Fabry Disease

Guide and Podcast

Podcast

Author and Contributing Experts to this Guide include:

Jessica Bucher Genetic Counselor, MSGC LinkedIn
Lut de Baere President of the Fabry International Network LinkedIn

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What Is Fabry Disease? 

Fabry disease is an inherited multi-organ metabolic disorder that is caused by a build-up of a type of fat called globotriaosylceramide (GL-3) in the body's cells.

It is also known as a lysosomal storage disorder because the part of the cell that holds a certain enzyme (lysosomes) cannot break down GL-3. When GL-3 can’t be processed properly, it produces symptoms that affect many parts of the body.

Cases range from mild to severe, depending on which type of Fabry disease you have, your age, and whether you’re a male or a female. Typically, if one person in a family has the condition, then there is a high probability that others in the same family have Fabry disease as well. However, the degree of severity is hard to predict. But overall, milder and late-onset forms of the disease are more common than severe forms.

In some cases, as it progresses, Fabry disease can be life-threatening and can cause kidney damage, strokes, and heart attacks.

Fabry disease is also known as:

  • alpha-galactosidase A deficiency
  • Anderson-Fabry disease
  • angiokeratoma corporis diffusum
  • angiokeratoma diffuse
  • ceramide trihexosidase deficiency
  • Fabry's disease
  • GLA deficiency
  • hereditary dystopic lipidosis

There are two identified types of Fabry disease. They are type 1 classic phenotype and type 2 later-onset phenotype, more commonly referred to simply as classic or later-onset.

Signs and symptoms of Fabry disease 

Fabry disease can be initially difficult to diagnose.

“There have been studies that had shown that individuals started showing symptoms on average about 16 years before they were diagnosed correctly with Fabry disease. The symptoms tend to overlap with many different conditions,” according to board-certified genetic counselor Jessica Bucher.

When signs and symptoms do appear, they can include:

  • Pain in the extremities (typically hands and feet)
  • Heat intolerance
  • Cutaneous lesions or small marks that are red to blue-purple, mostly on the lower trunk area of the body, and often a thickened area of skin where that mark is (angiokeratomas)
  • Sweating abnormalities, including reduced or absent sweating (hypohidrosis or anhidrosis) 
  • Lung fibrosis that can cause interstitial lung disease
  • Obstructive airway disease
  • Cloudiness in the front part of the eye (corneal opacity)
  • An otherwise unexplained stroke 
  • Left ventricular hypertrophy (thickening of the left ventricle of the heart) 
  • Mitral valve prolapse
  • Atrial fibrillation
  • Poor functioning kidneys 
  • Delayed puberty
  • sparse hair growth
  • malformation of the joints of the fingers (in rare cases)
  • Frequent bowel movements after eating
  • Protein or albumin in the urine
  • Digestive or gastrointestinal issues such as stomach pain, nausea, and vomiting
  • Tinnitus (ringing in the ears) or hearing loss
  • Dizziness and vertigo
  • Depression

Symptoms are usually milder in females, and some females with a known GLA mutation may not develop any symptoms at all.

“There are actually two variant forms, including the heart or kidney forms. And those individuals might only affect people later in life,” added Bucher.

Causes of Fabry Disease 

Mutations in the GLA gene cause Fabry disease. Other names for this gene also include:

  • AGAL_HUMAN
  • Agalsidase alfa
  • Alpha-D-galactosidase A
  • alpha-D-galactoside galactohydrolase
  • Alpha-galactosidase
  • alpha-Galactosidase A
  • ceramidetrihexosidase
  • GALA
  • galactosidase, alpha
  • Melibiase

This gene normally provides instructions for making alpha-galactosidase A, an enzyme that is active in lysosomes. Lysosomes play a critical role in conveying important information in cells.

Under normal conditions, Alpha-galactosidase A breaks down a fatty substance that contains three sugars called globotriaosylceramide (GL-3).

"An enzyme is a protein that helps the body with the breakdown of certain metabolic processes. I think of enzymes sometimes like a line at a car factory, and if an individual is slacking off on their job, then the car can't be made appropriately, or perhaps that process doesn't work at all. Enzymes work in that same way," says Bucher.

When the GLA gene mutates, it can alter the structure of the enzyme and keep it from effectively breaking down globotriaosylceramide. Normally, this molecule degrades as part of the recycling of old red blood cells and other types of cells.

The result is a build-up of globotriaosylceramide in cells throughout the body, especially in cells lining blood vessels in a person's skin, kidneys, heart, and nervous system. The greater the build-up, the more progressive the damage is to the cells, leading to outward signs and symptoms of varying severity.

The GLA gene can mutate in many different ways. Currently, more than 370 mutations have been identified and associated with Fabry disease. Some of these mutations only decrease but do not eliminate the enzyme's activity. When this happens, milder forms of Fabry disease result or late-onset forms may only affect the kidneys or the heart. 

Mutations may only affect a single amino acid in alpha-galactosidase A. In other cases, mutations may delete part of the GLA gene or add extra genetic material to trigger an abnormal function. In other cases, a mutation may include directions that will trigger a premature stop signal to instructions for the gene to make alpha-galactosidase A.

Genetic Pattern of Inheritance of Fabry Disease 

The GLA gene is located in the X chromosome, making it an “X linked genetic condition.”

“Females typically have two X chromosomes, and males have one X chromosome and one Y chromosome. Individuals who have Fabry disease typically have a mutation or a spelling error. When our body reads through that certain chapter of our body's instruction manual, it may find that there is a spelling error on the X chromosome in the GLA gene,” according to Bucher.

