Fabry disease is an inherited disorder related to an enzyme deficiency and causes many symptoms. This discussion on Fabry disease features both a patient who has this condition, Jerry Walter, and nephrologist Dr. Gerald Hladik, who is the Doc. J Thurston Distinguished Professor of Medicine and Chief of the UNC Division of Nephrology and Hypertension.
“Growing up, I didn’t know I had Fabry disease, as is the case in most families. So, things were hard sometimes. Physical activity was hard, being in the heat was hard…It all made sense later on in life when I was diagnosed.”
– Jerry Walter
Ron Falk: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.
As the newest addition to our series where we discuss different genetic diseases, today we will talk about Fabry disease. We are going to be talking about Fabry disease with a patient who has this condition, Jerry Walter, and with his kidney doctor, Dr. Gerald Hladik.
We welcome today United States Army Colonel Jerry Walter, who has Fabry disease. He also is the founder and president of the National Fabry Disease Foundation.
We welcome Dr. Gerald Hladik, who treats Jerry for his kidney disease, for Fabry’s. Dr. Hladik is the Doc J. Thurston Distinguished Professor of Medicine and Chief of the Division of Nephrology and Hypertension at UNC.
Welcome, Jerry Walter and Jerry Hladik.
Jerry Walter: Thank you, Dr. Falk.
Gerald Hladik, MD: Thanks so much.
A genetic disease causing an enzyme deficiency
Falk: Let’s begin by asking the question of, what is Fabry’s disease?
Hladik:Fabry’s disease is an inherited, X-linked genetic lysosomal storage disease. The lysosomes are that part of the cell that basically help recycle materials in the cell. Basically, they are your body’s cellular digestive system. What happens in Fabry’s disease is a deficiency of a very important enzyme called alpha-galactosidase A, which results from a genetic mutation.
This enzyme deficiency leads to a buildup of a fatty material in the cell, that mucks up the cell—it’s called a substrate. The formal name is globotriaosylceramideor GL-3 in blood vessels. It affects the kidneys, the heart, the nerves, and essentially every cell and organ in the body.
Falk:So just in brief, then, Fabry disease is a disease where the cell can’t get rid of a normal product that is supposed to be digested, that is supposed to be metabolized, and now, because of an enzyme deficiency, that material accumulates.
Falk: And an enzyme is something that normally breaks down proteins, fats, and carbohydrates. We all have them—it’s how you digest food. You break down food by a variety of enzymes. This is an enzyme that’s in a cell, trying to help process a normal constituent of all of us.
Hladik: Correct, and within the cell of Fabry disease, the culprit is a fatty material.
Falk: That fat, then, accumulates inside the cell, damaging the cell’s ability to function.
Falk: When that cell becomes damaged, it will have different effects, depending upon where that cell was. If it’s in the kidney, it would damage the kidney. If it were in another part of the body, it could potentially damage another part of the body.
Hladik: Precisely, and we know that the organs that are predominantly involved are the kidney, the heart, the vasculature—and that has ramifications for injury to the brain, for example.
Falk: When you say vasculature, you’re talking about blood vessels everywhere?
Falk: All sizes?
Hladik: All sizes, virtually every cell in the body. This accumulation starts very early. In fact, you can see accumulation of these fat byproducts at the level of the placenta.
Falk: From the very outset, this lack of this enzyme results in accumulation over time of deposits of this material.
Hladik: That’s right.
Falk: The material is called..?
Hladik: Globotriaosylceramideor GL-3 for short.
Falk: That’s easier to say than trying to say the whole name. If one could have the enzyme and give it back, it would help ameliorate the condition.
Hladik: Right, it doesn’t cure, but it certainly does delay the progression of the disease.
Falk: There are different kinds of Fabry’s disease, is that right?
Hladik: Yes, there are. The most well-known form of Fabry’s disease that comes to attention, so-called “classic Fabry” manifests during childhood, with episodes of painful crises. These are episodes of severe pain due to neuronal injury that lasts several hours to days. They’re triggered by stress, lack of sleep, extremes of temperature, and even physical exertion. This begins in childhood. Children also experience a variety of GI symptoms—diarrhea, nausea, vomiting, abdominal pain—they may have heat or cold intolerance. In fact, they’re unable to effectively sweat.
Falk: Those are the conditions that are primarily seen in children.
Hladik: That’s right, and then by the time of adolescence, we start to see organ injury.
Falk: But there are all types of what is encompassed under the term Fabry’s.
Hladik: That’s right, there are some non-classic forms. There’s a cardiac variant that often presents later in life, and there are certain mutations that cause a renal variant that may not have primary injury to nerves, for example.
Falk: They are more difficult to diagnose, because they don’t have this systemic total body presentation.
Hladik: That’s correct, and in fact, with the cardiac variant, it’s estimated that perhaps three percent of patients who have unexplained left ventricular hypertrophy later in adulthood may in fact have the cardiac variant of Fabry disease.
