RCCX Genetic Module Theory

NOTE: This page is modified from a summary of findings available at the RCCX and Illness website.

The RCCX Gene Module is postulated to be the origin of a wide range of over-lapping chronic medical and psychiatric illnesses and medical conditions, including myalgic encephalomyelitis (ME). This theory has been published but not peer reviewed.

Theory
Sharon Meglathery MD, a board certified psychiatrist and previously also board certified in internal medicine, with 20 years of practice experience, developed chronic illnesses in 2009. Her illnesses included, but was not limited to: mast cell activation syndrome (MCAS), Postural orthostatic tachycardia syndrome (POTS), Chronic fatigue syndrome (CFS) and raised intracranial pressure (ICP) in the setting of Ehlers-Danlos syndrome, Hypermobility Type (hEDS or EDS-HT).

Meglathery was motivated to figure out the basis for all these co-occurring conditions. She carefully examined her patients, herself, the literature and people on the various chronic illness forums to see what characteristics people with these illnesses have in common. She stated that she had found a psychological profile, now dubbed CAPS (CYP21A2 mutation associated Psychiatric spectrum) which could predict the development of chronic illness. From there, she was able to assess many of the characteristics of this population and their families. Then, she learned of the unique properties of the RCCX Module and how its genes could explain all of her observations, as well as results of the research since then.

Meglathery says the RCCX Theory explains the co-inheritance of a wide range of overlapping chronic medical conditions in individuals and families (EDS/hypermobility, autoimmune disease, 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 (FM), toxic mold, Epstein-Barr virus infection, mast cell activation syndrome (MCAS, POTS, etc.) and why many are associated with varying degrees of hypermobility, with the degree of hypermobility unrelated to the degree of physical or psychiatric illness. Meglathery further postulates that CYP21A2 mutations are the genetic diathesis (predisposition to abnormal/diseased medical conditions) which predisposes to all of the psychiatric conditions in the vast majority of affected people.

RCCX Theory
Co-inheritance of the highly mutable genes of the RCCX module (CYP21A2, TNXB, C4) may confer vulnerability to familial clusters of overlapping syndromes of chronic illness (hypermobility, autoimmune disease, CFS/ME, MCAS, POTS, psychiatric illness, etc.). CYP21A2 mutations may be the genetic diathesis of the stress-diathesis model of disease for both psychiatric and medical illness. This pathway predisposes to chronic psychiatric illness via: Low basal and spiking cortisol in utero and in infancy leading to CAPS (CYP21A2 Mutation Associated Neuropsychiatric Spectrum), putting the person at risk for developing severe PTSD brain circuitry (dissociative circuits) and all forms of psychiatric illness due to exaggerated stress response, low basal arousal and resultant harm-avoidance and threat circuits (except schizophrenia which can be co-inherited via C4 mutation). CYP21A2 mutations also predispose to medical illnesses, such as ME/CFS, POTS, MCAS, FM, chronic Lyme disease and are the final common pathway of stress-induced mitochondrial shutdown in ME/CFS due to overwhelmed 21-hydroxylase triggering inflammatory cascades. Additionally, the genes of the RCCX Module have been found to co-segregate, creating overlapping "rare" genetic syndromes within families and individuals.

The RCCX module genes include:
 * CYP21A2 which codes for a crucial enzyme involved in the acute stress response (21-hydroxylase), mutations are associated with an exaggerated stress response in the setting of low basal cortisol and congenital adrenal hyperplasia


 * TNXB which codes for tenascin X, an important matrix protein implicated in hypermobility, and


 * C4, a gene involved in the complement system and implicated in schizophrenia, CVID (common variable immune deficiency), MS, lupus and other autoimmune diseases.

