Severe epilepsy in infants: Azureans make an important discovery

Thanks to their discovery, around the world, very young patients suffering from an extremely severe form of epilepsy began to be successfully treated with drugs that were already on the market, but which until then had been withheld from them for fear that they would continue to aggravate theirs symptoms. The cheerful epilogue to the research carried out by the teams of Dr. Massimo Mantegazza, Director of Research at the IPMC (Institute of Molecular and Cellular Pharmacology) in Sophia Antipolis (1).

Dravet Syndrome

Go back to the recent past to understand the progress of these discoveries. Less than a year ago (Read our October 17, 2021 issue) this world expert on the excitability of neurons made a significant discovery in the field of a disease other than epilepsy: migraine. He was able to decipher the mechanisms involved in triggering seizures based on a specific study model: a rare and severe form of migraine called “familial hemiplegia type 3” linked to mutations in a gene called SCN1A. “These genetic mutations affect a sodium channel (Nav1.1.) that is very important for the excitability of certain neurons and therefore for the proper functioning of the brain. They are also implicated in Dravet syndrome, a very severe epileptic encephalopathy.”, introduces Massimo Mantegazza. In addition to epileptic seizures, young patients with this syndrome – the disease usually begins in infants aged 6 months to one year – show cognitive and autistic disorders as well as ataxia (impaired balance and movement coordination). These disorders are caused by a loss of function of the sodium channel. “ Unfortunately, these young patients cannot benefit from traditional anti-epileptic treatments whose mode of action is to block this type of channel; In fact, by knowing that these channels are already dysfunctional in them, the risk is that their symptoms will continue to worsen.

Use of conventional antiepileptic drugs

Massimo Mantegazza and Sandrine Cestèle, based on an empirical observation by a German neurologist and their expertise in the field, became interested in an even more serious form of epilepsy than Dravet syndrome. “Here, too, mutations are found in SCN1A, but with an even more severe phenotype; epileptic seizures sometimes occur in the first few hours of life.”

As part of an international collaboration, Massimo Mantegazza’s team analyzed the mutations involved and their impact on channel function. And then, surprise: “We found that the function of the canal was increased in contrast to Dravet syndrome.”

Excellent news that has allowed these patients to consider the use of antiepileptic drugs that block these channels. Given the severity of the pathology, around fifty infants aged from a few days to 2-3 years were treated around the world without wasting time. With success, because neurologists report a significant reduction in the frequency of seizures in the vast majority of them. “It seems important to treat early and with higher doses than the “classic” to prevent sequelae of attacks. »

Studies in a larger number of patients are underway to determine the optimal dose.

“Many other questions remain unanswered, in particular we must try to understand why even a very moderate increase in channel function leads to such severe symptoms,” concludes Massimo Mantegazza. A great question that is moving the teams at Sophia Antipolis today, and the hope that the answer will open up new therapeutic avenues for these very serious epilepsies of genetic origin.

1. This research has just been published in the journal Brain.

2. Opening that allows the transport of sodium ions across cell membranes.

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