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Discovery of epilepsy gene paves way for more effective treatments

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  • Discovery of epilepsy gene paves way for more effective treatments


    August 4, 2009 -- A genetic defect that could be responsible for up to half of all cases of epilepsy has been identified by scientists. In about 50 per cent of cases, the onset of epilepsy is linked with an obvious cause, such as a head injury, brain tumour or another neurological disease. In most other cases the condition is believed to have a genetic basis — but so far little progress has been made in identifying the genes responsible. The latest study, which is published today in the journal PNAS (Proceedings of the National Academy of Sciences), shows that a mutation in a gene called ATP1A3 can lead to a severe form of epilepsy in mice. If the findings translate to human beings, they could pave the way for more effective treatments.

    The team behind the study has already begun screening a large archive of DNA samples from epileptic patients to ascertain whether the same genetic flaw predisposes people to the disease. They say that the 99 per cent match between the mouse and human versions of the gene means there is a good chance that it also plays a role in human epilepsy. In both species the gene is involved in regulating levels of sodium and potassium in the brain. Imbalances in these chemicals have already been linked with epilepsy in humans. In epilepsy sufferers, the brain is hyperexcitable, meaning that when stimulated there is a much bigger increase in neuronal firing than in a normal brain. Sodium and potassium affect how easily neurons fire.

    “It’s equivalent to salty water conducting electricity better than tap water. When there’s more sodium present in the brain, the conductivity of neurons increases and they fire more often,” said Steve Clapcote, a neuroscientist from the University of Leeds, who led the study. The ATP1A3 gene regulates the levels of sodium and potassium in the brain by producing an enzyme that works as a sodium-potassium pump. In a strain of mouse called Myshkin, which has been bred to have epilepsy, a defect in the ATP1A3 gene means that an inactive version of the enzyme is produced, leading to sodium and potassium imbalances. As a consequence the mice have regular seizures.

    The study went a step farther in isolating the cause of the epilepsy by cross-breeding the epileptic mice with normal mice that had been genetically engineered to have an extra copy of the ATP1A3 gene. The extra copy compensated for the faulty version, resulting in offspring that were free of epilepsy and had normal levels of the sodium-potassium pump enzyme. “An imbalance of sodium and potassium levels has long been suspected to lead to epileptic seizures, but our study is the first to show beyond any doubt that a defect in this gene is responsible,” Dr Clapcote said.

    Epilepsy affects about 1 in 200 people in Britain. But despite being a relatively common condition, anticonvulsive medication — the most common treatment — is ineffective in more than 30 per cent of cases. Its side-effects can also have a big impact on quality of life. If the study’s findings translate to humans, it could open up new avenues for treatment. One possibility would be to give patients a synthetic version of the sodium-potassium pump enzyme to help to regulate levels of these chemicals in their brain. Alternatively, drugs could be designed to stimulate the inactive enzyme. Designing specifically tailored drugs will be a long-range project, says Professor Mark Rees, a specialist at the University of Swansea, who is also involved in the DNA screening project. “But any piece of the jigsaw that takes us a step towards designing the drugs is to be welcomed,” he said.

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