From RCCX Theory to Stress-Induced Mitochondrial Shutdown
On the
Path...
June 2016: With exciting news from the Ron Davis, PhD, Robert Naviaux, MD PhD, CFS/ME front, the RCCX Theory becomes even more relevant, as now we know that toxic stress turns on the final common pathway in CFS/ME. (Paper released August 30, 2016, http://www.pnas.org/content/early/2016/08/24/1607571113)
See how ... (after the introduction).
Welcome to the RCCX Theory Website:
If you have been making your way through the website and understand Part I (Previously, Theory For Patients), skip the text in blue and proceed straight away to RCCX Theory Part II.
For those who don’t know, I am Sharon Meglathery MD, a physician (board certified in Psychiatry and previously, Internal Medicine) who developed CFS (chronic fatigue syndrome), MCAS (mast cell activation syndrome), POTS (postural orthostatic tachycardia syndrome) and raised ICP (intracranial pressure) in the setting of EDS-HT (Ehlers-Danlos Hypermobility Type). I spent 7 years trying to understand how these chronic illnesses fit together by observing my own illness, observing patients in my office, being active in online chronic illness forums, reading everything I could find and being lucky enough to have a smart friend send me a paper about the RCCX module (Martha Cassell), which explained all of my observations and the published research findings.
In July 2015, the RCCX Theory was born. 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 is linked with neighboring C4 and can be co-inherited with this gene). This website contains everything you need to understand the subtleties of this theory.
In this section, I will review The RCCX Theory as it stands now. If you read it back in February 2016, you may see a few changes.
If you are not familiar with the theory, on first blush, you may be skeptical as the RCCX Theory defies many common myths which are still widely held by patients and doctors alike. If the RCCX Theory is challenging what you have been told about EDS, CFS/ME or MCAS, etc., you may want to start with the Background Section which explains why these myths exist, why they no longer make sense given the mounting evidence against them and demonstrates how years of my clinical observations, the medical literature, my personal health experiences/experimentation and probably your health or clinical experiences actually jibe with the RCCX Theory, rather than these myths. If your personal and family history doesn’t match the list of RCCX associated conditions or associated syndromes (please take a look below), then the RCCX Theory is probably is not relevant to you. As these mutations are extremely common, I expect that most people with EDS-HT/ Autoimmune/Psychiatric Illnesses/Adrenal Fatigue/gender fluidity/genius qualities and a high number of people with FM/CFS/ME/Lyme/Mold/EBV/Autism/MCAS/POTS will fit the RCCX Theory.
In the RCCX Theory Part I section, the RCCX Theory is described in a more detailed and less technical manner, showing how it explains why so many of us and our family members have so many rare diseases (how can that happen by chance?) and then explains how the RCCX Theory can explain ALL of the many of the syndromes associated with chronic illness (see the pathophysiology diagram). You may wish to start there.
RCCX Theory: Summary
In Brief: (Much more detail to follow)
- Co-inherited gene mutations of the RCCX module may explain presence of clusters of genetic illness in families and individuals involving hypermobility/fibosis (TNXB gene), chronic medical illness (CYP21A2 gene, i.e. EDS-HT, CFS/ME, FM, POTS, MCAS, etc.), psychiatric illness (CYP21A2 gene) and autoimmune diseases (C4 gene).
- CYP21A2 gene mutations could confer a stress vulnerability for the development of chronic medical illness (EDS-HT, CFS/ME, FM, POTS, MCAS, etc.) via "21hydroxylase overwhelm" and via PTSD-wiring from CAPS (CYP21A2 Mutation Associated Neuropsychiatric Spectrum) plus negative events.
- CYP21A2 gene mutations create a hormone milieu which could affect the developing brain, making it a "brain wired for danger" by age 5, also known as CAPS (CYP21A2 Mutation Associated Psychiatric Spectrum). CAPS likely predisposes to 4/5 of the major psychiatric illnesses (anxiety disorders, mood disorders, attentional disorders, autism spectrum).
- Both "21hydroxylase overwhelm" and PTSD wiring associated with CAPS could turn cause stress-induced mitochondrial shutdown
To Whom Does this Theory Apply?
In many families, a cluster of the following 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 autistic features.
And the kicker, these issues may be found on both sides of the family because I believe that people with CAPS (the psychological profile which I believe is associated with CYP21A2 mutations) are attracted to each-other as they share sensitivities, emotional sensitivity and intellectual gifts. 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. Many will react strongly to stress.
If this sounds like your family (albeit a dramatic version), I am writing this for you.
Likely RCCX Gene Mutation-Associated Conditions Which Cluster in Individuals and Families:
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!)
- Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT)
- Chronic fatigue Syndrome (CFS)/Myalgic Encephalomyelitis (ME)
- Fibromyalgia (FM)
- Chronic Lyme Disease, Gulf War Syndrome, Toxic Mold/Biologic Illness
- Mast Cell Activation Syndrome (MCAS): histamine intolerance, migraines, diarrhea, sinus pain, burning eyes, syncope, distractibility, brain fog, irritability, interstitial cystitis, hyper-adrenergic POTS, etc., depending on location of the mast cells
- Postural Orthostatic Tachycardia (POTS), Dysautonomia, Orthostatic Intolerance, Low Blood Volume
- Pain Syndromes: Neuropathic Pain Syndromes/Chronic Regional Pain Syndrome/Myofascial Pain Disorder/Frequent Dislocations/Dysmenorrhea/Chronic Headache/Migraines/Interstitial Cystitis/Vulvodynia/Temporomandibular Joint Disorder (TMJ)
- GI Syndromes: Irritable Bowel Syndrome/Cyclical Vomiting/Gastroparesis/Food Intolerance/Gut dysbiosis/Candida Overgrowth/Leaky Gut /Malabsorption/Small Intestine Bacterial Overgrowth
- Raised Intracranial Pressure Conditions: Pseudotumor Cerebri/Benign Intracranial Hypertension/Posterior Reversible Encephalopathy/Acquired Chiari Malformation
- Neurological Issues: Neuropathies/Pain Syndromes/Uncoordinated Swallow/Vertigo/Central Apnea/Sleep Paralysis/Dysautonomia/Seizure-Like Episodes/Dystonia/Narcolepsy/White Matter Lesions/Small Fiber Polyneuropathy (Erythromelalgia)/Restless Leg Syndrome/Brain Anatomic Abnormalities (big Amygdalae-fear and emotional center; small anterior cingulate; chiari malformation, hydrocephalus)
- Mitochondrial Disorders/Cell Danger Response
- Immune Dysregulation: Combined Variable Immunodeficiency (CVID)/IgA Deficiency/Fungal Infections/Recurrent HSV Infections/No Colds for Years, Severe Bacterial Infections, Inability to Clear Strep/Epstein Barr/Mycoplasma/Chlamydia/Candida, Dysbiosis, Small Intestinal Bacterial Overgrowth, Multiple Sclerosis (MS), Autoimmune Disorders-Classic and Non Classic, i.e. Mixed Connective Tissue Disorders/Eosinophilic Disorders, High TGF Beta/Inflammatory Conditions (Endometriosis, etc.), Chronic Inflammatory Response Syndrome (CIRS)
- Psychiatric Issues: Runs the Gamut: Psychiatric Conditions due to Dysautonomia (Panic/Anxiety)/ADD/Hyperfocus/Autistic Wiring/Sensory Processing Disorders/Psychosis/Schizophrenia/Chronic Illness: Stress and Loss/PTSD/Mood Disorders (Bipolar/Unipolar)/Chronic Insomnia/Generalized Anxiety Disorder/Obsessive Compulsive Disorder/Phobias/Obsessive Compulsive Personality Disorder/Paranoid Disorders/Emotional Dysregulation/Compulsive Behaviors/Sensitivity/Harm Avoidance or Conversely, Adrenaline Addiction/Thrill Seeking Behaviors
- Hormonal Disorders: Congenital Adrenal Hyperplasia, Sex Hormone Disorders-Cystic Ovaries, Acne, Water +/- Fat Associated Weight Gain, Breast and Tissue Swelling, Fertility issues, Hot Flashes/Night Sweats; Adrenal Gland Issues: Adrenal Fatigue, Addison's, High Stress Cortisol/Low Basal Cortisol, Low Aldosterone; Pituitary Hormone Abnormalities-ACTH, TRH-Mediated Thyroid Disorders; Autoimmune Hormonal Issues (i.e. Hashimotos's Thyroiditis), etc...
- GU/Renal Issues: Fibromuscular Dysplasia, Diabetes Insipidus, Interstitial Cystitis, Vesicoureteral Reflux
- 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, Abnormal Scarring, Stretch Marks, 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 believe that the degree of hypermobility only relates to the musculoskeletal issues and that the chronic illness issues are completely separate. Thus, it is not necessary to have a diagnosis of EDS to have many of the issues most people relate to a diagnosis of EDS and associated with chronic illness.
It is impossible to test for even a fraction of the TNXB mutations associated with clinical illness and my guess is that TNXB mutations may be associated with enough hypermobility to meet criteria for EDS sometimes, but most often they are associated with only mild hypermobility or possibly even stiffness. 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.
What is the RCCX Module:
There is a part of the genome, nestled among the immune system genes called the RCCX module. This module breaks the rules of genetics in that it mutates often (even between generations) and it allows contiguous (side-by-side) gene mutations to be co-inherited at a very high rate, meaning that it allows for several “rare” genetic conditions to be found in one individual.
There are 4 genes in the RCCX module and their mutations have been shown to travel together often within individuals and families:
RP1: function unknown
TNXB: codes for tenascin X, a protein found in the extracellular matrix of collagen
- Mutations sometimes associated with EDS
- Mutations often associated with joint hypermobility NOT meeting criteria for EDS
- Mutations possibly associated with stiff or even normal-seeming tissues depending on the mutation,
- Mutations have been associated with TGF beta abnormalities implicated in fibrosis
C4 :codes for a protein involved in the complement system of the immune system
- Mutations implicated in autoimmune diseases, immunodeficiency/CVID, schizophrenia
CYP21A2: codes for the key enzyme, 21hydroxylase, which is involved in the acute stress response. 21hydroxylase helps to make cortisol from 17 hydroxyprogesterone and aldosterone.
- Mutations result in an exaggerated stress response (high acute stress response cortisol), low basal cortisol and elevated CRH (corticotropin releasing hormone, aka CRF) which directly turns on the immune system and inflammation.
