What Are Lysosomal Storage Diseases?

Podcast Transcript

Dr. Scott Steele: Butts & Guts, a Cleveland Clinic podcast, exploring your digestive and surgical health from end to end.

Hi everybody. And welcome to another episode of Butts & Guts. I'm your host, Scott Steele, the Chair of Colorectal Surgery here at the Cleveland Clinic, in beautiful Cleveland, Ohio. And I'm very pleased to welcome two guests here today, talking about something that we have never talked about before on Butts & Guts, and that is lysosomal storage disease. And I'll call it LSD for all the listeners out there.

We're very pleased to have, first, Dr. Angelika Erwin, who's a geneticist and Interim Medical Director at the Center for Personalized Genetic Healthcare. Angelika, welcome to Butts & Guts.

Dr. Angelika Erwin: Thanks for having me.

Dr. Scott Steele: Also pleased to have Dr. Rabi Hanna, who's the Chair of the Department of Pediatric Hematology, Oncology and Blood and Marrow Transplantation at Cleveland Clinic Children’s. Rabi, welcome to Butts & Guts.

Dr. Rabi Hanna: It's my pleasure to be with the team.

Dr. Scott Steele: So to the both of you, I always like to start out with getting a little bit about your background. So where are you from? Where'd you train? How come to the point that you're here at the Cleveland clinic, Dr. Erwin, we'll start with you.

Dr. Angelika Erwin: I'm a clinical geneticist and also trained internal medicine. And I did my training at Mount Sinai Medical School in New York City. And then for my husband's training, we moved to Cleveland in 2014. And I joined the Cleveland Clinic, which was a wonderful choice because I really was able to follow my passion and start a Lysosomal Storage Disease Program.

And in the meantime, we've really built up a very successful program, multidisciplinary program that involves many different specialties. Because as you will hear, patients with LSDs have a multisystem disorder and they need a lot of care from different specialists. And so I'm very happy to be working with Dr. Hanna, among others, in providing excellent care to those patients.

Dr. Scott Steele: Well, we're certainly very excited and proud to have you here. And so Dr. Hanna, back over to you. What brought you here to the Cleveland Clinic?

Dr. Rabi Hanna: Thank you so much for this really important question. I came to the clinic because I think it does truly exemplify the patient first. And I was trained in medical school and trained back in Syria. And then came to the United States, initially at Duke University, where it triggered my passion for genetics. I have done a lot of training there with metabolic and lysosomal storage disease before I decided to pursue more training in blood and marrow transplantation at the University of Washington and Seattle Children’s.

And from there, I was recruited here to start our Pediatric Blood and Marrow Transplantation Program. And had the opportunity to work with great colleagues, like Dr. Erwin, to build the programs that it is patient centered. And bring all the care to the patient, especially when it is multidisciplinary like LSD patients’ needs.

Dr. Scott Steele: Well, again, we're super excited to have you here. And thanks to the both of you for freeing up time to join us on Butts & Guts. So Dr. Erwin, we'll start with you. So can you tell us a little bit more about lysosomal storage diseases? What they are, and what are the different kinds of LSDs?

Dr. Angelika Erwin: Sure, yeah. So the LSDs are a group of more than 50 different disorders, and they are caused by disturbances of the metabolism within the lysosomes. And the lysosomes are part of the cell where many different substrates are being broken down. So you could also say that the lysosomes act as the digestive system of the cell, in which all different kinds of substrates, cell debris are digested, so that they can then be further excreted from the body. And the way they're caused is by enzyme deficiencies.

So for the breakdown or the digestion of these different substrates, enzymes ... or you can think of those as little motors. Almost like little Pac-Mans, are necessary. And if one of those motors or those enzymes are not working at full capacity, then a specific substrate can start accumulating in the lysosomes because it cannot be broken down by the cell. And so over time, the accumulation of those substrates in the lysosomes can lead to damage of the cells in different organs of the body. And that can lead to the formation or the cause for lysosomal storage disorders.

Now, I've already mentioned that there are more than 50 different lysosomal storage disorders. So they really present in a very different way. And depending on where in the body, the substrate accumulation is happening, the disorders can look very, very different. And so some of the lysosomal storage disorders, for example, type one Gaucher disease, affects mostly organs such as the liver, the spleen, the bone marrow, whereas other LSDs can lead to accumulation of substrates also in the brain cells. And that can cause intellectual disability and neurological decline.

So in general, every lysosomal storage disorder is unique and presents in a very different way, because it does affect very different parts of the system of our body.

Dr. Scott Steele: So let's dig in a little further there. So you mentioned there's more than 50 types and they can have a lot of different wide ranging manifestations to them. But give me a little bit more. So who's at risk for developing LSDs? What are some of the symptoms of the more common ones? And is it young, is it old? Is it elderly, is it babies? I mean, take us a little bit more in depth here.

