Gene Mutation Can Cause Permanent Brain Damage After Concussion Parents should determine whether their child has this mutation before starting contact sports

by | C3 mutation, Concussion/TBI

Key Takeaways

  • A somewhat rare mutation in an inflammatory gene, C3, can cause severe post-concussion syndrome & more
  • The mutation known as rs147859257 can lead to uncontrolled inflammation, defective killing of bacteria, & more
  • Both AncestryDNA & 23andMe query this mutation—the information can be found in your raw data
  • If you have this mutation and injure your brain, you must stop the inflammation to prevent permanent damage
  • If you have this mutation, avoid high-contact sports or activities that increase your risk of a head injury

    • My primary motivation for creating this blog is to educate people so they will find out whether they or their children have this mutation, which can be easily determined with AncestryDNA or the new 23andMe kit. But first, I’ll tell you about the gene, how I discovered I had this mutation, and its impact on my life.

    Mutation in Complement Component 3 (C3) Is Discovered

    The mutated gene is an immune gene called Complement Component 3 (C3 for short), and my particular autosomal dominant mutation (rs147859257, K155Q) occurs in about 1/180 people (~1.7 million people in the U.S. or ~40 million in the world) but is most prevalent in those with northern European ancestry and almost nonexistent in Asians.1,2,3 I learned I had this mutation when my genome was sequenced by Illumina as an adjunct to a Future of Genomic Medicine conference. Of the 20,000+ protein-coding genes in the genome, Illumina analyzed large chunks of 1690 genes causally related to disease, including C3 since it is definitively linked to Age-related Macular Degeneration (AMD) and other disorders.1,2

    There are three molecular consequences of my particular mutation:

    1. The C3 protein, which amplifies the inflammatory cascade, cannot be inactivated normally, which leads to out-of-control or exacerbated inflammatory responses.
    2. C3 is also important in killing certain types of pathogens (encapsulated bacteria, TB, yeast) through a process called opsonization, which is defective with this mutation, and
    3. Having extra activated C3 leads to an excess of its unmutated subcomponent C3a, which likely sits on mast cells at a higher level than normal and primes them for too-easy activation and release of histamine and other inflammatory mediators.

    How did I Connect this C3 Mutation to Brain Damage after Concussion?

    Ironically, at this genomics conference in March 2016, I was stricken with food-poisoning and upon rushing to my bathroom to throw up, I fainted and fell backward, hitting the back of my head against a hard concrete floor. I came to shortly thereafter choking on vomit and with a 10+ cm goose egg on my right occiput. My sister checked that my pupils were constricting normally, so I chose NOT to go to the ER (in my miserable state with food poisoning spewing from both ends, getting into a car would have been a nightmare). By the morning, the food poisoning had subsided. I was weak, and my head was tender and sore, but I felt I was on the mend. However, about seven days later, my life changed for the worse when I almost passed out while driving (likely a seizure aura though I never actually had a seizure), and then I started having issues with lights, noise, thinking clearly, sleeping, visual problems, dizziness, and super low blood pressure. I messaged my PCP, who grounded me from driving until a neurologist, cardiologist and endocrinologist cleared me. Little did I suspect at the time, but these “Post-Concussion Syndrome” (PCS) symptoms would continue to worsen for months due to out-of-control inflammation in my brain and would ultimately leave me with some permanent deficits. For someone whose self-worth was largely defined by her intellect, this outcome was devastating.

    Except for one doctor, the rest were either no help or made my situation worse. I was told that I would be better in a month and to just rest (in their defense, that’s what I was taught in medical school too — basically two statements — that PCS happens in some patients and that it goes away in a month with rest, though I’d have expected the neurologist to be a little more helpful). When that month passed and my symptoms kept worsening, I had to find my own solutions. Over the next several months, I tried hyperbaric oxygen therapy, transcranial magnetic stimulation, ketones, tons of supplements (following Dr. Dale Bredesen’s protocol for ameliorating cognitive decline; trying high dose omega-3s; plus many other ideas), neurofeedback, meditation, yoga and more.4 There are a few therapies with possible benefits I haven’t yet tried, but I explored most and spent many thousands of dollars in the process. Some were likely helpful. Some may have been harmful, but most didn’t seem to affect me one way or another. As I “rested” and read up on my newly uncovered C3 mutation, I began to put the pieces together that this mutation was likely involved in my worsening health and cognitive decline.