- Mutations are also associated with autosomal recessive congenital adrenal hyperplasia (CAH), usually diagnosed in infancy due to its association with extreme salt wasting (due to low aldosterone) and dangerously low cortisol. A milder form, non-classical CAH, presents later in life.
- It is highly likely that there are MANY uncharacterized (mild) mutations which, in homozygous or even heterozygous forms, would cause a wide range of clinical presentations.
- Carriers of CYP21A2 mutations have BOTH an exaggerated stress response AND are at risk for 21 hydroxylase failure resulting in inability to make cortisol and aldosterone with subsequent 17 hydroxyprogesterone and androgen build up. Called "21hydroxylase overwhelm" going forward. This is a stress-vulnerable switch which can result in severe chronic illness if flipped.
- I believe that "21hydroxylase overwhelm" is the basis for many aspects of chronic illness as theoretically, this can be causally linked with many of the syndromes associated with chronic illness, including: MCAS, POTS, immune dysfunction, etc. (See Pathophysiology Diagram below). For more information about this, please see RCCX Theory Part I.
- Additionally, I believe that the presence of this mutation can lead to a distinct psychiatric profile, CAPS (CYP21A2 Mutation Associated Neuropsychiatric Profile, discussed below), brain structural and wiring abnormalities, and sometimes psychiatric illness (ADD, Anxiety, PTSD, Mood disorders, autism, and even psychosis if brain inflammation often associated with MCAS).
The RCCX Module is Responsible For Co-Segregating Genetic Diseases and Syndromes in Individuals and Families
Evidence is mounting that mutations of RCCX genes are extremely common in the general population (e.g. CYP21A2 mutations are likely present in about 20% of the population) and exert significant health effects. Most of the SNPs associated with mutations in these genes have not been characterized as they mutate so often. Further, there are so many insertions in this region that it is often difficult even to identify SNPs at all. Occasionally, genetic testing will reveal a SNP but the clinical significance is never clear as they have not yet been characterized. This is why we can’t use 23andme or whole exome sequencing yet to reliably find all of these mutations.
The genetics literature continues to provide more and more examples of overlapping clinical pictures caused by mutations of these genes travelling together. The recognition of this is in its infancy, but by most indications, should be quite prevalent.
These overlapping syndromes would be expected to run together in families and in individuals, resulting in multiple “rare” conditions being present in one individual or throughout a family (see specific list of conditions). We would see elements of the following conditions running through families:
- Hypermobility/EDS/collagen abnormalities/high TGF beta (TNXB)
- Autoimmune diseases, immunodeficiency disorders, like CVID, schizophrenia, autism (C4)
- Characteristics of CAH (CYP21A2) which include adrenal and sex hormone abnormalities (low basal cortisol with high acute stress cortisol, sex hormone abnormalities dependent on clinical status), gender fluidity, and as I have posited, brain structural and circuit abnormalities (CAPS psychological profile, wiring for danger, special abilities-see below), chronic illness: psychiatric (ADD, Anxiety, Mood, Autism) and medical (CFS/ME/Lyme/FM/immune dysfunction via CRH/MCAS/POTS etc.)
This is exactly what is seen in real life. Families containing geniuses, people with CFS/ME/Lyme/FM, hypermobile folks, gay/transgender people, people with autoimmune diseases, people with endometriosis, people with subcutaneous adipose disorders, etc, etc. See the full list above.
CYP21A2 Mutations Likely Underlie Chronic Illness
As stated above, The RCCX Theory posits that severe acute stress (e.g. toxic mold exposure, Borrelia Bugdorferi infection, physical or emotional trauma, etc.) or prolonged stress can set in motion severe chronic illness in a stress-vulnerable person (a CYP21A2 mutation carrier with perhaps additional other specific susceptibility genes specific for the inciting infectious or toxic agent, making it a particularly strong stressor). The CYP21A2 mutation contains an evolutionary switch which is flipped as the person desperately tries to make enough cortisol to handle the stress, triggering 21 hydroxylase overwhelm and then possibly stress induced mitochondrial shutdown. Dauer-like response or stress-induced mitochondrial shutdown has very recently been discovered in patients with severe CFS/ME by Ron Davis PhD and Robert Naviaux MD PhD (initially described by Naviaux). The symptoms which occur after 21 hydroxylase is overwhelmed are the same, independent of the trigger. For more information about this, please see RCCX Theory Part I.
There are still many people who believe that these chronic illness conditions are completely separate in pathophysiology, e.g. all of the symptoms associated with EDS are solely caused by a genetic defect of collagen, all of the symptoms of Lyme disease are caused by Borrelia Bugdorferi, all symptoms of CERS are caused by the inciting agent, etc.
But, everyday, it is becoming more clear that these conditions all go down a common pathway. There are just too many very specific overlapping symptoms for it to be any other way. The RCCX Theory unites all of the findings:
For me, the most compelling piece of evidence that all of these conditions have a common mechanism is the psychological profile, CAPS, I have discovered which is invariably present in hypermobile psychiatric patients who develop chronic illness and is present in the vast majority of other people who develop chronic illness. I believe that it is a reliable marker for vulnerability to chronic illness. It is characterized by having increased threat detection and enhanced stress response and comes some gifts, if present in moderation: enhanced empathy (ability to read emotions in others), sensory sensitivity, superior pattern recognition/information processing, times of intense hyperfocus/obsession/special interests and unusual abilities (often in music, arts or abstract thinking). I have found that with any stress (even minimal trauma), the threat response circuits seem to be reinforced (epigenetic changes may be further strengthening these connections), creating PTSD-like wiring and reactions. I have found that these stress-induced/primed circuits in the brainstem and limbic system can be associated with the emergence of bursts of emotional dysregulation, dysautonomia, motor and sensory syndromes (hallucinations, dystonia, catatonia, cataplexy, non-dermatomal sensory symptoms, non-epileptic seizures, etc.) and inappropriate states of consciousness (fight/flight, freeze, shutdown).