Females have two copies of the X chromosome, so one altered copy of the gene in each cell more often than not leads to less severe symptoms in females than in males. In some cases, there may be no symptoms at all.

“A clinical occurrence called lyonization takes place when females actually turn on or off certain X chromosomes. They only use one of the X chromosomes, and females who turn off the non-working copy of the GLA gene would not have as significant features as a female who turns off the working copy of the GLA gene.”

“People only use one of those GLA genes even though females have two. That's why males, who only have one GLA gene don't have that other safety net. That means they will have Fabry disease more severely typically than females,” says Bucher.

The chance of inheriting a mutated GLA gene for Fabry disease depends on whether it came from the father or the mother.

For each pregnancy:

  • A woman with Fabry disease has a 1 in 2 chance of passing on the mutated GLA gene to her son or daughter.
  • A father with Fabry disease will always pass on the mutated GLA gene to his daughter. But the father will never pass on the mutated GLA gene to any of his sons, because sons always get their X chromosome from their mother.



Risk Factors for Fabry Disease 

Studies indicate that Fabry disease affects one in 40,000 to 50,000 people in all ethnic backgrounds in the United States.

That includes variable forms in people who went undiagnosed and may continue to be undiagnosed because they have no symptoms or only mild symptoms.

Because it is an X linked genetic condition, males are more likely to develop Fabry disease and typically have a more severe form.



Complications Associated with Fabry Disease 

Several life-threatening complications can arise from Fabry disease. Some of these include:

  • Renal failure resulting from progressively worsening kidney damage.
  • Cerebrovascular complications, including heart disease, heart attacks, or strokes caused by the accumulation of fatty deposits that block the flow of blood to certain parts of the body.
  • Left ventricular hypertrophy, an enlargement, and thickening of the walls of your heart's main pumping chamber.
  • Neurological manifestations, including hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, headaches, hemiataxia and dysmetria, cerebellar gait ataxia and in some cases, cerebral hemorrhage, lesions (white matter lesions).
  • Proteinuria, the presence of higher than normal amounts of protein in a person's urine.



Diagnosis of Fabry Disease 

Diagnosing Fabry disease can take place in two different ways.

For males, an enzyme blood test can measure the level of alpha-galactosidase A. Males with classic Fabry disease have virtually no alpha-galactosidase A enzyme (less than 1% of normal). Males with a non-classic Fabry gene mutation have some of the enzyme but will still be very low. 

A DNA test can analyze the GLA gene and look for a mutation. A DNA test is required when testing a female because enzyme levels may be low or near-normal in females. DNA tests are performed using blood or saliva. 

If a family member has Fabry disease, testing for the GLA gene can be targeted to that specific mutation or that particular address in the gene instead of looking through the entire GLA gene for the mutation.

The age at which Fabry disease is diagnosed can vary quite a bit. Often it is driven by symptoms if there is no known family history of the condition.

When it is known that a parent has Fabry disease, a genetic counselor may discuss the possibility of a prenatal genetic test via chorionic villus sampling or amniocentesis if the parents are interesting in knowing that information during the pregnancy. In some states, newborns are automatically screened for Fabry disease on their newborn screening panel.

“It’s best to discuss prenatal testing options with a genetic counselor since there is variability in individuals who have Fabry disease. By doing prenatal testing, it may not be certain how severely an individual will be affected based on that prenatal testing result. Especially if the couple identifies that a pregnancy is female,” said Bucher.

“There's also the option of pre-implantation genetic diagnosis. It’s possible to test an embryo after a couple of goes through IVF treatment. The couple’s doctor can test that embryo to determine if the embryo has a GLA gene mutation. They would only implant embryos that do not have that GLA gene mutation," she added.

“Fabry can have a wide range of age of onset and severity, but for males, the median age of onset is around nine years of age. But people don't usually get diagnosed on average until about 24 years of age,” said Dr. Jaime Barea, a clinical and a biochemical geneticist, and the chief medical officer at DNAFeed, a genetic counseling company

For females, the condition is usually milder, but it can be as severe as in males. The median age of onset is a little bit later at 13 years of age. But they don't get diagnosed until about 31 years of age. But in both cases, in both sexes, there are many people out there that have symptoms and get diagnosed much later in life,” added Dr. Barea.

Some people might be diagnosed later than age 25 if they have the renal variant. People who have the cardiac variant may not show signs until after age 40.

Often, a person may have Fabry disease but may not have been diagnosed with it and end up suffering without proper treatment. That frequently happens because Fabry disease can be hard to diagnose.

“Even though it runs in families, I feel like this is a condition that is very underdiagnosed, so people are suffering more than they should without the proper treatment,” said Dr. Barea.

Barea also explained that genetic counselors must be a bridge between patients and help them understand how they might be eligible for testing through different sources. "Directing them to the proper providers is vital, so if they do have the condition, and a test confirms it, they can get the proper treatment and management."

That’s a sentiment that’s also echoed by Lut De Baere, president of Fabry International Network and the president of the Belgium Patient Organization for Rare Diseases.

“Genetic counselors are very important. They must educate the family because it's such a family disease. When you find one, you must do a family pedigree so that you can see if others are affected,” said De Baere.

“General physicians are not always aware of the disease, so there is a lot of education to do for that. They need to be aware when people, including children, have some symptoms, like tingling in their hands, or they get the red spots on the skin. They must be aware, and perhaps check to see if it's Fabry disease,” added De Baere.