    Why do I Think this C3 Mutation Caused the Out-of-Control Inflammation and Severe PCS?

    Studies in mice have shown that C3 is implicated in causing brain damage after stroke and traumatic brain injury (TBI) (a concussion is a mild TBI or mTBI) because the inflammation that follows these events can cause a large amount of tissue destruction. If you block the inflammation, for which C3 is key, you can prevent subsequent damage. When mice were engineered to lack C3 altogether, mice that experienced “strokes” showed 34% less brain damage,5,6,7,8 and mice that had TBIs also demonstrated significantly less brain cell death and dysfunction.9,10,11,12 It makes sense that having an overactive version of this gene would cause even more inflammatory damage in the brain. Also, in another brain disease, West Nile Virus encephalitis, C3 is believed to be the cause of synapse loss and memory deficits.13 Furthermore, in addition to being a main contributor to the inflammatory process, C3 is the major protein in the brain responsible for pruning synapses in development, meaning another of its major functions is actually to cut connections in the brain.14,15

    With an out-of-control, mutated C3, my brain was overcome with inflammation, which didn’t start to settle down until five months later. It took months longer for my cognition, blood pressure, vision and other issues to stabilize though not necessarily return to normal. In future posts, I’ll describe in detail my symptoms, everything I tried and the probable results of my N=1 experiment. I’ll also describe many other conditions that we’ve realized are connected to this mutation by studying my family’s genetics and medical histories. See how to test for this mutation here.

    My Child Has This Mutation — What Should I Do?

    First of all, do not panic. Though this is not a great mutation to have, I think some of its effects can be minimized with lifestyle choices and proactive behavior. My purpose is to empower you and not to scare you. Many treatments are on the horizon, and there may be current medications that can decrease the long-term consequences. That said, you may want to seriously reconsider whether you allow your child to play sports that are more likely to result in a head injury. I believe that having this mutation and experiencing a concussion or multiple subconcussive events may make Chronic Traumatic Encephalopathy (CTE), dementia and Parkinson’s more likely. Though my ApoE genetics do not put me at increased risk of Alzheimer’s, having this C3 mutation and now a history of a significant concussion with prolonged PCS absolutely puts me at increased risk of dementia, Parkinson’s and ALS. Having considered this information, a family member of mine with this mutation will continue to play soccer, but at least we are aware of his genetic sensitivity and are armed with knowledge about what we can do and try if he experiences a head injury.

    Therapies on the Horizon

    It’s important for you to know that there are C3 inhibitors being developed, and several are in clinical trials though none of their original “orphan” indications is for TBI (so we might have to petition to have them used for TBI).16,17 I think these inhibitors may even become standard treatment for anyone experiencing a stroke or a TBI (if insurance will cover it), not just those with a C3 mutation. Also, a drug in development at UCSF and Calico called ISRIB (Integrated Stress Response Inhibitor) looks like it might prevent learning and memory problems secondary to TBI in mice by blocking a maladaptive cellular stress response from shutting down protein production.18,19,20 I will keep tabs on these drugs to know when they are approved by the FDA, and if you join my mailing list or follow my blog, I will communicate that to my readers. Other drugs that tamp down inflammation are being developed, and if they can cross the blood-brain barrier, they might be able to help people with this mutation as well. An option slightly further in the future may be gene therapy to fix this mutation, but though we are getting close, the current gene therapy technologies are still not ideal and have off-target effects that might hurt us more than our mutation.

    Is There Anything I can do now to Stop the Inflammation?

