The RCCX hypothesis blog by Remy is the third in a series of blogs by Health Rising which highlight hypotheses produced by health care professionals which attempt to shed a new light on the chronic fatigue syndrome / fibromyalgia spectrum of diseases.

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Chronic illness is exploding in modern times. Many different causes and treatments have been proposed for these illnesses, but what if there were a common genetic thread linking them all together?

According to Sharon Meglathery, MD, who suffers from this disease constellation herself, that common genetic thread just might be found on the gene complex called RCCX. Combining her own personal experience and family history with her clinical experience working with patients, the RCCX theory of chronic illness was born.

What is RCCX?

RCCX is not your typical genetic “SNP”. In fact, this complex is completely ignored in the standard genetic testing done by companies like 23andme, which helps explain why these common gene mutations (up to 20% of the population) have escaped detection up until now.

RCCX is, instead, a complex of four different genes, located on the Major Histocompatibility Complex (MHC) region of chromosome 6. Variations in the RCCX complex may contribute to disease susceptibility.

The genes comprising the RCCX cluster code for enzymes and proteins which substantially influence responses to stressors and cell danger signaling. They also affect innate immune responses as well as synaptic and dendritic pruning in the brain, sex hormone levels, fluid and salt balance, and the integrity of the extracellular matrix (ECM).

The genes that make up the RCCX cluster are as follows:

R = RP1 (also known as STK19)

C = C4 (complement 4)

C= CYP21A2 (steroid 21-hydroxylase)

X = TNXB (tenascin-X)

Essentially, these genes make multiple copies of themselves, which are called copy number variations. They often behave as one unit with the genes deleted and duplicated together, instead of as four separate units. RCCX is the only place in the human genome where genes travel together in this way. Because of this, people can inherit two (or more) rare diseases simultaneously at a much higher rate than would be expected by chance.

The RCCX genes are very unstable and can mix and match, mutating often for evolutionary reasons. This mixing and matching creates family histories filled with the chronic illnesses that are associated with these genes. It is not at all unusual for a patient to have a sibling with one manifestation, a parent with another, and for their children to be affected as well. In fact, this family history pattern may be the biggest clue to detecting RCCX currently available.

These related disorders are wide ranging and variable and likely include the most common comorbidities with ME/CFS, including EDS, POTS, MCAS, fibromyalgia, limbic/sensory sensitivity, immunodeficiency, autoimmunity and autism.

The RCCX complex is theorized to confer an inherited susceptibility to ME/CFS due to the presence of homo- or heterozygous CYP21A2 mutations, with or without co-inheritance of a TNXB mutation, and also with or without a C4 mutation. These mutations may be mild or severe, creating the varying presentations and levels of illness seen clinically.

CYP21A2 Mutations

CYP21A2 mutations can explain many aspects of ME/CFS. It is not uncommon for this illness to begin with an acute stress, such as an infection, and then progress to changes in the endocrine, immunological and autonomic nervous systems.

Stress causes the 21-hydroxylase enzyme, coded for by CYP21A2, to become “overwhelmed”. This would explain why there may be many different triggers for ME/CFS, rather than one specific trigger that is the same for everyone affected. Milder mutations may create a sort of stress “switch” whereupon the symptoms are not experienced until a certain threshold is reached.

It is known that carriers of CYP21A2 mutations prior to this overwhelm have an exaggerated stress response and low basal cortisol levels, and this likely creates PTSD wiring in the brain, with dysautonomia and elevated danger responses over time.

This theory also neatly ties in with Dr. Robert Naviaux’s work on the Cell Danger Response in chronic illness, as the mitochondria become stressed and enter into a dauer state.

Under conditions of prolonged stress, those with CYP21A2 mutations who make defective 21-hydroxylase must now make more than double the amount of a normal person in order to try to cope with the stress. This creates a vicious cycle of high cortisol levels during stress along with lower and lower basal cortisol until the 21-hydroxylase enzyme becomes overwhelmed and cortisol and aldosterone levels plummet. In response to the low basal cortisol, Cortisol Releasing Hormone (CRH) is increased, with all the associated negative symptoms of MCAS intolerance and sensitivities.

In addition, progesterone levels can, in time, go from being very low due to the exaggerated stress response to very high during enzyme overwhelm, and along with this, bioactive copper can possibly be depleted. With copper depletion, B vitamins may not methylate properly.

Inflammation and MCAS symptoms from CRH excess and immune dysregulation can cause brain fog and other symptoms, ultimately rendering the affected person increasingly intolerant of stress of any sort. Meglathery believes that much, but not all, of the dysautonomia experienced in ME/CFS and related conditions stems from the aberrant danger response caused by CYP21A2 mutations.

Essentially, Meglathery posits that CYP21A2 mutations can produce a brain that is wired to detect and respond to danger as a result of hormonal influences going all the way back to the womb. Over time, she believes that this “stress wiring” becomes more prominent. The popularity of brain retraining programs, like Gupta or DNRS that help to overcome a particularly large and reactive amygdala state, suggest that many ME/CFS patients have found this to be the case.

In addition, Ron Davis recently presented the hypothesis that people with ME/CFS symptoms are driven to try to “push through” stress, thus keeping the alarm system turned on. Both of these statements can potentially be explained by the CYP21A2 mutations and the RCCX complex associated personality profile.

However, nothing about the RCCX theory suggests a psychological illness as the cause of disease or CBT as a primary treatment. Stress can come from a wide variety of sources, be it physical, emotional or infectious.

