Using Precision Medicine to Unravel the Sacred Disease: Genetics as a Tool in the Epilepsy Clinic

Epilepsy is a common neurological condition that is characterized by recurrent, unprovoked seizures. At Children’s Hospital of Philadelphia (CHOP), seizures are the most common reason for patients to be admitted to the neurology floor or to one of our pediatric intensive care units. While not every seizure happens in the setting of epilepsy, many children who are admitted to CHOP will require ongoing treatment and care for epilepsy.

The reason why children develop epilepsy is often unclear. Genetic factors are increasingly recognized as a causative factor. Physicians on the neurogenetics team and the epilepsy team in CHOP’s Division of Neurology are leaders in recognizing and treating genetic epilepsies and have pioneered many of the diagnostic technologies and treatments used to both understand why some children develop seizures and find the best available treatment for these conditions. We currently think that up to one-third of children with severe epilepsies may have genetic findings that explain their disease and that we can identify.

Finding the needle in the haystack

In the last five years, epilepsy genetics researchers have identified more than 30 new genes that cause epilepsy — a rate of gene discovery that exceeds the speed of gene findings in any other disease. This was made possible by the application of novel technologies, which are referred to as “next-generation sequencing” technologies. While clinicians used to examine one gene at a time, these novel technologies allow us to look at a large number of genes in parallel.

The human genome consists of approximately 1 million base pairs, which can be compared to an entire library of books. In most cases, finding the causative change in a gene requires researchers to find a single position in the entire genome that is altered, basically a single misspelled word in the entire library.

Dennis Dlugos, MD, head of CHOP’s Epilepsy Program, and Ingo Helbig, MD, are part of a large international collaboration between scientists and physicians that was able to significantly increase the number of genes that we currently know in human epilepsies. Some of the genes that were confirmed in these studies — such as the SCN2A gene and the DNM1 gene — are frequently found in children with severe epilepsies. New genes for epilepsies are discovered virtually every month, and neurologists at CHOP are part of the ongoing effort to find new causes for epilepsies.

Treatment with precision medicine

Once a genetic cause for a child’s epilepsy is identified, neurologists at CHOP try to find treatments that are specific to patients with a certain gene finding. For patients with Dravet Syndrome, one of the most common genetic epilepsies, which is caused by changes in the SCN1A gene, CHOP clinicians are at the forefront of new medication trials, including studies that assess the effect of cannabidiol and fenfluramine in patients with Dravet Syndrome.

For patients with mutations in the KCNT1 gene, neurologists at CHOP are maintaining a national database to monitor the response to quinidine, a promising medication that was initially used by David Bearden, MD, and Ethan Goldberg, MD. In addition to using novel medications for patients with known genetic causes in epilepsy, physicians in the Division of Neurology also try to find treatment options for genes that were just identified. For example, under the guidance of Eric Marsh, MD, Director of the Neurogenetics Program, CHOP was the first center in the world to treat a patient with a mutation in the very rare GRIN2D gene with magnesium and ketamine, which dramatically improved the patient’s condition.

Counseling, diagnosis and collaboration

Helping families affected by epilepsy understand genetic diagnoses and find support and resources is an emerging subspecialty of genetic counseling. Holly Dubbs, CGC, is the Epilepsy Genetic Counselor in the Division of Neurology and is one of the first clinical counselors in the United States to specialize in counseling epilepsy families, provide access to novel diagnostic technologies, and connect families with the patient community. Fully engaging the expertise of genetic counselors is likely to become a major focus in epilepsy genetics in the years to come, given the increasing complexity of genetic diagnosis and the current advances in diagnostic technologies.

However, even though we are constantly increasing the number of patients with positive genetic findings, we cannot find a causative gene in up to 70 percent of children who have epilepsy for no apparent reason. In order to help push the envelope of new discovery, many families ask to be included in research studies. The CHOP Epilepsy Genetic Research Project (EGRP) offers families the opportunity to participate in research studies. This project is part of the Genomics Research and Innovation Network (GRIN), a unique collaboration between CHOP, Boston Children’s Hospital and Cincinnati Children’s Hospital Medical Center.

In addition, our Division of Neurology is currently building a unique biorepository. This “biobank” will allow families to provide researchers at CHOP access to biological samples that will help further understanding about their child’s disease.