Note: For all of my new readers who may just be getting to know Armand, his disease, and his journey, please start with these links. They tell a short but powerful summary on how we learned about what was wrong and my initial impressions, thoughts, feelings, and the best information I could find at the time, explained as best as I could for my close friends on my personal Facebook page.
What is GM1 Gangliosidosis?
GM1 Gangliosidosis is an autosomal recessive lysosomal storage disorder that generally attacks the nerve cells in the brain and spinal cord.
Okay, what did all that jargon mean?
Autosomal recessive refers to Armand’s genetic makeup. Without going too deep into it, most of your physical traits are passed on from your parents at a DNA level. We each have two chromosomes, one of which comes from each parent. For you to exhibit a recessive trait, that gene has to be on both the chromosomes you get from your parents. If you only get one, you’re simply a carrier, but the more dominant gene is what is exihibited. For instance, if you have blue eyes, then both of your parents each passed on the blue gene to you. If you have brown eyes, you might still “carry” the blue gene, but the brown gene is the more dominant one. In the case of GM1, Lindy and I were both carriers, but each also had a dominant non-defective gene that kept us from being affected. Unfortunatly, we both passed on the carried gene to Armand, so he doesn’t have that non-defective gene to help out. There is a 25% chance of this happening for each child she and I would’ve had.
Lysosomal storage refers to how the defect works. Your body produces certain fats called lipds that are used for cellular energy, as well as in the cell membrane itself. Certain enzymes, called lysosomes, break down these lipids into more usable parts. These lipids can be further broken down by a second lysosome, and on further down. In GM1, there is either a deficiency or defect in the enzyme beta-galactosidase, which means that those lipids don’t get broken down far enough, and end up building up in the cells (hence, “storage”). When these cells become too full of the lipid, it becomes toxic and the cell dies.
Is there a cure?
Not for GM1, there is not. Other lysosomal disorders do have treatments and cures via injecting a synthesized version of the enzyme directly into the bloodstream, where it makes it’s way to the affected tissue(s). Because GM1 affects the brain and spinal cord, it is very hard to cross the blood-brain barrier, unlike other tissues, say, the liver or heart. Some related lysosomal disorders, such as Hurler’s Syndrome, have seen a lot of positive results from bone marrow transplants; GM1, however, has not as of this point.
How would a bone marrow transplant work (if it does work)?
The main obstacle is the blood-brain barrier; the blood vessels there have special junctions that make it hard to introduce anything into the brain, ironically so it doesn’t cause damage. What we do know is that some of the cells that make up the brain do come from the bone marrow. A hematopoietic bone marrow transplant, which is what Armand is currently up for, uses stem cells from either adult donor blood, or umbilical cord blood. By using chemotherapy to effectively destroy Armand’s bone marrow (and his immune system), and then introducing new stem cells from a (non-GM1-affected) donor, the theory goes that it would create new cells in the brain that could produce the deficient enzyme. While this has happened in other disorders, it is not proven to be highly effective with GM1, and researchers don’t yet know why. If it does work, most likely it would not “cure” him, as much as it would simply slow down the progression. He would still end up slowly being affected by the disorder until a better treatment or cure comes along. My hope upon hope is that if we do the transplant, it would slow progression enough for something in gene replacement therapy (which is still finding data using mice) or chemical chaparone therapy to have a breakthrough before it’s too late. I won’t get into how those therapies work just yet. The two major hiccups with a bone marrow transplant is the lack of data on how effective it is, and the number of complications that have a liklihood of arising, including death — 10% of all hematopoietic bone marrow transplant patients do not even survive the treatment itself, due to infection, rejection of the new marrow, or other complications.
(UPDATE: For the time being, the bone marrow transplant will not be an option. There is not enough data to show it would be effective, and the doctor who would have performed the surgery was concerned that it might actually accelerate his progression. This is not to say it won’t ever happen, but it’s not on the table at the moment.)
What about the medicine therapy? How does that work?
The therapy is purely theoretical at the moment, although nothing about it is totally experimental. The idea essentially boils down to introducing a drug called miglustat (brand name Zavesca) into a cocktail of anti-inflammatory drugs. Miglustat is currently an effective treatment for another lysosomal storage disorder, Gaucher’s disease.
Going back to my earlier comment about how lysomal storage disorders work, Gaucher’s disease is a deficiency in a different enzyme, that breaks down a larger lipid. This lipid eventually would get broken down into ganglioside, which is what Armand’s little body has trouble with. Miglustat restricts the body’s production of the lipid in Gaucher’s disease, meaning less of it overall in the body — storage becomes less of a problem, and the body continues on from there.
Essentially, your body produces lipid A, and enzyme 1 breaks that down to lipid B, which is broken down or pushed out of the body by enzyme 2. And so on and so forth down the line. Armand has trouble with, say, lipid E. Gaucher’s disease is affected by lipid C. If miglustat limits production of C, that means less to get broken down to D, and eventually E. The idea is that maybe Armand’s body could cope with less of E.
That sounds promising! What’s the catch?
It’s not FDA approved for GM1, and the idea for the therapy is currently only theoretical. Armand would be one of the first to have this tested on. The very very limited data from other patients is promising, but it is not enough to really say one way or another. This type of testing is called off-label prescribing, and it is neither illegal nor unethical — in fact it’s quite common. The FDA allows pharma companies to show on the label symptoms or diseases for which the drug has been shown to be both safe and effective; but it cannot regulate the actual prescription of the drugs themselves. So while a drug cannot be labeled for something that has not been tested, a physician can prescribe it for any use he or she sees fit. The issue with this, however, is if the insurance company will approve the drug for it’s off-label use, and miglustat is very expensive ($30-40,000 per year). If Lindy’s health insurance will not cover it, there’s no way we could afford that in any way shape or form, so it would be almost a moot point.
I did ask the doctors if this treatment was mutually exclusive from the bone marrow transplant, and they said no. However, the treatments would have the be staggered — the transplant first (which may help any non-neurological problems), and about 6 months later start on the drug therapy to save his little brain.
I will continue this as more questions come up, new information comes along, or as I think of it.