Neurology: Gene Mutation Discovered In Infant Epilepsy

A team of researchers at the Karolinska's Institutet and the Karolinska University Hospital in Sweden have discovered a new theory that might explain severe early infant epilepsy, including mutations in the gene encoding of the protein KCC2. The findings are published in the journal Nature Communications.

"Epilepsy occurs in many different forms. Earlier associations with KCC2 have been observed, such as a down-regulation of the protein after brain damage that increases the tendency for seizures, but firm evidence for this disease mechanism has been lacking so far", says Anna Wedell, senior physician at Karolinska University Hospital and professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet, in a news release. "Through our discovery we have been able to prove that a defective function of the KCC2 protein causes epilepsy and hence that an imbalance in the brain's chloride ion regulation system can be the reason behind the disease. The next step is to investigate to which extent this imbalance occurs in more common variants of epilepsy."

In this recent study, researchers identified mutations in the gene encoding of the transport protein KCC2 via a large-scale genetic analyses of a family with two affected children at SciLifeLab in Stockholm. Another family with children carrying mutations in the same gene were also identified. The children in both families demonstrated similar symptoms that can be connected to a severe variant of infant epilepsy with MPSI (Migrating Partial Seizures of Infancy.)

KCC2 constitutes a chloride channel specifically localized in the brain and have earlier been shown to play a major role in synaptic inhibition by maintaining a low concentration of chloride ions inside the neurons, according to the study authors. Normally the amount of KCC2 increases shortly after birth, causing the signal substance GABA to switch from being stimulating to being inhibitory.

"Mutations in the gene encoding KCC2 prevent this switch which makes GABA remain stimulatory, incapable of inhibiting the signals of the brain", adds Dr. Wedell. "The neurons then discharge at times, when they normally should not, giving rise to epilepsy."

With detailed investigations of both normal and mutated forms of the KCC2 cell expressions, scientists have demonstrated that the identified mutations led to disrupted chloride ion regulation as well as an imbalance in the system-bringing about severe infant epilepsy, a potentially treatable disease.

"Clinical trials are ongoing with a drug that, if successful, will compensate for the disrupted regulation and ameliorate the disease in small children with epilepsy," Dr. Wedell concluded.

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