Hello All, I'm hoping that you have read the Background section before coming here, but I'm guessing many of you have not (as I probably would have jumped to the "meat" myself). For you, I will do an introduction and a summary of what I figured out in the Background section which will be in blue. For those coming from the Background section, skip the blue part and stay tuned for the rest of the story. As you read this, keep in mind that I am writing for the layperson, so I explain difficult concepts as best as I can. I will continue to bold important points for the skimmers.
I am Sharon Meglathery MD (aka Dr. Sharon, stripey14), a physician (see About Section) who developed mast cell activation (MCAS), postural orthostatic tachycardia syndrome (POTS), raised intracranial pressure, chronic fatigue syndrome (CFS) and a host of other potentially disabling syndromes in the setting of Ehlers-Danlos Syndrome (EDS-HT) in 2009. I was shocked to learn that somehow medical education has completely missed an epidemic affecting so many gifted young people (mostly women), leaving the patients to fend for themselves. I have spent 7 years obsessed with a long list of seemingly connected, overlapping syndromes, gathering patient observations in my clinic and in the forums, scouring the scientific literature, dealing with my own illness and often having to experiment on myself. Early on, my broad medical background revealed that several commonly held assumptions about these conditions must be false. By letting those assumptions go, I was able to find a neuropsychiatric marker, dubbed CAPS, which predicts a higher risk of chronic illness regardless of hypermobility status which has stood the test of several years. From there, a lucky break revealed a set of candidate genes which pulled all of my observations together. The knowledge of these genes changed the course of my illness by presenting novel treatment options, and I expect will pave the way for new pharmaceuticals which will help us.
I believe that the RCCX Theory solves some of medicine and psychiatry's greatest mysteries. The RCCX Theory explains the co-inheritance of a wide range of overlapping chronic medical conditions in individuals and families (EDS/hypermobility, autoimmune diseases, chronic fatiguing illness, psychiatric conditions, autism, etc.). It explains the underlying pathophysiology of chronic fatiguing illnesses with so many overlapping features (EDS-HT, CFS, Chronic Lyme Disease, Fibromyalgia, toxic mold, Epstein Barr Infection, MCAS, POTS, etc.). And finally, it reveals the gene which I believe confers a predisposition toward brilliance, gender fluidity, autistic features, and stress vulnerability, as well as the entire spectrum of psychiatric conditions (other than schizophrenia which can be co-inherited). This website contains everything you need to understand the subtleties of this theory.
The first part of the RCCX Theory was born in July 2015. I tried desperately to share it, but I was not successful using traditional methods. I released the first version of this website in February 2016. The website was designed so that the theory would be accessible to everyone, patients and researchers alike. I also included downloadable versions of a Summary for Scientists, Journal Article (now outdated) with references and my pathophysiology diagrams for easy transport. I hoped it would go viral and the information would get to scientists who may be interested in pursuing this.
Developments Since Initial Release of the Website in February 2016: In the first couple days of release, I was approached by Karen Herbst MD PhD, Endocrinology who was interested in helping me prove this hypothesis. She and I started a non profit corporation to fund studies exploring the role of the RCCX Module in Chronic Illness. Unfortunately, we have realized that studying the genetic portion of this could be too complex for even a university genetics lab, given the complexity of the RCCX module. We also came to see that endocrine testing is also fraught with difficulty, given the way that the clinical response to stress is very dependent on the overall stress load and length of time a person is stressed (CFS studies show normal stress response followed by high fatiguability on rechallenge) and the fact that no testing has been able to reliably distinguish CYP21A2 carriers from normals. We decided to proceed with a questionnaire demonstrating that the RCCX comorbidities run in individuals and families as a way to get researchers interested. I spent 2 years gathering info from people fitting the RCCX phenotype to make the questionnaire as comprehensive as possible. (I run a discussion group on FB called RCCX and Chronic Illness Discussion). I completed it and gave it to Karen and her team in January of 2018 and had to cut back my involvement due to my health issues. There has not been much progress since then, but I do have permission to share the questionnaire with other interested researchers. All funds collected through the RCCX Project will go to any viable research effort looking at the role of the RCCX module in chronic illness and Ron Davis PhD as a default. I am no longer fund-raising.
In June 2016, a pilot study conducted by Robert Naviaux MD PhD and Ron Davis PhD revealed that mitochondrial shutdown triggered by stress is the likely final pathway in CFS/ME. With this news, I updated the website in July of 2016. I added RCCX Theory Part II to demonstrate how the RCCX Theory provides several highly likely paths to mitochondrial shutdown, including a psychiatric path which I explained fully in the new CAPS section. I edited the rest of the website to show that "CAPS" now stands for CYP21A2 Mutation Associated Neuropsychiatric Spectrum which is a more accurate name than the previous one. The website also now reflects that there are probably many afflicted with chronic illness who are actually homozygotes for mild CYP21A2 mutations, in addition to the heterozygotes I had discussed previously. I believe this is true because people with CAPS are attracted preferentially to other people with CAPS.
By March 2017, there were many developments, all heading in the direction of RCCX Theory, so I decided to add a quick New Developments Section until I could sit down and really write the next chapter. I am increasingly confident that Ron Davis PhD et al. will arrive at the RCCX Theory probably sooner than later as he has said that there seems to be a genetic predisposition to "pushing through" which leads to chronic illness by repeatedly telling the body to shut down the Kreb's cycle. I strongly believe that carriers of CYP21A2 mutations with CAPS are predisposed to pushing through stress because of higher than normal arousal when stressed and then fighting against low basal cortisol to continue to be productive. We also know that many of those with EDS (those with CAPS, I believe) have high adrenaline/sympathetic nervous system tone which can also allow this to happen. Further, it is becoming clear that some folks respond amazingly well (in terms of energy and cortisol production) to bioactive chelated copper supplementation (this is special copper not the usual supplement), myself included. I think those with mutations for defective (as opposed to low amounts) of 21 hydroxylase may be at risk for bioactive copper deficiency which adds a layer of heme-containing enzyme failure and inappropriate heme deposition in places like the brain (heme has recently been found to be inappropriately deposited in brains of people with MS, which I believe is very much an RCCX comorbidity) and maybe in the urine (?pyroluria). More about that can be found in the New Developments section.
How you Can Help:
Pleasecontinue to distribute this theory widely to other patients so that they can know that help may soon be on the way.
Talk about it.
Write about it on your websites.
Please like the Facebook page: RCCX and Chronic Illness for updates.
My email address is firstname.lastname@example.org for questions and suggestions.
Join the FB discussion group: RCCX and Chronic Illness Discussion to expand and refine the theory.
Disclaimer: The purpose of this website is NOT to recruit patients, give treatment recommendations, sell supplements, get attention, be controversial or become famous. I live a quiet, reclusive life with a small, local and full medical practice. This illness and this discovery has made my life very complicated. To Whom Does this Theory Apply? I assume that most of my audience consists of chronically ill patients who suffer from one and probably many of the chronic syndromes/symptoms/diseases which I will list shortly. Please understand that I am NOT saying that everyone with these diagnoses fits in this group; rather I am saying that in many families, a cluster of these diagnoses will be found and I believe that those families are likely to contain the gene mutations I discuss. For example-you may see a family with a member, often female, diagnosed with or suspected to have Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT), postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS). Then in the extended family, you may find autoimmune diseases, i.e. multiple sclerosis, cutting and eating disorders, "possible bipolar disorder," gender fluidity, a highly successful and innovative genius, someone with chronic fatigue syndrome (CFS) or fibromyalgia (FM), someone with severe post-traumatic stress disorder (PTSD) and someone else with bouts of psychosis. The children who are more scrutinized in this day and age, may be diagnosed with attention deficit disorder (ADD), sensory processing issues plus or minus Asperger's Disorder (I know, I know, not in the DSMV:>)). And the kicker, these issues may be found on both sides of the family because I believe that we are attracted to each-other. There is a characteristic psychological profile which goes with this: sensitive, emotional, often gifted and we tend to surround ourselves with others who share these traits.) The degree of hypermobility ranges from none to severe in this family and correlates with the degree of musculoskeletal involvement (joint pain/dislocations/surgeries required to stabilize joints) and orthostasis/"dysautonomia," but not with the other "sick" symptoms which tend to develop later in life only in some, mostly women but not always. Many will react strongly to stress. If this sounds like your family (albeit a dramatic version), I am writing this for you.
Of note: These conditions can occur due to other genes, thus occurring without these clusters. Many people with MCAS and POTS, together or alone have these for a different reason. What I am writing is NOT relevant to them. (However, if you have bendy joints and MCAS and POTS, I am talking to you!)
Over time, it has become clear to anyone who frequents the chronic illness forums, sees patients with an open mind or keeps up with the literature in this field that there seems to be a frequently disabling epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting mainly young, vibrant, talented people (predominantly women) and if you look, many, but not all, have joint hypermobility (double jointedness, ligament laxity). These are (to name a few and I'm probably leaving some out inadvertently):
Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT)
Misc.: Extreme Temperature Dysregulation (Dysautonomia or not), Multiple Chemical Sensitivity, High Adrenaline/Noradrenaline (also called norepinephrine) States, Erythromyalalgia, Raynaud's, Livedo Reticularis, Evidence of Poor connective tissue integrity (dislocations, bruising, bleeding, petechaie, calcific aortic valves, Mitral Valve Prolapse, etc),Dry eyes, Tinnitis, Subcutaneous Adipose Disorders (Lipidema, Dercum's Disease), Left Handedness, Gender Fluidity (LGTB, lack of traditional gender roles)
Perhaps: Medullary Sponge Kidney, Pyroluria, disorders of copper and zinc regulation, Early Onset Parkinson's Disease
I will refer to all of these under the rubric of "Chronic Illness" going forward.
