It was a few months ago when I felt as though I couldn’t lift the weight of my head, and I had trouble walking because my legs felt so weak. I decided to make my way to a hospital. I waited for hours until I finally got to see a doctor. In the few seconds I saw him, he prescribed me some medications and then sent me on my way. It wasn’t until a couple weeks later that I realized I was losing my hearing. At that point I knew something was definitely wrong, so I decided to go back.
The doctors decided to dig deeper and run some more thorough tests. Based on my symptoms, they began to consider mitochondrial diseases. They performed a DNA test on my mom, my dad and I. I sat with my fist closed tightly as they located the popping vein in my arm and stuck a tiny needle in it. The purpose of this test is to determine whether or not there are any mutations present in the mitochondria’s DNA sequence. They also performed a biochemical test, which required a biopsy and they took a sample of my liver. This test let them know if my mitochondria, the most important organelle in aerobic cellular respiration, is working properly and effectively at the rate it should be. These tests assess mitochondrial function and duplication, while looking for any mutations in the sequence of my DNA.
They sent me home with no new knowledge, except for the fact that the test results may take up to 6 weeks. Thankfully, they came in two weeks early. At this point I felt weaker than ever before. My thought process had slowed, as I constantly delayed answering people when I was asked questions and I’d been vomiting almost every second day. I went back to the hospital, and they placed me in one of the beds. I looked to my right and saw a little kid getting his arm casted. He must’ve taken a hard fall during recess. After 30 minutes, the doctor finally came in and he started talking all his medical jargon which I couldn’t understand. All I want is for Dr. Hayword to speak a language I was able to comprehend.
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| Figure 1: Composition of mitochondria demonstrating the locations of the DNA present in the structure and how it is throughout the entire structure. |
“What we believe you have falls under the category of disorders where there is a drop in mitochondrial DNA which has a great effect on many tissues throughout the body. This DNA, which is present throughout the entire mitochondria, is important in maintaining its structure, since it is where cellular respiration and energy production takes place in every human cell. (refer to figure 1) When there is a mutation in the DNA sequence, it isn’t harmful at first, but over time, the DNA duplicates and the mutations will accumulate, causing your symptoms.” explained Dr. Hayword. He continued with his medical talk while I sat in bed with a confused look on my face. “This disease causes mutation in the TK2 gene which causes TK2-MDS. TK2 Mitochondrial DNA Depletion Syndrome. This gene is responsible for providing instruction for the production of thymidine kinase 2, an enzyme whose task is to produce and maintain mitochondrial DNA. It allows the recycling of nucleotides, the building blocks of DNA, which can fix errors in the DNA sequence. When there are mutations in the TK2 gene, it reduces thymidine kinase 2 activity, which means there are less nucleotides to repair DNA.” I was still sitting there trying to understand how this could happen to me. Of all people, why me?
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| Figure 2: Demonstrates the way mutations pass on to the next generation. In this case, the picture to the very right is representative of this situation because the child received both recessive genes. |
“The reason I ordered tests for mom and dad as well is because this is an autosomal recessive pattern of inheritance. This means the mitochondrial disease is a result of both parents having the specific mutated gene and both of these genes being passed on to the child. (refer to figure 2) Looking at the test results, both of you have the mutated gene. There was a 25% chance of your child receiving both recessive genes, and looking at her tests, both were inherited. This is a very rare disease as only 16 people in the world have had it. It is normally more fatal in babies and children, but you’ve managed to go through most of your teenage years with it, which is a good sign.”
All that was going through my head was “please let there be a cure… please let there be a cure”. To my luck, there is no cure, but there are treatments. I asked Dr. Hayword what he believes is the best approach and he suggested Nucleoside bypass therapy. The goal of this treatment is to restore the nucleosides until there are enough again. This is an oral treatment, taken in the form of a pill. These nucleosides would allow for the repair of mutations in DNA sequences. The only downfall is that this treatment was only available in the United States which means OHIP doesn’t cover the costs and my parents had to spend about $23 400 in one year for my treatment. Although it may have been expensive, it was all worth it in the end.
Here I am, at the age of 17, still alive and I feel stronger and stronger each day. I’ve still got a while to go in the hospital but it’s alright because I’ve already become friends with my roommate and every now and then in the hospital, the nurses and I have a few wheelchair races down the halls. Today, with the help of CHEO staff, we were able to have a bake sale in the main lobby and we raised approximately $500 which will be sent to the University of Calgary, as they have the infrastructure to investigate the role of mitochondrial DNA and dynamics in disease. Although $500 doesn’t compare to the $250 000, they received from the Canadian government, I hope to one day be able to say, I helped find the answer to curing Mitochondrial DNA Depletion.
