Building on our 30+ year focus on Fabry, we look at the many ways that research, advocacy and efforts to expand awareness of the disease have affected patients, care partners and healthcare providers.
Fabry disease is a rare inherited disorder caused by an altered gene. A person who inherits this variant gene is unable to produce an enzyme called alpha-galactosidase, which is necessary for the breakdown of a fatty substance in the body called globotriaosylceramide or GL-3. In people living with Fabry, GL-3 accumulates in cells throughout the body, eventually causing cell damage. Symptoms of Fabry in children and adolescents typically include pain, impaired sweating, skin rash, a distinct whorl pattern on the cornea of the eye, hearing impairment, and potentially kidney problems. Symptoms can become life threatening, and Fabry disease can affect both males and females of all ethnic and cultural backgrounds.
As one of the early industry partners to join in the effort to advance research related to Fabry, we have been on the front lines in witnessing and shaping many historic changes. We have also been privileged to work with many of the founding pioneers in Fabry research, patient care and advocacy over the past 30+ years. Their perspectives today highlight the many ways that the experience of living with Fabry has changed and will continue to change in the years ahead.
Dr. Robert Desnick, Dean for Genetic and Genomic Medicine at the Icahn School of Medicine at Mt. Sinai in New York City, remembers meeting with families in the very early days of diagnosing and treating Fabry disease. In many cases, those families had met with multiple doctors before they reached his office. In most cases, it was recurrent severe pain that drove them to seek medical help.
Dr. Desnick recalls, “In the early days, I remember a story about one boy who was evaluated by his pediatrician for severe recurrent pain in his hands and feet. The highly respected and experienced physician did not have a clue what was going on. Later, a second son from the same family came in, and still there was no diagnosis. It was not until a third son came in that the physician considered a genetic factor like Fabry. For families that did not have multiple family members affected, the path to diagnosis often was even more challenging.”
The diagnostic journey of Minnesota resident Tim Nelson highlights many of the challenges in the early years. “I first noticed it probably when I was seven or eight years old. The first symptoms I noticed was not sweating, which caused me to overheat and then caused migraines. When I was in my twenties, I was seeing a dermatologist, nephrologist, cardiologist, and neurologist. It took another 10-15 years to get diagnosed. At this point in time, I was in stage three kidney failure, and right on the borderline of stage four kidney failure. There were so many things that were missed that were red flags. A lot of people were not diagnosed with Fabry disease until their kidneys quit working.”
Nelson often contrasts his own 31-year journey to diagnosis with the experience of his daughters Stephanie and Sarah, both of whom were diagnosed in a matter of hours using dry blood spot testing, a form of genetic testing.
Sarah Nelson spotlights the impact that delayed diagnosis can have. “I think for my dad, going so long without a diagnosis, I can’t even fathom what he went through. He told us stories about his mom and dad taking him to doctors and he was told time and time again that it was in his head. And that’s what he believed, even though he knew that there were real symptoms there. He was being told by a professional that it was in his head, so it must be true.”
The fact that the genetic variant for Fabry disease is passed from a parent to a child has reinforced the importance of family screening in diagnosis. Following a diagnosis of a first relative, screening of other family members on average can identify five others who are living with Fabry. Physicians are also much more likely to associate symptoms with Fabry in families where someone has been previously diagnosed.
While a diagnosis was at least an explanation for many families, the next message from a doctor in those early days was often heartbreaking. “We told families to have hope and that research was underway…because that was all we had at that time.” Dr. Desnick says. Many clinicians report that the diagnosis was “devastating” for families, and that this only got worse as symptoms progressed. Feelings of isolation and despair were common.
Not surprisingly, the few specialists in the field in the early days noted that many patients and caregivers were interested in learning about any advances in research that could inspire hope. When they read about the discovery of the genetic variant associated with Fabry, the sequencing of the gene itself and then the first success in synthesizing the gene, they were encouraged by the progress.
