By Studying His Own Disease, Grad Student Hopes to Help Others

Even before Wolfgang Pernice, PhD, knew he had Charcot Marie Tooth disease–an inherited neuromuscular disorder–he had already found the inspiration to study it.

Dr. Pernice’s father, a law professor in Berlin, was the first person in his family known to have CMT. The condition slowly progresses over time, causing muscle atrophy and weakness in the lower limbs. By the time Dr. Pernice was in his teens, his father was still walking but with crutches.

That didn’t stop the Pernices from visiting the Great Wall of China. Walking with crutches, the elder Pernice embarked on the steep ascent, pulling himself along the thin handrail one step at a time. Other tourists made remarks in Chinese as they marched past.

“We thought they were chiding my dad for being in the way, but it turns out they were saying ‘here is a real man,’” explains Dr. Pernice.

CMT is inherited, and Dr. Pernice knew there was a chance he also had the disease. It wasn’t until the family returned to Germany from the China trip that he started noticing symptoms. “I was never formally diagnosed, but as my legs got thinner and weaker, it got harder to do Tae Kwon Do and other sports,” says Dr. Pernice.

Having CMT gave him a sense of purpose, Dr. Pernice says. Inspired by his father’s positive attitude toward living with the disease, he switched plans to study law and focused on pursuing a career in biomedical research. He entered Columbia’s Pathobiology and Molecular Medicine Program in 2011 and has just finished his PhD in the lab of Liza Pon, PhD, professor of pathology & cell biology. His research on asymmetric mitochondrial inheritance in yeast cells is remotely relevant to CMT (mitochondrial quality is a factor in many neurodegenerative diseases). But he held out the hope that he would one day be able to identify the gene responsible for his CMT, and that of many others.

To get closer to patient-centered research, Dr. Pernice joined Columbia’s Med-into-Grad program, an initiative funded by the Howard Hughes Medical Institute that pairs basic science grad students with practicing clinicians. Dr. Pernice selected Michio Hirano, MD, professor of neurology at Columbia and chief of the Division of Neuromuscular Medicine—and Dr. Pernice’s physician—to be his mentor. According to Dr. Hirano, 5 percent of the division's patients have CMT.

Soon, the grad student shared his desire to unmask the hidden CMT gene mutation. “I fully appreciated his aspirations, as many of my patients are highly motivated to find the cause and treatments for their diseases. Of course, what distinguished Wolfgang from my patients was that he was the first with the scientific skills to actually study his disease,” says Dr. Hirano.

With the help of the pathology department’s genomic sequencing lab, Dr. Pernice began to hunt for the gene in the evenings and on weekends. “Basically, I worked on this whenever I had a spare moment,” says Dr. Pernice.

He began by isolating DNA from his own blood, and later from his family, to look for genetic mutations previously associated with neurological diseases, including CMT. The samples did not yield any clues.

Next, he turned to whole exome sequencing, which focuses on genes that encode for proteins. After filtering many candidates, he homed in on a gene mutation that has been associated with certain types of cancer but has never been associated with neuromuscular diseases.

“I think most endeavors to identify a new genetic disease arrive at this point. You figure out the genetics, you have the candidate, but how do you know whether it’s the right one?” asks Dr. Pernice.

The process of vetting genes can be arduous, explains Dr. Hirano. Genetic studies of the affected family and of others with CMT are needed to show that the mutation occurs in those with the disease. Functional studies, in animal and cellular models of CMT, are also needed to show that the mutant gene causes an abnormal phenotype.

But if the gene’s link to CMT is confirmed, research showing how the gene causes disease could point toward a possible treatment.

“It’s not my ambition to study my case in isolation,” says Dr. Pernice, who adds that identification of the gene will likely be just one more puzzle piece to add to the emerging picture of CMT pathobiology.

Dr. Pernice hopes that his findings, which he plans to submit for publication, will inspire other researchers to resolve these questions. He plans to take a break from mitochondrial research for a while to identify actionable therapeutic targets for patients with novel genetic diseases. In the meantime, he completed his first New York City Triathlon with his friends Nick De Veaux and Arda Bozyigit, raising more than $8,600 for muscular dystrophy research.

Is he hopeful that his research and fundraising efforts might lead to a cure for CMT? “Well, I am going to find out!”