Pompe Disease, mTOR, & TFEB
The following should not be taken as medical advice. Please speak with a certified medical practitioner before making any changes in your day-to-day life involving Pompe Disease.
At the Pompe Warrior Foundation (PWF) we understand how intimidating a diagnosis of Pompe Disease can be to a family and/or an individual. During the initial months following a Pompe diagnosis, the amount of new information, concepts, and even medical vocabulary can be overwhelming. Taking the time to get caught up on the latest research concerning Pompe has the potential to substantially improve your understanding and communication with your doctor about your treatment plan. Educating yourself or finding an educated person to help teach you is step one on your personal path to conquering Pompe Disease.
The first paper we suggest reading is Lysosomal storage diseases: from pathophysiology to therapy. This paper is not free to the public but it is available to your doctor. Ask your doctor to print off one copy for them and one copy for you to take home. After reading through the research paper, bring up your questions and comments with your medical team.
The paper above specifically covers the latest findings in lysosomal biology. Pompe disease is mentioned numerous times throughout the paper and the latest therapies being attempted in research are discussed. Figure 1 is a graphic that could be used by your medical team for devising an improved treatment plan for your specific presentation of Pompe Disease.
Its important to note that Pompe disease falls under two categories. A Lysosomal Storage Disease (LSD) and a Glycogen Storage Disease (GSD).
For an overview of glycogen metabolism you can check out this free textbook from 2002 on the National Center for Biotechnology Information’s (NCBI) website. (NCBI is a part of the US National Library of Medicine.)
Chapter 21 Glycogen Metabolism
- Section 21.1Glycogen Breakdown Requires the Interplay of Several Enzymes
- Section 21.2 Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation
- Section 21.3 Epinephrine and Glucagon Signal the Need for Glycogen Breakdown
- Section 21.4 Glycogen Is Synthesized and Degraded by Different Pathways
- Section 21.5Glycogen Breakdown and Synthesis Are Reciprocally Regulated
In the last section, 21.5, Pompe disease is specifically discussed, and there is a picture from an electron microscope showing the skeletal muscle of an infant with Pompe Disease. The third subsection of 21.5, 21.5.3 Glycogen Metabolism in the Liver Regulates the Blood-Glucose Level, is another resource that could assist you in communicating with your medical team about your different treatment options.
After familiarizing yourself with lysosomal biology, glycogen metabolism and the latest research on Pompe disease, circle back to the definition of Pompe Disease.
From Merriam-Webster online:
This definition states that, “the abnormal accumulation of glycogen…results from a deficiency in a lysosomal enzyme”. All other processes involving glycogen metabolism in the human body remain unchanged. Here is a graphic to show what that means.
Remember that another name for Pompe Disease is Glycogen Storage Disease Type 2, which is abbreviated in the above graphic as GSD II. GSD II does not affect glucose metabolism, fructose metabolism or the other pathways involved with glycogen metabolism. Since all other glycogen/glucose/fructose metabolism pathways work in Pompe Disease, PWF started asking our medical team a few questions.
- Is there a way to not use the glycogen path (see above diagram) that involves acid maltase? Pompe Disease= GSD II = Acid Maltase Deficiency
- Is there a faster way to clear out lysosomes in the body once they have gotten stuck on a glycogen molecule?
These questions led us to the following three papers. All three papers are free to read. These papers connect the dots between the ketogenic diet, mTOR and transcription factor EB (TFEB).
- The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway https://www.ncbi.nlm.nih.gov/pubmed/21371020
- mTOR Signaling in Growth, Metabolism, and Disease https://www.ncbi.nlm.nih.gov/pubmed/28283069
- TFEB at a glance https://www.ncbi.nlm.nih.gov/pubmed/27252382
From the third study above, TFEB at a glance, the following graphic, Mechanism of TFEB activation, shows one side is red and has an up arrow next to the word mTOR and a down arrow next to the word TFEB. The other side is green and shows a down arrow next to mTOR and an up arrow next to TFEB. We are now testing the idea that a properly formulated ketogenic diet has the ability to shift a person’s metabolism over to the green side of this graphic more often. This allows TFEB to move down to the nucleus and express itself.
The next graphic is also from the paper TFEB at a glance, and it shows the processes that happen when TFEB moves to the nucleus and is expressed.
By using a properly formulated Ketogenic Diet, we think its possible to overexpress TFEB and limit lysosomal-glycogen buildup in the body. PWF is hypothesizing that the overexpression of TFEB is a treatment that would improve the standard of care in Pompe Disease.
Take your time with the studies and links on this page to educate yourself on Pompe Disease and what we are trying to accomplish at PWF. We would love to hear your thoughts, comments and questions as well. Please contact Don at email@example.com.