For those of you with EDS, it is important that I clarify a few points. My theory pertains to those who have not been found to have a specific disease-causing collagen mutation, i.e. those who fall into the hypermobile and classical types. I will show you that I believe that we have life-long issues due to poor collagen and inflammation from TGF beta resulting from a TNXB mutation PLUS a propensity for other stress-triggered systemic issues similar to those with other chronic illnesses from an adjacent gene, CYP21A2. I will show you why the current assumption that TNXB mutations are a rare cause of EDS-HT is incorrect, and I will show you why, today, it is impossible to test for even a fraction of the TNXB mutations associated with clinical illness. I know that this goes against the EDS teaching/knowledge base, but keep reading and you will see why I have come to these conclusions.
_____________________________________________________________________________________________________________________ (Continued From the Background section)
Conclusions Reached in the Background Section Based on Observations, Research and Reasoning:
A person, usually female with a genetic vulnerability (familial) is exposed to prolonged stress or a strong stressor (i.e. Epstein Barr Virus, Borrelia borgdorferi-Lyme) which results in a cascade of physiological events causing characteristic chronic illness involving multiple overlapping, co-morbid syndromes/symptoms/diseases, medical and/or psychiatric (list above). This vulnerable person is frequently hypermobile or has hypermobility in the family and has a distinct pre-illness psychological profile involving a heightened stress response, high emotionality/sensitivity, "autistic features" (sensory sensitivities, hyperfocus, strong special interests, etc.) of a varying degree and quite often, special abilities. This psychological profile, which I have named CAPS, may be a very powerful tool for getting to the bottom of all of this because if you can locate a vulnerable population, you can start looking for genetic markers.
If the above starting point contradicts what you believe about these illnesses, PLEASE read the Background Section because I address false assumptions which are EVERYWHERE in the medical literature, on the forums and even in the minds of prominent experts.
********************************************************************************************************************************** Evidence emerged in June 2016 (4 months after writing this section) from a pilot study involving severely ill patients with CFS/ME conducted by Ron Davis PhD and Robert Naviaux MD PhD that a stress-activated mitochondrial shutdown is clearly apparent, so the reasoning on which the RCCX Theory is based is sound. ***********************************************************************************************************************************
The Genes and Properties of The RCCX Module Explain Everything! For here on out, the information is very technical, but I desperately want everyone who reads this to understand. I am sure that after this is written, the scientists out there will criticize my over-simplifications and the misuse of some terms, but I think I can make this understandable for all without being too inaccurate.
To get everyone up to speed with genetics: We receive a chromosome containing genetic information from each parent. This gives us two copies of each gene. Genes tend to sort independently, so it would be very unusual to have 2 specific genetic diseases occurring together more often than dictated by chance. So if a genetic disease occurs in 1/5000 people and another occurs in 1/2000 people, the chance that someone would have both diseases is 1/10000000. Not likely at all. This is why anyone who has studied genetics has a very hard time understanding how people with EDS-HT, presumably due to a collagen gene mutation, could have such a high rate of diseases/symptoms known to be associated with other genetic mutations. For example, people with EDS-HT have a high rate of MS, CVID, autism and other autoimmune diseases known to be caused by mutations of the C4 gene. This high rate of having both "rare" diseases is MUCH HIGHER THAN WOULD OCCUR BY CHANCE. Since triggered EDS-HT seems to be exactly the same illness as CFS, ME, FM, etc. and has the same clinical associations (white matter brain lesions, MCAS, raised ICP, small fiber polyneuropathy, elevated acute stress response, dysautonomia, CAPS, etc.), EDS-HT must have the same predisposing gene, one that is somehow connected to C4. If you don't believe this, go back to the Background section where I discuss the false assumptions associated with EDS-HT in more detail. Further, it seems highly unlikely that collagen genes can cause abnormal brain development, hormonal issues, white matter brain lesions and raised intracranial pressure and it's even a stretch to understand how abnormal collagen/tissue can lead to other conditions like MCAS, neuropathic pain, etc. (although you can get there with some convoluted thinking). Further, why was the hypermobility not necessary for severe illness in families with varying amounts of hypermobility? EDS-HT' s association with all of these conditions makes no sense if the rules of genetics hold and a collagen gene is involved and the cause of severe illness. The EDS experts have skirted around this issue, saying things like "lots of issues, think of tissues" which is starting to wear thin. Until I became familiar with the RCCX module, these impossible conflicting findings kept me awake at night.
That's why the article that Martha Cassell sent me blew my mind. It demonstrated that the RCCX module is the only place in the genome where many of the rules of genetics are broken. There are frequent mutations between generations, so a child could have a mutation in a gene which neither parent has, i.e. could be hypermobile when the parents are not. Further and most interestingly, genes in the RCCX module have been shown to travel together, i.e. mutations in TWO contiguous (side by side) genes can be INHERITED TOGETHER and cause BOTH diseases in the recipient and mutations can span across two genes, also causing two rare genetic diseases to be present in the same person. The RCCX module is like this because it is part of the major histocompatibility complex, class III genes of the immune system, a system which benefits from frequent DNA change to keep up with an ever changing world of bacterial and viral pathogens which are also frequently mutating to avoid destruction. The important piece here is that while some of the genes in the RCCX are not immune system genes, they also mix and mutate often.
My jaw fell open when I saw what the four genes of the RCCX module do:
CYPA21A2: codes for 21 hydroxylase, the enzyme which converts 17hydroxyprogesterone to cortisol and aldosterone. This is the MOST IMPORTANT enzyme in the acute stress response! The disease associated with this gene is called congenital adrenal hyperplasia (CAH). It is autosomal recessive (see below) and results from inheriting two, known and characterized, bad copies of this gene. We can test for the particular mutations associated with CAH because they have been characterized due to their clinical severity. There are many, many uncharacterized mutations of varying degrees of severity out there which remain undiscovered. Congenital Adrenal Hyperplasia, due to 2 copies of these characterized mutations, is associated with dangerously low cortisol, low aldosterone, high 17hydroxyprogesterone and high androgens (male hormones). As I will show, many of the syndromes/symptoms/diseases in the chronic illness list can be set in motion by this enzyme not functioning properly.
C4: codes for a complement component of the immune system and is involved in dendritic pruning. Mutations have been shown to be present at a higher than normal rate in many autoimmune diseases, including lupus, autoimmune hepatitis, multiple sclerosis and immunological diseases, like CVID and chronic inflammatory states leading to cardiovascular disease. Recently, it has been linked with schizophrena and it has a role in autism (It is thought that it's involvement in these conditions has to do with its role in developmental dendritic pruning). As mentioned above, C4 mutations have also been linked to many of the comorbidities/syndromes/symptoms/diseases seen in the chronic illness population! Further, there is a study showing evidence that mutations of the C4 gene may frequently co-occur with mutations of CYP21A2: People with cardiovascular disease and known mutations of C4 were found to have hormonal abnormalities you would expect with CYP21A2 mutations.
TNXB-codes for tenascin X, an extracellular matrix protein which contributes to the formation of collagen. Some of you will stop right here and think "isn't TNXB a rare cause of EDS-HT"? Yes, the NIH site says this and yes, the editor who rejected my paper said this, too, BUT this is one of those pernicious, progress-blocking assumptions which is NOT TRUE. Early studies demonstrated that people with one copy of a SPECIFIC mutated TNXB gene known to result in less than normal amounts of tenascin X (called TNX haplo-insufficiency) have EDS-HT without stretchy skin and people with two copies of this mutation have EDS-HT with stretchy skin (often called EDS, Classic Type). The EDS expert who is the reported source of the assumption that "TNXB is a rare cause of EDS-HT" was referring to THIS ONE SPECIFIC mutation. In the past year, TNXB mutations have been found to be frequent and varied. Abnormal tenascin X is now being found to be associated with very common conditions, like calcific aortic valves, and vesicoureteral reflux. A follow-up study of the latter linked this condition with hypermobility. My guess is that some of these TNXB mutations may not even be associated with much hypermobility. Further, mutations of TNXB and mutations of CYP21A2 have been shown to co-occur frequently in the same person, meaning that these mutations of these two genes often travel together, in contiguous mutations and in mutations which span both genes, creating individuals with both congenital adrenal hyperplasia and EDS at a high rate. The only conclusion one can reach when reading these studies is that there are MANY MUTATION VARIANTS for these genes and they often travel together. Since we haven't begun to characterize anywhere near all of the possible TNXB mutations and most of these mutations involve lengthy insertions, 23andme and programs such as livewello and promethease are not helpful for determining if we have this mutation or not. We need to ask for more bench research to characterize these mutations/variances and provide clinical correlations. I imagine that many of the mutations could cause mild hypermobility (easily missed), but would be linked with CYP21A2 placing the person at risk for chronic illness. This could explain why the degree of hypermobility doesn't correlate with the degree of illness from non-musculoskeletal or orthostatic symptoms.
Genetics 101 And How Being a Carrier for An Autosomal Recessive Disease Can Be Associated with Vulnerability For Disease I need to provide some more information about genetic diseases before I continue:Autosomal dominant diseases become apparent when a significant mutation is received from one parent and a "normal variant" gene (no clinical abnormality associated with it) is received from the other parent . EDS-HT is presumed to be primarily autosomal dominant (although autosomal recessive types are known to occur, i.e. two mutated copies of haplo-insufficient TNXB as discussed above). Autosomal dominant diseases are generally common, depending on the frequency with which the gene is present in the general population.
Other genetic diseases are referred to as autosomal recessive which means that you need to receive a mutated gene from each parent to manifest the disease. These diseases are very rare, as you need both parents to be carriers and then there is a 1/4 chance of an affected child. People who have one good gene and one mutated gene for an autosomal recessive disorder are called heterozygotes or carriers. Sometimes, while they will not have the disease, they will have some abnormalities as a result of having one bad gene. For example, if the bad gene codes for a protein, they might have less of that protein than a normal person (or some amount of abnormally formed protein) but not so little (or so different) that they have a disease; if the bad gene codes for an enzyme, problems could occur if there is a high demand for that enzyme and the mutated gene produces a non-functional enzyme. Enzymes facilitate reactions, meaning that they must be present for one reactant to become another. This is VERY IMPORTANT to my theory. Please google enzyme if you don't fully understand what an enzyme does. So, as stated above, if a person is a carrier for a mutated gene which produces a non-functioning enzyme and if the enzyme is in high demand, there is a possibility that there won't be enough enzyme for important reactions to occur. This will result in a build-up of ingredients (precursors) and a shortage of products. Generally, carriers are considered to be clinical healthy, but they can have some vulnerabilities in situations where the gene product (i.e. enzyme) is necessary in greater than normal amounts.
