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EP interview with Dr. Cynthia Tifft.

EP conducted a telephone interview with pediatrician and geneticist, Dr. Cynthia J. Tifft, Chief of the Division of Genetics and Metabolism at the Center for Neuroscience and Behavioral Medicine at Children's National Medical Center, in Washington, D.C. Dr. Tifft is working with the Hall family children. Dr. Tifft provided information about gangliosidoses (GANG-lee-oh-sih-DOE-sees), including GM1 gangliosidosis, the diagnosis of the Hall children. Highlights of the interview follow.

Exceptional Parent {EP}: In layman's terms, how would you describe gangliosidoses?

Dr. Cynthia J. Tifft, MD, PhD, FAAP, FACMG {CT}: In order to describe gangliosidoses, you really need to describe what a lysosomal storage disease is, because gangliosidoses are one of approximately 40 to 50 different lysosomal storage diseases.

If you can remember from basic biology, there are cells, and inside the cell there is another structure called the nucleus where all the genetic information is. There are other things inside the cell, little bags of things--we call those bags organelles, as a group, and one of the different kinds of organelles is called a lysosome. A lysosome is just like the body's recycling center. So, there are 40 or 50 different kinds of enzymes there, and large molecular compounds that need to be broken down by the body go into those lysosomes. And then they're chopped away one little piece at a time from the end inward, so it's just like chopping away at a piece of chemical, and each of the little chop bites takes a different enzyme.

So, for example, if you had a recycling center that recycled glass and paper and plastic, and the conveyor belt to recycle the plastic broke down, and that was all stopped and all the plastic coming in was just sitting on the conveyor belt ... and the glass and the (paper) were fine, they were working ... let's say there are 40 or 50 of those. Well, the plastic starts to build up. And pretty soon, because that conveyor belt doesn't work, there's so much plastic in the recycling center that the whole thing is full of plastic and everything kind of breaks down. Gangliosidoses are one of the compounds that are broken down in these lysosomes, so they're like the plastic conveyor belt.

If you start with GM1 ganglioside, which is one of the larger gangliosides, you have to chop off the last sugar first. In other words, GM1 ganglioside, one sugar, gets chopped off. and it makes a compound called GM2 ganglioside. And then there's another enzyme that chops off the end sugar for GM2 ganglioside and makes ... basically, you're chopping it off one little sugar at a time. But you've got to go from the outside in. So, if you're missing the enzyme that does the first chop, you're stuck. And then the GM1 builds up in the lysosome, just like plastic builds up in the recycling center.

{EP}: And why would the enzyme be missing?

{CT}: It's missing on a genetic basis. There's a genetic change. Genes come in pairs, and the enzyme necessary to break down GM1 ganglioside is called beta-galactosidase. So, in every cell of everybody's body there are two genes for beta-galactosidase--one you got from your mom, one you got from your dad. But if there's a genetic change in one of those genes so that the enzyme doesn't work, then you'll only have half the amount of beta-galactosidase you need. So, if you have half the amount you need, you're a carrier for beta-galactosidase. Now, fortunately for most people, you only need about ten to twenty percent of beta-galactosidase activity in order to be perfectly fine. So, if you're a carrier and you have fifty percent activity, you're fine. You don't even know you are a carrier.

But, if both parents are carriers--in other words, they've got one beta-galactosidase gene that works and one that does not work--if you go to have kids, each parent can only pass one copy of each gene. So, if the partner is also a carrier and they have one gene that works and one gene that doesn't work, if you sit down and work out the numbers--you know it's random, 50/50, which gene you give your kid--if both parents are carriers, one time in four, each parent passes the gene that works and the child has two working copies, has perfectly normal, 100 percent activity, and is fine.

Two chances out of four, one or the other parent passes the gene that doesn't work and the other parent passes the one that does. So, there's two out of four chances the child will be a carrier just like the parents.

But one chance out of four, both parents pass the gene that doesn't work, and if they both pass the gene that doesn't work, now the child has no working copy of beta-galactosidase. That's the child that gets GM1. Their enzymes don't work, so they're not going to break down enough GM1 to clear the recycling center.

So, when you ask the question, in how many instances are there multiple children in a family with GM1--well, the only way you can have GM1 is if both of your parents are carriers. And the risk for each pregnancy to have a child with GM1 is one in four. You can actually do the math, that if you have a one in four chance, the chance that you would have three kids with GM1 is a quarter times a quarter times a quarter, or 1 in 64. So, not very common. But it's not impossible.

