Potassium-chloride co-transporter gene, KCC2, implicated in EIMFS, a childhood epileptic syndrome

Rajalaxmi Natarajan, PhD
Wed, 12/23/2015

Early infantile epileptic encephalopathies (EIEE) are a group of severe seizure disorders that occur in early childhood. Epilepsy of infancy with migrating focal seizures (EIMFS, also previously known as migrating partial seizures of infancy) is one of these.

EIFMS is characterized by focal seizures, which means the seizures come from a local site of the brain, rather than the whole brain.  Interestingly, in EIFMS patients, seizures are multifocal which means they arise from multiple sites.  In addition, the seizures migrate from one region of the brain to another.  Initially, children with EIMFS experience sporadic seizures but soon these become very frequent (5-30 episodes per day) and occur simultaneous with a regression in developmental skills.

Currently, the prognosis for children with this disorder is bleak. Often seizures are not controlled by anti-convulsants, ketogenic diet, vagus nerve stimulations or other therapies. Many of these children die due to other complications and the ones who survive have developmental disabilities and continue to experience frequent seizures.

The biological cause for this seizure disorder is not understood. It is a rare condition and in most instances does not appear to be inherited. Spontaneously arising mutations in some ion channel genes (e.g. KCNT1 or SCN1A) have been observed in a few EIMFS patients but not others. Also, there is no clear understanding of how this disorder is produced in the brain or why it progresses.

Therefore, it is exciting that a recent study published by Stödberg and others in Nature Communications has identified mutations in potassium-chloride co-transporter, KCC2, as a novel genetic cause of EIMFS.

They found that in a cohort of 42 EIMFS patients, four children from two unrelated families had missense mutations in SLC12A5, a gene that makes a protein called KCC2. Using many genetic and genomic tools such as single-nucleotide polymorphism (SNP) mapping and exome sequencing of parents and patients, they confirmed that mutations in SLC12A5 were the most plausible cause for the seizure disorder in these four patients.

Laboratory experiments showed that the SLC12A5 mutations discovered in these patients were sufficient to render KCC2 co-transporter completely or partially non-functional. Normally KCC2 is found in the outer membrane of cells but the investigators found that the mutant proteins could not find their way to the cell surface.  Interestingly, deleting KCC2 gene function in zebra fish, fruit fly and mice recapitulated the severe developmental and motor defects seen in EIFMS patients.

Normally, KCC2’s job is to maintain a low level of chloride inside the cell.  It does this by constantly pumping chloride from the cell. Under these circumstances, when an inhibitory neurotransmitter acts on the cell, it causes the movement of negatively charged chloride ions into the nerve cells and this inhibits the electrical activity of the cell.

The authors postulate that in the absence of a normal KCC2 chloride removal mechanism, chloride ions build up in nerve cells. Thus when inhibitory neurotransmitters act all the excess chloride ions in the cells are released from the nerve cell and this leads to an excessive electrical activity of nerve cell which likely contributes to the generation of seizures.

In short, this study shows that the described mutations in KCC2 impair its function, which may be the cause of seizures in some EIFMS patients.  However, it is important to remember that only four patients in this cohort carried SLC12A5 mutations while the other 38 patients did not exhibit any defects in KCC2 function. This suggests that while SLC12A5 mutations may contribute to disease onset and progression in a subset of EIFMS patients, they are certainly not the only cause of EIMFS.

Thus, in order to develop therapies for EIMFS patients, it is important to not only elucidate how KCC2 dysfunction leads to EIMFS but also to identify other genes and possibly other factors that produce this syndrome.

Tommy Stödberg et al., Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizuresNature Communications. 2015 Sep 3;6:8038. doi: 10.1038/ncomms9038

Learn More about EIFMS (Migrating partial seizures of infancy)