Sodium channel blockers proposed as first-line therapies for KCNQ2 encephalopathy

Rajalaxmi Natarajan, PhD
Mon, 07/13/2015

Early infantile epileptic encephalopathies (EIEEs) are a heterogenous group of seizure disorders that begin in infancy. Some of them are present at birth whereas others arise later in infancy. In the recent years, advances in gene sequencing techniques have identified numerous genetic mutations that are thought to be responsible for many of the EIEEs.

Correlations between gene mutations and disease symptoms are not always straightforward. It has emerged that mutations in the same gene can sometimes result in different symptoms among patients. In fact, mutations in certain genes can result in a wide spectrum of seizure disorders, some more severe than others. A case in point are the epilepsies due to mutations in potassium channel gene, KCNQ2.

The first identified mutation in KCNQ2 gene was associated with benign familial neonatal seizures (BFNS), a mild condition where the affected children outgrow their seizures without any interventions and have normal cognitive/motor development. However, other mutations in the same gene lead to KCNQ2 encephalopathy, a severe seizure disorder that also causes motor and cognitive deficits.

So far, there are no clear guidelines on how to optimally treat KCNQ2 encephalopathy. A recent study¹published in the journal Epilepsia has compared the effectiveness of a number of anti-epileptic drugs (AEDs) on a small group of KCNQ2 encephalopathy patients. To our knowledge, this is the most detailed analysis of the effects of various AEDs on KCNQ2 encephalopathy.

Patients recruited in the study had developmental impairments of varying severity and experienced severe seizures. All of them were treated with a number of AEDs, either alone or in combination, until they were free from seizures. The authors report that 93% of their patients became seizure-free, of whom 80% had attained it by the time they were 13 months of age. Interestingly, majority of the patients responded to sodium channel blockers (53% for carbamazepine {CBZ} and 33% to phenytoin {PHT}) and the remaining responded to other AEDs (topiramate and levetiracetam). In 3 patients, CBZ or PHT treatments were discontinued for a period of time and seizures quickly recurred only to stop again when the drug was re-administered. This further emphasized the effectiveness of these drugs.

Thus, the authors propose that sodium channel blockers (CBZ and PHT) can serve as first-line therapies in newborns with KCNQ2 encephalopathy. The authors state that newborns with unexplained seizures and with known mutations in KCNQ2 would be good candidates for an early treatment with these drugs.

While this preliminary study of 15 patients is promising, it is important to remember, based on cell culture studies, that depending on the nature of KCNQ2 mutations, overall outcomes may vary between patients. It is also intriguing that sodium channel blockers are able to stop seizures associated with potassium channel dysfunction. Further studies are warranted to understand the underlying mechanism, which will most likely help in better prediction of outcomes among patients.

In a nutshell, this study provides an initial demonstration that sodium channel blockers could be an effective therapy against a severe, albeit rare, seizure disorder. A large-scale standard randomized trial is required to confirm these observations. Recruiting adequate number of newborn participants for clinical trials, especially for a rare genetic disorder is not easy and therefore, a large multi-center or perhaps, even a multinational collaborative effort would be required to achieve this.

Reference:

Pisano et al., Early and effective treatment of KCNQ2 encephalopathy. Epilepsia, 56(5):685-691, 2015.