I have also found that classic psychiatric illnesses almost always present with CAPS, with or without the PTSD wiring. In fact, I believe that CYP21A2 mutations are the genetic basis for the development of four of the five major psychiatric illnesses (anxiety disorders, mood disorders, ADD, autism), with C4 (next door) +/- co-inherited CYP21A2 being responsible for the 5th, schizophrenia (shown in January 2016). The fact that in April 2015 it was shown that these major psychiatric illnesses are likely part of a spectrum with similar genetic underpinnings fits very nicely with the RCCX Theory.
See the Background section to read about the discovery of CAPS and its associations and the CAPS section to read how CAPS develops and presents. The hormone milieu one would expect with the CYP21A2 mutation explains the findings in the CAPS, a "brain wired for danger" as this milieu is very similar to what would be seen in a child experiencing very adverse circumstances/trauma.
More of these overlapping symptoms can be found on the forums, as some of this has not yet made it into the literature. Further, it is also becoming increasingly clear that the above RCCX co-morbidities run with these conditions in individuals and within families.
Additionally, the RCCX Theory may also end up explaining some of the other off-center theories of chronic illness, such as the role of pyroles in chronic illness (21 hydroxylase contains heme moiety. It is possible that heme moieties could rise to high levels if the body was trying unsuccessfully to make 21 hydroxylase in an attempt to raise cortisol to appropriate stress levels). Also, the idea that 20% of the population is at risk for MCAS at times of stress (those with CYP21A2 mutations) jibes with orthomolecular psychiatry’s claim of histamine being a major player in psychiatric illness (I believe that it's actually MCAS which is histamine PLUS other mediators).
There is no evidence that I have found anywhere which contradicts the RCCX Theory and I have read everything I can find!
As long as specialists continue to say that any co-morbidity overlap is due to chance alone, we will never move forward.
I believe that Ron Davis PhD (a premier CFS/ME researcher) sees this as well, as he has included people with EDS in his CFS/ME studies.
RCCX Theory Part II: From RCCX Theory to Stress-Induced Mitochondrial Shutdown (Added to RCCX Theory in July 2016):
In June 2016, Ron Davis, PhD and Robert Naviaux, MD PhD demonstrated that stress-induced mitochondrial shutdown, a hypometabolic state similar to hibernation, occurs in severely ill CFS/ME patients in a pilot study. This response is believed to be a normal, possibly temporary physiological response to stress which seems to be prolonged in CFS/ME, perhaps due to maintaining forces. I suspect that these findings are relevant to all of the chronically ill people mentioned in the previous section, as the RCCX Theory proposes a shared stress vulnerability mediated by CYP21A2 mutations. As stated above, I believe that this stress vulnerability unites many groups of people with chronic illness, some hypermobile and some not, (see above) and thus, mitochondrial shutdown is likely to be a relevant process to all.
PTSD is a known risk factor for turning on this response, as is a variety of toxic external and internal stressors, according to Naviaux MD PhD who initially discovered and described this process.
I believe that CAPS, which I believe is due to spiking cortisol levels in the setting of low basal cortisol during gestation and infancy from the presence of one or more CYP21A2 mutations, may be one of the most common risk factors for the development of PTSD. (See below for details.)
I also believe that there are several other ways that RCCX mutations can cause mitochondrial shutdown by increasing the body’s stress load:
Based on my observations and the evidence demonstrating that features of RCCX mutations are highly present in the chronically ill population (see the rest of the website), I believe that the RCCX mutations are responsible for creating the level of toxic stress necessary to cause mitochondrial shutdown indefinitely in a high percentage of people with chronic illness. But why would we have genes which predispose us to chronic illness?
The RCCX Module Is Designed to Adapt to Changing Environments; C4 and CYP21A2 Confer the Ability to Cope with New Pathogens and Changing Levels of Environmental Stress
Evolutionarily, our immune system is designed to battle frequently mutating pathogens by having the capability of generating extremely varied components due to highly mutable genes. Most of these genes are within the MHC class III region of the genome. The RCCX module sits in this region, even though C4 is the only known immune system gene in the RCCX module. The C4 gene is able to produce a highly diverse complement protein gene product, also called C4, which is able to adapt exceptionally well to new threats through frequent and varied mutations. C4 is also very much involved in neurodevelopment by controlling the process of dendritic pruning, altering the communication between neurons.
At first glance, it is unclear why CYP21A2, coding for the major enzyme in the acute stress response, would be located in such a mutation-prone part of the genome. The literature suggests that it just happens to be there, but I believe that this is part of a very clever plan to allow for adaptation to changing levels of stress from generation to generation and throughout the lifespan of the person.
