The genetics of epilepsy: bringing hope to families

The Prime Minister’s Prizes for Science – awarded at Parliament House in Canberra tonight – recognise excellence in science and science teaching. This year, we asked four prizewinners to reflect on their work and factors that influenced their careers. The A$300,000 Prime Minister’s Prize for Science went to the University of Melbourne’s Professor Sam Berkovic and Professor Ingrid Scheffer for their work that changed the way the world thinks about epilepsy.

Twenty years ago doctors tended to regard most forms of epilepsy as acquired rather than inherited.

In other words, they believed epilepsy was mostly due to injury: the result of things like a crack on the head in a car accident, a bad fall in the playground, a tumour or something having gone wrong in labour. Parents felt responsible, and the resulting guilt was enormous.

Together with genetic scientists, we discovered the first gene for epilepsy in 1995. Since then we have been involved in finding a genetic basis for many epilepsies. Finding genetic answers has been of profound importance for families.

It all started when one of us (Sam) was doing postdoctoral work in the mid-1980s at the Montreal Neurological Institute, a world centre for epilepsy research. This generated interest in the pioneering twin studies on epilepsy performed in the 1950s in the US. If a form of epilepsy is found to be much more prevalent in both identical twins than in both non-identical twins, it is likely to have a genetic basis.

The partnership begins

Back in Melbourne, we started working together on epilepsy in 1991 (Sam supervised Ingrid’s PhD) studying large families in which many individuals had epilepsy. Sam also continued to study twins and genetic factors in epilepsy in collaboration with the National Health and Medical Research Council’s Australian Twin Registry.

We discovered a large family in South Australia, 27 members of which suffered from epilepsy across six generations. We carefully detailed the type of epilepsy in each family member and this led to the first of many novel epilepsy syndromes that we have described.

By 1995, with the help of Professor Grant Sutherland, Professor John Mulley and colleagues at the University of Adelaide, the family’s epilepsy gene was linked to a particular region of chromosome 20.

One of Sam’s fondest memories was in 1995 when he took a phone call from a collaborator in Germany who had finally nailed the gene we were hunting.

Its protein product was responsible for a pore in the cell membrane, known as an ion channel, which regulated the response to a particular brain chemical known as acetylcholine. Many of the genes linked to epilepsy are now known to be associated with ion channels.

Ingrid’s PhD thesis was completed in 1998 and described four new epilepsy syndromes based on family studies. While the genes for two syndromes were discovered in 1995 and 1998, over the past two years with the revolution in molecular genetic technology, the genes for the remaining two syndromes have been discovered.

With the help of others we have tracked down more than half of the 30 or so genes directly linked with forms of epilepsy. We’re collaborating closely with other scientists including geneticists, bioinformaticians and neurophysiologists in Australia and overseas to try to find and understand the genes and how they cause epilepsy.

Our research stems from the rigorous description of the syndromes or forms in which epilepsy comes, so that doctors can diagnose the condition and advise patients and carers as to the prognosis and potential treatments.

Better treatments for patients

From there, we work with molecular scientists, physiologists and imaging scientists to drill down and understand more about the underlying biology with the aim of developing targeted treatments for each disease and improving long term outcome.

The importance of unearthing genetic links for epilepsy goes beyond providing peace of mind to people with epilepsy and their carers. One example of its impact is a particular gene, which codes for a protein that transports the important energy source glucose into the brain, where we showed that it causes a far broader range of epilepsies than had previously been recognised.

That condition can be managed by a diet which substitutes fats for glucose and carbohydrates as an energy source for the brain. With collaborators, one of us (Ingrid) has produced an enticing cookbook for people on this special diet which is indicated for other epilepsies as well.

Our work also revealed the basis of “vaccine encephalopathy” — epilepsy seemingly caused by vaccination. Dravet syndrome is a severe epilepsy in which one of us (Ingrid) has long had an interest.

It begins in a previously normal baby with a slowing of development and seizures that are hard to control. But it was not known to be related to “vaccine encephalopathy”, where similar symptoms occurred after vaccination.

Having talked at length about Dravet syndrome we suddenly realised that one of (Sam’s) long-term “vaccine encephalopathy” patients had the condition. Together, we tracked down a genetic basis for the vaccine-related disease and deepened the understanding of Dravet syndrome. We found that epilepsy was inevitable for those with the wrong genetic signature. Vaccination was just one possible trigger.

Prizewinners together

The strength of our partnership lies partly in our ability to communicate and bounce ideas off each other. We have different backgrounds and perspectives — one (Sam) concerned with adult epilepsy and one (Ingrid) with childhood epilepsy. Through our work we’ve become very close friends, and trust each other’s thoughts and instincts.

Our work has been recognised through winning awards for epilepsy research, being elected fellows of the Australian Academy of Science, and awarded the Order of Australia. But it’s never been at the same time and our partnership has never fully been recognised.

So this is the first award we can enjoy together. Moreover, we are particularly pleased that it recognises clinical research which is a passion for both of us and is essential in taking discoveries in back to the patient, and for understanding unsolved clinical problems with the basic science tools now available to us and our collaborators.

Further reading:
Epigenetic code cracker: why skin cells are skin cells and not neurons
To make gas-absorbing ‘sponges’, start with a whole lotta holes

Ingrid Scheffer receives funding from the National Health and Medical Research Council (NHMRC), the National Institutes of Health (NIH) and several non-government philanthropic bodies.

Samuel Berkovic receives funding from the National Health and Medical Research Council (NHMRC), the National Institutes of Health (NIH) and several non-government philanthropic bodies.