Diagnosing & treating Fabry disease
Falk: How then, do you diagnose Fabry disease, especially in an older individual, in whom the classic manifestations in childhood are not apparent?
Hladik: Well, certainly you have to look at the family history to see if there’s this pattern of an X-linked inheritance of cardiomyopathy in a family that remains unexplained.
Falk: What’s a cardiomyopathy?
Hladik: That’s an injury to the heart where the heart no longer functions normally. The pumping of the heart is impaired.
Falk: The muscle is no longer able to contract like it should.
Falk: What about other organs? How do you detect it there?
Hladik: The best way to detect it in organs is with biopsy, but we rarely have to do this, because we can often make the diagnosis with blood or genetic testing.
Falk: What kind of tests are there?
Hladik: There’s an enzyme that we can measure in the blood. We can actually measure alpha-galactosidase A, and that’s what we use to diagnose the disease in men.
A level less than three percent essentially makes the diagnosis. Now you have milder forms where the enzyme is between three and thirty-five percent, and in that range in males, further genetic testing is necessary to make a definitive diagnosis. It turns out, in females, that measuring the enzyme level in the blood is not sufficient to make a diagnosis. In those cases, you actually have to do genetic testing.
Falk: Are we now past the era when one has to do a biopsy? For example, a kidney biopsy to determine whether a patient has Fabry’s disease?
Hladik: Well, there are, in rare circumstances, patients who may have a borderline low enzyme level activity, where there is kidney disease that’s otherwise unexplained, where you may want to consider doing a renal biopsy.
Falk: How often does a biopsy need to happen, when compared to ten or fifteen years ago?
Hladik: I would say it’s quite rare. I can’t put a number on it, but I have not had to do this in my clinical experience.
Falk: Because the enzyme testing and the genetic testing is now so good.
Hladik: That’s right.
Falk: How then, does one treat Fabry disease, of all kinds?
Hladik: The cornerstone of therapy is enzyme replacement therapy. This became available in the US in 2003, it was available in Europe in 2001. Now, it’s not cheap, and it’s not convenient. It requires an intravenous infusion every two weeks.
Falk: Wow. We’re going to talk more about that enzyme replacement therapy in a subsequent podcast, so let’s move back to the patient and your interaction with them.
Common concerns that people with Fabry have
Falk: When you see someone with Fabry for the first time, what kind of concerns are the most common?
Hladik: As you can imagine, there are many concerns. One of the biggest concerns is fear of what lies ahead. There’s also a lot of questions that arise. Patients ask, “How will I suffer? Can I lead a normal life? How will this impact my family? Can I have children? What’s the risk of passing the disease on to children? What about the pain of Fabry disease—can it be controlled?”
Falk: Why is there pain? Is that because of the neuropathy?
Hladik: That’s correct. Remember, during childhood that’s often one of the first manifestations of disease—these painful crises.
Falk: And how do you answer all those questions?
Hladik: Well, I think what we want to do first is give patients hope that there is effective treatment for Fabry, that the outcomes have improved considerably, and that we’re on the cusp of new discoveries that will help transform treatment and improve their lives in the future.
Falk: Jerry Walter, you are a patient with Fabry’s disease, and someone who had an illustrious career in the armed forces, and now are the president of the National Fabry Disease Foundation. Tell us a little bit more about you.
Walter: Thanks, Dr. Falk. I learned I had Fabry disease when I was about twenty-five years old—not through testing, but my mother was in the hospital for an unrelated issue. The physician noticed that her eyes were bulging, and bulging eyes is not a symptom of Fabry disease. But it caused the physician to look closer, and he found a characteristic corneal whorling that’s in the majority of people with Fabry disease. She was diagnosed, which led to about eighteen other people in my family being diagnosed with Fabry disease.
Falk: By chance, in other words. Because eye bulging is definitely not part of this disease.
Walter: That’s right.
Falk: It made the physician look more closely at your mother’s eyes.
Walter: Yes, very fortunate for our family, and for the health and well-being of everyone.
Falk: Tell us a little more about you, after the discovery in your mom.
Walter: I’d like to go back a little further. Growing up, I didn’t know I had Fabry disease, as is the case in most families. So, things were hard sometimes. Physical activity was hard, being in the heat was hard. I had low self-esteem because of the things I couldn’t do. You know, I always felt a little bit inadequate because of limitations. It all made sense later on in life when I was diagnosed.
Experiencing and coping with symptoms
Falk: Let’s go through those symptoms in a little bit more detail. What does heat do to somebody who has Fabry’s?
Walter: Well, we don’t sweat properly, so anhidrosis or hypohidrosis—reduced sweating or absence of sweating causes pain, makes you feel bad. Life is hard in that way. If you get out in the sun where you exercise too much, and you don’t sweat, it makes you feel bad and gives you pain. It triggers the peripheral neuropathy I think that happens with Fabry.