Hey Dalia!
ReplyDeleteReally interesting story you wrote! Upon further research, I learned that some other symptoms may occur, such as; hepatomegaly, seizures and sensorineural hearing loss. I was curious as to how exactly does the depletion of mtDNA directly cause these symptoms. As you mentioned, the TK2 gene helps maintain mtDNA. More importantly, it helps ensure that the mitochondria works properly. The role of the mitochondria is to produce energy through the process of oxidative phosphorylation (Rogers, 2016). If the TK2 gene cannot maintain the mtDNA, then the mitochondria will produce less energy. As a result, the movement muscles in your body; like your legs, neck and arms; won’t receive the energy necessary and will result in your body feeling weak overall. I was also curious as to why the disease is especially fatal in infancy as opposed to adulthood. During childhood, their brains are still developing and sensitive to experiences. For symptoms like seizures or drooping eyelids, if they suffer these from a young age they are susceptible to permanent brain damage and visual cortex damage, making it especially deadly for children (“Mitochondrial Myopathy”, n.d.). Adults on the other hand have fully developed brain, and although they can still suffer from damage, it isn’t permanent unless it is a severe reaction/symptom.
Works Cited
Rogers, K. (2016, May 13). Mitochondrion. Retrieved November 11, 2017, from
https://www.britannica.com/science/mitochondrion
Mitochondrial Myopathy Fact Sheet. (n.d.). Retrieved November 11, 2017, from
https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Mitocho
ndrial-Myopathy-Fact-Sheet
Hey Dalia, awesome blog! I really liked the way you twisted it into a story. It made it very unique, personalized, and interesting to read. Furthermore, it made me empathize more with the narrator when they said that there was no cure. You mentioned that nucleoside bypass therapy was however an option for treatment. This peaked my interest, so I decided to research this form of treatment further. I found that nucleoside bypass therapy is quite a controversial topic, especially in the case of an infant named Charlie Gard (Wheatstone, 2017). Mitochondria often need to split and duplicate in order to create an efficient amount of energy for the human body. In order to duplicate the mitochondria, however, the DNA found in mitochondria must be duplicated as well. This becomes a big problem when damaged DNA is being duplicated constantly. In Charlie’s case, the rare disease affected his body’s RRM2B gene; the gene responsible with producing nucleotides (the A,T, C & G base pairs contained in the double helix structure of DNA). This means that he is unable to make the nucleotides that his body needs to function properly. Developed by Dr. Michio Hirano, the nucleoside bypass therapy treatment basically means providing the body with the compounds it is lacking to produce nucleotides called nucleosides. These nucleoside supplements are ingested orally and are transformed into nucleotides when they get to the mitochondria. (Kegel, 2017) Nucleoside bypass therapy has only ever been tested in a clinical trial on 18 children with a different type of mitochondrial depletion syndrome; one that affects the TK2 gene instead of the RRM2B gene (Begley, 2017). While this form of treatment has shown success thus far, there has been no research or evidence that ensures that nucleoside bypass therapy would work in Charlie’s case. His form of mitochondrial depletion syndrome is so rare that no clinical trials have taken place in North America (not even on mice) for it. Many believe that it would be a bad idea to perform nucleoside bypass therapy on Charlie as it has not yet been tested on his specific type of mitochondrial depletion syndrome. Hirano believes that it may work based only off of the fact that patients with the type of mitochondrial depletion syndrome that affects the TK2 gene and patients with the type of mitochondrial depletion syndrome that affects the RRM2B gene show similar symptoms. Hirano believes that if there’s even the slightest possibility that the treatment may help him, that they should try it. Furthermore, many physicians believe that too much damage has been done to his brain for nucleoside bypass therapy to provide much help. This reminded me of how in the story, the narrator has the type of mitochondrial depletion syndrome that affects the TK2 gene instead of the RRM2B gene, and it got me thinking. Do you think that there is a point for patients (with the type of mitochondrial depletion syndrome that affects the TK2 gene) where too much damage has been done, and nucleoside bypass therapy cannot help them? Also, what are your thoughts on the controversy surrounding Charlie’s treatment?