Dr. Angelika Erwin: First of all, most of the lysosomal storage disorder are inherited in a recessive way. And that means that a person usually has to have two mutations to develop the disease. And so we think of genes as instructions or blueprints for those certain enzymes in the lysosomes. And if there is a mistake in the blueprint, then the body is unable to form the enzyme properly. Now, we inherit one copy of each gene from both parents, so we have two copies for most of our genes. And if the parents are each carrying a mutation on one of the copies of their genes, and they both passed down that mutation to a child, then that child may end up not being able to produce a proper enzyme and may end up having a lysosomal storage disorder.

Now, when we think about the ages that are affected, it really ranges from infancy to later or adulthood. And that depends largely on how much residual enzyme activity we have left in the body. So if we have a mutation in our genes that causes the enzyme to either not be produced at all, or to work at a very low capacity, we usually have onset of disease in early infancy or childhood. However, if we have a mutation in the enzyme or in the gene that causes an enzyme to be produced but not work at full capacity, there may be some residual enzyme activity. And so those patients may start accumulating substrate over time, but symptoms may only occur when they're adults. And so that is what we call the later onset diseases.

So let me give you some examples. Some of the most common disorders are a type one Gaucher disease, which I just mentioned. And so here we really have patients who present at a very young age with extremely large spleens and livers, with very low platelets, but they are neurologically normal. Now, we can have mutations in the same gene that cause quantitative disease in adulthood. And the oldest patient that I have diagnosed with type one Gaucher disease was in her 80s. And she presented only in her 80s with very, very low platelets. And we still started her on treatment because it seemed very effective.

Now, other mutations in the same gene can cause more severe types of Gaucher disease that also affects the brain. And so then we talk about type two and type three Gaucher disease that can be much more severe, present at a very young age also, and have a very shortened lifespan. So it is really a matter of how severely affected is the enzyme function, and what is the location of the gene where the mutation is happening that will have an impact on the disease severity. And also then, the types of organs that are affected.

Dr. Scott Steele: Lots to unpack there, because it just seems like it could be all over the map. So how would one even go about diagnosing these diseases? I mean, especially if, it's one thing if you have somebody that's really, really ... a lot of symptoms. But if the symptoms are a little bit more subtle, how do you go about doing that?

Dr. Angelika Erwin: So it is very complex, because these disorders tend to present in very different ways. And somebody has to have a very high level of suspicion in many cases, especially if the presentation is more subtle and not as severe, maybe not as early onset. And so often, the first step is to, first of all, have the suspicion for this disorder. And then send the appropriate testing. And so for many of those disorders, the first step would be enzymatic testing, to see is there very severely decreased enzyme activity that can be detected.

And then the next step is often to send genetic testing, to confirm the diagnosis. And also be able to test other family members to see if they may also be affected. In some cases we diagnose one patient in the family, and we then end up testing the siblings of this patient and find out that the sibling is also affected, but maybe too young to manifest the symptoms. And therefore has not presented clinically.

What we now also started seeing more and more is that we are able to diagnose these patients very, very early on through newborn screen. Historically, the lysosomal storage diseases have not been part of the newborn screen. But as we are discovering more and more treatments, more and more states are adding those disorders to the newborn screen so that we are really able to identify those patients right after birth. And then start treating them as soon as possible, or as soon as they start developing symptoms.

Now, at this time, we know more than 50 lysosomal storage disorders. We have between one and five of those disorders on the newborn screens, depending on the state, but more and more states are adding those disorders. And I predict that in the future, we will be screening for those disorders on the newborn screen and are able to identify those patients earlier.

Dr. Scott Steele: So let's shift gears to you, Dr. Hanna. And so let's talk a little bit about the treatment. So now you take somebody ... and again, I know that it's depending on the LSD and depending on what the manifestations are, this could be all over the map. But let's just ... what treatments does Cleveland Clinic offer for LSDs? And if you will, what seem to be the most effective, what are some of the risks and benefits, and how do you go about breaking this all down? Because I am sure that, depending on who comes in, this can be very emotional.

Dr. Rabi Hanna: Thank you so much for this really important question. As you heard from Dr. Erwin, that this is really a heterogeneous group of diseases, and even the same disease can manifest at the different symptoms and signs, depending on the age. So here at Cleveland Clinic, the benefit of this comprehensive program we can offer from A to Z. We can treat the patient, we don't treat the disease. And what I mean by that, depending on the severity of the patient, depending on the severity of the disease, we have different therapies that can range from mild, like something supportive care. And monitoring for possible complication by having them see the experts in terms of gastroenterology, and neurology, ophthalmology. To something more like enzyme replacement therapy that are being infused through the vein.