Let me illustrate how a clinically "healthy" carrier for a non-functioning CYP21A2 mutation (or a person with 2 mutated copies of partially functioning genes) could possibly develop chronic illness: Cortisol is a hormone needed for a normal stress response. Cortisol is made from 17hydroxyprogesterone by the enzyme called 21hydroxylase. 21hydroxylase is coded for by the CYP21A2 gene in the RCCX module. If a carrier for a CYP21A2 mutation which makes no functioning 21hydroxylase or a homozygote for partially functioning 21hydroxylase has chronic stress and needs to make lots of cortisol all of the time, it is possible that there may not be enough 21hydroxylase available to make the amount of cortisol the body needs. In this case, cortisol levels would be abnormally low for the amount of stress, 17hydroxyprogesterone would be abnormally high causing symptoms and some of the 17hydroxyprogesterone would be used by an enzyme coded for by CYP17 to make an abnormally high amount of androgens (male sex hormones) also causing symptoms. As I will show later, the symptoms caused by these hormonal abnormalities are shockingly familiar to those with chronic illness. Further, high cortisol releasing hormone (CRH), released when cortisol is too low can turn on devastating inflammatory cascades, including mast cell activation. (High CRH has recently been found to be associated with FM).
The Startling Implications of the RCCX Module: Pulling It Together CYP21A2, the gene responsible for a crucial enzyme in acute stress response has a myriad of mutations which frequently travel with a wide variety of mutations of TNXB, a gene which is associated with EDS-HT and other conditions with tissue abnormalities (varying degrees of hypermobility and possibly stiffness). C4, the gene whose mutations are associated with CVID, MS and other autoimmune diseases as well as schizophrenia/autism is in this grouping and frequently travels with CYP21A2 as well. Clinically, CVID, MS, autoimmune diseases, autism and possibly schizophrenia are often associated with EDS-HT, probably linked via contiguous or spanning TNXB and C4 mutations.
Please understand that I don't believe that everyone with chronic illness has congenital adrenal hyperplasia (CAH), associated with two known (diagnosable) severely mutated copies of CYP21A2. People with CAH are almost always detected at birth because of severe cortisol deficiency and life-threatening salt and water loss, and those with chronic illness are usually quite healthy prior to getting sick (other than possibly some physical symptoms under times of stress). It is certainly possible that less severe non characterized mutations which are unable to be diagnosed currently could be present in homozygous form and the person is not affected enough to be diagnosed at birth, but is at risk for chronic illness. The chance of having a recessive disease is rare, but this is a commonly mutated gene and I believe that people with CAPS are drawn to each-other (i.e. mate preferentially), so the risk might not be so rare. That said, I believe that carriers of CYP21A2 mutations, i.e. heterozygotes for currently non diagnosable CAH and diagnosable CAH (not receiving treatment), are the most prevalent population with a vulnerability for chronic illness. We know that at least 10% of the population carries the common well-characterized CYP21A2 mutation and my guess is that many more carry currently unrecognized mutations. Recall that CAPS, the psychological profile which I believe results from CYP21A2 mutations expands on the Highly Sensitive Person (HSP) profile shown by Elaine Aron PhD which she found to be present in between 15 to 20% of the population. The presence of CYP21A2 mutations could explain why large numbers of people are becoming ill after exposure to a significant stressor or prolonged stress with all of the symptoms/syndromes which can be caused by the associated enzyme, 21hydroxylase becoming overwhelmed. Further, it can also explain why the number of people with these illnesses is skyrocketing as day-to-day life becomes more complicated and over-stimulating and why more women are affected by men (higher overall progesterone levels in women increasing emotional stress, MCAS (progesterone activates mast cells) and ligament laxity which increases the stress challenge of low blood volumes due to low aldosterone). The stress of this endocrine and inflammatory cascade could certainly turn on CDR resulting in the mitochondrial shutdown recently demonstrated in severe CFS/ME.
Could CYP21A2 mutations be the genetic diathesis for the stress diathesis hypothesis for chronic medical and psychiatric illness which has been sought for decades? I believe that they are.
Non-Stressed Person With CYP21A2 Mutation This is a good place to look at the clinical implications of being a non-stressed carrier of a CYP21A2 mutation in more detail. We can speculate that carriers may have mild hormonal abnormalities (changing with stress levels) which can shape brain development, stress response and sexual characteristics, depending on the severity of the mutation and whether the person has one mutation or two. I cannot emphasize enough that this would be a DYNAMIC condition, dependent on the degree of functionality of the product of the mutation, the amount of stress present at any given time, as well as the person’s ability to handle the stress. Hormone levels would be normal at some times and abnormal at others with subtle clinical significance.
Currently, carriers of the known CAH-causing CYP21A2 mutations are not diagnosed or studied clinically, but there was a small study which sought to determine why the common (tested) form of CYP21A2 mutation is so common in the gene pool, assuming that it must confer some survival advantage. Carriers were found to be asymptomatic, but it was found that they have an exaggerated acute stress response, increased cortisol with ACTH stimulation and at baseline, they were found to have lower than normal cortisol (low basal cortisol). This certainly explains part of the CAPS profile (psychological profile) which I found in people at risk and with chronic illness: over-arousal in times of stress often leading to anxiety/harm avoidant behavior and sometimes "adrenaline addiction" which would alternate with under-arousal and a strong desire to self-stimulate with compulsive behaviors (eating, smoking, etc.).
Stress, cortisol and testosterone have been shown to affect amygdala size in utero and even more profoundly during the first few years of life. The brain structural abnormalities described in hypermobiles by Eccles can be explained by the hormonal issues as a result of having CYP21A2 mutations. The large amygdalae (fear and emotional center in the brain) would go with slightly higher than normal testosterone and spiking cortisol from the exaggerated stress response during development . Interestingly, children exposed to adverse events (depressed mother, for example) in early childhood have been found to have larger than normal amygdalae. This goes with the idea that he CAPS brain is actually a "brain wired for danger" with highly developed threat circuits and larger than normal structures involved in the threat response. This finding, including androgenation is often found in autistic children.
Interestingly, many of characteristics which I see in my female patients with CAPS, e.g. a longer than normal ring finger (longer than index finger), a tendency toward competitiveness and much higher levels of some forms of success jibe with the research demonstrating the effects of higher than average testosterone exposure in women. I describe clinical findings in people with mild CAH (untreated) and speculate about what might be seen in undiagnosed people with CYP21A2 mutations who have not been triggered into illness yet in my Journal Article. Many of them I have also seen in my patients, myself and on the forums. An intriguing finding is a possibly higher rate of homosexuality and gender role rejection which I have also noted in these populations. By the way, high intelligence is a debated finding but some studies suggest it. Seems to fit so far.
Person With CYP21A2 Mutation Stressed Past the Tipping Point When 21 Hydroxylase Is Overwhelmed and Can't Keep up: The CYP21A2 Mutation Stress-Diathesis/Clinical Syndromes Cholesterol is made into progesterone and androgens i.e. male sex hormones, even in women, by the adrenal gland. The gene CYP21A2 (found in the RCCX module next to TNXB (EDS-HT) and C4 (CVID, MS, autoimmune diseases, schizophrenia)) codes for the enzyme 21 hydroxylase which converts progesterone into 2 very important hormones, cortisol and aldosterone. See pathophysiology diagram below. We know that "asymptomatic" people with CYP21A2 mutations make more cortisol than normal people during the acute stress response, i.e. have an exaggerated stress response, and that they have lower than normal basal cortisol when not stressed. As discussed above, sometimes carriers with one good gene and one non-functional mutated gene or homozygotes with 2 partially functioning mutated genes for an enzyme (e.g. 21 hydroxylase) mutation can get into trouble clinically if the body suddenly faces a higher than normal demand for the enzyme. Again, when this happens, the ingredients/precursors (e.g. progesterone, cholesterol) build up and get shunted onto other pathways (into androgens-male hormones and a small amount into estrogens) and the products become deficient (e.g. cortisol and aldosterone). This sets into effect a whole host of clinical syndromes-those due to high precursors/shunted products (e.g. high progesterone, androgens, cholesterol), those due to low products (e.g. low cortisol, low aldosterone). A word about the "low cortisol". There is quite a bit of clinical evidence that the high acute stress response (high stress cortisol) remains until the end (until "the wall is hit" as I call it), but basal cortisol trends downward as he person becomes chronically ill. Single cortisol measures will reveal cortisol levels all over the map (high at times, but mostly low with a skewed circadian rhythm). A whole host of "downstream" effects from having abnormal levels of these precursors, shunted and regular products would occur.
I believe that there is an evolutionary basis for having the CYP21A2 gene located in the highly mutagenic RCCX module. First, mutations can range from producing no functioning 21 hydroxylase to producing abnormally functioning 21hydroxylase to producing normal 21 hydroxylase in normal amounts. People can have zero, one or two mutations of various types which builds in a very wide range in terms of the amount of 21hydroxylase available for chronic/prolonged or severe acute stress. This allows for a wide range of stress adaptation capability in the population. Further, the exaggerated stress response in people with CYP21A2 mutations increases the probability of 21hydroxylase getting overwhelmed because the need for cortisol is higher. I believe that this is a cleverly designed switch to remove people who are not adapted to the current level of environmental stress from the gene pool, by first interfering with reproduction and later causing chronic illness (see RCCX Theory Part II) .
