While Gregor Heinrich never could have imagined that testicular cancer was related to his problems with vision and gait, learning he was positive for KLHL11 protein biomarkers meant he could receive treatment for both the cancer and the illness behind it.

When Gregor Heinrich visited Mayo Clinic in Jacksonville, Florida, in November 2019 seeking a second opinion for puzzling symptoms thought to be related to multiple sclerosis, he wasn’t sure what doctors might discover. Plagued by peculiar vision and balance issues for six months, he theorized that ear abnormalities might be the source of the problem.

“I thought I had maybe crystals in my ear,” says Gregor, who lives in Boca Raton, Florida.

While Gregor didn’t have ear crystals, what his Mayo Clinic team uncovered as the root of his medical concerns did sparkle — at least when examined using tissue immunofluorescence. Autoantibodies to Kelch-like protein 11, or KLHL11 — discovered by Mayo Clinic scientists in 2019 and detected in Gregor’s cerebral spinal fluid — emit a unique sparkles pattern when stained during immunofluorescence testing.

Gregor Heinrich with his wife, Amy

Identifying the KLHL11 biomarker using advanced testing from Mayo Clinic Laboratories (Test ID: K11CC or K11CS) allowed Gregor’s medical team to confirm a diagnosis of testicular cancer-associated paraneoplastic encephalitis. In addition to causing an array of neurological problems, the condition is associated with cancer in more than 70% of patients.

“When a patient comes in to see the neurologist, they don’t expect to be diagnosed with malignancies,” says Gregor’s Mayo Clinic neurologist, Sebastian Lopez, M.D. “But his clinical presentation, the inflammatory findings in the spinal fluid, in addition to the biomarker, the KLHL11 antibody, were all very helpful to us to narrow down the diagnosis.”

Gregor was more than a little surprised to hear that he had testicular cancer. “It was tough to hear, but then it was very good to hear the second part: that it’s got a 95% cure rate,” he says.

A diagnostic odyssey

Gregor’s diagnosis at Mayo Clinic capped a months-long journey through a spectrum of tests and misdiagnosis. Gregor’s first symptoms appeared in February 2019 as balance problems. Next, his vision changed.

“It was like things were not at a standstill,” Gregor explains. “The only way I can describe it is as if you’re on one of those merry-go-rounds as a kid and you get off, and all of a sudden you see everything moving. So if I was trying to watch TV, if I was trying to read, nothing would stay still. Things were always constantly moving, sometimes worse than others.”

Exams and testing performed locally produced inconclusive results that led to a diagnosis of suspected multiple sclerosis. Dissatisfied with that conclusion, Gregor sought advice from a multiple sclerosis specialist at a nationally recognized medical center. MRI testing there revealed a mass near Gregor’s spine, which, when biopsied, was negative for cancer. Hoping for more conclusive results, that specialist sent Gregor’s samples of blood and spinal fluid to Mayo Clinic’s Neuroimmunology Laboratory and referred Gregor to Mayo Clinic.

“Given the clinical, radiographic, and spinal fluid evaluation of Mr. Heinrich, it was felt that multiple sclerosis was not the right diagnosis,” Dr. Lopez says. “Because we know that some patients who present with inflammation in the brainstem and cerebellum can have that process triggered by an underlying malignancy, we requested additional testing.”   

That testing was for the KLHL11 biomarker, and Gregor’s samples were sent to neurologist and laboratory medicine physician Divyanshu Dubey, M.B.B.S., in Mayo Clinic’s Neuroimmunology Laboratory. Although Mayo Clinic’s KLHL11 autoantibody evaluation had yet to be formally implemented, Dr. Dubey’s evaluation of Gregor’s samples revealed the antibodies’ trademark sparkles pattern, which was confirmed using a cell-based assay.

“We’ve known about this antibody for about 20 years, and we have been calling it sparkles,” Dr. Dubey says. “When we took patients samples and added them to slices of mouse brain for the tissue immunofluorescence assay, we saw these very punctuate dots in certain regions of the brain, which looks like sparkling stars in the night sky.”