Treatments and Care Options for Fabry Disease 

Currently, there is no cure for Fabry disease.

There are several possible treatment and care options for someone who suffers from Fabry disease. They include:

Enzyme replacement therapy (ERT) with agalsidase-alpha (Replagal) or agalsidase beta (Fabrazyme) helps normalize kidney and heart functions, and blood supply to the brain. Patients getting ERT typically receive the enzyme every other week to slow the progression of the disease, reduce complications, and possibly prevent long-term complications.

An FDA approved chaperone therapy is called Galafold, or migalastat. It stabilizes the body's dysfunctional enzyme so that it can work better. Migalastat is a pill taken daily that is only prescribed for specific GLA gene mutations that have been shown to respond to this drug.

Other treatments will focus on mitigating individual symptoms:

  • To prevent pain and burning sensations, phenytoin (Dilantin), carbamazepine (Tegretol), or gabapentin (Neurontin) can be prescribed. Opioids are sometimes prescribed for severe pain.
  • Antiplatelet drugs such as aspirinticlopidine, clopidogrel (Plavix), and aspirin-dipyridamole (Aggrenox) are prescribed to prevent recurrent ischemic strokes.
  • In some cases, heart bypass surgery is needed to mitigate heart problems. If the heart condition is bad enough, a pacemaker may also be implanted to regulate the heart's rhythm.
  • Warfarin (Coumadin) may be prescribed to prevent cardioembolic strokes.
  • A kidney transplant or hemodialysis may be required for patients with severe Fabry disease that has progressed to kidney failure. 
  • To ease gastrointestinal problems, a doctor may prescribe pancrelipase (Ultrase), metoclopramide (Reglan), or H2 blockers, including ranitidine (Zantac), cimetidine(Tagamet), famotidine (Pepcid), and loperamide (Immodium).
  • ACE inhibitors and blockers are prescribed for proteinuria due to kidney damage.
  • Patients with hypertension may be prescribed antihypertensive medications to keep blood pressure under control.
  • Skin rashes don’t always cause discomfort, but when they do, they may bleed, and can be removed with laser treatment. 
  • Hearing loss is often gradual, but at times, it can be sudden, requiring the implantation of a hearing aid.

“For some people, diet changes can help. Things like eating smaller meals, taking probiotics, and avoiding some specific foods to decrease some of the GI issues that you might have.

“A big part of this condition is pain. Besides getting the pain medications with your doctor, there are also alternative treatment strategies for pain that people may use like physical therapy or acupuncture. Because sometimes even with traditional treatments like enzyme replacement therapy, not all the complications of Fabry disease can be resolved,” said Dr. Barea.

Currently, there is no known cure for Fabry disease. However, there is a gene therapy approach in the clinical trial experimental stages that might one day lead to a cure. The idea is to introduce a healthy copy of the GLA gene to restore normal levels of the alpha-galactosidase A enzyme.

For many people, insurance may very well cover the costs for treatment.

“Insurance is very complicated, and it's getting more so every year. But most people with insurance that get diagnosed with a condition do have a lot of their treatments covered because it is an established treatment option, and FDA approved for the condition,” added Dr. Barea.

The Prognosis for Fabry Disease 

The complications from severe or advanced Fabry disease can be fatal.

This does have an impact on the prognosis for someone with Fabry disease and is reflected in the fact that the life expectancy in males with Fabry disease is 58 years vs. 74 years in the general population. 

In females, the average life expectancy is 75 years for someone with Fabry disease, in comparison to the female general life expectancy of 80 years.

The severity of the symptoms will determine the prognosis of what the quality of life will be.



What to do Next: Living with Fabry Disease 

There are several resources that you can access to help you get more information on Fabry disease:

Start with the Fabry International Network for a good patient-centric place for information. The organization is connected to more than 50 countries and 64 patient organizations around the world. 

The National Fabry Disease Foundation (NFDF) supports the Fabry disease community and is an excellent resource for patients and families affected by this condition.

The National Institute of Neurological Disorders and Stroke has extensive information about the disease as well.

Also, access the International Center for Fabry Disease at the Icahn School of Medicine at Mt. Sinai in New York.

The National Kidney Foundation has information on Fabry disease.

ClincialTrials.gov also maintains a Fabry disease registry and can give you information on current testing and trials related to this condition. 

Fabry Support & Information Group

Phone: (660) 463-1355

Website: http://www.fabry.org

Fabry Disease

Hear from the experts in our conversations on a rare genetic disease: Fabry Disease. We cover Fabry disease diagnosis, new treatment options, and how to connect with the Fabry community.

Experts in this episode include:

  • Jessica Bucher, a board-certified genetic counselor and graduate of Northwestern University

  • Dr. Jaime Barea, he is a clinical geneticist at the University of California-San Diego.

  • Lut de Baere. She is the President of the Fabry International Network and gave us a deeper look at their organization, which supports patients diagnosed with Fabry disease with events, resources, updated information and much more.

More resources and information for you: raredisease.com/fabry

Transcript

Nate: You're listening to the Rare Disease Connection, a production of Aspect Health and raredisease.com. There are roughly 7,000 rare diseases and estimates are that a rare disease affects nearly one in 10 Americans and hundreds of millions of people worldwide. When you hear numbers like that, it's clear that rare diseases aren't so rare and it's impossible to know how many rare diseases go undiagnosed. What we do know is this, with continued advancements in technology and testing, more people than ever are finding out that they or a loved one, or someone in their family has a disease that up until yesterday they'd never heard of. If that person is you, you have more questions than answers and that's why we're here.