    Disclaimer and reminder — I am not your physician, nor am I a licensed physician in any specialty. My only intent is to educate and empower you (please read my complete disclaimer at the bottom of this webpage), but here is my personal plan of action for now:

    Since C3 inhibitors are not yet commercially available, in the event of another concussion, I think the best way to shut down the excess inflammation would be to take high-dose steroids, which can inhibit C3 but can also cause a lot of side effects. For comparison, in autoimmune encephalitis, which likely has a more severe immune response than a concussed brain with out-of-control C3, a review reports that this condition is treated with 1 gram of methylprednisolone daily for 3–5 days (though they also use many more intensive therapies at the same time like IVIG, plasmapheresis, immunotherapies, and chemotherapies).21 If I have another concussion, I plan to request that my physician prescribe steroids at this or a similar dose for at least that timeframe. It does worry me to stop after only a few days since my inflammation lasted for over eight months, but maybe it would be enough to halt the inflammation. However, looking at the research, I’m uncertain whether one should start steroids immediately or wait a day or two after the injury before starting. In smaller, controlled amounts, C3 can supposedly promote neuroregeneration, which presents us with the Goldilocks Dilemma where you don’t want too little or too much, but I would not wait longer than a few days since by day seven, my inflammation was out-of-control and damage had already taken place. I do think I had other traits that possibly made my inflammation worse than the average person (perimenopausal woman with low progesterone and sleep issues), but it seems like most PCS cases show the pattern of severe deficits starting between one and two weeks post-concussion. Since there has not been a randomized controlled trial, we are working in the realm of best-guessing and balancing of risks. I would also likely ask my doctor to prescribe mefenamic acid which is an NSAID (related to ibuprofen) but also inhibits the NLRP3 inflammasomes in Alzheimer’s disease mouse models, which might be another avenue to tamp down inflammation.22 You need to discuss these options with your physician (I’d print out the papers and bring them for supporting evidence) because you may have health conditions that would make taking any of these drugs problematic.

    So, My Simplified Current Plan to Prevent PCS:

    1. Avoid injuring my head (no skiing, snowboarding, biking, contact sports, amusement park rides; drive carefully)
    2. If injured, visit my doctor and get prescriptions to stop the inflammation — take steroids after a few days for 3-5 days + Mefenamic acid at the recommended dose for no longer than 7 days (I have no contraindications).
    3. If these drugs don’t prevent the development of neurological symptoms/PCS, consider other options I’ve already explored (a future post).

    My Future Plan:

    1. Gene therapy (when it’s safe & effective) to fix mutation and/or
    2. C3 inhibitor + ISRIB
    (I haven’t touched on the likely exorbitant cost of these drugs and gene therapy but will do so in a future post.)

     

    References:

      1. https://www.ncbi.nlm.nih.gov/pubmed/24036952
        Seddon JM, Yu Y, Miller EC, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature Genetics. 2013; 45(11):1366-1370.
      2. https://www.ncbi.nlm.nih.gov/pubmed/24036950
        Helgason H, Sulem P, Duvvari MR, et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nature Genetics. 2013; 45(11):1371-4.
      3. https://www.ncbi.nlm.nih.gov/pubmed/25629512
        Cheng C-Y, Yamashiro K, Jia Chen L, et al. New loci and coding variants confer risk for age-related macular degeneration in East Asians. Nature Communications. 2015; 6:6063.
      4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221920/
        Bredesen DE. Reversal of cognitive decline: A novel therapeutic program. Aging. 2014; 6(9):707-717.
      5. https://www.ncbi.nlm.nih.gov/pubmed/16778128
        Mocco J, Mack WJ, Ducuet AF, et al. Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ Res. 2006; 99(2):209-17.
      6. https://www.ncbi.nlm.nih.gov/pubmed/16552422
        Yang S, Nakamura T, Hua Y, et al. The role of complement C3 in intracerebral hemorrhage-induced brain injury. J Cereb Blood Flow Metab. 2006; 26:1490–5.
      7. https://www.ncbi.nlm.nih.gov/pubmed/22761695
        Ducruet AF, Zacharia BE, Sosunov SA, et al. Complement Inhibition Promotes Endogenous Neurogenesis and Sustained Anti-Inflammatory Neuroprotection following Reperfused Stroke. PLoS ONE. 2012; 7(6):e38664.
      8. https://www.ncbi.nlm.nih.gov/pubmed/29921716
        Alawieh A, Anderson M, Adkins DL, et al. Acute Complement Inhibition Potentiates Neurorehabilitation and Enhances tPA-Mediated Neuroprotection. J Neurosci. 2018; 38(29):6527-6545.
      9. https://www.ncbi.nlm.nih.gov/pubmed/29437855
        Alawieh A, Langley EF, Weber S, et al. Identifying the role of complement in triggering neuroinflammation after traumatic brain injury. J Neurosci. 2018: 2197-17.
      10. https://www.ncbi.nlm.nih.gov/pubmed/16545803
        Leinhase I, Schmidt OI, Thurman JM, et al. Pharmacological complement inhibition at the C3 convertase level promotes neuronal survival, neuroprotective intracerebral gene expression, and neurological outcome after traumatic brain injury. Exp Neurol. 2006;199(2):454-64.
      11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778697
        Hammad A, Westacott L, Zaben M. The role of the complement system in traumatic brain injury: a review. Journal of Neuroinflammation. 2018;15:24.
      12. https://www.ncbi.nlm.nih.gov/pubmed/29018286
        Peterson SL, Nguyen HX, Mendez OA, Anderson AJ. Complement Protein C3 Suppresses Axon Growth and Promotes Neuron Loss. Scientific Reports. 2017;7:12904.
      13. https://www.ncbi.nlm.nih.gov/pubmed/27337340
        Vasek MJ, Garber C, Dorsey D, et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature. 2016; 534(7608):538-543.
      14. https://www.ncbi.nlm.nih.gov/pubmed/28826529
        Presumey J, Bialas AR, Carroll MC. Complement System in Neural Synapse Elimination in Development and Disease. Adv Immunol.2017; 135: 53-79.
      15. https://www.ncbi.nlm.nih.gov/pubmed/29606485
        Coulthard LG, Hawksworth OA, Woodruff TM. Complement: The Emerging Architect of the Developing Brain. Trends in Neurosciences. 2018; 41(6): 373-84.
      16. https://www.ncbi.nlm.nih.gov/pubmed/29199277
        Ricklin D, Mastellos DC, Reis ES, and Lambris JD.The renaissance of complement therapeutics. Nat Rev Nephrol. 2018; 14(1):26-47.
      17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4987232
        Mastellos DC, Reis ES, Yancopoulou D, et al. From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage. Immunobiology. 2016; 221(10): 1046–1057.
      18. https://www.ncbi.nlm.nih.gov/pubmed/28696288
        Chou A, Krukowski K, Jopson T, et al. Inhibition of the integrated stress response reverses cognitive deficits after traumatic brain injury. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(31):E6420-E6426.
      19. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6120582/
        Tsai JC, Miller-Vedam LE, Anand AA, et al. Structure of the nucleotide exchange factor eIF2B reveals mechanism of memory-enhancing molecule. Science (New York, NY). 2018;359(6383):eaaq0939.
      20. https://www.ncbi.nlm.nih.gov/pubmed/29599245   
        Zyryanova AF, Weis F, Faille A, et al. Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor, eIF2B. Science (New York, NY). 2018;359(6383):1533-1536.
      21. https://www.ncbi.nlm.nih.gov/pubmed/29399043
        Shin Y-W, Lee S-T, Park K-I, et al. Treatment strategies for autoimmune encephalitis. Therapeutic Advances in Neurological Disorders. 2018; 11:1756285617722347.
      22. https://www.ncbi.nlm.nih.gov/pubmed/27509875
        Daniels MJD, Rivers-Auty J, Schilling T, et al. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nature Communications. 2016;7:12504.


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