Conditions associated with RCCX gene mutations
Meglathery states that the following are associated with RCCX gene mutations
 * 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 Syndrome; Malabsorption Syndromes
 * 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, e.g., enlarged amygdalae, small anterior cingulate, Chiari malformation, hydrocephalus
 * Mitochondrial Disorders
 * Immune Dysregulation: Combined Variable Immunodeficiency Disease (CVID); IgA deficiency; chronic fungal infections; recurrent herpes simplex virus (HSV) infections; no colds for years; severe bacterial infections; inability to clear chronic bacterial and viral infections (strep/Epstein Barr/mycoplasma/chlamydia/candida), dysbiosis; small intestine bacterial overgrowth (SIBO); classic and non classic autoimmune disorders, e.g., multiple sclerosis (MS); mixed connective tissue disorders; eosinophilic disorders; high TGF beta; inflammatory conditions (endometriosis); Chronic Inflammatory Response Syndrome (CIRS)
 * Psychiatric Issues: Dysautonomia (Generalized Anxiety Disorder, ADD, Hyperfocus); Autistic spectrum; Sensory Processing Disorders; Psychosis; Schizophrenia; Chronic Stress; PTSD;]] Mood Disorders; Chronic [[Insomnia; Obsessive Compulsive Disorder; Phobias; Paranoid Disorders; Emotional Dysregulation;
 * Hormonal Disorders: 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 Disease, Cortisol dysregulation, Low Aldosterone); Pituitary Hormone Abnormalities (ACTH, TRH-Mediated Thyroid Disorders); Autoimmune Hormonal Issues (Hashimotos's Thyroiditis)
 * GU/Renal Issues: Fibromuscular Dysplasia; Diabetes Insipidus; Interstitial Cystitis; Vesicoureteral Reflux (urine backing up into kidneys)
 * Miscellaneous Issues: Extreme Temperature Dysregulation (with/without Dysautonomia), multiple chemical sensitivity, High Adrenaline/Noradrenaline (norepinephrine) States; Erythromelalgia; Raynaud's Phenomena; Livedo Reticularis; Poor Connective Tissue integrity (dislocations, bruising, bleeding, petechaie, calcific aortic valves, Mitral Valve Prolapse); Dry eyes; Tinnitis; Subcutaneous Adipose Disorders (Lipidema, Dercum's Disease), Left Handedness, Gender Fluidity (LGTBQ); lack of traditional gender roles
 * Possible other inclusions: Medullary Sponge Kidney; Pyroluria; disorders of copper and zinc regulation​; early onset Parkinson's disease; Ion-Associated Illnesses

Stress vulnerability
Meglathery believes these genes, particularly C4 and CYP21A2, sit in the most highly mutagenic part of the genome because mutations of these genes provide novel ways of responding to ever-changing environments in terms of response to pathogens/brain wiring for C4 and stress response/brain wiring for CYP21A2. She posits that only one copy of a CYP21A2 mutation is necessary to create a stress vulnerability in its recipient. This vulnerability can have catastrophic consequences in settings of severe acute or chronic/prolonged stress, resulting in medical and/or psychiatric illness. she believes this is an evolutionarily programmed response to very high stress, resulting in decreased procreation and ultimately, the removal of the mutation from the gene pool.

There are two reasons for this stress vulnerability, according to Meglathery. There is CYP21A2-induced low basal and spiking cortisol in utero and infancy, leading to a brain "wired for danger" which then develops full PTSD-like wiring as stress continues. Under prolonged stress, the body can no longer make adequate 21-hydroxylase which then initiates inflammatory cascades/mast cell activation with or without the addition of the C4 mutation (which adds autoimmune disease and increases the severity of the inflammatory response).

Therefore, a child carrying a CYP21A2 mutation has the same brain as a child raised in adverse circumstances, with enlarged limbic structures (amygdala), wired-in dysautonomia and primed connections in the limbic and neuroendocrine systems. However, there are some benefits with a constant state of increased threat detection and enhanced stress response, such as: enhanced empathy, sensory sensitivity, superior pattern recognition/information processing, times of intense hyperfocus/obsession/flow and unusual abilities (in music, arts or abstract thinking).