The next point is that people with CYP21A2 mutations may have more acute stress reactions than normal people because that unique psychological profile (CAPS) makes them prone to stressing out due to its association with perfectionism, high emotionality, obsessiveness, sensitivity to sensory stimulation. Ironically, it is this exaggerated stress response which may explain why so many people with CAPS are so harm-avoidant and perfectionistic. With each mistake comes a big jolt of adrenaline and arousal. Also, this physiology explains why some of us rev ourselves up to get projects done, whipping up that acute stress response (remember the "turbo" I described in my story in the Background Section in blue?) to overcome that baseline lower than normal cortisol or arousal and racing us toward a 21hydroxylase deficiency. With a higher frequency of acute stress reactions which dump more cortisol than a normal person, it certainly makes sense that a person with CYP21A2 mutations could easily become 21hydroxylase deficient.
Again, I want to stress that this would be a DYNAMIC problem, dependent on the form of the mutation (and there are MANY forms as discussed above), the amount of stress present at any given time and the person’s ability to handle the stress. Hormone levels could be normal at some times and very abnormal at others with subtle clinical significance.
This is a good point for me to insert my first pathophysiology diagram, RCCX Theory Part I: CYP21A2 Mutations May Confer the Genetic Diathesis of the Stress-Diathesis Model for Chronic Psychiatric and Medical Illness.
I am sorry that this is handwritten and hard for some of you to read. Printing a downloadable version may make this easier to follow. This diagram shows a simplified version of the production of cortisol and aldosterone involving 17hydroxyprogesterone and the effect of a 21hydroxylase enzyme block (red dashed line under "Progesterone"). It demonstrates the immediate and downstream effects of increased 17hydroxyprogesterone, low cortisol and low aldosterone. You can see the symptoms caused by each hormonal abnormality listed under the hormone and you can see via the connecting arrows, how these hormonal abnormalities can cause the medical diagnoses/syndromes so many of us have (MCAS, POTS, dysbiosis, adrenal fatigue, autism, CAPS, etc.). I’m sure you will recognize many of your symptoms. Note, the acute stress cortisol stays high initially while basal cortisol drops, causing brake, gas, brake, gas, brake until there is no more gas ("hitting the wall").
The Path to Chronic Illness: Prolonged Stress or Severe Acute Stressor (infectious) Tipping Us Into 21 Hydroxylase Deficiency So, when we are confronted with a prolonged stressor and the enzyme is overwhelmed, the hormone levels become abnormal. Below, I will discuss what symptoms are associated with each possible hormonal abnormality, but I would like to show you the overall picture first.
I think this is a good place to define stressor. A stressor is anything which requires increased cortisol for the body to cope with it. It can be a physical trauma, a surgery, a dental procedure, standing up if you have low blood volume and are hypermobile, thinking about childhood abuse (PTSD), worrying, taking an exam, physical exertion or even having an intense conversation with a friend. (Some of you will note that these are the well-known triggers which make us more sick with chronic illness.) I find that there are good emotional stressors and there are bad ones. Good emotional stressors are predictable and bring a sense of mastery, despite being a little tiring. These are tolerated and sometimes sought after in people with CAPS prior to becoming ill, in my experience.
Bad stressors cause negative emotions like frustration, helplessness, irritability and they seem to extract a bigger toll, perhaps by generating a more prolonged stress response because these emotions are rarely resolved quickly without some training. Invalidation which so many of us face from doctors, family members and society is a very bad stressor and very toxic for us! (There was actually a recent study showing that when doctors validate complaints in patients with chronic illness, they do better.)
Anyway, as discussed above, I posit that there is a tipping point at which 21hydroxylase becomes overwhelmed and I believe that bad stressors tend to take us there faster. This tipping point is more easily reached for people with hypermobility/TNXB mutations and for women because of the higher stress of maintaining blood pressure in these groups (both have floppy, lax vessels very much affected by progesterone levels and progesterone/estrogen increase likelihood for MCAS, a HUGE stressor). People with an infectious/inflammatory trigger sometimes hit this tipping point rapidly with no prodromal symptoms due to the nature of their immune response to some of these agents (e. g. Borrelia Burgdorferi, EBV, toxic mold, fluoroquinolones) . Other genes can determine the severity of the reaction to these agents. For most people from what I have observed, as time goes on and the tipping point is hit repeatedly, inflammation, immune changes and bad emotional stressors (loss, invalidation, desperation, helplessness) lower the tipping point by increasing the body's demand for cortisol, so the person is symptomatic nearly all of the time. See next pathophysiology diagram below. This is why few recover from chronic illness and those few who do have made changes which have decreased their stress load by treating downstream effects and their acute stress response with mindfulness/grounding/therapy. (More on how to do this later.)
Specifically, in the case of prolonged stress, the acute stress response is turned on all of the time, partially due to the perceived inescapability of the stressor and partially due to the CAPS tendency to focus on danger by worrying, hyper-focusing and problem solving. It would proceed like this: We are in a stressful situation and we start to have intermittent increased anxiety/irritability, feeling revved up, usually with insomnia. We may even progress to clinical hypomania. Additionally, there may be some breakthrough hormonal abnormalities, like acne, menstrual changes, hot flashes, water retention, increased competition and aggressiveness. Increased laxity and worsening orthostasis/dysautonomia with adrenaline dumping may also be noted. An appointment with a psychiatrist/dermatologist/PCP is made. As we transition from mild to severe, the system may vacillate back and forth, with the acute stress response still packing a punch, especially now in response to lowered blood volume (with high cortisol, high adrenaline, high noradrenaline, hyper-adrenergic POTS), but over time, the baseline low arousal become more pronounced, characterized by worsening, crushing fatigue. This was the "turbo faltering" in my story in the Background section. At this point, I believe that the person with a CYP21A2 mutation is in very dangerous territory. Many patients come to see me at this stage, thinking they have burn-out or depression.
At this point, if you are aware, you usually see some mild MCAS symptoms (allergy symptoms: hives, migraines, food intolerances, asthma, diarrhea, irritability, brain fog, increased distractibility and escalating sensory issues). CRH, the hormone released by the hypothalamus telling the body (via the pituitary) to make cortisol when cortisol is inappropriately low, is released in a pulsatile fashion. CRH is the most potent activator of mast cells in the body and found to be high in FM (Published by Dr. Theoharides, 1/16). It also decreases stomach acid, possibly contributing to dysbiosis and malabsorption; it stimulates the sympathetic nervous system causing the release of even more adrenaline and nor-adrenaline (norepinephrine) and it directly turns on the immune system. CRH release may be the master switch which propels a person with CYP21A2 mutations into irreversible chronic illness by effecting downstream changes which place an insurmountable and persistent stress load on the body. The demand for 21hydroxylase can now never be sated. I believe that people with CYP21A2 mutations who are exposed to Borrelia burgdorferi, the pathogen in Lyme Disease (which directly activates mast cells) and other strong infectious stressors, like EBV, jump straight to immune system activation, flipping the switch by bypassing CRH initially, but CRH rises later in response to the chronic stress of infection, locking them into chronic illness. Low blood volume/orthostatic challenges worsen (POTS), pain syndromes develop (via low cortisol, increased subluxations/injuries, inflammatory mediators affecting nerves, high 17hydroxyprogesterone), raised intracranial pressure/acquired chiari malformation can occur (via progesterone, low magnesium, brain inflammation from MCAS, etc.) and MCAS is present consistently;
With the immune system dysregulated, dysbiosis becomes fully established with gut inflammation and malabsorption. The body becomes colonized with new pathogens (through the porous gut and other pathways) and SIBO can occur. Pathogens already present start to cause problems (fungus-athlete's foot, herpes virus-cold sores, low virulence bacteria and viruses like mycoplasma, etc), the ability to fight serious infection drops and in many, the ability to fight the viruses which cause colds increases. The body is now under tremendous physical stress and the person is under tremendous negative emotional stress, both of which increase the cortisol deficit and sustain the growing list of medical issues. If brain inflammation is part of the picture (likely as part of MCAS), we get psychosis and severe mood disorders plus or minus the physical issues.This is a downward spiral which few escape. Now, I am going to outline the symptoms of each hormonal disturbance and each syndrome (including causes) for those of you who can't read my handwriting on the diagram.
The Effects of Specific Hormone Abnormalities Associated with Decompensated CYP21A2 Mutations High 17hydroxyprogesterone in People with CYP21A2 Mutations I have been surprised by the claims of naturopaths that progesterone is a great hormone to give people with chronic illness. It’s touted to have a variety of positive effects including: sleep improvement and relaxation. Despite this, almost every person I’ve seen whom I suspect has a CYP21A2 mutation reports a very bad reaction to exogenous progesterone, often complaining of irritability, fatigue, water retention and excessive sleepiness. Progesterone is high pre-menstrually and during menopause and I think we can all agree that typically, women don't feel good at these times. Progesterone activates mast cells, causing them to degranulate. Asthma and other mast cell symptoms increase premenstrually and at menopause, times when progesterone is known to be high. CAH is the only disease state associated with higher than normal progesterone, and interestingly, untreated people with CAH report feeling terrible until they receive cortisol titrated to decrease the levels of 17hydroxyprogesterone down into normal range. The clinical effects of high progesterone or progesterone:estrogen imbalance have not been adequately studied in my opinion.
There is a very informative study designed to see if athletic performance would be affected by physiologically high progesterone (normal women examined pre-menstrually). The researchers found many ill effects from physiologically elevated progesterone in normals: increased basal temperature, shivering/sweating with small temperature changes, shortness of breath/panting, muscle weakness, increased ligament laxity (another study found this to be very significant to injuries in EDS), breast tenderness/swelling, increased heart rate, water retention/swelling/edema, decreased glucose tolerance, cognitive issues, irritability/mood swings and orthostasis (low blood pressure, worse in EDS). Further, progesterone elevation for longer periods of time are known to be associated with hair thinning and irregular menses/polycystic ovaries. Raised intracranial pressure is also a known side effect of treatment with progesterone.