Among patients with the KLHL11 autoantibodies, a consistent pattern was identified. “The patients had walking difficulty,” Dr. Dubey says. “Some of them had double vision, some had slurred speech or could not swallow. All of them were men, and most of them had testicular cancer.”

A goal realized

While discovery of the testicular cancer-associated paraneoplastic encephalitis was a breakthrough — made through a collaborative 2019 research study by Chan Zuckerberg Biohub, Mayo Clinic, and the University of California, San Francisco — understanding how to best test patient samples and then develop a clinical test usable by physicians across the world was equally important.

“Since the discovery of KLHL11, one of our goals has been to come up with such an assay,” Dr. Dubey says.

That goal was realized in June 2021 with the launch of the first KLHL11 autoantibody evaluation, developed in Mayo Clinic’s Neuroimmunology Laboratory under the leadership of Dr. Dubey along with the lab’s directors, Sean Pittock, M.D., and John Mills, Ph.D.

The assay first screens patients for the protein biomarker using a cell-based assay that employs innovative slide-scanner technology. That allows for greater testing volumes by eliminating the need to manually review each test result. Positive results are then confirmed using tissue immunofluorescence. By enabling more rapid diagnosis, the test sets the stage for better treatment outcomes.

“We are starting to find some of these patients earlier in their disease course, and these are the patients who show the best response to therapy — some of them becoming completely normal, but so far it’s the minority,” Dr. Dubey says. “Most of the patients we know of are many, many months into their disease course, and by that time, there’s not a lot we can do as far as reversing neurological disability. Among these patients we try to focus on stabilizing the disease course.”

A collaborative effort

Shortly after diagnosis, Gregor underwent a plasma exchange. During that procedure, centrifugal force was used to separate and remove his blood plasma, which housed the aberrant chemical molecules directing the cytoxic KLHL11 immune response. Once cleared of the troublesome proteins, his blood received a plasma alternative and was returned to his body. A little more than a month after his diagnosis, on Dec. 2, 2020, Gregor had surgery to remove an egg-sized tumor, identified as a germ-cell seminoma. From January through March, he received chemotherapy, and since then he’s remained on immunosuppressive medications.

Gregor still faces some issues. He cannot run, and his vision isn’t perfect — objects occasionally appear blurry, and he struggles to gauge depth perception, especially at night. He continues receiving follow-up care and monitoring both locally and with Dr. Lopez and his Mayo Clinic team. But Gregor’s symptoms have greatly improved. “I can see people clearly. I can read a clock on the wall. I’m able to function and need to just recognize that I have to be a little careful at times,” he says.

Looking back, despite his surprise when he learned the source of his puzzling problems, Gregor reflects that the news really was not unwelcome.

“As frustrating as it was, it’s a blessing that these neurological symptoms led me to this because I knew something was significantly wrong,” Gregor says. “I’m extremely grateful that Mayo Clinic and Dr. Lopez, specifically, found out what this was and took immediate corrective answers to provide treatment.”

In the same way that establishing interdisciplinary teams around patients with paraneoplastic disorders enhances their care, collaboration between neurologists, pathologists, and laboratorians to develop laboratory testing that detects problematic antibodies is essential to pinning down a diagnosis.

“Many of these patients are seen at multiple institutions before they come to see us. Many of them are given an alternative diagnosis for their neurological symptoms,” Dr. Dubey says. “Our collaborative efforts between the Neuroimmunology Lab and the managing clinicians has helped find answers and select appropriate treatment for these patients.”

Gregor considers himself extremely lucky. “I’ve reconciled myself to the fact that I’m very fortunate,” he says. “I’m going to continue to exercise and keep myself healthy, continue to work, keep a positive attitude, and do what I can within my abilities. I feel very fortunate where I’m at to where I could have been.”

Learn more about Gregor’s story in this video:

To learn more about how Mayo Clinic developed the test to detect KLHL11.