Falk: When did you enter the armed forces?
Walter: Initially when I was eighteen years old.
Falk: Help me understand—you had a diagnose of Fabry’s made at the age of twenty-five and you must have gone through basic training when you were eighteen. How on earth did that work?
Walter: Well, I think we found that it’s common for kids to have a lot of the initial symptoms of Fabry disease–pain, lack of sweating, GI issues–then for many children they get better as they become older teens and on through their early twenties. You seem to get a reprieve. Then I think that will end. Along with the fact that I started in the Air Force, that wasn’t as bad as the Army, so you only had to do a one mile run once a year in the Air Force to pass your physical fitness test. That helped quite a bit.
Falk: That’s not true in the Army, though.
Walter: That’s not true, no.
Falk: You were in both, the Air Force and the Army, so you managed to get through basic training at the age of eighteen.
Walter: Right. I think I had a reprieve in symptoms, which helped—not entirely, because I still struggled quite a bit. I was an underachiever in the Air Force physically. More so in the army. I got out of the military after eight years in the air force, went to school, got back in the military, and then I went through some really, really difficult times physically but I just seemed to always get through it.
Falk: Explain or describe some of those difficult times.
Walter: Well, they made us sweat a lot more, or made us do things that would cause people to sweat a lot more, but of course, I didn’t, so I overheated easily.
Falk: Did you pass out?
Walter: I never passed out. The worst situation I could remember, was we were on a fifteen-mile road march in the Army. Luckily, it was at night, and it was raining a little bit, which made it better for me, but still the kind of hot and tired that I was, was different than most of the people around me.
By the end of the road march, everyone had something of mine—someone was carrying my weapon and my rucksack, my canteens, and everything. I had my shirt off and was dumping canteens of water over my head, I was beet red in the face, but I made it. At the end of the march, of course I had lost control of my bodily functions, I was really in tough shape—but I survived the march. That’s sort of the story of my entire military career: I survived it.
Falk: But that’s quite the story of that march, because you had no idea why you couldn’t do it.
Walter: Right. As a kid, it was always the same. I would have to stop doing things other kids were doing. We would play baseball and I would have to quit early. We would do one thing or another, and I would quit early. I always walked away hanging my head, thinking it was just me, I wasn’t tough enough. Of course, I had six brothers, which made that even worse. Some of them were over-achievers physically and I was the underachiever.
Falk: As you have moved on in age, what are the symptoms that have bothered you now the most?
Walter: So, we can separate the symptoms into two things—quality of life, and life-threatening. The quality of life symptoms of course are pain and chronic GI problems which have ruined my life from time to time..
Walter: For me, irritable bowel syndrome, like diarrhea symptoms. So, I just did the best I could. I could get some medications that would help a little bit, but it wasn’t until enzyme replacement therapy that that really got better.
Today, it still flares up. Pain, overheating from not sweating, GI symptoms, were always bad. Of course, later on in life it turns into heart disease, kidney disease, lung disease—which I have all of. I have a pacemaker defibrillator, thickening of the left ventricular wall of the heart. Chronic kidney disease—but for me, unlike a lot of people with Fabry, my kidneys have held up pretty well, so I’m chronic kidney disease stage one and I seem to be stable, thanks to Dr. Hladik for keeping me that way.
My heart has caused me some problems—that’s the worst thing that’s going on with me now.
Learning to adapt
Falk: Through all of this, how have you managed your career? – because you’ve managed it incredibly well.
Walter: Well, I think fortunately for me, being an underachiever physically, and being on the bottom of the pile, I did a lot of things to make myself an overachiever in other ways. I learned skills: I became a strategic planner, an operations officer, I did courses on analytical decision making on lots of other things. They made me a financial manager. So, I took these courses and learned extra skills and became more valuable to the organizations I’ve worked for. They could easily have overlooked me, being an underachiever in the physical department, but I always passed the test.
Although, I would say that for a person with Fabry disease, for instance, you get a lot of chronic swelling, edema, in the lower legs. Anytime that I thought I was in trouble on a given day that we were doing a physical activity, a test, I could go to the clinic and say, “Look at my legs,”and get a reprieve for a short time. You always had go back and make it up, but on days I knew I wasn’t going to do well, I got a break, went back and took my test a week later, and would pass it. I found ways to compensate and to get through, and then later on was behind a desk the last two-thirds of my career.
Falk: Anybody with a chronic condition learns how to adapt, and everybody who learns to adapt figures it out best for themselves.
Walter: Right. It wasn’t always easy, but it worked. I felt guilty sometimes taking that road and saying I can’t do this, knowing if I do this today I’m going to fail, so I’m going to do it another day when I have a better chance of passing.
