Researchers based at the University of Tübingen in Germany believe they have discovered a treatment for a rare kind of genetic epilepsy.
KCNA2 epilepsy is caused by mutations in the KCNA2 gene on chromosome 1, which encodes a potassium channel in the brain. It is one of several severe early-onset epilepsies, or encephalopathies, that include symptoms of developmental delay, intellectual disability, ataxia, chorea, spasticity, hypotonia, or autism.
KCNA2 mutations are heritable from either parent and are either ‘gain of function’, resulting in an increased flow of potassium into the brain, or ‘loss of function’, leading to a reduced flow of potassium into the brain. Individuals with this kind of epilepsy can also have a combination of both types of mutation.
Although different types of anticonvulsants are used by clinicians to treat KCNA2 epilepsy, they are often not very effective and the seizures often do not resolve.
It has previously been recognized that blocking the KCNA2 potassium channel could be beneficial for treating patients with gain of function mutations in this gene, but has not previously been tested.
In this study, which was published in the journal Science Translational Medicine, the researchers tested whether a potassium channel blocker 4-aminopyridine –approved to treat multiple sclerosis symptoms– could help treat seizures caused by KCNA2 gain of function mutations.
The researchers recruited 11 patients (aged 7 months to 38 years) with this type of epilepsy and mutations across nine different centers to test the effects of this treatment in a small trial. They found that nine of the patients benefited from the treatment.
Six patients who were experiencing daily absence, myoclonic, or atonic seizures became almost completely seizure free (barring a few seizures with a different ‘provoked’ cause). The treatment was less effective at targeting tonic-clonic seizures, with only two patients showing significant benefits.
All nine patients who responded to the treatment had improvements in their gait, speech, cognition and alertness, as well as improvements in coordination and balance. Notably, no significant side effects of the treatment were observed in the group, although the study sample was small.
This kind of epilepsy is rare and so suffers from the problem all rare diseases experience in that companies are often reluctant to fund expensive trials of drugs that may only benefit small numbers of people.
“Epilepsies caused by KCNA2 gene mutations are very rare diseases. Worldwide, not many more than 50 cases are known,” reports study leader and neurologist Holger Lerche, a senior clinician and researcher at the University of Tübingen.
“We are all the more pleased when we can help these patients individually with so-called drug repurposing: The use of drugs that are actually approved for other diseases.”
The research team acknowledges their study was small and that more work is needed to confirm these findings, but suggests that 4-aminopyridine could be a good option for some of these patients.
“Our report suggests a well-tolerated new therapeutic option, based on disease mechanism, for an otherwise largely pharmacoresistant, untreatable, severe developmental, and epileptic genetic disorder,” the authors conclude.
