get rid of methylating B vitamins because don't need. Get rid of quercetin because don't need. People on the copper forum showing labs with low basal cortisol and spiking cortisol after treatment with copper. Well from November until February 2017. Was able to stop ketotifen for 3-4 weeks with no MCAS coming back (had tried to do this many times in the past unsuccessfully). Then stopped berberine for about a week. While losing energy, I cleared weeds I am allergic to. Had very localized allergies (runny nose) instead of MCAS brain fog etc. I think this is because MCAS is run by CRH and the localized stuff is IgE-related.
Then I was bed-bound. I was sleeping all day most days, in a dream state when awake, unable to stand and walk around as I could feel the blood draining from my head, short of breath, weak muscles (I could exercise as long as I pumped my legs, but not as strong), unable to start any projects or do anything, could not hold a thought, heavy arms and legs, no GI symptoms, no MCAS symptoms, no malaise other than bone-crushing fatigue, salt craving and I could not eat enough bacon with salt on top to satisfy myself (something I NEVER eat as I am a health fanatic). Turns out these symptoms are due to whatever berberine treats in me (I am sure it's high 17OHprogesterone from the 21 hydroxylase block which berberine treats by inducing CYP17 and shunting this into estrogen and testosterone). These symptoms started 1 week after stopping berberine while on the copper and resolved with adding back berberine. These symptoms were disabling and I wonder if 17OHprogesterone is actually one of the causes of some of us sleeping all day every day. Then a week later, MCAS came back and I had to go back on quercetin, ketotifen at high doses (with antihistamines on baord intially as symptoms were severe). Then, finally, I went into severe adrenal fatigue on the copper with no stress tolerance at all. All of the strength gain, energy etc. was completely gone. I stopped it and over a week, regained my pre-copper health status (which was pretty good. Able to step on the accelerator when needed). What I think happened and what I think copper does for some of us: The RCCX Theory posits that people with presumed RCCX comorbidities (see list on other website pages) are carriers for CYP21A2 mutations which bring with them exaggerated stress response, low baseline cortisol, brain wiring for danger (called CAPS), and a stress vulnerability in the form of a switch triggered by prolonged stress which shuts off ability to make cortisol, causes salt wasting, causes 17OHprogesterone build up (with sleepiness and orthostasis) and turns on inflammatory cascades, starting with MCAS. Under conditions of prolonged stress, those with CYP21A2 mutations which produce defective 21 hydroxylase must make more than double the amount of 21 hydroxylase of a normal person for the same stressor. Also, the amount of 21 hydroxylase needed is determined by the level of stress which is just continuing to rise because of illness in a ever going positive feedback loop. The amount needed can never be made. In those people copper gets depleted (because heme containing enzymes need copper), the heme enzymes unravel, including 21 hydroxylase.
(Here is an article describing a study showing that this unraveling happens with SOD with copper deficiency and is corrected with chelated copper : http://blogs.oregonstate.edu/linuspaulinginstitute/2014/06/18/copper-meets-sod-als-story/ "When SOD1 is lacking one of its metal atoms (it has one copper and one zinc atom), it “unfolds” and starts causing damage. Instead of helping to protect motor neurons, it becomes toxic. Since copper is carefully controlled in the body for a variety of reasons, including potential toxicity, most copper therapies are very difficult to use. CuATSM, however, is capable of delivering copper atoms in hard-to-reach places in the body. As described by Dr. Beckman and his colleagues in the The Journal of Neuroscience, CuATSM fed to laboratory animals with ALS actually delivered copper to motor neurons of the spinal cord. Although the animals wound up producing more mutant SOD1, the extra copper allowed SOD1 to stay in its properly folded, protective form."
So back to us: With copper deficiency and enzymes unraveling, we experience severe adrenal fatigue, an inability to methylate B vitamins (especially if MTHFR mutations are present), low neurotransmitters, abnormal heme in the urine (pyroluria, controversial I know) and brain, ie.e multiple sclerosis: https://www.specialtypharmacytimes.com/news/the-impact-of-hemoglobin-levels-on-multiple-sclerosis).
The Naviaux/Davis dauer response gets initiated because the body is very stressed (with or without the copper depletion and this happens in others vulnerable to stress-nonRCCX- as well).
Then if the person repletes copper, the enzymes work, the cortisol shoots up way above normal and in some people, I believe thatm this causes the 21 hydroxylase switch to trip again and 17OHprogesterone builds up again, MCAS becomes severe again and there is severe adrenal fatigue with no ability to make adequate cortisol at all. This is what happened to me-I am sure of it.
I am now off of copper, but expect that I will do cycles of it to keep my enzymes online.
Again, not medical advice and I don't know if berberine or copper is safe in the long term or even short term for some people. Just discussing ideas and describing my experience.
Psychiatry: Thoughts All of this is preceded with "I think", so no advice and not proven. So, I believe that CAPS is danger wiring which gets worse with negative experiences. We start off with lots of fight/flight and then we move toward freeze (parasympathetic and sympathetic) and shut down (opiates) being part of dissociative reactions to subtle and often not recognized triggers connected with memory networks. Intially, use of sympatholytics could be helpful to block PTSD/dissociative circuits from developing, but later they would increase the low arousal states which become more problematic. Later is where LDN comes in. Some respond well to LDN because the excess opiates are serving to increase fatigue and brain forg, but some feel very impulsive and jacked up (fight/flight) with the addition of LDN and presumed removal of shutdown associated opiate effect. The NT derangements are downstream and thus variable, so there is no predictable effect exerted by antidepressants. SSRI's can be helpful to increase resiliency and decrease sticky thoughts, but MCAS affects serotonin levels (high if dumping) so many don't tolerate. I find many don't tolerate NE increase because of the high arousal states early on with this. Most effective in my opinion is treatment out there for PTSD-mindfulness, grounding, safety, help with sensory gating, being in the body, connection to people/animals, grattitude, awe, art music, etc.
I believe that the PTSD research is very relevant to us. It is clear that if people are able to discharge energy via fight/flight after a traumatic event, they fare much better than those who are trapped, helpless or in shutdown. I wonder if riding my bike while listening to music is allowing me to discharge some of the toxic stress which builds up prior. (Of course, I can't advocate riding a bike with headphones on while singing, but it makes me wonder...I know it REALLY helps).