Nate: With Rare Disease Connection and our additional resources on raredisease.com and yourdna.com, we bring together the people whose expertise can explain what you're facing from diagnosis to prognosis, to treatment options, all the way to questions like who do I talk to? Who are the people who've been through this before? You'll find those answers here. It's been said to us that being told you have a rare disease, feels like you've been dropped into the middle of the ocean without a life raft. It's a sinking feeling, no doubt. But there's a world full of doctors, geneticists, academics, genetic counselors, patient organizations, other patients and their families all within your reach. And we're here to connect to you. This is Rare Disease Connection. (music)

Nate: Hey everyone. This is Nate, cohost of Rare Disease Connection and confounder of Aspect Health. I'm excited to bring to you some recent conversations we've had with experts from around the world about a very specific rare genetic disease, Fabry disease. Of course, every disease we cover here on Rare Disease Connection comes with a loaded set of questions about what the disease is, who it affects, and what your plan of action can be if this disease affects you or a loved one.

Nate: We figure who better to answer those questions for you then the experts that you otherwise might not be able to track down? Well, they're here with us to talk all things Fabry, so let's get started. Our first conversation is with Jessica Busher, a board certified genetic counselor and graduate of Northwestern University. Let's let her introduce herself and then we'll talk through defining this disease, how it's diagnosed and who it affects.

Jessica Bucher: I graduated from the Northwestern genetic counseling program back in 2010 and since then I've primarily worked in pediatric genetics, first at Lurie Children's Hospital in Chicago and then at Advocate Lutheran General. I did a little bit of prenatal in my career as well. I was the clinic coordinator for the Marfan Syndrome Clinic and also participated in many of the planning meetings for the conferences that we held there. Since then, for the last two years I've been living in Bratislava, Slovakia, and have started my own contracting business and worked a little bit with some other genetic organizations while I live abroad. But hope to return to the US soon.

Nate: Very nice. The topic today is Fabry disease. Speaking from your experience as a genetic counselor, what immediately comes to mind when you hear the words Fabry disease?

Jessica Bucher: When I hear about Fabry disease, I'm automatically thinking about the surprise because we recently rolled out the newborn screening program in the state of Illinois. We were really shocked at actually how common and how frequently this condition was coming up. It's also an example of a condition where treatment is really exciting and there are a lot of clinical trials in progress, but also the therapy that we're using in this condition can really hopefully make a difference for many people who are diagnosed earlier rather than later.

Nate: Okay. Let's talk about the science behind the causes of Fabry disease. What is the genetic pattern of inheritance for Fabry?

Jessica Bucher: Fabry disease is an X linked genetic condition, which can get somewhat sticky and complicating. But when you think of our gender, we know that females have typically two X chromosomes and males have one X chromosome and one Y chromosome. Individuals who have Fabry disease typically have a mutation or a spelling error. When our body reads through that certain chapter of our body's instructor manual, the GLA gene, and it may find that there is a spelling error on the X chromosome in the GLA gene. Males who only have one copy of the GLA gene because they have one copy of the X chromosome, typically have the condition. While individuals who are females may or may not have symptoms of the condition.

Jessica Bucher: That's because there is a complicated clinical thing called lionization where females actually turn on or off certain X chromosomes. They actually only use one of the X chromosomes and females who turn off the non-working copy of the GLA gene would not have as significant features as a female who turns off the working copy of the GLA gene. So we really only use one of those GLA genes even though females have two. But that's why males who only have one, they don't have that other safety net, they have Fabry disease more severely typically than females.

Nate: What are some of the signs and symptoms of Fabry disease?

Jessica Bucher: Fabry disease is a condition that can be really difficult to diagnose based on the first signs and symptoms. In fact, there's been studies that have shown that individuals started showing symptoms on average about 16 years before they were actually diagnosed correctly with Fabry disease. The symptoms tend to overlap with many different conditions. Some of those symptoms include pain in the extremities, typically the hands and the feet, certain cutaneous lesions or small marks that are red to blue-purple in color, and it's mostly on the lower trunk area of the body. There's also likely a thickened area of skin where that mark is. People can also have sweating abnormalities of any kind really, and cloudiness of the front part of the eye.

Jessica Bucher: Some people where you might think this could be Fabry disease is somebody who might have had an unexplained stroke or left ventricular hypertrophy. That means thickening of the left ventricle of the heart and poor functioning kidneys. That's an area where we find a lot of people who were not previously diagnosed with Fabry disease. That might include protein in the urine or albumin in the urine. People can also have digestive, gastrointestinal issues or ringing of the ears or hearing loss.

Jessica Bucher: Fabry disease can also lead to more serious complications. That might include progressive kidney damage, heart attack and stroke. Some people might have milder forms of the disorder and others might have more severe, so it's variable. That's what we call it in genetics when certain individuals might have a more severe form and others might have a more mild form. There are actually two variant forms including the heart or kidney forms. And those individuals might only affect people later in life.

Nate: Who actually gets Fabry disease? What population is affected by Fabry and how common is the disease itself?

Jessica Bucher: Fabry disease affects males and females of all ethnic backgrounds. Symptoms are typically more common and severe in males, as I mentioned before, because of that X inactivation. And we previously thought that Fabry disease affected about one in 50,000 individuals. But with the recent newborn screening studies, the condition was identified in as many as one in 3,000 newborns in several populations. That's including those variable forms, so much higher than we had originally thought. That's because many people with variant forms maybe went undiagnosed or there's possibly a lot of people out there who don't know they have Fabry disease and have been undiagnosed their entire life.