With any stress (even minimal trauma), the threat response circuits are reinforced and epigenetic changes can further strengthen these connections, creating PTSD-like wiring and reactions. 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), all of which Meglathery observed clinically. This corresponds with findings of the landmark Adverse Childhood Experiences study, linking childhood adverse events with adult chronic illness, medical and psychiatric.

CAPS as a marker of illness
In Meglathery's experience, people with classic psychiatric illnesses almost always have CAPS as a backdrop, with or without the PTSD wiring. She found that CAPS 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, leading her to believe that it is a reliable marker for vulnerability to chronic illness. She believes that CYP21A2 mutations are the genetic basis for the development of four of the five major psychiatric illnesses (anxiety disorders, mood disorders, ADD, autism). Schizophrenia, with its basis in C4 (situated next to CYP21A2), is responsible for the fifth. These psychiatric illnesses share similar genetic underpinnings, which Meglathery says supports the RCCX Theory.

Her theory also shows congruence with that of Naviaux in which he postulates a hibernation-like state in long-standing CFS. Meglathery believes the effect of 21-hydroxylase overwhelm, PTSD brain wiring, downstream effects from TNXB mutations, and C4 mutations trigger and maintain an adaptive shutdown response of the mitochondria. This stress-induced mitochondrial dysregulation has 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.

While some mutations affecting these genes have been characterized (some TNXB and CYP21A2 mutations), evidence suggests there are many more uncharacterized genes. Many involve lengthy insertions and are therefore very difficult to study. These genes would have highly variable clinical effects, depending on the nature of the mutation. ​CYP21A2 mutations are in upwards of 20% of the population and C4 mutations are also extremely common, according to Meglathery.

Silent epidemic
Over time, it became clear to Meglathery that there is an epidemic involving a large number of syndromes/symptoms/diseases with overlapping symptoms affecting mainly young, vibrant, talented people (predominantly women). She found that many of these people manifesting different signs and symptoms, but not all, have joint hypermobility (double jointedness, ligament laxity). Clusters of the above chronic illness conditions are found in many families and individuals. For example, a family member, often female, who is hypermobile, very fatigued and suffers from severe allergy symptoms and orthostatic intolerance (EDS-HT, MCAS, POTS, CFS) has children who may be diagnosed with attention deficit disorder (ADD), sensory processing issues and/or autistic features. In the extended family there often is at least one of the following: autoimmune disease; cutting (self-injury) and eating disorders (anorexia, bulemia); mood disorders; gender fluidity; a highly successful and innovative genius; someone with CFS or FM; someone with severe PTSD and/or someone else with bouts of psychosis. Many family members will react strongly to stress. The degree of hypermobility 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 in some, mostly women.

​To date, no gene has been found to explain the prevalence of EDS-hypermobility type, in the general population. Nor why these individuals become so ill with such a wide range of not easily explainable symptoms, including: psychiatric issues; white matter lesions; hormone disruptions; autoimmune diseases; and MCAS, and why some individuals with hypermobile relatives develop these same conditions without hypermobility. As discussed above, TNXB mutations are common with CYP21A2 (hormones, inflammation, psychiatric issues) and C4 (autoimmune) gene clusters. TNXB mutations are associated with most cases of calcified aortic valves and vesicoureteral reflux (urine backing up into kidneys) but not always associated with enough hypermobility to meet criteria for EDS.

Criticism
There are many people who believe that these chronic illness conditions are completely separate in pathophysiology, i.e., all symptoms associated with EDS are solely caused by a genetic defect of collagen, all of the symptoms of Lyme disease are caused by Borrelia burgdorferi, all symptoms of CIRS are caused by the inciting agent, etc. However, it is becoming more clear that these conditions all go down a common pathway. Further, it is also becoming increasingly clear that the above RCCX co-morbidities run with these conditions in individuals and within families.

