NEUROLOGY

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Genetic Basis For Drug Response In Childhood Absence Epilepsy

 

Childhood absence epilepsy (CAE), also known as pyknolepsy, is an idiopathic generalized epilepsy which occurs in otherwise normal children. CAE is characterized by absence seizures, 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 old. About one third of children with CAE also have problems with attention. Mild automatisms are frequent, but major motor involvement early in the course excludes this diagnosis. The EEG demonstrates characteristic “typical 3Hz spike-wave“ discharges. Prognosis is excellent in well-defined cases of CAE with most patients “growing out“ of their epilepsy. Thus, while many children will stop experiencing absence seizures by the time they reach adolescence, others go on to develop more severe seizures.

 

Consider two children who have CAE. They both take the same drug — one child sees an improvement in their seizures, but the other does not. A new study, published online in the Annals of Neurology (25 March 2017) 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. For the study, the authors investigated whether there may 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. The current 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.

 

The results suggest knowledge of specific gene variants in children with CAE may help predict what drugs would work best for them. For example, two specific forms of the calcium channel genes appeared more often in children for whom ethosuximide did not work. 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 authors conducted additional experiments using the form of calcium channel gene that was associated with ethosuximide failure in patients. 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 patients’ response to the drug. According to the authors, they were able to identify a potential link between genes and the children’s’ responses to certain treatments, and they were also able to clearly show that one variant caused a change in how a key calcium channel responded to ethosuximide, thus confirming what was found in the clinical trial. The authors added that more research is needed to learn about the specific genes involved in CAE and the ways that they influence the effect of anti-epileptic drugs, and that there is a need to determine which factors, other than genetics, may play a role in treatment response.

 

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