Where is my Lysosome?

And what's wrong with Gracie's?

For those of you not sitting in on doctor's office visits, here's the (relatively) short answer. Hurler Syndrome is one of many nasty disorders in a class of diseases called "Lysosomal Storage Diseases". These are just one category in a larger group of genetic problems known as "Inborn Errors of Metabolism."


Error? What error?

As the name suggests, the error is in a chemical that operates out of the lysosome on the catabolic side of cellular metabolism. That is, it's a mistake in breaking down a chemical (catabolism), as opposed to a mistake in making one (anabolism). Specifically, it's a mistake in breaking down a chemical called a glycosaminoglycan (a GAG), which is one of the chemicals that the body uses to make bone and cartilage, and other kinds of connective tissue. Chondroitin Sulfate is an example of a GAG, probably the one most people have heard of, but it isn't the one that Gracie is unable to metabolize. She is unable to break down another one called Dermatan Sulfate.

Why can't she break down Dermatan Sulfate?

Enzymes break down chemicals in the cell. If you're missing one, you have trouble. A simple example is lactose intolerance. If you're lactose intolerant, you don't make sufficient lactase (the enzyme) to break down lactose (the the milk chemical), and you get gas and diarhhea from milk products. Dermatan sulfate is a big molecule with lots of little components, one of which is iduronic acid, which is broken down by alpha-L-iduronidase (see how the names match up?). alpha-L-Iduronidase is the enzyme Gracie is missing, so she can't break down the GAG, so it accumulates (gets "stored") in her cells.

Was it something she ate?

Nope. All of your your cells make the GAGs and break them down. You can't prevent MPS by not eating GAGs. Your body just makes them, no matter what you eat, because you need them to make bones and cartilage and membranes and stuff. You have to have them, and you have to get rid of them, too. So, even though it's called "metabolism" it's not something you can control through food, like the Atkins diet or something. There are some inborn errors of metabolism, though, that can be controlled by watching your diet. (PKU is a good example. Stay away from phenylalanine from birth, and you're ok. Otherwise, you're in big trouble.) Unfortunately, MPS is not one of them.

Why can't she just take medicine for it?

ERT (enzyme replacement therapy) is just that. It's as simple as it sounds. You put alpha-L-iduronidase into her body and it goes into her cells and breaks down the iduronic acid in the Dermatan Sulfate and everything works like it's supposed to. There's only one problem.

The blood-brain barrier

The brain cells are protected from things like infections and poisons by a layer of cells that are bound to each other more tightly than those in the bloodstream in most of the body, and that is the blood-brain barrier. As a result, only very tiny molecules can squeeze through these tiny spaces between the cells. A bacterium is way too big, and the alpha-L-iduronidase enzyme is also too big. this means that you can't get enzyme to your brain cells by injecting it into the body, unless you put it "behind" the blood-brain barrier. You could do this with a spinal cord injection, but someone died in a clinical trial of this method, so they're not doing it anymore until they find out what happened.

HSCT (hematopoietic stem cell transplant), or cord blood transplant, is a way of introducing enzyme-producing cells into Gracie's body, so that she can make her own enzyme. Then, it will be made in all her cells, and it won't have to cross the blood-brain barrier as a chemical in the blood. This means that she can get enzyme made in her brain cells, and deterioration of her brain will stop.

Isn't wikipedia amazing?