I would assume that the progesterone levels in women who have decompensated due to stress and having a CYP21A2 mutation would have MUCH HIGHER (17hydroxy) progesterone levels than the women in these studies and consequently, much more severe symptoms. I believe that high progesterone produces some of my most incapacitating symptoms and that many of the consequences of high progesterone increase the acute stress response, making recovery more difficult. I think this is a good place to return to my story to illustrate this (found in the Background section): This passage describes symptoms I developed after I have gotten rid of all of my MCAS symptoms with quercetin and ketotifen:
"Several months later, I developed 1+ pitting edema (swelling due to fluid retention) in my feet and ankles, puffy hands; my breasts became tender and swollen; adipose tissue started to appear, my period stopped, and, instead of being cold all of the time, I was overheated and sweaty. My joints started subluxing. Again, I had severe orthostasis (feeling faint with standing) but without the pronounced tachycardia (high heart rate)/anxiety I had experienced with POTS/MCAS. I couldn’t raise my arms above my head without dizziness and I was short of breath, weak, struggling to ride my bicycle. I cut out all non-essential routines. The disgust/jolt/run episodes returned and a deep, crampy pain in my leg muscles became more prominent. I only slept for about an hour between episodes, each ending in a night sweat followed by intense shivering. I would wake up retching, and in the morning, I was sore and irritable. My hair was thinning. I was now active in multiple forums (EDS, CFS, POTS, MCAS, chronic Lyme) and these same symptoms were described in much younger women, so I knew this was not menopause...
I tried berberine, an alkaloid used in Chinese medicine to favorably alter gut flora. All of the symptoms disappeared within 12 hours and over the next couple of weeks, my LDL dropped 60 points, I lost 15 pounds, my periods restarted and my elevated blood sugar normalized. From this point onward, I started cycles of berberine whenever my orthostasis, subluxations, pain and fatigue creeped back.
Because my mast cells were in lock-down when I developed these symptoms and the entire syndrome initially disappeared with berberine treatment (the sweats and shivering returned), I knew that this was a separate/discrete previously unrecognized medical syndrome associated with chronic illness with probably one cause. With my attention directed towards the RCCX module, I realized that high 17hydroxyprogesterone was the cause of this syndrome and that the berberine had likely rescued me by increasing the enzyme which shunts 17hydroxyprogesterone to androgens and estrogen (coded for by CYP17), something it does significantly with the first dose (see the diagram). Unfortunately, there are very serious issues with berberine (possible brain damage, increased risk of breast cancer, gut flora changes and others), and I really would prefer to decrease my 17hydroxyprogesterone some other way.
I am at the point now that if I am off of the berberine for more than a few days, these symptoms come right back. It has similarly helped patients of mine who have opted to try it. Please DO NOT take berberine without discussing the risks and benefits with your doctor. It may be associated with some bad side effects if used for any length of time (possibly brain damage, antimicrobial effects with resistance, etc.) and it has many drug interactions, sometimes requiring dose adjustments of your other medications. I keep my dosing very low and I worry about it. Also, remember the dynamic nature of this process. You may not have high 17hydroxyprogesterone all of the time, even if you have a CYP21A2 mutation. In the past, there were times when I didn't have these symptoms and taking berberine had very little effect for me."
I believe that the unstable progesterone levels in women with CYP21A2 mutations before chronic illness (may be low if acute stress response using it up quickly with adequate, working 21hydroxylase and high when 21hydroxylase overwhelmed) makes them vulnerable to a host of progesterone-caused issues, including irregular periods, dysmenorrhea, severe PMS, cystic ovaries, intermittent mast cell activation and highly variable amounts of orthostasis/blood pooling due to its effect on ligaments and blood vessels, more pronounced in hypermobiles, all of which may increase the overall stress load on the body. This may explain why chronic illness in women often develops during times of hormone shifts, especially when the amount of progesterone increases: puberty, pregnancy and menopause. The extra progesterone during these times in concert with life stressors is enough to tip the balance in terms of 21 hydroxylase deficiency. Unfortunately, the timing of this has served to keep the elevated progesterone syndrome under wraps as the symptoms of it seen in chronic disease are too often blamed on "normal menopause in a hypochondriac." However, if you look in the forums, you will see many much younger women developing these symptoms, including menopause as part of their chronic illness. Women's higher progesterone levels may one reason that they develop chronic illness at a higher rate than men. The especially deleterious effect of progesterone on hypermobiles (increased laxity causing increased dislocations, lower blood pressure, more adrenaline dumping, POTS) may explain the high propensity for hypermobiles to become chronically ill in the probable presence of CYP21A2 mutations.
As an aside, men with CYP21A2 mutations are probably intermittently exposed to higher than normal levels of progesterone. The CAH literature has been suggestive of higher rates of gender fluidity in people with CAH and this has been my experience with both men and women with suspected CYP21A2 mutations, although most are typically gendered and heterosexual. Men I have seen with CAPS often relate that they have many women friends. I've had several male patients under high stress develop MCAS, symptoms of high progesterone and psychotic symptoms in concert and one told me that he felt like he "had PMS" and the other believed that he was "changing into a woman". Anecdotal, but interesting.
I also want to remind that am see that many are spared the progesterone symptom complex as they never hit a complete 21 hydroxylase block, rather they can't make the cortisol they need and run through the progesterone/cholesterol at a very high rate, remaining estrogen dominant, but with low cortisol and possibly low aldosterone.
High Androgens in People with CYP21A2 Mutations High androgens (male sex hormones) are associated with acne, increased body hair, menstrual abnormalities, aggression/competitiveness and sometimes sex role rejection in women. Women exposed to high androgens in utero often have a ring finger which is longer than the index finger (proof of high androgens in utero, called increased D4 to D2 ratio). Interestingly, there have been a few studies linking this pattern with success in the business world. Female patients who I have suspected have CYP21A2 mutations invariably have this hand pattern and many have the other reported aspects of high testosterone. In men, the effects of high testosterone are less noticeable. Many of my CAPS men report very high libidos which they can find very distracting.
Low Aldosterone in People with CYP21A2 Mutations Low aldosterone is associated with loss of sodium in the urine. Have you ever met a person with hypermobility or chronic illness who didn't crave salt? Water follows sodium, so low blood volume and dehydration are common. Low blood volume and dehydration cause more problems in the hypermobiles due to blood pooling (exacerbated by high progesterone), resulting in POTS, fatigue and brain fog due to low brain perfusion (low blood pressure). Having chronically low aldosterone increases the acute stress response, perpetuating the chronic illness.
Low Basal Cortisol in People with CYP21A2 Mutations with High Acute Stress Response Cortisol until "the Wall is Hit" When looking at cortisol levels, it is important to understand that cortisol levels fluctuate throughout the day (circadian pattern) and that cortisol levels need to match the stress load. More is needed if the person has a chronic infection or chronic stress load like chronic illness. Many people forget this when they compare their level to the "normal" level. Inappropriately low basal cortisol is associated with decreased stress tolerance, fatigue, body pain, low blood pressure and low blood sugar. Low blood pressure contributes to POTS, fatigue and brain fog, as above, worse in hypermobiles and those with high progesterone. Low basal cortisol results in the hypothalamus releasing CRH. As discussed below CRH, high CRH turns on many pathways which increase the stress load on the body, also making chronic illness self-perpetuating. Additionally, as the acute stress response cortisol levels remain high initially, the extra catecholamines liberated in response to high CRH can be very distressing in terms of anxiety, jitteriness, POTS and exhausting all at the same time. The acute stress response cortisol would eventually drop and at this point, "the wall is hit". This is when I take a very small dose of prednisone which is always very helpful (not so helpful at other times and not currently recommended by MD's who treat chronic illness).
Syndromes Common in Chronic Illness Explained by Presence of CYP21A2 Mutations High CRH in People with Suspected CYP21A2 Mutations CRH is released in the hypothalamus in response to low cortisol. It acts in many places. CRH is the most powerful activator of mast cells that there is in the body. Just a few weeks ago (Jan 2016), Dr Theoharis Theoharides released his finding of high CRH in FM (will be published in March 2016).I believe that all of us with probable CYP21A2 mutations (as evidenced by the presence of my psychological profile CAPS) have high CRH driving our MCAS primarily (plus progesterone and estrogen elevations from 21hydroxylase overwhelm and perhaps opiates from PTSD submission responses). Keep in mind that people who don't have CAPS likely have other mechanisms for their MCAS, as I believe that CAPS is caused by CYP21A2 mutations. (I have seen several people with MCAS who don't have CAPS.) CRH causes the blood vessels around the gut to dilate, further decreasing blood pressure and blood volume, contributing to POTS (again, worse in hypermobility and high progesterone) and brain fog. It increases adrenaline/noradrenaline and the sympathetic nervous system (fight or flight) fueling the stress response and making POTS hyper-adrenergic. It directly stimulates inflammation in the brain by increasing cytokines, turning on the immune system. High CRH and MCAS have been highly associated with psychosis and mood disorders. It decreases stomach acid contributing to vitamin deficiency issues (vitamin D, B's and magnesium. Low vitamin D increases pain and causes malaise. B vitamins help with stress tolerance. Low magnesium is linked with anxiety, adrenaline release and raised intracranial pressure.) and gut dysbiosis (the gut becomes colonized with candida/other fungi/unusual bacteria which ferment food, can make alcohol and cause more inflammation resulting in increased intestinal permeability which has been linked with brain fog and possible autoimmune diseases/immunological dysfunction).