Jessica Bucher: The symptoms of Fabry disease are caused by an underlying genetic mutation or spelling error in the GLA gene. If an individual has a mutation in that GLA gene, then their body may not be able to produce an enzyme called alpha galactosidase A. An enzyme is a protein that helps the body with the breakdown of certain metabolic processes. I think of enzymes sometimes like a line at a car factory, and if an individual is slacking off on their job, then the car can't be made appropriately or perhaps that process doesn't work at all. Enzymes work in that same way.

Jessica Bucher: This specific enzyme, the alpha galactosidase A works in the lysosome of the cell, which I like to think of as a recycling plant of the cell. It helps with break down and reuse of different materials and proteins. Alpha galactosidase A typically breaks down a fatty sugar compound called GL3. So someone with Fabry disease may not have enough active alpha galactosidase A, and that's active enzyme, leading to a buildup of GL3 in the cell. That then causes a buildup in the tissues of the body and this buildup is what causes those symptoms. Someone has extra GL3 in certain tissues. Individuals with the milder form of Fabry disease may have some working alpha galactosidase A, while individuals with a more severe forum may make little to no working alpha galactosidase A.

Nate: At what age does Fabry disease appear?

Jessica Bucher: Classic Fabry disease may show symptoms on average around age six to eight in males and age nine in females. But the atypical, or as we said, the variant forms may show symptoms much later. For example, later than age 25 might be the renal variant and individuals who have the cardiac variant may show signs later than age 40.

Nate: Let's talk about the actual diagnosis of Fabry disease. Explain the current landscape for genetic tests for Fabry.

Jessica Bucher: Genetic testing for Fabry disease typically starts with a visit to a genetic counselor or a doctor. The testing may be recommended based on symptoms of Fabry disease, maybe a family history of Fabry disease or more recently, newborns are automatically screened for Fabry disease regularly on their newborn screening panel in certain states. Luckily, in the US there are a few laboratories that actually offer free enzyme and GLA gene testing for Fabry disease as part of sponsored programs. So while the visit to the doctor or the blood draw might be a cost to the patient, the cost of the genetic testing may not actually be a concern.

Jessica Bucher: The enzyme test measures the percentage of that alpha galactosidase A enzyme. The GLA gene testing is a DNA test or a spell check, looking for spelling errors, also known as mutations or pathogenic variants that cause Fabry disease. Ordering the right test is important though, and that's because a female with Fabry disease might have normal alpha galactosidase A enzyme levels, but they still may have a positive GLA gene test which identifies a mutation. Also, if a family member has Fabry disease, the testing for the GLA gene maybe targeted to that specific mutation or that specific address in the gene instead of looking through the entire GLA gene for the mutation.

Jessica Bucher: In summary, it's best to discuss that testing with a healthcare professional, but it's interesting to see that newborns are now being diagnosed much earlier, leading us to understand that more people than we thought have Fabry disease and we're also actually identifying parents who have had Fabry disease and never knew it.

Nate: Are there actual prenatal tests for Fabry disease?

Jessica Bucher: There are prenatal tests for Fabry disease, especially if a parent is identified to have Fabry disease and the mutation is identified. It is then possible to test that current pregnancy for Fabry disease via the process called chorionic villus sampling or amniocentesis, that's early in the pregnancy. And it would be best to discuss these options with a genetic counselor since there is variability in individuals who have Fabry disease. By doing the prenatal testing, it may not be certain how severely an individual will be affected based on that prenatal testing result. Especially if the couple identifies that a pregnancy is female.

Jessica Bucher: There's also the option of pre implantation genetic diagnosis if there is a known genetic change identified in the family and that is performed by testing an embryo. So after a couple of goes through IVF treatment, the individuals' doctors would be able to test that embryo to determine if the embryo has a GLA gene mutation and they would only implant embryos that do not have that GLA gene mutation.

Nate: Jumping I guess to the other side of your work as a genetic counselor. Talking more about the emotional side of this and dealing with a diagnosis. What is your best advice for someone who is diagnosed with Fabry disease or who has a child or loved one who is diagnosed?

Jessica Bucher: My best advice is to seek treatment and trust in your care team to recommend a good treatment plan, since earlier treatment is typically better. There are different plans for individuals now that there is even newborn screening and process and we're catching the symptoms so much earlier than we ever could have, leading to hopefully better outcomes. It's also important to tell your family members about the genetic condition. It's not easy to talk about these things to family members, but because individuals might not know that they're at risk and it may be difficult to diagnose, you may be saving them that 16 years that the symptoms began until they receive a diagnosis.

Jessica Bucher: Lastly, it's really important to make sure that individuals with Fabry disease have a good support system and that includes mental health support. That's because depression, anxiety and other mental health concerns are more common in individuals with Fabry disease. That might be because of the pain crises that they've been experiencing or it may be because they were coming to physicians or other healthcare providers with nonspecific symptoms and people were telling them that it was something else and they feel a mistrust in their providers. So it's really helpful to provide that mental health support.

Nate: Thanks to Jessica for her insights there. Whether you've interacted with a genetic counselor yet or not, they play an invaluable role in the journey of anyone diagnosed with a rare genetic disease.

Nate: Our next conversation is with Dr. Jaime Barea. He's a clinical geneticist at the University of California, San Diego.