Another major advance in understanding of Fabry was research that identified the two forms of the disease: classic and late-onset or non-classic. Patients with classic (also known as Type 1) Fabry disease have little or no functional a-Gal A enzymatic activity (<1% of normal mean) and marked accumulation of GL-3/Gb3. Classically affected individuals develop typical symptoms in childhood or adolescence. As the disease progresses, it can lead to severe health risks including cardiomyopathy, renal failure and stroke. The incidence of the classic phenotype is about 1 in 40,000 males and 1 in 20,000 females. While females were incorrectly thought to be asymptomatic carriers, research has shown that many females present with symptoms consistent with Fabry disease, albeit in varying degrees of severity and age of onset compared to their male counterparts.
In contrast, males with later-onset or non-classic Fabry have varying levels of residual a-Gal A activity and typically develop symptoms in adulthood. With later-onset Fabry, symptoms are more likely to be associated with single-organ cardiac or renal dysfunction. While the severity of disease in Fabry can vary widely, even patients with less severe forms of Fabry will experience disease progression. Understanding the distinction between classic and later-onset /non-classic Fabry drove many important advances in efforts to diagnose and treat patients.
The power of bringing patients together
In addition to physical symptoms, Fabry often led to feelings of isolation among both patients and families, a situation that has changed significantly since the early days. As late as the 1990s, most patients had never seen or even heard of another person living with Fabry outside their family. Many did not even recognize the symptoms in their own family members.
“I can remember one young man in the 1970s who was having a very difficult time with his diagnosis. He was withdrawn and severely depressed. At the time I knew of another patient, a 35-year-old man, in the area. I arranged for them to meet and just talk. There was no agenda, no specific messages. And that one meeting inspired an amazing change in the young man. We really saw the power of connecting patients with each other,” said Dr. Desnick.
Tim Nelson confirms the feelings of isolation: “When I was a kid, it was hard for me to do anything. If friends were going out to the park or something, I couldn't do it because I could only be out there maybe five, 10 minutes, and all of a sudden, you know, I hurt. I didn’t do a whole lot with friends because of the disease.
For many patients, the only other people they knew with Fabry were in their family.
“Growing up I knew I had Fabry, but it was just because Dad and my sister Sarah had it,” explained Stephanie. “Once I got to kindergarten and first grade I realized that we were a little bit different, but we had each other to lean on and Fabry was just something we learned how to deal with.”
The establishment of the first patient advocacy organizations including the Fabry Support and Information Group and the National Fabry Disease Foundation together with the very first opportunities for patients to meet with other patients in person represent pivotal moments in the experience of living with Fabry. The dawn of the internet age made it even easier for patient and caregivers to access information and to connect with others. Over the years, we also have supported many efforts to build broader awareness of Fabry among healthcare providers and at-risk families and communities. Together, these actions have transformed the emotional experience of living with Fabry for many families. Both online and in person, patients now can access many opportunities to reach out for information or support or to share experiences with other families.
Sarah offers a perspective on the very personal need to be your own advocate: “Growing up with Fabry disease, a big aspect of it has been advocacy. From a young age, we would have to go in every single year to all of our school teachers and tell them: ‘Okay, my name is Sarah. I have Fabry disease, and this is how it affects me A, B, and C, and if I start to feel this way, this is what would help me.’ So, advocacy has been a very large aspect of being, learning to be confident in yourself, and being able to feel like you can use your voice to speak of how you’re feeling.”
Focusing on the long term
Specialists in the treatment of Fabry at every level highlight the change in counseling patients about the future. Today, clinicians play a vital role in helping patients plan for their futures. Dr. Desnick notes that many clinicians have now expanded their focus on patient management to include strategies in life-planning and balancing a full range of work and family responsibilities. He also notes many encouraging advances in understanding of Fabry in women, a focus that was not fully appreciated previously.
“We have gone from a period when patients with a diagnosis went home with little hope to one where they can now instantly access information, connect with other patients and families and participate in clinical research. As research continues, you can certainly feel the optimism among both patients and clinicians. There is certainly reason to believe that progress will continue,” Dr. Desnick concluded.
Dr. Robert Desnick and the Nelson family were compensated for their time in development of this article.