New genetic theory claims epileptics may cop a double whammy

Some individuals born into families with a history of epilepsy may be doubly, even triply cursed, according a new theoretical model of the world's most common inherited brain disorder.

Adelaide-based biotechnology company Bionomics has announced that its researchers have developed a so-called digenic -- two-gene -- model of epilepsy.

Bionomics, through its collaboration with leading epilepsy researchers at Adelaide's Women's and Children's Hospital, and Melbourne University, leads the world in the field -- it has identified seven different genes that, in mutant form, contribute to inherited forms of epilepsy.

Their work has helped to transform medical science's understanding of epilepsy - according to Bionomics CEO Dr Deborah Rathjen, some 3 per cent of the population suffers from some form of epilepsy, and recent studies showed that 75 per cent of all epilepsies were inherited, while a minority of individuals developed epilepsy after brain injuries.

Prof Sam Berkovic, who developed the digenic model, heads the Epilepsy Research Institute at Melbourne's Austin and Repatriation Medical Centre, and is on Bionomics' scientific advisory board.

His model offers an explanation for the often bewildering clinical complexity of epilepsy. Not only are there many different forms of epilepsy, involving different ion-channel genes, symptoms can vary widely even in within multi-generational families with a well-characterised mutations.

Nearly all the mutations identified so far involve ion-channel genes that are normally active in brain tissue -- the flow of electrically charged sodium, potassium and calcium ions across nerve-cell membranes propagates signals through nerve networks.

Mutations to these ion channels can cause neurons to misfire, or to fire repeatedly, producing the seizures typical of epilepsy.

"The puzzle is that so far, in all the epilepsies we've cracked, even when the phenotype (symptoms) is homogeneous, the genotype is not," Berkovic said.

This suggests that some individuals may carry mutations in one or more other ion-channel genes, in addition to the mutation initially identified as the cause of the disorder. In most cases, these mutations would be inherited independently, so even siblings would carry different combinations of genes.

Conspicuous by its absence

The picture -- and Berkovic's model -- is further complicated by the findings of his Melbourne University colleague Prof Steve Petrou, who has been studying a transgenic 'knock-in' mice carrying a mutant human ion-channel gene involved in a form of epilepsy called absence epilepsy.

Petrou has shown that mice carrying a single copy of the mutant gene have a 5 per cent risk of developing epilepsy, but mice with two copies of the gene all develop epilepsy.

Berkovic said this may explain why parents with no detectable symptoms of epilepsy may have children with epilepsy. Each parent probably carries a single, mutant copy of a particular ion-channel gene, and on average, one in four of their children inherit a 'double whammy' -- one mutation from either parent, and develop severe epilepsy.

Rathjen said Berkovic's new model "adds another component to the company's world-leading ionX drug discovery platform for epilepsy", describing it as "a significant advance" in the understanding of epilepsy genetics.