RCCX Theory unites all of these findings

 * White matter lesions
 * Erythromelalgia / small fiber polyneuropathy
 * Autonomic nervous system dysfunction / Postural orthostatic tachycardia syndrome (POTS) / Orthostatic intolerance (OI)
 * Mast cell activation syndrome (MCAS)
 * Neuropathic pain syndromes
 * Autism
 * Enlarged Amygdala
 * Raised intracranial pressure / Chiari malformations
 * Dysbiosis
 * Salt and water loss
 * Low baseline cortisol
 * Association with autoimmune diseases
 * High adrenaline / exaggerated acute stress response

Common mechanism
According to Meglathery, the most compelling piece of evidence that all of these conditions have a common mechanism is the psychological profile 'CAPS' which is universally present and allows prediction of who is at risk for developing chronic illness. CAPS is very often associated with hypermobility, but not always. It is very clear that CYP21A2 mutations are responsible for both CAPS and chronic illness (medical and psychiatric), whether or not they have the often accompanying TNXB mutation (which brings with it complications of musculoskeletal/structural issues and TGF beta).

Interestingly, a very large study involving the Swedish registry (1,780 with EDS, 1,722 siblings of EDS patients, 10,019 with hypermobility syndrome and 11,082 hypermobility siblings) showed a substantially higher risk for autism spectrum, bipolar disorder, ADHD and depression in EDS patients, hypermobility syndrome patients and their non-affected siblings. This study confirms Meglathery's observation that psychological issues in hypermobile people are rampant, and not dependent on the presence or degree of individual hypermobility, but rather the presence of hypermobility within the family. A seven year study demonstrated that therapy was very helpful in decreasing issues with schizophrenia. Meglathery believes therapy decreased the patients' acute stress response, which decreased the stress burden and subsequently decreased the aberrations which happen when 21-hydroxylase is overwhelmed in someone carrying a CYP21A2 mutation. Characterizing RCCX variances may be the direct way to provide genetic tests for who is at risk for chronic illness. Effective prevention and treatments would follow naturally from this.

These conditions can occur due to other genes, but they occur without these clusters. For example, MCAS has many triggers and POTS often is associated with the vasodilating effects of excessive liberation of histamine. Also, it is important to remember that there are quite a few downstream issues which affect all of these conditions and muddy the waters. For example, most people with the RCCX gene module have raised intracranial pressure which affects pituitary hormones, making hormonal issues appear to be secondary rather than primary. Also, because of C4, and possibly other causes of autoimmune issues, there are also autoimmune hormone disorders.

Treatment
Treating MCAS, correcting MTHFR enzyme deficiencies, using Low-Dose Naltrexone (LDN), maintaining adequate hydration/salt repletion, correcting dysbiosis, incorporating anti-inflammatories, supporting mitochondria, using immune system enhancers, practicing mindfulness/grounding/brain retraining and stress reduction are overlapping treatments which seem to help.

Research help is needed
There are many variances in this RCCX region which have not been characterized or even identified. This part of the genome needs to be explored and variances linked with the clinical picture (CAPS or chronic illness-medical or psychiatric). After developing and refining her hypothesis Meglathery set up a [www.rccxandillness.com|website] in February 2016 to expose her theory and generate interest in research. Within eight hours of release an endocrinologist, [Karen Herbst] MD PhD, an international expert in subcutaneous fat disorders, contacted Meglathery. Herbst is also convinced that the RCCX module is involved in these conditions, given the high rate of hypermobility, chronic fatigue and psychiatric illness in this population.

The team is moving forward. Herbst is devising ways to demonstrate the clinical correlates of CYP21A2 mutations and Meglathery is creating a uniform way to detect and diagnose CAPS. "We need a very sophisticated genetics team to correlate our findings with RCCX mutations.  If you are interested, please do not hesitate to contact us" - Meglathery.

Online presence

 * Website
 * Facebook
 * Email: info@rccxandillness.com

Learn more

 * RCCX Theory - Pathophysiology Diagrams
 * The no longer current journal article introducing the early version of the RCCX theory