Treating Epilepsy

BY LASYA KAMBHAMPATI

Image from Yale Medicine, 2019

Epilepsy is one of the most common neurological disorders, affecting over 3.4 million people in the U.S. alone.2 There are over a dozen different types of epilepsy, which makes it hard for doctors and researchers to determine the exact cause of each type.5 Epilepsy’s mysterious origins make the task of finding a cure or effective treatment significantly harder. Dr. Erin Heinzen, an associate professor at the University of North Carolina at Chapel Hill, is on a mission to change the outlook of epilepsy research. While in pharmacy school, Dr. Heinzen recognized the lack of effective treatments for neurological diseases. “Instead of trying to make the old medications that weren’t great work better,” Dr. Heinzen decided to “retrain as a human geneticist to figure out what causes epilepsy better.” In doing so, she would be able to eventually design better medications for epilepsy.1 This realization inspired her to take a step back and join the effort to create better medicines, particularly for epilepsy.1 Specifically, she hopes to identify the genetic cause of neocortical focal epilepsy, a condition characterized by seizures that originate in the neocortex and are restricted to a certain section of the brain. The lack of definition of brain lesions that cause neocortical seizures makes it difficult to identify and target problematic regions for treatment.6 Dr. Heinzen identifies genetic variants associated with neocortical focal epilepsy by sequencing samples taken from human patients with the disease.1 As a last resort for patients consistently struggling with seizures, doctors perform a procedure in which they remove the part of the brain that is ‘acting up.’ The Heinzen Lab receives some of these samples and analyzes them for genetic anomalies that could represent causal factors of epilepsy. Interestingly, the Heinzen Lab has identified inconsistencies in the genetic mutations found throughout the brain. In order to determine whether these mutations are somatic or inherited, they compared the genetic sequence to the DNA sequence in blood samples from the patient.1Oftentimes, identified mutations proved to be unique to specific parts of the brain and were not found throughout the whole body. These mutations present in a mosaic fashion and are believed to have occurred during development.3,4 The earlier in development the mutation arose, the more widespread the variant would become. The Heinzen Lab hypothesizes that neocortical focal epilepsy might result from these localized mutations. To verify this, the lab seeks first to identify mutations of interest. However, many of the samples that the lab receives have 10-15 somatic variants, making it difficult to determine which

Dr. Erin Heinzen

Figure 1. Neuronal cells viewed under fluorescent microscopy gene(s) contribute to epileptic behavior. To narrow down the pool, Dr. Heinzen’s team uses a complex probability calculation based on known information about the gene and its function to determine the gene’s likelihood of causing epilepsy. One example of a mutation identified by the lab’s probability calculation falls in the SLC gene, which encodes a protein product responsible for the transportation of galactose from the cytosol to the Golgi in a process called glycosylation.4 When the amount of galactose transported to the Golgi is reduced, glycosylation decreases. Since glycosylation plays an important role in protein regulation, this reduction significantly impacts hundreds of proteins throughout the entire cell. As a result, this specific mutation acts as a lethal gene on the X-chromosome. Males conceived with this mutation usually do not survive, as every cell would have this deficiency .1,4 Women have two X-chromosomes, one of which is inactivated as a Barr body. This fact increases their likelihood of survival even with the mutation, which presents itself in a mosaic pattern: active in some cells and inactive in others. However, the Heinzen lab’s findings present new problems. One of the main challenges and critiques that Dr. Heinzen faces relates to the lab’s use of patient samples.1 Since surgery represents a last resort technique to help patients and technological advancements have steadily reduced the need for surgical intervention, acquiring large numbers of patient samples has grown increasingly difficult. Lacking samples to test for mutations makes the research process very difficult. Additionally, since the samples only originate from epileptic patients, the lab does not have access to control samples. Many of the somatic mutations identified by the Heinzen Lab may be present in the general population, but because there is no control group, there is no way to confirm each mutation acts as a differential factor between healthy and epileptic individuals. The lab seeks to circumvent this problem by using samples from deceased donors and tumor cohorts to construct a core genome. Then, they can statistically estimate the likelihood each identified somatic mutation is the causal factor of neocortical epilepsy. Dr. Heinzen hopes to continue pursuing this research in the coming years by looking for more epilepsy-linked genes in the somatic and germ line. The discovery of new mutations might someday lead to the development of life changing therapies to combat epilepsy. A development like this would help the millions of people suffering with epilepsy by providing them with effective treatments.

References

1.Interview with Erin Heinzen, Ph.D. 2/9/21. 2.CDC. Epilepsy Fast Facts. https://www.cdc.gov/epilepsy/about/fast-facts.htm 3.Campbell I.; Shaw C.; Stankiewicz P.; Lupski J.; CELL PRESS. 2015, 31, 382-390. 4.Heinzen E.; GENETICS & DEVELOPMENT. 2020, 65, 1-7. 5.Columbia Neurosurgery. Neocortical Epilepsy. https:// www.columbianeurosurgery.org/conditions/neocorticalepilepsy/