MCAS Explained By CYP21A2 mutations Lawrence Afrin writes 60-70 page journal articles and recently released a book about all of havoc mast cell activation can wreak. I'm only going to hit the high points. I believe that many of us have some degree of MCAS which goes on in the background and revs up at times of stress and with hormonal changes. MCAS is probably mostly caused by high CRH due to our lower than adequate basal cortisol as 21 hydroxylase becomes overwhelmed. High progesterone and estrogen during 21hydroxylase overwhelm may play a role, as can high opiates in PTSD shutdown/submission dissociative loops (probably common in traumatized people with CAPS). Mast cells are the sentry cells which first detect foreign invaders and degranulate, releasing a host of mediators including histamine and for this reason, they are activated by many pathogens, like Borrelia Burgdorferi and even stress itself. Indiscriminate allergy symptoms are typical. Symptoms of MCAS reflect where the mast cells are gathering. A short list includes: In the body: GI/food intolerance/increased intestinal permeability, hives, burning eyes, flushing, asthma, hyper-adrenergic POTS, interstitial cystitis; In the brain: migraines, brain fog, fatigue, psychiatric issues. With severe active MCAS, I found that I was completely unable to gate sensory experiences, i.e. I could NOT take an exam with someone typing in the same room. I was overstimulated by everything. Even busy visual stimulation was overwhelming. I was very distractible and my memory was affected. Lab testing is usually negative. If you have these symptoms in concert with the other symptoms associated with CYP21A2 mutations and/or you are hypermobile, you should have a trial of MCAS treatment. False assumptions block access to diagnosis and treatment with MCAS. In my experience, MCAS is common as demonstrated by significant empiric treatment response in most people with chronic illness.
Immune System Issues explained by CYP21A2 mutations plus or minus C4 mutations There are several reasons why people with CYP21A2 mutations can have immunological issues and my guess is that the presentation depends on whatever underlying processes dominate. These processes include:
Possible presence of C4 mutation associated with autoimmune diseases, i.e. multiple sclerosis, lupus, etc. Of note autoantibodies to glandular tissue can cause many hormonal issues separate from the CYP21A2 abnormalities, confusing the picture.
Immune system dysregulation with presence of C4 mutation: i.e. CVID, IgA deficiency, etc.
CRH triggered cytokine release
MCAS resulting in a shower of immune mediators with degranulation
Gut dysbiosis with resultant increased intestinal permeability causing inflammation
Colonization of GI tract, respiratory system, skin, nerves, GU tract with organisms of low pathogenicity (fungus-candida, herpes virus, mycoplasma, chlamydia, etc.) triggering a low grade immune response. Reactivation of viruses (herpes, etc.)
Most of us with chronic illness report: initial trouble clearing the mono virus (EBV) or recovering from viral illness followed by increased propensity for bacterial and fungal overgrowth syndromes (athlete's foot, vaginal candida, gut candida which produces alcohol) and serious bacterial infection (strep, pseudomonas) in conjunction with a relative invulnerability to the common cold. I didn't have a cold from 2009 through January 2016, but I had my appendix rupture (abdomen full of pseudomonas) followed by multiple bacterial wound infections and strep throat multiple times. A smaller group of people with chronic illness have a much different picture characterized by nearly constant upper respiratory infections, often viral, lymphadenopathy and chronic sore throats.
I believe that people with chronic illness are affected to some degree by all of the above processes affecting their immune systems. These multiple processes create a mess of abnormal cytokine profiles and evidence of various ongoing infections (including evidence of herpes reactivation) in people with chronic illness. In my opinion, these perturbations are examples of "downstream effects" and exploration of them is not going to lead directly to the underlying predisposing problem. While treating these colonizations/reactivations and using immunological agents to fix the cytokine profiles/boost aspects of the immune system (natural killer cells) may provide symptomatic relief and reduce the stress burden, I believe that the vulnerability to illness remains, i.e. the presence of CYP21A2 mutations. These immunological hypotheses to explain CFS/FM are missing the fact that there is a psychological profile present prior to the development of the illness. Something which preceded the abnormal immune profile created that brain in the vulnerable people.
Raised Intracranial Pressure (ICP) Explained By CYP21A2 Mutations I am quite convinced that many of us with chronic illness have raised ICP which results from downstream issues due to CYP21A2 mutations. Unfortunately, this is an area which is very confusing in the medical literature. Problems with nomenclature and false assumptions are rampant. The EDS-HT folks have been talking about chiari malformation (the cerebellum being squished by cranium and vertebrae) and hydrocephalus for a quite few years, but only a few small studies talk about the possibility of raised ICP in CFS, FM, etc. The symptoms of raised ICP are rampant in all of these conditions if you look for them: tinnitis (ringing in the ears), head pressure, imbalance, trouble with eye tracking, trouble swallowing, difficulty with fine movements (like writing) and stiff neck/neck pain. I have seen several patients in person and many on the forums who have been diagnosed with chiari malformation without the presence of hypermobility. Further, there are two mysterious conditions associated with raised ICP, affecting mainly women and often diagnosed in chronic illness: benign intracranial hypertension and pseudotumor cerebri. I believe that it is revealing that exogenous progesterone has been shown to trigger these. Finally, many of us are found to have empty sella syndrome on MRI and/or evidence of pituitary hormone abnormalities. Empty sella syndrome is due to raised ICP squishing and obscuring the visualization of the hypothalamus and pituitary on imaging and it is often associated with brain-derived hormonal issues which complicate the diagnosis of someone having CYP21A2 mutations by hormonal testing (see below). The presence of pituitary hormone abnormalities has been a major red herring in the search for the cause of chronic illness, as it suggests that the adrenal issues may be due to the pituitary gland rather than the adrenal gland.
The EDS-HT literature explains that chiari malformation results from a dynamic process involving pressure pushing the cerebellum down into hypermobile vertebrae in the neck which can occur or worsen as a person ages and the vertebrae stretch open. Diamox (acetazolamide) which decreases intracranial pressure provides symptomatic relief for many EDSers with chiari symptoms but despite this, most people are sent for surgery by the EDS experts because of the belief that loose vertebrae contribute. I personally believe that raised ICP in EDS results from downstream effects of CYP21A2 mutations primarily and can be addressed without surgery some of the time, as it was in me. Interestingly, the chiari malformation literature talks about acquired chiari malformation from raised ICP and Diamox is the treatment of choice for this.
CYP21A2 mutations could cause raised intracranial pressure:
Via magnesium deficiency (associated with posterior reversible encephalopathy)
Due to inflammation from high CRH
MCAS induced brain inflammation
Cortisol withdrawal as the levels plummet
Decreased venous drainage due vascular inflammation due to elevated TGF beta in EDS-HT (in conjunction with theTNXB mutation)
Interestingly, my first bout of high ICP symptoms responded to treatment with magnesium and my second bout (while on magnesium), identical in symptomotology, responded to MCAS treatment.
Pain Syndromes Explained By CYP21A2 mutations There are multiple possible mechanisms here as there are multiple types of pain we experience.
High progesterone increases laxity which is associated with a higher rate of injury and subluxation, especially in the hypermobile folks. When I have what I think is high progesterone, I dislocate my fingers just washing the dishes.
Low cortisol is associated with increased body pain. The cortisol can be basally depressed before we become sick and then it drops further. Patients of mine who have received low dose cortisol from naturopaths report that their overall body pain level decreases. I have noted this when I take just one dose of very low dose prednisone when I "hit the wall" every couple of months
Low magnesium (due to decreased stomach acid from high CRH) increases the tendency for muscle spasm, creating very tender balls of muscle all over the body.
MCAS is associated with neuropathic pain, bone pain, migraines and abdominal pain.
Complex Regional Pain Syndrome (CRPS) (now felt to share pathophysiology with FM) and other neuropathic pain conditions likely are mediated by inflammatory mediators liberated by an aberrant immune system (see Immune System Issues above).
Psychiatric Conditions Explained By CYP21A2 mutations The presence of CYP21A2 mutations would cause abnormal brain development in utero and in infancy from high acute stress cortisol/androgens. These brain structural/wiring changes would be what one would expect if an androgenized child was raised in an adverse environment until age 5. Children raised in stressful conditions have an enlarged amygdala (fear and emotional center) and a higher tendency to develop PTSD as well as other psychiatric issues. I believe that CAPS, CYP21A2 Mutation Associated NeuroPsychiatric Spectrum is a brain wired for danger with the large amygdala (seen in EDS and I imagine present in others with chronic illness) and enhanced threat wiring. This would explain the exaggerated acute stress response, mild dysautonomia and low basal arousal present in patients with CAPS. A more in-depth description can be found in the CAPS Section.
Briefly, in my experience, most well people withCAPS have more than a few of these characteristics (all related to being wired for danger detection):
Anxiety/over-arousal during times of stress (evidence of high adrenaline) with resulting insomnia and sometimes manic-like characteristics
Under-arousal during times of low stress (often leading diagnosis of ADD, and to compulsive behaviors-eating, smoking, etc... and sometimes thrill-seeking behaviors to increase arousal)
High emotionality/sensitivity/reactivity to environmental stimuli, sensory processing disorders (usually over-stimulation in places with a lot of noise or chaos)
A strong ability to read emotions in others but often social awkwardness and inappropriateness in response ("mindblindness"-thinking others know how they are feeling and assuming others see the world the way they do.)
Easily traumatized by "small" events (horror movie or off-hand comment by another person for example)
Easily distracted when not hyperfocused, shiny object syndrome (sometimes meets criteria for ADD), hypervigilant
A tendency toward nonconformity, special abilities (the type varies-but often includes very gifted musicians, scientists, etc...), hyper-focus and obsession with certain areas of interest (orienting response) to them leading to often remarkable accomplishments, in concert with the special abilities.
Exceptionally good at processing large amounts of information and reaching conclusions, picking out patterns, seeing small details others miss
A fascination with systems, understanding "why"
Sense of urgency tends to increase goal-directed behaviors, cutting down on "small talk"
People with this profile can be highly successful due to their abilities and tenacity. It is no coincidence that if you dig, you will see that hypermobility and chronic illness surrounds people with amazing accomplishments and abilities-geniuses, celebrities, mavericks.
In my clinical experience, sensitive people with CAPS are easily traumatized (due to the exaggerated acute stress response) and the effects of this trauma perpetuate the acute stress response. So, while this brain is associated with some great gifts, with negative experiences, more psychiatric conditions can become apparent. . (The psychiatric literature is starting to describe some of these in the hypermobile population):
With obsessional worrying and harm avoidance, comes obsessive compulsive disorder (strong thoughts followed by compulsive-need-to-be-performed-behaviors), generalized anxiety disorder, obsessive compulsive personality disorder (perfectionism, high standards for self and other), all aimed at preventing more bad events and further acute stress reactions.
