RCCX Genetic Module Theory

NOTE: This page is modified from a summary of findings available at: www.rccxandillness.com/downloads.html

Sharon Meglathery MD, a board certified psychiatrist and previously also board certified in internal medicine, with 20 years of practice experience developed chronic illness in 2009. Her illness included, but was not limited to: mast cell activation (MCAS), postural orthostatic tachycardia syndrome (POTS), chronic fatigue syndrome (CFS) and raised intracranial pressure (ICP) in the setting of Ehlers-Danlos Syndrome, Hypermobility Type (EDS-HT). ​I believe that I have discovered something incredible...

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. EDS-HT, MCAS, POTS, CFS/ME and raised ICP were just the tip of the iceberg.

First, she found a psychological profile, now dubbed CAPS (CYP21A2 Mutation Associated Neuropsychiatric 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 the results of all 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 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 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.). (The RCCX module has been noted to allow for co-inherited mutations at a very high rate.)

CYP21A2 mutations may be the genetic diathesis of the stress-diathesis model of disease for both psychiatric and medical illness. The enzyme 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 predispose to medical illnesses, such as ME/CFS, POTS, MCAS, FM, chronic Lyme disease and the final common pathway of stress-induced mitochondrial shutdown in ME/CFS due to overwhelmed 21hydroxylase 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 (21hydroxylase), mutations are associated with an exaggerated stress response in the setting of low basal cortisol, congenital adrenal hyperplasia (severe characterized mutations)

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

C4, a gene involved in the complement system and implicated in schizophrenia, CVID, MS, lupus and other autoimmune diseases.

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. I believe that 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 2 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. With prolonged stress, the body can no longer make adequate 21hydroxylase 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 (see diagram below).

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. This is a brain wired for danger. There are some benefits with a constant state of increased threat detection and enhanced stress response: enhanced empathy (ability to read emotions in others), sensory sensitivity, superior pattern recognition/information processing, times of intense hyperfocus/obsession/flow and unusual abilities (often 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 jibes with the findings of the landmark ACE study, linking childhood adverse events with adult chronic illness, medical and psychiatric. Children with CYP21A2 mutations develop CAPS, are at a very high risk for PTSD and I believe have a major predisposition for chronic medical and psychiatric illness.

In Meglathery's experience, people with classic psychiatric illnesses almost always have CAPS as a backdrop, with or without the PTSD wiring. 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 5th. , schizophrenia (shown in January 2016). The fact that in April 2015 it was shown that these major