Discovering, Optimizing Epilepsy Therapies with Genetics

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 genetic 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.

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 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.” Therefore, the study team notes, inhibition of KCNT1 might be a way to treat MPSI by normalizing potassium current through mutated KCNT1 channels.

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 treatment — comprising some 210 days — the patient had been completely seizure-free for more than four months, and mostly seizure-free (save for during illness, and when her dosage needed to be adjusted) for more than 90 percent of her treatment time. Encouragingly, the patient showed developmental improvements during this time, 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. And 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.”

Indeed, in an accompanying commentary, Boston Children’s Annapurna Poduri, MD, MPH, writes that Drs. Bearden and Goldberg’s study “is an elegant illustration of the potential for genetic diagnosis in epilepsy to influence treatment and to lead to specific, targeted treatment.”

“The promise of precision medicine offers hope for many patients with epilepsy, and it is patients with refractory epilepsies like MPSI who most urgently need this kind of paradigm-changing approach to treatment,” she notes.

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.

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