High adrenaline, over-stimulation, trauma response from to past failures, excessive perfectionism, sensitivity and obsessionalism without a goal can be paralyzing, as there is no "safe place" and everything feels so urgent that there is no logical place to start. The common chief complaint: "I'm stuck" or "I procrastinate" or there may be meltdowns/shut down avoidance/numbing in high demand settings, if there is more pronounced danger wiring (autistic features) or PTSD wiring (see below) has developed.
The strong emotions can be very negative, with a pervasive sense that something is wrong or something bad will happen. Guilt, shame and fear can predominate. Depression sets in.
Acute stress responses lead to insomnia with worsening dysautonomia and adrenaline dumping. Hypomania and sometimes mania can ensue.
A constant sense of not being safe added to mindblindness can lead to paranoia, paranoid personality disorder. With C4 mutations, chronic paranoid schizophrenia can probably be seen.
The exaggerated stress response wires in phobias and threat brain circuits are reinforced resulting in severe PTSD symptoms including hypervigilance, worsening dysautomia with flight/fight (sympathetic nervous system), freeze (sympathetic and parasympathetic) and shutdown/submission (opiates) responses which occur automatically with conscious and unconscious triggers. These dissociated brainstem and limbic system circuits produce intrusive dysphoric emotional states, dramatic visual flashbacks (can seem hallucinatory), motor threat responses like dystonia, cataplexy, catatonia, non-epileptic seizures, tremors, paralysis, etc., sensory issues like non-dermatomal sensory symptoms, nonspecific brainstem issues like vertigo, nausea/vomiting, swallowing/lump in throat and "forgetting to breathe"/breath holding, etc. All of these can happen in response to subtle changes in the environment or even just thoughts/memories/dreams. Additionally, further constriction of social behaviors also occurs.
People with CAPS have an even greater vulnerability to psychiatric illnesswhen CYP21A2 is overwhelmed:
High adrenaline/noradrenaline (dumped to keep blood pressure up) associated with POTS/orthostatic intolerance
Causes anxiety (worse if TNXB mutation/hypermobility present)
Further increases the risk of developing PTSD and PTSD itself is associated with an elevated sympathetic nervous tone (increased startle). (PTSD is a major risk factor for Cell Danger Response (Naviaux MD PhD) which causes severe chronic illness.)
Can lead into psychotic mania, especially if MCAS is present
MCAShas been linked with mood disorders and psychosis and I have on many occasions seen someone develop psychotic symptoms at the same time as they developed worsening MCAS symptoms.
High progesteronecauses cognitive issues, irritability, mood swings, worsening PMS/PMDD.
Vitamin and mineral deficiencies causing psychiatric symptoms. Low magnesium can cause severe anxiety, vitamin D efficiency can cause malaise, increased pain, B vitamin deficiencies decrease ability to handle stress (MTHFR mutations can worsen this).
Chronic pain can cause brain changes resulting in depressive symptoms.
The psychological effect of thelosses and invalidation which comes with chronic illness should never be overlooked!
If C4 mutation comes with the CYP21A2 mutation, there may beautoimmune brain issues and schizophrenia.
Why Is it So Hard to Recover From Chronic Illness? As discussed above, I believe that chronic illness is triggered by an exaggerated acute stress response in people with CYP21A2 mutations which overwhelms the ability of 21 hydroxylase to make cortisol, resulting in a build-up of cortisol precursors and a deficiency of basal cortisol (with acute stress high cortisol remaining intact until the "wall is hit") and aldosterone. These hormonal effects cause a variety of downstream syndromes which wreak havoc on the body as discussed above. As more and more derangements/syndromes occur, the more stress the body is under and the more demand that there is for cortisol. This makes chronic illness self-perpetuating as shown in the following diagram:
The only way to stop this is to treat all of the downstream issues and decrease the acute stress response. Supplementing cortisol in a physiological stress-responsive manner may help (see below for treatment).
These Symptoms and Syndromes Make Sense, But Don't Quite Fit The Testing I've Had Done I imagine that many of you with chronic illness agree with me that there are major hormonal issues at play. You can see how they can cause your symptoms, but you are thinking that you went to the best endocrinologists or naturopaths for full endocrine panels and you weren’t really helped. Further, some of the testing you've had contradicted what I am saying above. There are many reasons for this and I can explain them:
Again, hormone levels are a DYNAMIC process, meaning that hormonal systems are in a constant state of flux based on what the body is facing at any given moment. A loud unexpected noise can change stress hormone levels at that instant. "Normal" levels are never absolute because they must take into account what was going on with the body, i.e. a normal or slightly low cortisol in the setting of a highly stressed body is VERY abnormal. People with CAH, i.e. possessing two copies of known/characterized/diagnosable severe CYP21A2 gene mutations sometimes have "normal " cortisol and 17hydroxyprogesterone levels, even after stimulation with ACTH.
Assays to measure hormone levels can be difficult to compare and interpret. The assays used by MD's look for dramatic changes in levels and will not pick up subtle abnormalities. The assays used by naturopaths are not as well-validated or accepted by the medical community, but are sensitive to subtle abnormalities.
Treatment which is too little or too late: Small aberrations in stress hormone levels may signal big problems if your body is extremely stressed and not able to mount a stress response. MD’s are taught to ignore cortisol levels which are mildly low because it is thought that very few people have an enzyme block causing this and the possibility of causing adrenal suppression with exogenous cortisol is real. MD's will see a mildly decreased cortisol level and won't know about the rip-roaring inflammatory storm in your body from MCAS, etc. so they will tell you that you are fine and offer you no treatment, unless you are in adrenal crisis. Naturopaths will treat a slightly low cortisol but, by the time they do it, the horse is usually out of the barn and down the road as it is not the lowish cortisol which necessarily causes the big problems. Rather, it is the high CRH wreaking havoc (released by the body in response to the physiologically abnormal low basal cortisol which turns on the immune system and sends the mast cells into uproar, increasing the body’s stress load and need for cortisol, stimulating the release of more CRH). This is why we go down the drain and can’t climb out. At that point, cortisol supplementation (as provided by a naturopath) is like a drop in the bucket.
Progesterone on the panels is not 17hydroxyprogesterone. A 17hydroxyprogesterone level can be ordered, with or without ACTH stimulation, but it never is unless CAH is suspected based on severe hormonal issues (like you have a beard). Most sex hormone issues in women are put down to polycystic ovarian syndrome (PCOS) without ever checking 17hydroxyprogesterone (see below) anyway. 17hydroxyprogesterone is never tested in chronic illness, despite a small study years ago demonstrating that it is high in CFS!! As mentioned above, because this is a dynamic process, 17hydroxyprogesterone is often normal even in people with full-blown CAH (two severe, bad genes). Some people with CYP21A2 mutations may even have low 17hydroxyprogesterone, low standard progesterone and low cholesterol prior to developing chronic illness due to increased consumption of these in the exaggerated stress response.
Raised Intracranial pressure affects pituitary hormones. As mentioned above, it is very likely that many of us have raise intracranial pressure due to downstream issues with CYP21A2 mutations. Raised ICP can affect pituitary hormones which signal with the adrenals and other glands muddying the waters with thyroid and other endocrine issues, etc.
Those with C4 mutations (also common in us, I believe) are prone to auto-antibodies and many of those are endocrine in nature. I believe that C4 mutations are responsible for the autoimmune thyroid issues so many of us have and can be the reason behind why our cortisol may be mildly low for years (due to CYP21A2 mutation) and then suddenly non-existent (due to an autoantibody being superimposed).
Why Have CYP21A2 Mutations Been Missed For So Long? The CYP21A2 gene has flown under the radar as a contender for chronic medical or psychiatric illness. Back in the 1980’s there was a lot of attention focused on the hypothalamic-pituitary-adrenal axis as a source for psychiatric and medical illness, but many of the issues above muddied the water: Dynamic issues, assay issues, raised ICP/pituitary issues and auto-antibody issues diverted the attention away from the adrenal gland. Over time, we no longer asked ourselves why the adrenal gland seems to be so abnormal in chronic illness. There was no reason to think that the gene CYP21A2 or the rare autosomal recessive disease congenital adrenal hyperplasia could have anything to do with it. CYP21A2 carriers were felt to be "fine" and in fact, the majority of those who aren't fine are probably mostly women who are notoriously felt to be "anxious" when they present with odd stress-related symptoms (see below). That one study showing high 17hydroxyprogesterone in patients with CFS faded into the distance. The scientific community moved on and focused on what I believe are downstream effects of the primary hormone disorder, cytokines, the immune response and mitochondrial dysfunction. However, now with the discovery of the frequent marriage of TNXB and CYP21A2 mutations and the number of co-morbid illnesses conferred by the C4 mutations, we must take another look at the findings of the older studies focusing on hormonal abnormalities associated with these conditions. In my Journal Article, I extensively review the literature, looking for evidence of these hormone disorders in the chronically ill and in EDS-HT and I find it. You’ll have to read the paper to see that.
As mentioned previously, most carriers for CYP21A2 are not usually diagnosed and are probably not grossly symptomatic (except they may see a psychiatrist for that exaggerated stress response as part of CAPS). The only people who are checked for the common (testable) 21 hydroxylase mutations in adulthood are women with acne/excessive hair, fertility, polycystic ovaries or menstrual abnormalities, and this is a last resort test, usually. I have spent some time following an online support group for women with hormonal abnormalities resulting in infertility, menstrual abnormalities or polycystic ovaries who have been misdiagnosed for years with polycystic ovarian syndrome when they actually have CAH. This happens because doctors aren't as familiar with CAH as they are with PCOS and don't think to test for it. In the few that are tested, most of those who are carriers are probably not told because currently, it is taught and believed that being a carrier is clinically insignificant (perhaps another false assumption). In this support group, many women report feeling terrible until CAH was recognized and treated and further, there is a small group of women on there who were found to be carriers for CAH and they also report feeling terrible before they were treated-fatigue, GI distress, etc. Further, according to the patients on the site, there is a women's health physician in Philadelphia (actually at the institution where I trained) who thinks that carrier status for CAH warrants treatment if there is evidence of hormone disruption.
