Unprecedented advances in DNA technology over the past decade have led to increased recognition that some epilepsies are due to single genetic mutations. These disorders, which are generally rare and manifest in infancy or early childhood, can be clinically indistinguishable from epilepsies from other causes. Often not amenable to current medications or surgery, some genetic epilepsies may be candidates for novel gene therapies that are potentially curative. But they often go unrecognized.
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“Although genetic testing is now widely available, few neurologists and epileptologists feel comfortable interpreting the results and integrating them in their clinical decision-making, due to a lack of formal training in neurogenetics,” says Dennis Lal, PhD, MS, of Cleveland Clinic’s Genomic Medicine and Lerner Research Institutes. “At the same time, genetic counselors, who specialize in interpreting genetic tests, often lack needed disease-relevant knowledge to maximize the use of genetic information in guiding clinical management, so they cannot be expected to fully compensate for neurologists’ lack of training in neurogenetics.”
To address these gaps, Dr. Lal, one of the world’s few experts in epilepsy genetics, has spearheaded and taken on the directorship of the new Epilepsy Precision Medicine Fellowship at Cleveland Clinic. Now in its inaugural year, the one- to two-year fellowship emphasizes acquisition of a strong scientific grounding to foster expertise in the diagnosis and treatment of genetic epilepsies.
A combined research/clinical experience
Alina Ivaniuk, MD, became the first fellow to enter the as-yet-unaccredited program last spring; a second fellow is expected early next year. An active member of the International League Against Epilepsy, Dr. Invaniuk was attracted to the program because of its emphasis on precision medicine in the area of epilepsy genetics.
“The moment is extremely close when tailoring individualized treatment based on each patient’s disease characteristics and biomarkers will become the standard of practice,” she says. “Since I want to deliver the best possible care to my patients, I should possess the proper skill set for the future.”
Now four months into the fellowship, she is particularly impressed by the multidisciplinary aspect of her training, which she says makes her newly acquired scientific knowledge clinically relevant. She feels this is unique in epilepsy fellowships, which generally focus solely on either research or clinical realms.
“The program emphasizes research while keeping me as close as possible to the clinical team,” she explains. “This makes me fully aware of the unaddressed needs of clinicians, provides quick feedback on the applicability of my approaches and allows me to sharpen my clinical reasoning and neurophysiology skills.”
The science of genetic epilepsies is moving fast
In the early 2000s, the human genome was fully characterized in a seven-year process at a cost of some $3 billion. Since then, thanks to the development of new high-throughput sequencing techniques, the same feat can be completed in about a week for less than $200. This has enabled genetic testing to be integrated into routine clinical practice, allowing diagnosis of conditions that would not be possible with only EEG and imaging studies.
Treatment of genetic diseases is also advancing quickly. The framework is similar for treating any genetic disease: once the target gene is identified, a mouse model can be generated and various methods can be used to produce the missing protein and thereby correct the defect; one example is injection of the appropriate mRNA using a viral carrier.
“We have seen some genetic epilepsies in mice apparently cured with a single injection, even after two years,” Dr. Lal observes. “This makes us very hopeful that we will be successful in humans.” He adds that clinical trials are now underway for several genetic epilepsies, including Dravet syndrome. (See this previous ConsultQD post for more information on the early diagnosis of Dravet syndrome. Also available is a Neuro Pathways podcast episode with Dr. Lal on the state of gene therapy in neurological disorders.)
Meeting nuanced needs
Dr. Lal notes that variants in only about 30 genes account for approximately 80% of all cases of monogeneic epilepsies, “yet the clinical spectrum of these epilepsies is highly heterogeneous,” he says. Moreover, different variants within a single gene can confer clinically similar phenotypes while having quite dissimilar treatment needs. “This highlights the complexity of both diagnosis and management in this setting, and it underscores the need for the precision medicine approach we are advancing through this fellowship,” Dr. Lal explains.
He adds that this fellowship’s heavy emphasis on science and research is unique among the few epilepsy fellowship options available at other institutions, which are taught primarily by clinicians.
“My goal is to train a cadre of specialists who have state-of-the-art knowledge of genetic epilepsies and will be able to continue to follow — or lead — the field as the science advances,” Dr. Lal concludes.