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In Neurogenetics, Hoofbeats Mean Zebras, Not Horses


Every year, thousands are diagnosed with neurogenetic diseases—inherited diseases that affect the nervous system, such as Huntington’s disease, spinal muscular atrophy (SMA), and muscular dystrophies. Neurogenetics—genomic analysis for neurological conditions—not only helps identify these diseases, but it plays a role in care thanks to advances in gene therapy which are providing new hope.

In 2019, the first gene therapy treatment for a neurogenetic disease was approved for SMA. This therapy is just the beginning, and it’s marked a tipping point in genomic analysis as it reshapes the field of neurology.

“Neurology and genetics have been intertwined forever,” explains Tanya M. Bardakjian, MS, CGC, a senior genetic counselor and co-director of the Neurogenetics program at Penn Medicine. “Recently, there has been a lot of excitement in the world of both adult and pediatric neurodegenerative diseases. New techniques have come out to identify patients’ neurological conditions and there are different types of genetic therapies that are very hopeful, so there’s a resurgence and increased interest in the field.”

Genetics advancements took off with prenatal and pediatrics care in the 1990s, as many genetic diseases manifest at birth or in the early childhood years, but there are a number of neurological diseases caused by a genetic defect that manifests in adults.

Tanya M. Bardakjian, MS, CGC

“There’s a genetic connection to common neurological diseases such as Parkinson’s disease and Alzheimer’s disease that we weren’t addressing before. There are also a number of people who have a genetic disease which started when they were kids, but they’ve remained undiagnosed as tools for genetic testing didn’t exist when they were younger,” said Pedro Gonzalez-Alegre, MD, PhD, an associate professor of Neurology and co-director of the Neurogenetics program. “Now, they are coming to us as adults and we’re diagnosing pediatric diseases in people who are 45 years old, simply because the field has advanced.”

“Doctors are taught ‘when you hear hoofbeats, think horses not zebras,’ meaning a doctor should first think about what is a more common—and potentially more likely—diagnosis. But in genetics, we think of all the zebras,” Bardakjian said. “If a clinician isn’t as familiar with rare conditions, they may spend too much time looking for the proverbial horses. But neurogenetics prevents them from trying to make a square peg fit into a round hole.”

There are three types of patients the program generally cares for. First, there are patients who have seen many neurologists with symptoms but no diagnosed condition. “It’s common for patients to jump from doctor to doctor without an understanding of what’s happening to them. Based on symptoms, there are guesses for their conditions and they may be going through unnecessary treatments, tests, scans, spinal taps, and more,” Gonzalez-Alegre said. “One of the great benefits of diagnosing those cases is that we stop their ‘diagnostic odyssey’—we step in, do a test, and can bring them clarity with a diagnosis.”

Pedro Gonzalez-Alegre, MD, PhD

However, there are still patients who don’t understand the benefit that genetic testing can bring them. “We’re working very hard to help people understand that genetic testing will change their care for the better,” Bardakjian said. “While it may not change medical treatment for a patient, studies have shown and genetic counselors know that making a concrete diagnosis can give relief and a sense of psychological wellbeing for patients. Once they know their diagnosis, it brings closure, they find a community, and then they have hope for research to intervene.”

There are also medical conditions which have symptoms that can be treated, like hereditary spastic parapalegia (HSP), which is caused by over 100 different genes. The most common misdiagnosis for HSP is multiple sclerosis (MS). “Not being treated for MS is just as important as being treated. These patients think they have MS and have been getting treatments, getting infusions and MRIs, paying copays for these visits, and they don’t have MS. They have a genetic condition that’s not going to respond to that intervention. And by knowing this, we can improve their care,” Bardakjian said.

The second type of patients the program supports are those who were sent by other neurologists—their physician may suspect a specific set of genetic conditions, but may not be well-versed in ordering genetic tests or deciphering the findings. And, last but not least, the program also works with family members who may want or need counseling and predictive testing. 

“The goal of everything we do is to identify people with neurogenetic disease, make sure they are counseled appropriately and can adjust to these diagnoses—especially because it impacts the whole family when a genetic diagnosis is made. And once they are diagnosed we can find the right place for them to go for care,” Bardakjian said.

But neurogenetics isn’t all about diagnosing and counseling patents. When a patient knows their specific genetic condition, they can be primed for potential clinical trials and future care.

“The use of genetic material—gene and molecular therapy—to treat neurologic disease is going to explode in the next decade. We’re already seeing some of these treatments come to fruition, such as the therapies recently approved by the FDA to treat SMA, but there’s also a remarkable number of clinical trials today. Some of these will fail, but some will succeed,” Gonzalez-Alegre said. “A focus for us now is in preparing to apply those therapies as soon as possible. This includes getting ready to participate in clinical trials and ensuring our patients are prepared as well.”

Many clinical trials exist for neurodegenerative diseases based on specific subtypes of genetic conditions. “You have to find people with that genetic variant,” Bardakjian explains. “It’s the way clinical trials are starting to be done now for many diseases. We are trying to identify as many patients as possible to make sure that people who can get treatment, do.”

However, one challenge the field faces is misconceptions on price. “Long ago, neurologists were taught that genetic testing was expensive, but this isn’t the case anymore,” Bardakjian said. “Genetic testing laboratories have worked hard to make testing affordable. Genetic testing has to stop being considered a luxury. It really should be part of medical care for those at risk. A genetic diagnosis can impact care in so many ways.”

“We’re at the cusp of major change,” Gonzalez-Alegre said. “It’s difficult to predict, but we’re going to see a transformation in how we screen for, manage, and improve neurological diseases in adults that have previously been considered untreatable. Neurogenetics is revolutionizing how we provide healthcare for so many patients, and there’s more exciting change ahead.”


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