Why Do Some Patients Respond to Seizure Meds, While Others Do Not? Nebert, Daniel (nebertdw)

This [below] is a recent article from Pharmacy Practice News (PPN).

Professor Glauser is an example of one of my (many) “disciples” who (more than 20 years ago) quickly grasped the concept of “Genetic Risk Prediction” and applied it to his own specialty of treating seizures in children with psychotropic drugs. Now he has more grant money, collaborations, and fame than he can ever possibly deal with.

AND Tracy even used the correct standardized gene nomenclature –– rather than trivial names so often used by uninformed physicians. 🙂


APRIL 12, 2017

Why Do Some Children Respond to Seizure Meds, While Others Do Not?

By PPN News Staff

Consider two children who have childhood absence epilepsy (CAE), the most common form of pediatric epilepsy. They both take the same drug: One child sees an improvement in seizures, but the other does not.

Researchers identified the genes that may underlie this difference in treatment outcomes, suggesting there may be potential for using a precision medicine approach to help predict which drugs will be most effective to help children with CAE (Ann Neurol 2017; 81[3]: 444-453).

“A better understanding of genetic factors underlying a disease and the way that people respond to treatments may help health care providers select the best therapies for children with CAE,” said Vicky Whittemore, PhD, the program director at the National Institute of Neurological Disorders and Stroke (NINDS).

The study is part of a 32-center, randomized controlled clinical trial that compared the effects of the three most commonly used drugs in 446 children who were recently diagnosed with CAE. A team led by Tracy A. Glauser, MD, Director of the Comprehensive Epilepsy Center at Cincinnati Children’s Hospital Medical Center and a professor of pediatrics at University of Cincinnati College of Medicine, investigated whether there might be a genetic basis for different responses to three drugs used for CAE (ethosuximide, valproic acid and lamotrigine). The experiments focused on three genes that code for T-type calcium channels that are involved in CAE and one gene that codes for a transporter that shuttles the drugs out of the brain. T-type calcium channels help control the firing rate of brain cells.

They found that 80% (357) of children had informative short-term seizures. Of those, 242 were seizure free. Different polymorphisms were seen among the children. Two specific forms of the calcium channel genes appeared more often in children for whom ethosuximide did not work. In those not well controlled on ethosuximide, CACNA1H rs61734410/P640L and CACNA1I rs3747178 appeared more common.

Two other variants of the calcium channel genes were found in children for whom lamotrigine did work, but one form of the drug transporter gene was associated with a continuation of seizures. The ABCB1 missense polymorphism (rs2032582/S893A) was more common in those taking lamotrigine, who were not well controlled, while two CACNA1H polymorphisms (rs2753326, rs2753325) were more common in those who were not. In those who took valproic acid, no common polymorphisms were associated with seizure status, according to the researchers.

“Four T-type calcium channel variants and one ABCB1 transporter variant were associated with differential drug response in CAE,” the researchers concluded. These results suggest knowledge of specific gene variants in children with CAE may help predict what drugs would work best for them.

Dr. Glauser and his colleagues conducted additional experiments using the form of a calcium channel gene that was associated with ethosuximide failure. When cells in a dish containing this calcium channel variant were treated with ethosuximide, the drug had less effect on inhibiting the channel, suggesting that the genetic form of calcium channel may determine a patient’s response to the drug.

“We identified a potential link between genes and the children’s responses to certain treatments. We were also able to clearly show that one variant caused a change in how a key calcium channel responded to ethosuximide, confirming what was found in the clinical trial,” Dr. Glauser said.

CAE is a specific type of neurologic seizure in which children stare into space, unaware of their surroundings. The seizures are brief, often lasting less than 20 seconds, although children may have up to 100 of them per day. The disease usually begins in children who are between 4 and 8 years of age. About one-third of children with CAE also have problems with attention. Many children will stop experiencing absence seizures by the time they reach adolescence, although others go on to develop more severe seizures.

The study was funded by NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development –– both from National Institutes of Health.

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