Scientists at the Beth Israel Deaconess Medical Centre (BIDMC) in Boston, USA, have become the first to identify a gene that links brain development to a seizure disorder that persists throughout life. The results of their recent study have been published in
Nature Medicine Online.

The gene in question is known as LGI1, and it encodes a protein called epitempin. This is found in neurons throughout brain, including the temporal lobes (the lobes on either side of the brain, involved in hearing, speech, memory and emotion). The exact function of epitempin is not known, but studies suggest that it plays a role in the normal development of the brain, and in particular the function of potassium channels.

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is a form of genetic epilepsy that appears in childhood and persists into adulthood. It is characterized by frequent partial seizures (two to five per month), associated with sensory auras (these are mostly hallucinations involving sounds).

Studies have shown that many people with ADLTE carry a particular mutation in the LGI1 gene. However, how this defect actually causes epilepsy has not previously been understood.

Before describing the study carried out in Boston, it would be helpful to have some background information about the developing brain:

At birth the brain is full of excitatory synapses, which make the nerve cells 'fire.' However if this excitation is not curbed, it can grow out of control, causing the neurons to fire too much. This can lead to a number of conditions such as autism and learning disabilities, as well as epilepsy.

To avoid this, in the normal brain between the ages of one and five years, the brain undergoes a significant 'remodelling', whereby the excitatory synapses are 'pruned'. However, if the factors controlling this pruning are disturbed, the outcomes described above can result.

In this study, the team bred a group of animals to carry a mutant LGI1 gene (the same mutation that causes ADLTE) and a group that over-expressed normal LGI1. Using advanced techniques, they compared the activity of the LGI1 gene in both groups. A control group of 'normal' LGI1 models were also examined.

Interestingly, the researchers discovered that the LGI1 gene only became active at exactly the time of the major remodelling described earlier. They also noticed that in the 'mutant' group, the 'pruning' of excitatory synapses, was being prevented. This led to excess firing of neurons and brain wave activity consistent with epilepsy.

As might be suspected, in the animals that over-expressed the LGI1 gene, the pruning process was greatly magnified.

These findings indicate that the maturation of synapses is a particularly vulnerable time in brain development, a point at which a hereditary form of epilepsy can develop.

Knowledge of how the LGI1 mutation causes ADTLE is very valuable, as it will enable scientists to develop potential treatments that target this pathway in the future. It might also guide research into other genes that are active during brain development, and their possible links to epilepsy.

ADTLE has a significant effect on people's lives. Dr Matthew Anderson, senior investigator on the study commented:
"These partial seizures can have a significant impact on a patient's quality of life.

"Because patients can be disoriented and excessively tired following a seizure event, their day-to-day lives can sometimes be seriously disrupted. And when it comes to driving and other activities, there is still a real danger associated with this condition.

"One important reason to identify genetic causes of epilepsy is the hope that these discoveries will eventually lead to new therapies," he adds. "By identifying this new pathway, we may have found a new target for future drug development."

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