TNXB Mutations

The TNXB gene codes for tenascin X, which is involved in the arrangement of collagen in the extracellular matrix. Mutations can lead to abnormal amounts of TGF-beta as well as signaling problems. TGF-beta abnormalities have been found to be associated with endometriosis and other inflammatory sclerotic conditions as well.

Joint hypermobility is associated with TNXB mutations, which sometimes may be severe enough to meet the criteria for Ehlers-Danlos Syndrome.

TNXB mutations can also profoundly affect the function of the Extracellular Matrix (ECM).

C4 Mutations

Mutations in C4, the second “C” in RCCX, also contribute to either autoimmunity or immune deficient states. Complement C4 mutations are the most common causes of immune deficiency. CYP21A2 mutations plus or minus C4 mutations may also serve to explain the “subsets” found by Peterson in his recent research.

C4 also has another interesting wrinkle; it carries an endogenous human retrovirus, HERV-K. The impact of these retroviruses is unclear. Some believe that they are protective, but others believe they are pathogenic and linked to many diseases, like ALS. Either way, the presence of the HERV-K retrovirus should be investigated further.

Testing

Genetic testing with SNP targeting will find only a few of the most common and severe mutations and will miss the rest of those affected by milder mutations. It’s not possible to look up RCCX on 23andme.

The RCCX gene module is easily sequenced, however. The problem lies in distinguishing the pseudogenes from the expressing genes. A highly sophisticated genetics lab will certainly someday be able to characterize these mutations and develop testing that can be used outside the research setting, but so far it is not available.

Presently, clinicians can use a questionnaire, including a detailed extended family history looking for RCCX comorbidities, when seeing new patients. This may be especially useful for patients with hypermobile joints (though patients not being hypermobile does not necessarily rule out RCCX) to identify if the patient seems to fit the profile of a mutated RCCX cluster. Dr. Meglathery always does a physical examination, including a Beighton scale, on all new patients suspected of fitting the RCCX profile.

Dr. Meglathery feels that CRH and its receptors may hold the key to better managing this cluster of disorders. CRH turns on inflammatory pathways as well as mast cells and alters brain development in utero. It essentially turns stress into physical illness. Blocking these receptors or CRH release might prove to have beneficial effects on our population, which is also the hypothesis behind the recent study involving Cortene, a CRF2 agonist.

Measuring cortisol and other steroid hormones directly, unfortunately, is unlikely to be helpful in identifying problems with the RCCX complex. Changes in hormone levels are characterized by rapid and dramatic shifts that are unlikely to be caught at a single moment in time at testing.

Potential Treatment Avenues

At this time, treatment is very much focused on managing symptoms, just like those of us with ME/CFS already do. Since everyone will have different manifestations, the effective treatment will always be unique as well, but typically with some common ground.

Meglathery has found berberine helpful in her practice to decrease the high progesterone caused by the overwhelm at 21-hydroxylase, by shuttling progesterone to androgens and estrogens instead.

Antihistamines can help to treat the symptoms of excessive CRH release as well as other common MCAS medications like mast cell stabilizers. Treating MCAS, if it is present, is very important to lower the overall stress load on the body and stop the acute stress response which pushes 21-hydroxylase into overwhelm.

Hydrocortisone may be an option for treating low basal cortisol, with the caveat that it can exacerbate high cortisol states, lead to adrenal suppression and cause further hormonal derangement.

Polysaccharides like mannose or chitin or monosaccharides like n-acetylglucosamine may be helpful for proper function of the ECM. Treatment modalities such as acupuncture may also affect the ECM in beneficial ways.

For chronic immune deficiencies, IVIG may be useful (though difficult at this time to get approved by insurance). LDN may help as well.

Bio-available forms of copper may also be useful in the case of copper depletion. Meglathery has noted that some people with the presumed RCCX presentation in her practice do respond to bioactive forms of copper, like MitoSynergy, with increased energy, while others do not.

Stress management techniques, such as mindfulness or meditation, as well as trauma-releasing protocols like EMDR may also have value.

Potential Paradigm Shifting Theory

The RCCX complex theory demonstrates a complete paradigm shift in chronic illness that is very exciting. The RCCX complex is a way for researchers to explain the many various ways that chronic illness can present, and then ties them all together under one overarching genetic propensity umbrella.

Dr. Meglathery first published her theory on her website in the spring of 2016. She was the first to talk about how meeting a biological stress threshold could send people into disease, rather than any one particular specific trigger. She also was the first to conceive of the idea of a specific associated personality profile, though recently both Naviaux and Davis have also discussed this idea in their talks.

The RCCX theory is also the only umbrella that explains the high rate of autoimmune/immune deficiency diseases and hypermobility within ME/CFS individuals and their families.

The OMF is currently doing a genetics/metabolomics study in collaboration with Naviaux exploring the novel hypothesis that Janet Dafoe has termed “haplogenetics”. In this study, they are exploring the idea that illness occurs in a situation called heterozygosity, which occurs when one copy of a gene (we carry two copies, one from each parent) doesn’t work properly, resulting in altered gene expression. But what if it isn’t just one gene, but the combination of all the genes in the RCCX cluster? Could this be the missing link we are looking for?

Recently, scientific studies have only served to add more weight to the possibility that the mutations in RCCX are, in fact, the common genetic thread linking us all in chronic disease. But, of course, only time, more research and adequate funding will tell the tale for sure.

For further information on this topic, please visit the RCCX website. You can also join the RCCX and Chronic Illness discussion group on Facebook created by Dr. Meglathery.