What About the Other Theories of Chronic Illness: Right now, researchers are looking at cytokine profiles and trying to figure out why they are deranged, testing medications to shift the balance back. If these changes are "downstream" as I suspect they are, these medications will be helpful but ultimately not preventative or curative. Researchers are also looking at the possibility of stealth infections causing chronic illness. I believe that we are colonized with many stealth infections and also have secondary problems from viral reactivation (e.g. herpes, EBV), but again, I believe that these are downstream, i.e. they occur after the immune system is disrupted. Further, the pattern of mitochondrial shutdown suggests that there is NOT an acute infection. Treatment of these stealth infections can help with decreasing the stress load, but again, this most likely will not be curative. Other researchers are setting super computers on the task of figuring out which immune system genes are turned off or on in chronic illness, with the plan of working backwards to find the source of the vulnerability. The most promising finding thus far is the metabolic profile demonstrating characteristic mitochondrial function disruption in severely ill patients. The researchers (Naviaux and Davis) have suggested that this is a common pathway for a variety of triggers/stressors. The idea that stress triggers CFS/ME fits right with the RCCX Theory as CYP21A2 mutations are likely to be present in 20% of the population and confer a drastic stress vulnerability when present via 21hydroxylase overwhelm, via psychiatric illness, and via enhanced threat wiring/exaggerated stress response/CAPS.
Additionally, remember that I have found a psychological profile (CAPS) present prior to illness. Something caused this brain to form BEFORE the immune system was disrupted. CYP21A2 mutations would be expected to cause this profile and we know that UNTREATED patients with CAH have a wide range of psychiatric conditions.
A day rarely goes by when there isn't one more discovery of overlap symptoms/findings between all of the forms of chronic illness. In fact, Naviaux and Davis also believe that all of these illnesses likely overlap as they have included EDS and Lyme patients in their studies. Also, they have said that the pattern of mitochondrial shutdown is identical to that seen in Gulf War Syndrome and Autism.
Just recently, people with EDS were found to have white matter lesions, just like those with CFS/ME, MS, CAH, Chronic Lyme, and Toxic Mold. Small fiber polyneuropathy is commonly found in Gulf War Syndrome, EDS, fibromyalgia and CFS/ME. Raised intracranial pressure and MCAS unites these conditions as well. Poor stress tolerance, as well as decreased exercise tolerance is also frequently noted.
Diagnostic Issues: How Can I Be Tested? The short answer is that we don't have the DNA probes to do this because very few of these mutations have been characterized and the hormonal changes are dynamic and hard to catch...
If you have one of the genetics variants which has been characterized, available testing might work for you, but I think you will be very much in the minority.The mutations which I believe that most of us are carrying are still unrecognized. There are a few tests available for the contiguous mutations of TNXB and CYP21A2, but they are very expensive, and my guess is that again, few of us with these mutations would test positive with these probes. I thought about it testing myself, but then decided that the $3K would be better spent on getting this website set up instead. 17hydroxyprogesterone has been found to be high in the one published study on people with CFS. That said, it is reported that even with congenital adrenal hyperplasia (two bad genes instead of one), 17hydroxyprogesterone measurements are often normal, even when a stimulation test is done by giving ACTH before drawing the blood. I'm quite sure that my progesterone levels vary considerably with my stress levels, based on how my symptoms change and my varying response to berberine.
Treatment Considerations: The following is theoretical and NOT to be taken as advice for treatment. Work with Your Doctor! Using this theory, I have gone from nearly disabled on several occasions to well but fragile, i.e. prone to breakthrough symptoms under stress of any sort and I require many medications and supplements to stay balanced. I believe that it is the CYP21A2 mutation which makes us really sick under stressful conditions. Since we can't fix this mutation if present, we must recognize and accept that we are stress-vulnerable and that most of us have a psychological profile which brings us gifts but also amps up emotional stress, compounding our stress-vulnerability. If we can minimize our exposure to stress and adjust how we respond to acute stressors (emotional resiliency and grounding techniques, mindfulness), we might avoid a big trigger for chronic illness, i.e. having our 21 hydroxylase become overwhelmed. We might be able to rewire some of that threat circuit/PTSD wiring toward resiliency circuits (the brain has quite a bit of neuroplasticity). See CAPS section. If we are ill, we may be able to minimize relapses in conjunction with medication and supplements. This has been KEY to my recovery.
Additionally, maintaining adequate hydration, vitamins and minerals (correct MTHFR issues, check D, magnesium) form a foundation of physiological resiliency, valuable to those at risk and who are unwell. If we are hypermobile, we can reduce the stress of this physiology by maintaining adequate blood pressure (hydration), avoiding unnecessary surgeries and considering anti-TGFbeta treatment if the evidence for elevated TGF beta mounts. Those who develop chronic illness because of infectious stress (Lyme, EBV, etc.) do not have a chance for prevention, but these techniques are key to reducing the stress load after illness initiated.
Once there is evidence of MCAS or hormone disruption with stress (acne, menstrual changes, POTS, mood swings, hot flashes, water retention, etc...), more needs to be addressed to "right" the body enough to decrease the stress of having underlying inflammation. Aggressively treating MCAS, if present, is an example. Possibly decreasing or blocking 17hydroxyprogesterone directly (no common pharmaceuticals do that, berberine as a supplement does this BUT has possibly SEVERE side effects and drug interactions) or treating with stress-adjusted physiological doses of cortisol could perhaps be an option (very controversial and NOT recommended by MD's currently-but this recommendation may change if a CYP21A2 mutation is found). Florinef can combat the low aldosterone effects, but can also exacerbate raised intracranial pressure if present.
Raised ICP may respond to carefully monitored treatment with Diamox, but may also resolve with treatment with magnesium and treatment for MCAS, as happened with me. CRH antagonists might turn out to be a very good treatment to prevent MCAS and inflammation/immune system dysfunction from CRH. These are in development. Interestingly, there is a study showing that an experimental CRH blocker was able to quickly turn around psychotic depression (which I believe results from having CAH1 plus stress).
Inflammation/cytokines from immune system dysregulation are very stressful for the body. As mentioned above, elevated levels of these likely result from CRH-induced-MCAS, CRH directly, dysbiosis and possibly the presence of the C4 mutation. General interventions to decrease inflammation are probably helpful, specific treatment of MCAS certainly is, steroids in low doses and treatment of dysbiosis may have a role.The immunological drugs being developed may also decrease some of this burden. LDN may have a role in treating brain inflammation and chronic neuropathic pain syndomes via decreased microglial activation/inflammation and may treat PTSD dissociative symptoms perhaps via regulating endogenous opioids and oxytocin.
Anticholinergic syndrome (gastroparesis, chronic constipation, anxiety, brain fog) is also I believe, a downstream effect of all of this (see www.prettyill.com) and may respond to cholinergic support in my clinical experience.Mitochondrial issues, if present should also be addressed to decrease the stress load. I will emphasize again that this is a theoretical treatment regimen and we don't know if my theory is correct at this point in time. Do not do anything without the direction of your physician.
The mitochondrial findings are likely to lead to treatments in the near future for people who are noted to have evidence of it.
How Can We Prove This? So, now, I may have convinced some of you that this theory deserves a better look. When I realized all of this in July 2015, I thought, great, I'll do a small study and get it into the medical literature where clinicians would see it. I thought that I just needed to test 17hydroxyprogesterone levels in symptomatic patients (EDS-HT, FM, Chronic Lyme, CAPS) and myself and publish the results. Not easy for me to do as I am not university-affiliated, likely to get a grant or rich (chronic illness leads to downsizing, generally). Then I read that 17hydroxyprogesterone is often normal (even with preceding ACTH stimulation), even in people with CAH. In a small study, false negatives can obscure the truth, and this would have been a very small self-funded study. Further, in thinking about it, I realized that there is probably tremendous variability in the hormone presentations due to the highly mutagenic nature of the RCCX module, so hormone testing was out unless I had access to a sophisticated endocrinologist.
I knew that genetic testing would solve the issue for once and for all and would eliminate any blow-back I might get from anyone who didn’t like my theory because as they say on TV crime shows, you can’t argue with DNA. I initially thought that a service like 23andme plus livewello/promethease might be helpful. Unfortunately, though, due to the high rate of genetic mutations in the RCCX, there are probably MANY different mutations of CYPA21A2 and TNXB, many of which are not even characterized yet. The geneticists suggest this in their published results looking at these variants. When you read about CAH (or want to be tested for this mutation), you must remember that only a few of the better known, disease-producing mutations are discussed (or can be tested for). There are DNA probes available, but they only test for the common severe disease-causing mutations. It has been shown that the carrier rate for these well-known mutations is about 10% of the population. The carrier rate for the other less known variations is PROBABLY MUCH HIGHER and right now, there is no way to test for these genetically because the probes have not been developed. We won't know until someone spends some time sequencing CYP21A2 and looking for clinical correlates of genetic variations. Because of this, I decided that it wasn't worth the $3K per test to test myself or patients for the characterized mutations.
So, I spent 11 days on vacation writing up my theory for publication, hoping that by getting my theory into the medical literature, someone might see it and test it out. It was devastating when the editor's comments made it clear that he had missed the point of my work and still held assumptions which are no longer felt to be true (that "TNXB mutations are a rare cause of EDS", ugh, I wasn't even talking about EDS!). I started reaching out to scientists with genetics labs with an interest in these disorders, offering them my theory with no strings attached (i.e. they would not even have to acknowledge me if my theory led to fame or awards), but I received no response, despite reaching out over 10 times. My stress level was through the roof and I was getting really sick from this. This website was my last ditch effort and it has paid off! Disclaimer: The purpose of this website is NOT to recruit patients, give treatment recommendations, sell supplements, get attention, be controversial or become famous. I live a quiet, reclusive life with a small, local and full medical practice. This illness and this discovery has made my life very complicated.