Falk: How would you help patients who have that same feeling of guilt get over the guilt?
Walter: Well, I talk to patients all the time, and I tell people that you’re going to find things you can’t do, but I tell people, “Try everything, see what you can do. If you can’t do something, do something else. If you can’t run, ride a bike. If you can’t ride a bike, walk. Find other ways to stay healthy, physically and mentally.” Don’t feel bad about what you can’t do. It’s not your fault that you have Fabry disease, it’s not your fault that these things happen.”
Falk: Right. One feels guilty about not being able to do things at times, but in reality, with Fabry’s and other genetic diseases, there really should be no guilt, because there’s nothing the individual can do anything about.
Walter: The feeling that people should have is just the opposite. They should be proud that they’ve overcome a lot of these things and they push through them, they make it work, and they have successful lives and successful careers and manage what they have to deal with.
Falk: Regardless of the obstacles.
Falk: When did you meet Dr. Hladik?
Walter: Same time I met you, in 2008. I came to UNC for an unrelated problem—I had bacteremia. I had life-threatening bacteremia. It was the second bacteremia infection I had had in a year. You introduced me to Dr. Hladik, and we’ve been great partners ever since.
Hearing loss with Fabry disease
Falk: You’re wearing a hearing aid. Tell us about hearing loss in Fabry’s.
Walter: Well, hearing loss can happen suddenly or progressively. In my case, it’s been a progression. Hearing loss is usually complicated by other factors, other than just Fabry disease. In my case, Fabry disease is responsible for part of my hearing loss. I also worked around jet engines for many years, and I had bacterial meningitis, which took quite a bit. But in most people with Fabry disease, hearing loss is a concern. Mine was progressive. It’s one of the symptoms that doesn’t tend to start early. So, later in life you start losing your hearing, as many people do, but the loss can be much greater and often more sudden with Fabry disease.
Falk: Loud noises are not good for anyone with any kind of hearing loss.
Walter: I think it’s hard to deal with, but with all the technology today, I have hearing aids, I have this device I carry around with me sometimes. It’s a microphone that plugs right into my hearing aid. You can get other devices that help—I have a special phone. My hearing loss is pretty profound. Without hearing aids, I can’t hear anything, but I have the tools to keep me viable and communicating with the world.
Falk: That’s wonderful.
How the National Fabry Disease Foundation got started
Falk: Tell me about the National Fabry Disease Foundation and how it helps people with Fabry’s.
Walter: In 2005, I thought I was going to retire from the military in 2007. I was on my way to Washington, DC to retire the next day. Instead of retiring, I went into a coma.
I got to DC and I was disoriented, I made it to the clinic and gave them my wife’s phone number. They said “Let’s get your vitals,” and I said, “You better write this down.” A couple minutes later, I went into a coma.
I had severe bacterial meningitis and they told Angela I probably wouldn’t live through the night. That postponed my retirement. You can’t retire from a coma, and that put me in a situation where I went into a medical retirement process. The military kept me for four more years. I didn’t actually retire from the military until 2011. Meanwhile, I wasn’t up to speed for doing most things and I started the National Fabry Disease Foundation in 2005 intending to retire in 2007, and I didn’t, so my job while I was on medical retirement process was just forming the organization.
Having a supportive partner
Falk: What’s it like being married with Fabry’s disease?
Walter: Well, in my case, my wife is also very educated about Fabry disease. She’s a genetic counselor and I have the perfect partner to help me get through everything that I deal with on a daily basis. Between us, we’re pretty tough.
Falk: Patients with any kind of chronic disease, any kind of chronic condition, having a partner to help with all the vicissitudes that confront one is just so important.
Walter: Right, and she just understands. I think I’m a pretty tough guy, but she understands when I can’t do something or when we have to stop doing things because of Fabry.
A message of hope about Fabry
Falk: Right. One last and final question for each of you. If you could share one message for people about Fabry disease, what would it be? Dr. Hladik, let’s start with you.
Hladik: I think the key is that there’s hope on the horizon, and I think Jerry will tell you about how things have improved in his lifetime, so never lose hope.
Walter: I think that we’ve come so far, and the prognosis for people with Fabry disease is much brighter than it used to be. We have a definitive laboratory test, we have two treatments that are available and more to come. We have many symptoms that can be recognized to diagnose Fabry, so diagnosis is improving. I think our outlook for people with Fabry disease is much brighter than it ever was.
Falk: Thank you, Jerry Walter, and thank you Jerry Hladik, for joining us today.
Hladik: Thank you.
Walter: It’s been a pleasure to be here.
Falk: Thanks so much to our listeners for tuning in. We will be recording another episode with Jerry and Dr. Hladik focused on new treatment for Fabry disease, one of which is called Galafold. Please stay tuned. You can subscribe to the Chair’s Corner on iTunes, SoundCloud, or like us on FaceBook.