Jaime Barea: Hi, I am Dr. Jaime Barea. I'm a clinical and a biochemical geneticist. I'm also the chief medical officer at DNAFeed, which is a genetic counseling company. But as part of my clinical work, I treat patients with different genetic conditions and one of these rare conditions is Fabry disease.

Nate: And while I have you too, why don't you tell me just a little bit about what DNAFeed does and where that company is looking to enter the market?

Jaime Barea: Sure. DNAFeed is, like I said, a genetic counseling company. We provide a platform and we have genetic counselors that are licensed all over the United States. We help labs, doctors, clinics, hospital systems to be able to explain results to patients and doctors, and support them for all their testing needs. In terms of Fabry disease, since this is a condition that can be hard to diagnose, there's a lot of people living with Fabry disease out there that don't know they have it and they're suffering without proper treatment. So we want to be a bridge between patients and see what patients might be eligible for testing through different sources and help them along that journey. Explain what testing might mean and direct them to the proper providers so if they do in fact have the condition and it's confirmed by a test, then they can get the proper treatment and management.

Nate: Very good. All right, well let's jump in and talk about Fabry, Dr. Barea. Speaking from your experience as a professional, what immediately comes to mind when you hear the words Fabry disease?

Jaime Barea: When I think of Fabry disease, the first thing I think about is how since it can cause pain and multiple problems in people, but they're usually vague symptoms, so a lot of people are out there that are not diagnosed. They might be suffering from different conditions and they might have even seen different doctors, but they don't have a proper diagnosis so they're not getting the right treatment and the right management. Even though it runs in families, I feel like this is a condition that is very underdiagnosed so people are suffering more than they should without the proper treatment.

Nate: What age is Fabry typically diagnosed and who does it most typically affect?

Jaime Barea: Fabry can have a wide range of age of onset and severity, but for males, the median age of onset is around nine years of age. But people don't usually get diagnosed on average until about 24 years of age. Then for females, the condition is usually milder, but it can be as severe as in males. The median age of onset is a little bit later at 13 years of age. But they don't get diagnosed until about 31 years of age. But in both cases, in both sexes, there's many people out there that have symptoms and get diagnosed much later in life.

Nate: Let's talk a little bit about the prognosis, if you are diagnosed with Fabry. What's the general prognosis for someone with Fabry disease and also what's the estimated life expectancy?

Jaime Barea: Yeah, besides all the symptoms that come along with Fabry disease, there are longterm complications that come with them, which include worsening kidney damage and even more severe issues like heart attacks and strokes. According to the studies out there, the life expectancy in males with Fabry disease is 58 years compared to 74 years in the general population of the United States. In females it's not as severe but still significant, where instead of the average life expectancy of 80 years in the United States population, in females with Fabry disease, it is 75 years. But the thinking is that with newer therapies out there, this may improve life expectancy if people get treated on time.

Nate: Well, let's talk a little bit about those treatment and care options. I know Fabry is a disease that's got some interesting things happening. What are some of the treatment options that are there as of today?

Jaime Barea: The main treatment option that is approved by the FDA for treatment of Fabry disease in the United States, is called enzyme replacement therapy. And the main one is called Fabrazyme. The goal is to replace the missing enzyme individuals with the condition so their body can break down the substance that accumulates in the body, in the cells within the body and causes the damage. This is usually done by an infusion through their veins every other week. They have to go usually to an infusion center to do that. This replaces the enzyme that they're missing and the goal is to slow down the progression of disease and reduce complications. Studies are still out there, but it may even prevent the longterm complications of the condition.

Nate: If you're a potential patient for Fabrazyme and you have Fabry disease, how do you end up getting referred to that type of treatment? Is it through self-referral, is this referred by a doctor, prescribed by a doctor? How do you end up there?

Jaime Barea: It has to be through a doctor referral, but there are many care providers out there that are not familiar with Fabry disease. So many patients have to be their own advocates and hopefully get referred to a specialist that can test them for the appropriate condition and hopefully get the diagnosis right. Once they have the diagnosis then they have to be referred to a specialist with an expertise in Fabry disease. These are usually clinical geneticist or biochemical geneticist. But sometimes some pathologists or kidney doctors can have experience with the condition and can also may be able to treat it.

Nate: Has this changed in recent years? How has Fabry disease treatment options changed for those folks who may have it recently and is there anything new on the horizon?

Jaime Barea: Yeah, so good question. Enzyme replacement therapy has been out there for a while, but there's a new replacement therapy called [inaudible 00:19:59] therapy, which is a daily pill. It can't be used with everybody with Fabry disease, but certain people with certain DNA mutations can use it because it helps the enzyme in the body that's non-functioning to function better. This is easier to take because it's just a pill that you take every day and you don't have to go to the infusion center for these. Also, experts are recognizing that people need to be treated earlier on, so not wait till people have a lot of symptoms. Because that way they can hope to prevent or reduce some of the longterm complications better if they get treated earlier.

Nate: This may be belaboring the point, but you're the medical expert so I do want to ask some of these questions. Is there currently a cure for Fabry disease?

Jaime Barea: Currently there is no known cure for Fabry disease, but there is some gene therapy trials in the early stages that hopefully one day will lead to a cure. But we're many years away from that. And what they're trying to do is to introduce a healthy copy of a defective gene that these patients have to try to get normal levels of that enzyme and effectively reverse the condition that way.

Nate: If I'm heading into any of these treatment options, whether it's maybe finding one of those trials or trying to get a referral into Fabrazyme or one of these other treatments that may be coming along, what are the typical costs that I may face or financial burdens of Fabry disease treatment?

