Using Genetics to Discover, Optimize Epilepsy Treatments

A new study led by The Children’s Hospital of Philadelphia’s David Bearden, MD, and Ethan M. Goldberg, MD, PhD, supports the idea that the identification of specific genetics targets could lead to a sea change in the way epilepsy is treated. Published in the Annals of Neurology, the paper reports the case study of one young patient with migrating partial seizures of infancy (MPSI) who was successfully treated with a drug originally intended for cardiac patients.

Epilepsy affects approximately 2 million Americans. While there is no cure for epilepsy, about 70 percent of those who have the disease can have their seizures controlled with medication, according to the National Institute of Neurological Disorders and Stroke. However, MPSI is among the forms of epilepsy that present treatment challenges.

A rare, severe form of epilepsy that generally presents in the first few months of life, MPSI is characterized by frequent, treatment-resistant seizures, resulting in developmental delays and disabilities, and often leads to death in childhood. Drs. Bearden and Goldberg’s study is a close look at the effect the antiarrhythmic drug quinidine had on the patient’s seizures.

So why use a cardiac drug (and one also used to treat malaria) to treat epilepsy? Because MPSI is generally resistant to anticonvulsant drugs, the researchers decided to look elsewhere for ways to treat the disease. “MPSI is associated with mutations in a variety of genes,” the authors note, one of which is the potassium channel KCNT1. This gene, the authors point out, is activated in MPSI, and is “a known target of several cardiac drugs, including the antiarrhythmic drug quinidine, which operates as a pore blocker.” Inhibition of KCNT1 might therefore be a way to treat MPSI by normalizing potassium current through mutated KCNT1 channels, noted Dr. Goldberg, an attending physician and instructor of Neurology in CHOP’s Division of Neurology and the Department of Neurology at The Perelman School of Medicine at The University of Pennsylvania.

When the study team first saw the patient at age two, she was experiencing between five and 20 seizures a day. By the end her of seven-month treatment, the patient had been completely seizure-free for more than four months, and almost entirely seizure-free for more than 90 percent of her treatment time. Encouragingly, the patient showed developmental improvements, hitting several major milestones — saying her first words, and then her first sentences.

This “dramatic reduction in seizure frequency” seen during the patient’s treatment shows quinidine “may be at least partially effective in the treatment of MPSI associated with activating KCNT1 mutations,” the study team notes. Overall, the authors say their case “is illustrative of a new paradigm in epilepsy treatment in which rapid identification of genetic mutations could lead to targeted treatments with greater efficacy and fewer side effects than is possible with currently available antiepileptic drugs.”

To read more about Drs. Bearden and Goldberg’s study, see this month’s issue of Bench to Bedside. And to learn more about epilepsy research and treatment at CHOP, see Children’s Hospital’s Pediatric Regional Epilepsy Program, part of the Division of Neurology.