If a child is born into a highly stressful environment, then the exaggerated stress response known to be associated with CYP21A2 mutations would confer superior threat recognition and a more rapid response, both of which are clearly vital to survival in a dangerous environment. Further, it is highly likely that CYP21A2 mutations can, via epigenetic changes, adapt to changing levels of stress throughout the lifespan, allowing the person to thrive in an ever-changing environment. ("Epigenetic" gene changes refer to modifications in the gene after birth which affect its expression.) In the last several years, transgenerational epigenetic changes have been observed in other stress-affected genes, allowing stress-induced, presumably adaptive, genetic changes conferred on one generation to be passed on to at least several later generations. It stands to reason that this could happen with the CYP21A2 gene as well, making it a very important gene for survival.
While mutations and epigenetic changes are thought of as facilitating adaptation to hardship, it is highly likely that they can also bring about the removal of genes which are no longer advantageous.
What if the inherited CYP21A2 mutation is associated with a drastically high stress response for the current environment, as could possibly happen by chance or if transgenerational epigenetic effects occurred during a very stressful time several generations back?
This excessively high stress response would have no survival advantage and thus evolutionarily speaking, this CYP21A2 mutation should probably be removed from the gene pool.
And what about if the environmental danger/threat level becomes so high that a sensitive CAPS person is hypervigilant and jacked up at all times, unable to sleep ever?
From an evolutionary standpoint, it is not advantageous for this person to bring similarly wired children into this environment or to continue tolerating it as it is. Again, evolutionarily, there is a mismatch between the person and the environment and the mutated CYP21A2 should be removed from the gene pool.
(I bold the word "evolutionarily" to show that this is about natural selection and not about my personal preferences :))
I believe that CYP21A2 mutations may be programmed to be removed from the gene pool by two different built-in physiological mechanisms. The first, 21hydroxylase overwhelm may, initially, prevent procreation and with continuing stress, cause mitochondrial shut down, if the stress to stress response mismatch becomes excessive. The second physiological mechanism involves the CAPS brain transforming into severe psychiatric illness due to dissociative limbic (emotional) and brainstem (autonomic. motor and sensory) circuits, brain inflammation from MCAS and other downstream effects of CRH.
Regarding the first mechanism, 21hydroxylase overwhelm, it is necessary to remember that CYP21A2 mutations result in a vigorous acute stress response requiring high amounts of cortisol AND ironically, they also cause a decreased ability to produce functional 21hydroxylase, the enzyme which produces cortisol. At first this seems counter-intuitive, but it's a very clever way to build in a vulnerability to situations requiring excessive amounts of cortisol, i.e. a switch to turn on a cascade of events which could lead to removal of the gene from the gene pool. The switch gets flipped when the person is carrying a mutation with an inappropriately exaggerated stress response for the environment at hand or if a CAPS person is exposed to a very toxic/prolonged stressor or a very stressful/dangerous environment without escape. These situations result in an acute stress response which is woefully inappropriate, being turned on continually and never able to calm down.
These stress:stress response mismatch situations lead to an inadequate amount of 21hydroxylase being produced for the situation. In both cases, cortisol is being consumed at a tremendous rate. In the first case, it is being consumed for no reason other than an inappropriate gene mutation and in the second, something really toxic is happening. With this high cortisol demand, 21hydroxylase becomes overwhelmed and cortisol and aldosterone drop, decreasing the ability to respond to stress. CRH rises, turning on inflammatory pathways (MCAS, etc.), changing the immune system (immunodeficiency, dysbiosis) and sometimes, causing psychosis from brain inflammation. Additionally, there are major changes in sex hormone levels. Metabolic syndrome sets in from elevated cholesterol and dysbiosis. Malabsorption wipes out necessary vitamin stores. Without drastic changes in either the environment or the response to the environment, the fall-out from the flipped 21hydroxylase switch leads to chronic illness plus or minus mitochondrial shutdown.
As these hormonal, metabolic and inflammatory changes are additive in terms of stress load, it is probably very difficult to reset either the 21hydroxylase switch or the CDR switch once they are flipped in someone with a CYP21A2 mutation. The person succumbs to this toxic stress, in stages, first unable to procreate from the hormonal changes (high progesterone, high testosterone in women cause early menopause) and then unable to muster the energy to move due to the mitochondrial shutdown. Ironically, and perhaps by design, this hypometabolic state conserves resources and enhances survival (albeit a dwindling existence) in modern human society. However, In nature, mitochondrial shutdown for any length of time would lead to certain death by predator.
But, everyday, it is becoming more clear that these conditions all go down a common pathway. There are just too many very specific overlapping symptoms for it to be any other way. The RCCX Theory unites all of the findings:
- White Matter Lesions (CAH, EDS, CFS/ME, MS, Lyme, etc.)
- Erythromelalgia/Small Fiber Polyneuropathy (EDS, FM, Gulf War Veterans, CFS/ME etc.)
