Multiple doctors and multiple examinations could not figure out why Lauri Sieben had spent much of her life “never feeling quite right” physically. Fortunately for Lauri, that changed after her daughter Christy began working as a genetic counselor in Mayo Clinic’s Molecular Technologies Laboratory. After seeing similarities between the patient testing she was performing for the lab and the physical symptoms being experienced by her mom, Christy took a leading role in getting Lauri to undergo molecular and biochemical testing at Mayo Clinic. The results of that testing not only provided much-needed answers, but a promising path forward for Lauri.

Fabry disease is a rare genetic disorder that prevents the body from producing enough healthy alpha-galactosidase A (alpha-GAL) enzymes. Without functioning alpha-GAL enzymes, harmful levels of fat-like substances called sphingolipids build up in the blood vessels. Over time, this buildup can result in life-threatening damage to the heart, kidneys, brain, and central nervous system.

There are two recognized forms of Fabry disease: classic and late-onset/atypical. Symptoms of classic Fabry disease typically manifest during childhood and progressively worsen over time. People diagnosed with late-onset Fabry disease typically do not experience symptoms until their 30s or older. The first indication of trouble may be kidney failure or heart disease.

For Lauri Sieben, it was “horrendous tummy problems” that began in childhood and carried through into adulthood. “My mother told me she would take me to the doctor constantly while I was young because they couldn't figure out why I felt horrible all the time,” Lauri says.

Now in her late 60s and newly retired from her career as a scheduler for Mayo Clinic, Lauri had pushed through the mental and physical fog of “never feeling quite right” for decades before her symptoms took a turn for the worse. “Probably about 10 years ago is when the ringing in the ears, the dizziness, and the burning sensation in my hands began,” she says. “None of the doctors I went to could figure out what was going on.”

Nor could the electrocardiograms Lauri would have done in response to the shortness of breath and chest pain she was also experiencing. “The results would come back abnormal, but they didn’t point to a specific cause, so I was repeatedly sent back home without a diagnosis or treatment plan,” she says.

All of that began to change after Lauri’s daughter, Christy Koellner, began working as a genetic counselor in Mayo Clinic’s Molecular Technologies (formerly Molecular Genetics) Laboratory. “When I started, the very first thing I was doing was assessing new patient cases that came into the lab and making sure we had enough information to run the tests,” Christy says. “One of the testing rotations we had was molecular testing for biochemical disorders, and one of them was Fabry.”

As she settled into her new role with the Molecular Technologies Lab, it didn’t take Christy long to make a correlation between the patient testing she was performing, and the physical symptoms being experienced by her mom.

“I was starting to see patients coming in with ringing in the ears, dizziness, and TIAs (transient ischemic attacks), and I immediately started thinking about my mom,” she says. “She was experiencing the same things.”

At first, Christy thought it was just the result of her being a new genetic counselor not long out of graduate school. “In one of the medical school classes I had to take, they talked about ‘med school student syndrome,’ where it’s like everything you hear about, you see in somebody,” she says. “So initially, I thought, ‘I don’t know. I might just be thinking it’s Fabry disease because I’m directly working with it right now.’”

But then, after multiple conversations with physician colleagues Ande Rumilla, M.D., and Linda Hasadsri, M.D., Ph.D., about her mom’s search for a diagnosis amid her worsening health, Christy’s suspicions and resolve to get her mom tested for Fabry disease solidified.

“During the course of our conversation, I listed out everything my mom was experiencing — the ringing in the ears, the peripheral neuropathy, the chest pains, the decrease in sweating, the corneal problems, and it all just started to click,” Christy says. “It was like ‘check, check, check,’ for Fabry disease. After that conversation, I knew we had to get her tested.”

Testing brings answers, and treatment

At Christy’s urging, Lauri underwent molecular and biochemical genetic testing at Mayo Clinic a short time later. The results would give Lauri a mix of emotions. “It came back positive for Fabry,” she says. “It was honestly a bit of a shocker, but it was also vindication that all these things that have been happening to me all these years were happening. I wasn’t imagining them. After processing it for a bit, I was actually excited to find out what was wrong with me, and I was just hoping there was a treatment for it.”

With a diagnosis now in hand, the next step was getting Lauri the treatment she needed to manage her symptoms. That journey began just a couple of days later when she met with Eva Morava-Kozicz, M.D., Ph.D., a clinical genomics physician at Mayo Clinic who would become a key member of Lauri’s care team. “She saw me right away and was absolutely amazing,” Lauri says. “She jumped on top of everything and got everything going.”