I'm very happy to say there is now more than almost 14 enzyme replacement therapies. We reference them as an ERT, where we will give that through our infusion center to this patient. Some of the diseases will require weekly, some of them, every other week of infusion. And we are trying to really make this infusion center as possibly close to home experience as possible, by having art therapy, music therapy, even teacher. And that could make it really easier for this patient and their family. And some of the patient, where they have severe disease, we can offer them a bone marrow transplantation.

Some of this disease, as you heard from Dr. Angelika Erwin, will have neurological manifestation. Unfortunately, the enzyme that we give through the vein, they cannot cross the blood brain barrier. So if we can identify patient early in their disease status, and they have appropriately matched donor, we can use donor's bone marrow cells, that they can produce the normal lysosome or protein or enzyme, depending on the disease. And we will be able to, basically replace their immune system and hematopoietic with cells that can produce that enzyme. But we only reserve that for really the severe diseases, because despite that it can be effective therapy, it does have, unfortunately, some side effect and some limitation.

So it's not an easy answer to say which one it is the most effective, because it really depends on, one, the patient disease. Two, their manifestation and how old they are when they present to the doctor. So that's why it's so important to seek medical advice in an expert center as soon as possible. Because time, literally, can mean tissue and it can be injury to the brain that it will not be reserved. We could do bone marrow transplant sometimes in the age of three or four months. We know outcome for some diseases, like Hurler, it's better if we can do the bone marrow transplantation in the first year of life compared to later. Because transplant can stop further damage, but it will not reverse whatever damage occurred earlier to the different organs of the body.

Dr. Scott Steele: Let's jump into a segment I like to call Truth or Myth. Dr. Erwin, we'll start with you. Truth or Myth: diet plays a role in the development of LSDs.

Dr. Angelika Erwin: That's mostly a myth. Diet or dietary changes don't have any impact on whether or not someone who has a gene mutation for an LSD will develop the disease. Whether a specific dietary change can slow down the progression of the disease is under investigation in just be maybe one disorder that I'm aware of, which is the late onset Pompe disease.

There have been some studies done where patients were asked to have a higher protein, lower carbohydrate diet, but it really didn't show a significant impact on the progression of the disease. So I would call it a myth. Diet really does not impact whether somebody will develop an LSD or not.

Dr. Scott Steele: Let's stick with you. Truth or Myth: only people with a family history of these diseases can develop them.

Dr. Angelika Erwin: That's definitely a myth. And if we go back to the inheritance, most of the LSDs ... there are a few exceptions. But most of the LSDs are inherited in the autosomal recessive manner, meaning that the parents are carrying a mutation, each parent is carrying a mutation in the same gene. And then they have a 25% chance of having a child with a disorder. Now, obviously, once they have one child with a disorder, there is a higher risk ... there's a 25% risk of having a second child with a disorder. So then you have a family history of siblings in the same generation who have the same disease. However, the parents, the grandparents, the aunts, the uncles, none of them have the disease. So you really, in most cases, do not find a family history of this disorder in patients who have a lysosomal storage disorder.

There are a few exceptions though. So some of the disorders have X-linked inheritance, meaning that the mutation is on the X chromosome. And that means that males are usually much more severely affected than females. And those males usually inherit that mutation from their mother. So let's take the example of Fabry disease, which is, among the LSDs, one of the more common disorders. That is inherited through mutations on the X chromosome. And so there, we often see a family history. So here, once we diagnose one family member, we do family studies and we very often identify several other family members. And that's usually mother or father, and then aunts and uncles, cousins who also have this disorder. But in most cases, we do not find a family history.

Dr. Scott Steele: Dr. Hanna, let's go back to you. Truth or Myth: currently, there are no cures for LSDs.

Dr. Rabi Hanna: Oh, despite that I would love to say that it is a myth, it is unfortunately, current days, there is really no cure yet for lysosomal storage disease. Even when we do a bone marrow transplantation, it helps to stop and to cure the manifestation of that disease in some organs, but other organs, they will continue to be affected by the disease itself.

It's important to remember in our bone marrow transplant, we replace the cells that they produce the blood. And as long as the cells go to other places, like in the brain and the heart, it can protect these organs. But some others, like the bone, tend to be harder. And it is not getting enough replacement from these normal cells and continue to have manifestation from the disease.

But I'm optimistic. And who knows, in the next few years, we may be able to say we found a cure, that it is more generalized than bone marrow transplant.

Dr. Scott Steele: So let's stick right there with you, Dr. Hanna. So again, how have you seen the Cleveland Clinic really advancing the diagnosis and the treatment of these? And then furthermore, what do you see in terms of the future in terms of treatments for LSDs?