Jaime Barea: I mean, as we all know, insurance is very complicated and it's getting more complicated every year. But most people with insurance that get diagnosed with a condition do have a lot of their treatments covered by health insurance because it is a established treatment option and FDA approved for the condition. But there's always other things that come into play because people with this condition can have issues with pain, depression that can affect their work. So there's other complications that might be involved. But at least the main treatments should be approved and should be covered by insurance.

Nate: Well you mentioned some of the treatment earlier is better and this is somewhat unique as in some of the diseases that we talk about on the podcast. That it's something that can affect someone much later in life and can be around throughout life. Are there any lifestyle changes that can be made to the diet or similar to pull back some of these other related symptoms that may be occurring or are just directly towards the disease and the implications of it?

Jaime Barea: Yeah, there's no specific lifestyle changes that have clear evidence. But there are for some people, some diet changes can help a little bit like eating smaller meals, taking probiotics and avoiding some specific foods to decrease some of the GI issues that you might have. And then a big part of this condition is pain. Besides getting the pain medications with your doctor, there's also alternative treatment strategies for pain that people may use like physical therapy, acupuncture or things like that. Lifestyle things that they can use to help with those issues as well. Because sometimes even with traditional treatments like enzyme replacement therapy, not all the complications of Fabry disease can be resolved.

Nate: Speaking from the the holistic point of view, what is your best advice for someone who is diagnosed with Fabry disease or maybe has a child or a loved one who is diagnosed?

Jaime Barea: Where somebody that has the condition already, I think the most important thing is to make sure that you're being seen by somebody that has expertise in the condition because it can be a condition that is not easy to treat, it has a lot of vague complications. So you want to make sure that you're getting the right treatment, you're getting monitored regularly every few months to try to prevent some of the longterm complications which mostly include kidney issues or heart issues in the future as well. And that all your symptoms are being addressed not just by the traditional medications like enzyme replacement therapy, but also medications that might treat pain if that's something that's a big problem for them.

Jaime Barea: Then for people that have a child or are being first diagnosed with Fabry disease, they want to make sure that they're also being seen regularly to start treatment as early as possible before major issues come up because most experts believe that if you start treatment early, then that could try to prevent issues and reduce issues in the future.

Nate: Thank you, Dr. Barea.

Nate: Finally, we spoke with Lut De Baere. She's the president of the Fabry International Network and gave us a deeper look at their organization, which supports patients diagnosed with Fabry disease with events, resources, updated information and much more.

Lut De Baere: I'm Lut De Baere. I'm the president of Fabry International Network and also the president of the Belgium Patient Organization for Rare [inaudible 00:00:24:33].

Nate: Well, I'm curious just from speaking from your experience as a professional and just as an advocate, what immediately comes to mind for you when you hear the words Fabry disease?

Lut De Baere: It's a multi organ disease, so it's sometimes very severe, sometimes very mild. It depends on which type that you have, which patient and if you're a man or a woman, that's always different. When you diagnose one person with Fabry disease you find more affected persons in the same family. That's a real concern that the whole family is affected in fact. The symptoms are very various. I said it already, depending on the age, on the gender, the sex and the progression of the disease, it's hard to predict.

Nate: Well what are some of the services that you guys offer at the Fabry International Network and what kind of support do you provide for those families who are affected by the disease?

Lut De Baere: Oh, we give them the opportunity to meet each other annually. We have a, I don't know, meeting. This year we go to the Netherlands, next year we are going to Korea so we are not going to always the same place. We try to avoid that and we try to be always in the neighborhood somebody else so that we can attract them easily for us too, that they [inaudible 00:26:01] state.

Lut De Baere: On that expert meeting we give scientific information and the proper experts are there to explain everything to the patient organizations. We also include a workshop, so that's also very active because then they can talk in small groups about some topics. There's a lot of exchanging by people and are also very much differences in the diagnosis, the treatment and care from country to country too. And what we see the last year that the topic of social, psychological issues are welcome very heartily. So we spend a lot of time to that, to explain more of this and to let the experts talk about this issue because it's very interesting or they are very interested in that topic.

Lut De Baere: We have also a website on which we have sections and we update that regularly of all the upcoming and current clinical trials so they can see when there is an enrollment and how far the study is going. We have quarterly newsletters. We translate some scientific articles into lay language so they can read easily in their own countries' language and spread it amongst their members.

Lut De Baere: A new project that we want to start in 2020 is to organize a young adult weekend in which we can educate the young people. We also want to create a young board, so of young people so they can give us topics they want to discuss or some projects that they think are valuable for them or for all the Fabry patients because we think that the future is our young adults. Because we are all aging and we have to renew and make our board younger. That's what we want to do for that.

Lut De Baere: What we also do is when there's a new emerging Fabry based organization in the country, we try to advise them or to give some practical help. We do visit them if they want, so we try to help to organize themselves.

Nate: Well, you mentioned the website and it sounds like you guys have a pretty robust website. I know some patient organizations do and some do not. I'm curious, where do people with Fabry disease in your experience connect online? Where does that conversation happen? I mean, does some of it happen on your website? Is a lot of it happening on Facebook where these families are connecting and providing support and learning from one another?

Lut De Baere: Yes, they are a lot of Facebook groups in countries that [inaudible 00:28:41], but also international and are open Facebook groups so that it's very easy to be open in those. Especially the closed Facebook groups so then they can talk freely about their disease and about how they feel and the symptoms. They know that the other one on the other side knows or recognize what they are talking about. I think it's very helpful for them. And of course, we have the national patient organizations where they can connect.