That “everything” began with enzyme replacement therapy infusions at Mayo Clinic, a first line of defense against Fabry disease intended to give Lauri’s body the missing enzyme it needs to function properly. “It’s helping her body break down all the stored material and is preventing her from getting fatal kidney and heart disease and is also helping with the pain by preventing peripheral nerve damage,” Dr. Morava-Kozicz says. “Depression can be another symptom of Fabry disease, and this therapy can also help prevent that and other central nervous system symptoms.”

For Lauri, her body’s response to the enzyme infusions has been encouraging. “I’m definitely feeling better than I was before my diagnosis,” she says. “Everything’s not perfect, but a lot of the pain in my hands has gone away. I can tell when it’s time for another infusion because my hands and toes will start tingling again.”

“In the past, when we didn’t know that Fabry disease is a genetic condition, and we didn’t know it could be treated, we just treated the symptoms — the hypertension, the kidney failure, the heart disease,” Dr. Morava-Kozicz says. “But these patients died very early, and now that we have enzyme replacement therapy for Fabry disease, we can prevent that from happening.”

The right tests at the right time

That prevention, of course, cannot begin without accurate diagnostic testing to confirm the presence of Fabry disease, a process for which Mayo Clinic offers multiple approaches. “The bulk of our Fabry disease testing is done in our Biochemical Genetics Laboratory,” says Linda Hasadsri, M.D., Ph.D., a consultant in Mayo Clinic’s Division of Laboratory Genetics and Genomics who was part of the team that analyzed Lauri’s test results and confirmed her diagnosis. “Mayo offers everything from newborn screening for Fabry through dried blood spots to diagnostic testing done through our molecular lab to biomarker testing that helps us monitor the progression of the disease in affected individuals as well as their response to treatment.”

While other medical laboratories offer similar testing options for Fabry disease, Amy White, a genetic counselor in Mayo Clinic’s Biochemical Genetics Laboratory, says what sets Mayo Clinic apart is the biomarker testing that’s also used to add an additional layer of accuracy.

“We offer both urine ceramide trihexides and blood lyso, and those in combination or individually are an extra data point that can help us determine if a patient is truly affected by Fabry disease,” White says. “Sometimes there are DNA changes that are found, and we don’t know if they cause disease or not. Our biomarker testing is a functional test and another piece of the puzzle that can tell us whether a person is truly affected by Fabry disease.”

Not just a man’s disease

In addition to timely and accurate laboratory testing, an equally important component to Lauri getting the diagnosis and treatment plan she needed to manage her symptoms was breaking through the misconception that Fabry disease is a genetic disorder that only affects men. “When Christy and I first began suspecting and asking about Fabry disease, we had at least one clinician say, ‘No, that’s a man’s disease,’” Lauri says. “It was dismissed right away.”

Since Fabry disease is an X-linked disorder, White says it is true that Fabry is typically diagnosed in males more than females, but as Lauri’s case shows, it can still very much affect females.

“It’s a misnomer that females are just carriers of Fabry disease,” White says. “The majority of females who have a DNA change in the gene for Fabry disease do have symptoms, but those symptoms may present later in life, and they may present differently than they do in males.”

The challenge for physicians is then determining both when and how to test a patient suspected of having Fabry. “Clinicians who care for pediatric patients and have a male patient with unexplained burning pain in their hands and feet should definitely consider testing for Fabry disease given that we know that is a hallmark early sign of Fabry,” White says. “I’ve also encountered females who have had the burning hand and foot pain as early as age 8 to 10, but it’s much more common in males at that age. Females with cardiomyopathy are the next group of patients where we should think about Fabry disease in the differential diagnosis. And then, of course, any males or females with kidney disease moving toward kidney failure should also be assessed for Fabry. And finally, ophthalmologists may see corneal whirling in males or females with Fabry disease, and that could be the initial symptom that’s present and detected for this condition.”

Once Fabry is suspected, it’s important to understand which test to order to accurately confirm or rule out that suspicion. “For males, you can order enzyme or DNA testing, but with females, it’s really best to order DNA testing first because you can get false positives and false negatives with enzyme testing for females,” White says.

To which Dr. Hasadsri adds: “Fabry testing for females is tricky. There is a danger with female patients of only doing biochemical testing in that if that’s negative, you’re actually not done testing. You still need to do molecular testing to make an accurate diagnosis. Doing molecular-only testing can also be equivocal, so doing additional biochemical testing can help resolve variants of uncertain significance.”

For Christy, the benefits of having all of those testing options available in one place for her mom have been immeasurable. “My mom has always been a very light and airy person — very Zen-like. And after her diagnosis and treatment began, there was a veil lifted from her that I didn’t even know was there,” Christy says. “There’s more of a sense of peace that comes off of her now. It’s just so wonderful that we were able to get the testing she needed, and that it was all available right here at Mayo Clinic.”