Dr. Rabi Hanna: It is exciting time. Really, the Cleveland Clinic has been at the upfront, trying to advance the therapies. And we have been involved in many clinical trials to have enzyme replacement therapy to advance this. For an example, there is a study where I mentioned the enzyme replacement that is given through the vein cannot cross the blood brain barrier. So we are involved in a study for a disease called Hunter disease, where we inject this enzyme directly in the spine through a reservoir. And we really are seeing exciting results so far in terms of the neurological manifestation. And this patient can be as close as possible to normal cognitive function. But it is still important to finish the study, to make sure, one, it is safe. And second, that it is going to be effective.

In terms of the future, I feel it is so bright. I mentioned earlier that currently we don't really have cure, but there is so many ongoing clinical trials that is looking into gene therapy. So one of the major limitation of bone marrow transplant, that we have to find a different donor and that mean different immune system. And there could be limitation in terms of the interaction of either graft rejection, or sometimes what we call the graft versus host disease, and replacing basically a disease with another. It can be harsh for families to understand, and to go through that experience.

So the future is holding ... for many disease they are now doing phase two, and possibly soon, phase three studies. Where we are using the same hematopoietic cells from the patient. We are stimulating them, collecting the stem cell. And then in the lab, we are able to modify that gene that caused the disease, through what we call gene addition. And potentially with the newer technology, with gene editing using CRISPR methodology. And then give the cells back to that person. So it's your own cells correcting that and would really eliminate some of the bad complication that we see with BMT. So that's where I am hoping to see the future going.

It's so important also too, hopefully as we are developing this novel and innovative therapy, we make them accessible to many patient. Despite my excitement about the future, I do worry about how accessible this is going to be and the cost that could be on the patient or the healthcare system. But we are going to continue to be strong advocate to the patient and families so they can get these therapies when they become available.

Dr. Scott Steele: So for long time listeners of this podcast, we like to end with what we call quick hitters, where we get to know each of our guests a little bit better. So we'll go back and forth with this. So, Dr. Erwin, what's your favorite food?

Dr. Angelika Erwin: My favorite food is chocolate ice cream.

Dr. Scott Steele: Fantastic. Dr. Hanna?

Dr. Rabi Hanna: Pizza.

Dr. Scott Steele: I love it. Dr. Hanna, now you start. What's your favorite sport?

Dr. Rabi Hanna: Soccer.

Dr. Scott Steele: And Dr. Erwin?

Dr. Angelika Erwin: Skiing.

Dr. Scott Steele: Dr. Erwin, what's the last non-medical book that you read?

Dr. Angelika Erwin: Dr. Doolittle, to my children.

Dr. Scott Steele: Fantastic. Dr. Hanna?

Dr. Rabi Hanna: The Prophet, by Kahlil Gibran.

Dr. Scott Steele: And then tell us something that you like about here in Northeast, Ohio. Dr. Hanna?

Dr. Rabi Hanna: The weather. I think it is the four seasons. I enjoy that a lot.

Dr. Scott Steele: And Dr. Erwin?

Dr. Angelika Erwin: The central location. So you can really get to many places within a very short time.

Dr. Scott Steele: Fantastic. And so, Dr. Erwin, Let's start with you. So what's the final take home message regarding LSDs for our listeners out there?

Dr. Angelika Erwin: So my take home message is that lysosomal storage diseases are rare genetic disorders. That it can impact multiple organ systems, and affected individuals need multidisciplinary teams to really take care of them. And so my recommendation is to really seek out centers that have a lot of expertise and that have a very experienced multidisciplinary team, so that they can be offered the cutting edge approaches and treatments that they deserve.

And I think at Cleveland Clinic, we pride ourselves with being able to offer those services to our patients. And for us, the patients always come first.

Dr. Scott Steele: Well said. Well said. Dr. Hanna, anything to add to that?

Dr. Rabi Hanna: No. Very well said by Dr. Erwin. We really have a comprehensive program, and the soonest that the patient could come, they could benefit from early second opinion or care here.

Dr. Scott Steele: Fantastic. And so for more information on Cleveland Clinic's lysosomal storage disease program, please visit clevelandclinic.org/lsdiseases. That's clevelandclinic.org/l as in Lima, S, as in Scott, diseases. You can also call 216.636.1768. That's 216.636.1768.

And again, you've heard me say it many, many times, so please remember that it's important for you and your family to continue to receive medical care, regular checkups, and screenings. And rest assured, here at Cleveland Clinic were taking all the necessary precautions to make our facilities safe and protect our patients and caregivers.

To the both of you, thank you so much for joining us on Butts & Guts.

Dr. Angelika Erwin: Thank you for having us.

Dr. Rabi Hanna: Thank you so much.

Dr. Scott Steele: That wraps things up here at Cleveland Clinic. Until next time, thanks for listening to Butts & Guts.