Nate: Let's talk about the disease itself. I guess from your experience or from what you know, upon someone receiving a Fabry diagnosis, what are some of the more common misconceptions that a patient or a patient's family might have about the disease? Or what is maybe most often unknown that you would want to explain to them?

Lut De Baere: The most unknown is the fact of the people don't want or don't like to talk about the hassle and [inaudible 00:29:37] problems. Also, they're not open to talk to everybody about their mental supervision because there are a lot of depression among those patients. And that's something that they don't want to talk everybody. One patient to another one yes, they talk about that. But not really to everybody in the neighborhood of where they live.

Nate: What about their primary care physicians or maybe even I wanted to ask about genetic counselors? What role do those professionals play in the ongoing care and communication with a family that has this diagnosis?

Lut De Baere: Yeah, the general physicians are not always aware about the disease, so there is a lot of education to do for that. But they should be aware when people, some children have some symptoms, the tingling in their hands or not tolerating the warm or they get the red spots on the skin that they must be aware, have to check if it's Fabry disease. And of course when they see another person, a young one of 30, 40 years who has a heart attack or a brain attack, then they need to be alarmed and think about Fabry disease. But it's not so easy.

Lut De Baere: And the genetic counselors are very important because they must educate the family because it's such a family disease. When you find one, you must do a family pedigree so that you can see the other ones, it affects the other ones.

Nate: I have to ask you, in the US I mean, we have about 5,000 genetic counselors currently and there doesn't seem like there's enough of them. What's the status of that over in Europe? Is it hard to get to a genetic counselor? Are they often busy? Are there enough of them?

Lut De Baere: There are a lot of them. It depends from country to country of course. But in most countries it's well developed and there are a lot of them and they are very good. They have a good connection with the general practice, with all the specialists.

Nate: I guess advice from you or from what you've learned working around the disease, how can a Fabry patient optimize their quality of life after diagnosis?

Lut De Baere: That's a tricky one, it's very difficult. Of course, everybody has their own character and I said already that there are a lot of depression amongst them. So they feel sometimes very isolated and alone. It's not easy to live as a child with normal children and see [inaudible 00:32:16] play football or something like the others do. That's not always so easy to explain why you can't do that because you got [inaudible 00:32:23] and you are tired and such things. Others, when you're going to work and it's very difficult that you must say that I must go for my treatment one time in a few weeks and I feel tired, I can't do that. And physically I'm not always so good. It's not easy to handle with that. But I think it's very important to be positive as a patient but it's not so easy to do.

Nate: Well, and it sounds like engaging with an organization like yours could help that cause in a lot of different ways. Helping access to resources and other patients in the community. And just communicating is the best way to work through it.

Nate: You mentioned clinical trials as well as something that could be found on your website. I mean to your knowledge, have there been any developments in recent years for treatment options that have changed for Fabry disease? Or is there anything on the horizon that's new and interesting? Studies or trials or things that have come out?

Lut De Baere: If I look back 20 years ago there was nothing and then there were suddenly two therapies. The enzyme replacement therapy and then there was the oral therapy and now you have the gene therapy. So there's a lot of movement and a lot of companies who are involved and want to develop new treatments. So I think it's good that there is a lot of competition between the pharma industry, but it's on the other hand also very confusing for patients because they are not always sure what's the best thing to do. And if they must wait a little bit wait until there's a gene therapy or they start with ERT or the oral treatments. It's sometimes very confusing for patients. But it's promising, I think. Yeah.

Nate: I mean, all that said, I guess, what is your best advice? Your best course of action for someone or a family who receives the Fabry diagnosis? What are the first couple of things that they should do to get on the right path?

Lut De Baere: I think that the general advice for everybody is to not let your disease overrule your life. And that's important I think. But yes, you must live your life as good as you can. And if you can do something today, you don't need to wait till tomorrow.

Nate: And where can they find you? You mentioned the website. What is the website for the organization

Lut De Baere: For Fabry International Network?

Nate: Uh-huh (affirmative).

Lut De Baere: http://www.fabrynetwork.org/

Nate: Perfect. Nate: At the beginning we said that you may feel a bit like you've been thrown into the middle of the ocean without a life raft. We all find ourselves with a small bit of information like this, that only leaves us wondering, okay, what now? So really what now? We know that hearing from these experts is only the beginning for you. That's why we've taken the information here and added other resources, explanations, links and references for you and a downloadable guide on Fabry disease. You can get your free copy of that guide by going to raredisease.com/fabry, that's rare disease.com/F-A-B-R-Y. Go there and you can download a recap of this episode that lists all the key points as well as several links and resources for you to further explore.

Nate: Finally, if you need to speak with someone directly about Fabry disease right now or soon or just your personal situation, we're here to help. Visit raredisease.com/help, that's rare disease.com/H-E-L-P to get in touch. We are standing by. This is Rare Disease Connection, a production of Aspect Health and raredisease.com.

Clinical Trials

Fabry Disease Registry & Pregnancy Sub-registry

Sanofi

Learn More on ClinicalTrails.gov

Evaluation of a Screening Strategy of Fabry Disease in Patient With Renal Biopsy

University Hospital, Angers

Learn More on ClinicalTrails.gov

Screening of Fabry Disease in Patients With GI Symptoms

General University Hospital, Prague

Learn More on ClinicalTrails.gov

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