Once you have a child with GM1, you know that your risk is one in four. Now, if it's an infantile child that has onset very early, oftentimes the child will have gotten sick and the diagnosis will have been made before the family wants to have more children, and so there is prenatal diagnosis for this. You can know at 10 or 12 weeks in the pregnancy whether your child has GM1 or not.

{EP}: What distinguishes GM1 from other gangliosidoses?

{CT}: There's (only) GM1 and GM2 gangliosidosis, and they're very similar. They're only one step, one sugar, different in the pathway. The only thing that GM1 kids tend to have that GM2 kids don't is the bony changes. In the juvenile form, they're at risk for bone changes in their spine; they're at risk for dysplasia in their hips. Kids with GM2 would also have trouble walking, and they would probably end up in wheelchairs, but they wouldn't have the degenerative bony changes in their hips. So, really the only thing that distinguishes GM1 from GM2 is the bony change.

{EP}: Do you have any sense of (the number of) GM1 cases or infant, juvenile, and adult cases?

{CT}: For most of the adult GM1 cases, and I've never seen a case, there's a common mutation that produces adult GM1 in the Japanese population. So a lot of the people working on adult GM1 are Japanese physicians.

Infantile is more what we call panethnic: It can occur in any ethnic background. I would say infantile is the most common. I think we estimated there are 10-15 new cases of GM1 diagnosed in the U.S. every year. Now, for juvenile, it's less common than that. I would say, probably in terms of new cases diagnosed per year, five or less.

Adult, I don't know about in this country, because it's really much more common in Japan. I don't know of any adult GM1 patients.

{EP}: We had read online about a breed of cat with GM1.

{CT}: There's a cat model for GM1. There's a cat model for Sandhoff disease, which is GM2 gangliosidosis. And there are some naturally occurring mutations for these kinds of gangliosidoses. They're hard to find, and the colonies are hard to maintain. At Auburn University, they have a large-animal/ cat/vet-type presence, and then the other place where they have a lot of large-animal models is the University of Pennsylvania, in Philadelphia.

{EP}: Can much be learned, then, for humans from those (models)?

{CT}: Yes, as a matter of fact, there is a consortium of physicians called the Tay-Sachs Gene Therapy Consortium. They are working pretty much simultaneously on gene therapy for GM1 gangliosidosis and for GM2. Now, GM2 is Tay-Sachs or Sandhoff disease. They're actually two different diseases, but all three of these conditions are very, very similar to each other. And, so, they are working on gene therapy for that. They're hoping to have clinical trials up and running for one or the other or both of the conditions within the next three years.

What they're doing now is using what they know from mouse models and scaling up to large-animal models. As you might expect, to (do) something like this in terms of gene therapy, and for these rarer diseases, takes a phenomenal amount of dollars, and the National Tay-Sachs and Allied Diseases Association with other, private, donors has been trying to raise money for them to at least get these studies off the ground. They've applied to the NIH (National Institutes of Health) for what's called a program project grant, several million dollars in funding to be able to actually make it happen.

That's probably the hottest thing on the horizon at the moment. There are other types of therapies being currently worked on using small molecules. {EP}: My perception based upon what you're saying is there's some hope there.

{CT}: Oh, yes. But these are very difficult diseases to deal with because they involve the central nervous system. What you should know is that gangliosides are made by every cell. But the highest concentration of them are in the central nervous system. They're probably used for sending messages between neurons. Nobody's exactly sure what gangliosides do, but that's the thinking. They sit on the cell membrane of the neuron and probably help neurons communicate with each other. So, when you think about proposing a therapy that involves the brain, it's much more difficult than a therapy that involves the body.

For example, there are a number of lysosomal storage diseases for which there is therapy replacing the enzyme. They can artificially synthesize beta-galactosidase in large bioreactors, purify it, and give it back to the patient as an intravenous infusion every two weeks. You can do that for Gaucher go-SHAY) disease--it's farther down in the degradation pathway. Type I Gaucher disease doesn't have central nervous system problems. If you use intravenous therapy with enzyme replacement, you can actually get the enzyme to the cell that needs it.