ReplyDeleteReferences:
Begley, S. S. (2017, July 17). 5 Things to Know about the Experimental Therapy for Charlie Gard. Retrieved November 12, 2017, from https://www.scientificamerican.com/article/5-things-to-know-about-the-experimental-therapy-for-charlie-gard/
Kegel, M. (2017, July 24). Nucleoside Therapy Explained: Why Doctors Debate Treating Charlie Gard. Retrieved November 12, 2017, from https://mitochondrialdiseasenews.com/2017/07/19/nucleoside-therapy-explained-why-doctors-debate-treating-charlie-gard/
Wheatstone, R. (2017, July 24). What is nucleoside bypass therapy and could it have helped Charlie Gard's mitochondrial depletion syndrome? Retrieved November 12, 2017, from https://www.thesun.co.uk/living/4007891/charlie-gard-nucleoside-bypass-therapy-nhs/
Hi Dalia!
ReplyDeleteI really enjoyed reading your blog post that was in the form of a story! It made your topic entertaining and easy to understand. I wanted to learn more about this autosomal recessive disorder and so I looked into various versions that people can have. I learned that there are three forms of the disorder: myopathic, encephalomyopathic, and hepatocerebral.
The Myopathic form is focused on muscle weakness, where symptoms begin in early childhood. People eventually begin to lose their ability to walk, eat, and talk. If we look specifically at how individuals get diagnosed, doctors usually look at the concentration of creatine phosphokinase through a procedure known as venipuncture (US National Library of Medicine, 2017). The enzyme is present in the heart, brain, and muscles, and it helps produce ATP through phosphorylation of ADP. If there is an increased concentration of creatine phosphokinase, this usually means that there is muscle damage or breakdown because the increased enzyme concentration is a result of leakage from the muscle (Blocka, 2015).
The Encephalomyopathic form is more connected to the function of the kidney. Those who suffer from this disease have weak muscles, and they suffer from microcephaly, which is where the head is a smaller size than it should be. This specific form of the disorder affects infants (RRM2B-MDS, 2017). Lactic acidosis may be a serious problem for those suffering from this, which reminded me of my bio blog where I talked about how if you exercise for long periods of time, you start to feel cramps and burning sensations. This is a result of the muscles not receiving enough oxygen, and thus there’s an increased amount of lactate being formed as a result of lactic acid fermentation (Fermentation and Anaerobic Respiration, 2016). However, instead of the mild lactic acid issue when exercising, lactic acidosis in these infants is far more serious and life-threatening instead. Those, who have this disease only live into early childhood, compared to the other forms.
Lastly, hepatocerebral mitochondrial DNA depletion is related to the liver, and like the encephalomyopathic form, the symptoms are similar: inability to gain weight, lactic acidosis, and vomiting. Liver failure is the main cause of death for the infants who have this form of the disease as the liver is usually quite larger, and as a result neurological problems may form such as weak muscles (MPV17-related hepatocerebral...). A gene known as MPV17 leads to the production of an impaired protein which can cause this disorder.
I think you would have the myopathic form because most people who have the other form don’t live past infancy, and the other two focus in on kidney and liver failures. Which specific form of the disorder would you say you have written about?
Overall, you did a really nice job of writing the blog! Can’t wait for the next one.
Blocka, K. (2015, December 11). Creatine Phosphokinase Test. Retrieved November 12, 2017, from https://www.healthline.com/health/creatine-phosphokinase-test
Fermentation and anaerobic respiration. (2016). Retrieved November 12, 2017, from https://www.khanacademy.org/science/biology/cellular-respiration-and-fermentation/variations-on-cellular-respiration/a/fermentation-and-anaerobic-respiration
MPV17-related hepatocerebral mitochondrial DNA depletion syndrome - Genetics Home Reference. (n.d.). Retrieved November 12, 2017, from https://ghr.nlm.nih.gov/condition/mpv17-related-hepatocerebral-mitochondrial-dna-depletion-syndrome
RRM2B-MDS - Genetics Home Reference. (2017, November 7). Retrieved November 12, 2017, from https://ghr.nlm.nih.gov/condition/rrm2b-related-mitochondrial-dna-depletion-syndrome-encephalomyopathic-form-with-renal-tubulopathy
U.S. National Library of Medicine. (2017, November 6). Creatine phosphokinase test. Retrieved November 12, 2017, from https://medlineplus.gov/ency/article/003503.htm