- Autonomic Nervous System Dysfunction/POTS/Orthostatic Intolerance (all)
- MCAS (EDS, Lyme, Mold, Psychiatric, Autoimmune, FM, CFS/ME)
- Neuropathic pain syndromes/CRPS (EDS, Lyme, Psychiatric, Autoimmune, FM, CFS/ME)
- Autism (EDS, MCAS, high androgen states, neurovisceral syndrome)
- Enlarged Amygdala (autism, EDS)
- Raised Intracranial Pressure/Chiari (EDS, CFS/ME, mold, magnesium deficiency, elevated progesterone states)
- Dysbiosis (all)
- Salt and Water Loss (EDS, CFS/ME)
- Low Baseline Cortisol (all)
- Association with Autoimmune Diseases (All, anecdotally)
- High Adrenaline/Exaggerated Acute Stress Response (EDS, CFS/ME, CYP21A2 carriers)
- Treating MCAS, correcting MTHFR, LDN, maintaining adequate hydration/salt repletion, correcting dysbiosis, anti-inflammatories, mitochondrial support, diamox, immune system agents, mindfulness/grounding/brain retraining and stress reduction are overlapping treatments which seem to help these conditions.
For me, the most compelling piece of evidence that all of these conditions have a common mechanism is the psychological profile, CAPS, I have discovered which is invariably present in hypermobile psychiatric patients who develop chronic illness and is present in the vast majority of other people who develop chronic illness. I believe that it is a reliable marker for vulnerability to chronic illness. It is characterized by having increased threat detection and enhanced stress response and comes some gifts, if present in moderation: enhanced empathy (ability to read emotions in others), sensory sensitivity, superior pattern recognition/information processing, times of intense hyperfocus/obsession/special interests and unusual abilities (often in music, arts or abstract thinking). I have found that with any stress (even minimal trauma), the threat response circuits seem to be reinforced (epigenetic changes may be further strengthening these connections), creating PTSD-like wiring and reactions. I have found that these stress-induced/primed circuits in the brainstem and limbic system can be associated with the emergence of bursts of emotional dysregulation, dysautonomia, motor and sensory syndromes (hallucinations, dystonia, catatonia, cataplexy, non-dermatomal sensory symptoms, non-epileptic seizures, etc.) and inappropriate states of consciousness (fight/flight, freeze, shutdown).
I have also found that classic psychiatric illnesses almost always present with CAPS, with or without the PTSD wiring. In fact, I believe that CYP21A2 mutations are the genetic basis for the development of four of the five major psychiatric illnesses (anxiety disorders, mood disorders, ADD, autism), with C4 (next door) +/- co-inherited CYP21A2 being responsible for the 5th, schizophrenia (shown in January 2016). The fact that in April 2015 it was shown that these major psychiatric illnesses are likely part of a spectrum with similar genetic underpinnings fits very nicely with the RCCX Theory.
See the Background section to read about the discovery of CAPS and its associations and the CAPS section to read how CAPS develops and presents. The hormone milieu one would expect with the CYP21A2 mutation explains the findings in the CAPS, a "brain wired for danger" as this milieu is very similar to what would be seen in a child experiencing very adverse circumstances/trauma.
More of these overlapping symptoms can be found on the forums, as some of this has not yet made it into the literature. Further, it is also becoming increasingly clear that the above RCCX co-morbidities run with these conditions in individuals and within families.
Additionally, the RCCX Theory may also end up explaining some of the other off-center theories of chronic illness, such as the role of pyroles in chronic illness (21 hydroxylase contains heme moiety. It is possible that heme moieties could rise to high levels if the body was trying unsuccessfully to make 21 hydroxylase in an attempt to raise cortisol to appropriate stress levels). Also, the idea that 20% of the population is at risk for MCAS at times of stress (those with CYP21A2 mutations) jibes with orthomolecular psychiatry’s claim of histamine being a major player in psychiatric illness (I believe that it's actually MCAS which is histamine PLUS other mediators).
There is no evidence that I have found anywhere which contradicts the RCCX Theory and I have read everything I can find!
As long as specialists continue to say that any co-morbidity overlap is due to chance alone, we will never move forward.
I believe that Ron Davis PhD (a premier CFS/ME researcher) sees this as well, as he has included people with EDS in his CFS/ME studies.
RCCX Theory Part II: From RCCX Theory to Stress-Induced Mitochondrial Shutdown (Added to RCCX Theory in July 2016):
In June 2016, Ron Davis, PhD and Robert Naviaux, MD PhD demonstrated that stress-induced mitochondrial shutdown, a hypometabolic state similar to hibernation, occurs in severely ill CFS/ME patients in a pilot study. This response is believed to be a normal, possibly temporary physiological response to stress which seems to be prolonged in CFS/ME, perhaps due to maintaining forces. I suspect that these findings are relevant to all of the chronically ill people mentioned in the previous section, as the RCCX Theory proposes a shared stress vulnerability mediated by CYP21A2 mutations. As stated above, I believe that this stress vulnerability unites many groups of people with chronic illness, some hypermobile and some not, (see above) and thus, mitochondrial shutdown is likely to be a relevant process to all.
PTSD is a known risk factor for turning on this response, as is a variety of toxic external and internal stressors, according to Naviaux MD PhD who initially discovered and described this process.
I believe that CAPS, which I believe is due to spiking cortisol levels in the setting of low basal cortisol during gestation and infancy from the presence of one or more CYP21A2 mutations, may be one of the most common risk factors for the development of PTSD. (See below for details.)
I also believe that there are several other ways that RCCX mutations can cause mitochondrial shutdown by increasing the body’s stress load:
- TNXB (codes for tenascin X, a protein involved with collagen) mutations are associated with TGF beta abnormalities (fibrosis, inflammation, etc) and lax blood vessels (orthostasis), i.e. inflammatory and cardiovascular stress.