Gangliosides fall into a class of molecules called glycosphingolipids. The biggest part of the problem with GM2 and GM1 gangliosidosis is in the brain. There is a barrier called the blood-brain barrier which prevents large molecules from getting from the blood circulation into the brain. So, even if you had the beta-galactosidase enzyme, and if you made it in large quantities and tried to inject it intravenously, it would go to the rest of the body but it wouldn't get to the brain very well. So, the biggest problem and the biggest hurdle in trying to treat the gangliosidoses is that whatever therapy you use has to get to the brain, and if it's a large molecule it's not going to get there. Now, this has been a tougher nut to crack than some of the other glycosphingolipid diseases.

We're getting further than we were before, but it's hard, because these are lethal diseases. Part of it is, you can treat symptoms, but because it involves the brain, the brain gets sick, and parts of the brain die. Neurons begin to die, and once you've lost those, even if you find the therapy, you could help the sick ones, but you're not going to get back the ones that have died. There's a certain regenerative capacity to the brain, but it's not perfect. At some point, there are things that are not retrievable, even if you have the perfect therapy--once the kids have already started to show symptoms. And it's even truer with the infantile disease, which progresses much more rapidly.

{EP}: How did you get involved with this particular research?

{CT}: I am trained as a pediatrician and a geneticist, and when I was a post-doctoral fellow at the NIH, I worked with folks that were interested in lysosomal diseases, and I was part of the laboratory that created the GM2--the Sandhoff disease--mouse. And we have used that mouse in looking at therapies using bone marrow transplantation, using some of these small molecules--this is actually the same mouse model now that the Tay-Sachs Consortium is using to test the mouse for gene therapy.

{EP}: What do you think posed a difficulty in diagnosis of the Hall family children?

{CT}: With the juvenile and adult forms of these things, they're rare and people just don't think of them. And, I think, these guys were in the military system, and they hardly saw the same person twice, so that there was no longevity in experience ... seeing the patient and seeing the same patient over a year's time and realizing what was happening, how the decline was happening. And, so, that's part of it. That's a liability in cities with big pediatric practices where different people see your kid every time, too. It's not just the military.

But, even given that, if you look at it, the early symptoms are very non-specific. So, there are many other things that are more common diagnostically that are sort of more likely, because these are really rare. It takes a while to get from the common ones to the rare ones, and it takes somebody really sitting down and thinking about it to come up with (the correct diagnosis).

The key piece was not that the diagnosis was made; the key piece was that somebody somewhere said, you know, the genetics doctors need to see you. Because we deal with rare (diseases). So, you know, we're going to think about (these) probably faster than the average person just because that's the kind of thing we deal with.

Often for these things, a key piece is that instead of just being delayed kind of statically, you actually start to lose skills. And that's what's characteristic of these lysosomal diseases. You develop normally to a certain point, and then kind of plateau in your development, and then start to lose stuff you used to be able to do. And the red flag for us is the kid who is losing skills.

But, in all fairness, for most of these--particularly the late juvenile and adult cases--the diagnostic odyssey often takes on average about five years.

{EP}: It seems to me that ... for anybody who reads about this, one of the more striking things is to think of a geneticist.

{CT}: Yes, I think that's a good point. Sometimes families are reluctant to do that, which is why our no-show rate for new patients is often pretty high, because you can imagine the stigma attached if somebody's even suggesting that you have a genetic diagnosis. And, obviously, none of us have any control over which genes we pass our kids. But there is a stigma attached to having a genetic condition, and, so often, even when people are referred to genetics, it takes them two or three appointments just to get there ... It's sort of, too personal.

{EP}: It makes me think that the more education there is ... is rather key.

{CT}: Right now, the technology is becoming available and there is a whole push to get a number of lysosomal storage diseases as part of the newborn screening panel. It's basically, at this point, disorders for which there is a therapy. But since we think that GM1 and GM2 may have some therapies in the not-too-distant future, certainly the technology is there to do testing for these as part of the newborn screening. So, what you would pick up then would be children who are affected but still haven't shown any symptoms yet. And, obviously, therapy is going to be much more successful the sooner you deliver it. So then you begin to eliminate the damage to neurons that's already happening, that's irreparable. So, that's another thing that's kind of coming, I would say, in the next five to seven years, so that every newborn would get screening for some of these lysosomal disorders. We're working on it from several different angles. (Mobility)
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Publication:The Exceptional Parent
Article Type:Interview
Geographic Code:1USA
Date:May 1, 2008
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