- C4 mutations are associated with schizophrenia, autoimmune diseases and immunodeficiency conditions (MS, CVID, etc.), adding to inflammatory, immunological and psychiatric stress.
- CYP21A2 mutations are associated with BOTH an exaggerated stress response AND the possibility of overwhelming 21 hydoxylase, the enzyme making cortisol and aldosterone from progesterone. Mast cell activation syndrome (MCAS) and the immune system can turn on in response to elevated CRH (corticotropin releasing hormone) due to low basal cortisol, resulting in a variety of derangements in hormone levels, immune responses, inflammation and clinical syndromes (see above pathophysiology diagram, RCCX Theory Part I). This increases the stress load by adding hormonal, immunological, inflammatory, psychiatric (anxiety) and cardiovascular stress.
- As mentioned above, the exaggerated response to stress (spiking cortisol) in infants with CYP21A2 mutations may also result in a brain wired for danger (CAPS) which is stress vulnerable, associated with dysautonomia and emotional dysregulation. With negative events, the exaggerated acute stress response (and perhaps epigenetic effects-see below) could facilitate the development of severe, PTSD-like brain wiring which worsens the dysautonomia and emotional dysregulation, further increasing the acute stress response. This can result in distressing dissociative (dysautonomic, sensory, motor) syndromes via brainstem/limbic system circuits as well as other psychiatric illnesses (predisposes to 4 of the major psychiatric illnesses: ADD, Anxiety Disorders, Mood Disorders, autistic features). Brain inflammation from MCAS/CRH can complicate the picture, as can the addition of C4 mutations can result in schizophrenia or possibly more severe autistic features. (I have observed all of this clinically). This increases the stress load by adding cardiovascular and psychiatric stress.
Based on my observations and the evidence demonstrating that features of RCCX mutations are highly present in the chronically ill population (see the rest of the website), I believe that the RCCX mutations are responsible for creating the level of toxic stress necessary to cause mitochondrial shutdown indefinitely in a high percentage of people with chronic illness. But why would we have genes which predispose us to chronic illness?
The RCCX Module Is Designed to Adapt to Changing Environments; C4 and CYP21A2 Confer the Ability to Cope with New Pathogens and Changing Levels of Environmental Stress
Evolutionarily, our immune system is designed to battle frequently mutating pathogens by having the capability of generating extremely varied components due to highly mutable genes. Most of these genes are within the MHC class III region of the genome. The RCCX module sits in this region, even though C4 is the only known immune system gene in the RCCX module. The C4 gene is able to produce a highly diverse complement protein gene product, also called C4, which is able to adapt exceptionally well to new threats through frequent and varied mutations. C4 is also very much involved in neurodevelopment by controlling the process of dendritic pruning, altering the communication between neurons.
At first glance, it is unclear why CYP21A2, coding for the major enzyme in the acute stress response, would be located in such a mutation-prone part of the genome. The literature suggests that it just happens to be there, but I believe that this is part of a very clever plan to allow for adaptation to changing levels of stress from generation to generation and throughout the lifespan of the person.
If a child is born into a highly stressful environment, then the exaggerated stress response known to be associated with CYP21A2 mutations would confer superior threat recognition and a more rapid response, both of which are clearly vital to survival in a dangerous environment. Further, it is highly likely that CYP21A2 mutations can, via epigenetic changes, adapt to changing levels of stress throughout the lifespan, allowing the person to thrive in an ever-changing environment. ("Epigenetic" gene changes refer to modifications in the gene after birth which affect its expression.) In the last several years, transgenerational epigenetic changes have been observed in other stress-affected genes, allowing stress-induced, presumably adaptive, genetic changes conferred on one generation to be passed on to at least several later generations. It stands to reason that this could happen with the CYP21A2 gene as well, making it a very important gene for survival.
While mutations and epigenetic changes are thought of as facilitating adaptation to hardship, it is highly likely that they can also bring about the removal of genes which are no longer advantageous.
What if the inherited CYP21A2 mutation is associated with a drastically high stress response for the current environment, as could possibly happen by chance or if transgenerational epigenetic effects occurred during a very stressful time several generations back?
This excessively high stress response would have no survival advantage and thus evolutionarily speaking, this CYP21A2 mutation should probably be removed from the gene pool.
And what about if the environmental danger/threat level becomes so high that a sensitive CAPS person is hypervigilant and jacked up at all times, unable to sleep ever?
From an evolutionary standpoint, it is not advantageous for this person to bring similarly wired children into this environment or to continue tolerating it as it is. Again, evolutionarily, there is a mismatch between the person and the environment and the mutated CYP21A2 should be removed from the gene pool.
(I bold the word "evolutionarily" to show that this is about natural selection and not about my personal preferences :))
I believe that CYP21A2 mutations may be programmed to be removed from the gene pool by two different built-in physiological mechanisms. The first, 21hydroxylase overwhelm may, initially, prevent procreation and with continuing stress, cause mitochondrial shut down, if the stress to stress response mismatch becomes excessive. The second physiological mechanism involves the CAPS brain transforming into severe psychiatric illness due to dissociative limbic (emotional) and brainstem (autonomic. motor and sensory) circuits, brain inflammation from MCAS and other downstream effects of CRH.
Regarding the first mechanism, 21hydroxylase overwhelm, it is necessary to remember that CYP21A2 mutations result in a vigorous acute stress response requiring high amounts of cortisol AND ironically, they also cause a decreased ability to produce functional 21hydroxylase, the enzyme which produces cortisol. At first this seems counter-intuitive, but it's a very clever way to build in a vulnerability to situations requiring excessive amounts of cortisol, i.e. a switch to turn on a cascade of events which could lead to removal of the gene from the gene pool. The switch gets flipped when the person is carrying a mutation with an inappropriately exaggerated stress response for the environment at hand or if a CAPS person is exposed to a very toxic/prolonged stressor or a very stressful/dangerous environment without escape. These situations result in an acute stress response which is woefully inappropriate, being turned on continually and never able to calm down.
These stress:stress response mismatch situations lead to an inadequate amount of 21hydroxylase being produced for the situation. In both cases, cortisol is being consumed at a tremendous rate. In the first case, it is being consumed for no reason other than an inappropriate gene mutation and in the second, something really toxic is happening. With this high cortisol demand, 21hydroxylase becomes overwhelmed and cortisol and aldosterone drop, decreasing the ability to respond to stress. CRH rises, turning on inflammatory pathways (MCAS, etc.), changing the immune system (immunodeficiency, dysbiosis) and sometimes, causing psychosis from brain inflammation. Additionally, there are major changes in sex hormone levels. Metabolic syndrome sets in from elevated cholesterol and dysbiosis. Malabsorption wipes out necessary vitamin stores. Without drastic changes in either the environment or the response to the environment, the fall-out from the flipped 21hydroxylase switch leads to chronic illness plus or minus mitochondrial shutdown.
As these hormonal, metabolic and inflammatory changes are additive in terms of stress load, it is probably very difficult to reset either the 21hydroxylase switch or the CDR switch once they are flipped in someone with a CYP21A2 mutation. The person succumbs to this toxic stress, in stages, first unable to procreate from the hormonal changes (high progesterone, high testosterone in women cause early menopause) and then unable to muster the energy to move due to the mitochondrial shutdown. Ironically, and perhaps by design, this hypometabolic state conserves resources and enhances survival (albeit a dwindling existence) in modern human society. However, In nature, mitochondrial shutdown for any length of time would lead to certain death by predator.
The second way for CYP21A2 mutations to cause mitochondrial shutdown is via PTSD-like brain circuits. Maladaptive, epigenetic and catecholamine-induced changes in brain circuitry in response to traumatic events is becoming better understood every day. To my knowledge, no one has brought up the potential magnifying effects that CYP21A2 mutations may exert on this process by ramping up arousal and catecholamines even during mild negative events. It stands to reason that the CAPS brain is extremely vulnerable to PTSD wiring and this is what I see clinically and in myself. This PTSD wiring increases vulnerability to other psychiatric disorders and in turn, ramps up the acute stress response even further (via new triggers, dysautonomic brainstem and limbic circuits), greatly increasing the demand for cortisol and easily flipping the 21hydroxylase switch, potentially leading to mitochondrial hypometabolism as discussed above. Additionally. CYP21A2 mutation-associated PTSD wiring, and other psychiatric stress likely also lead directly to mitochondrial shutdown. Again this mitochondrial reaction is maintained by the high stress load and again, the maladaptive gene is effectively removed from the gene pool.
This latter mechanism would explain the results of the CDC Kaiser ACE study of 17,000 patients showing that early childhood adversity is correlated in a dose response manner with significant negative health effects, including headaches, mental illness (depression, psychosis, suicide attempts) and autoimmune/inflammatory diseases, with some people more vulnerable than others. I believe that the vulnerable ones are carrying CYP21A2 mutations.
The trick to treating all of this, I believe, is to convince the body that it IS adapted to the world by treating the downstream effects (stressors) and by decreasing the mind's tendency to allow the acute stress response to run unfettered, reinforcing PTSD wiring. The former is discussed at the end of RCCX Theory, Part I and the latter is discussed at the end of the CAPS section.
For more information about CAPS, please read the CAPS section.
This latter mechanism would explain the results of the CDC Kaiser ACE study of 17,000 patients showing that early childhood adversity is correlated in a dose response manner with significant negative health effects, including headaches, mental illness (depression, psychosis, suicide attempts) and autoimmune/inflammatory diseases, with some people more vulnerable than others. I believe that the vulnerable ones are carrying CYP21A2 mutations.
The trick to treating all of this, I believe, is to convince the body that it IS adapted to the world by treating the downstream effects (stressors) and by decreasing the mind's tendency to allow the acute stress response to run unfettered, reinforcing PTSD wiring. The former is discussed at the end of RCCX Theory, Part I and the latter is discussed at the end of the CAPS section.
For more information about CAPS, please read the CAPS section.
CONTACT INFORMATION:
Sharon Meglathery MD
Email: [email protected]
FACEBOOK: Page: RCCX and Chronic Illness; Discussion Group: RCCX and Chronic Illness Discussion
Office: Sharon Meglathery MD, 1661 North Swan Road, Suite 102, Tucson, AZ 85712
Sharon Meglathery MD
Email: [email protected]
FACEBOOK: Page: RCCX and Chronic Illness; Discussion Group: RCCX and Chronic Illness Discussion
Office: Sharon Meglathery MD, 1661 North Swan Road, Suite 102, Tucson, AZ 85712